National Coverage Analysis (NCA) Decision Memo

Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications

CAG-00383N

Expand All | Collapse All

Decision Summary

Emerging safety concerns (thrombosis, cardiovascular events, tumor progression, and reduced survival) derived from clinical trials in several cancer and non-cancer populations prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs). We reviewed a large volume of scientific literature, including basic science research, to see if these safety signals seen in randomized controlled trials could be reasonably explained in whole or in part by the actions of ESAs on normal or cancerous cells. In doing so we proposed conditions of coverage based on expression of erythropoietin receptors. The scientific understanding of this mechanism is a subject of continuing debate among stakeholders, continues to evolve, and can only be resolved through additional studies. We also reviewed a large volume of comments on the use of ESAs in myelodysplastic syndrome (MDS), a pre-malignant syndrome that transforms into acute myeloid leukemia (AML) in many patients. Though we continue to be interested in these specific issues, this final decision does not differentiate ESA coverage by the erythropoietin receptor status of the underlying disease, and we have narrowed the scope of this final decision to make no national coverage determination (NCD) at this time on the use of ESAs in MDS.

CMS has determined that there is sufficient evidence to conclude that erythropoiesis stimulating agent (ESA) treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions include:

  1. any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis;
  2. the anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers;
  3. the anemia of cancer not related to cancer treatment;
  4. any anemia associated only with radiotherapy;
  5. prophylactic use to prevent chemotherapy-induced anemia;
  6. prophylactic use to reduce tumor hypoxia;
  7. patients with erythropoietin-type resistance due to neutralizing antibodies; and
  8. anemia due to cancer treatment if patients have uncontrolled hypertension.

We have also determined that ESA treatment for the anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia is only reasonable and necessary under the following specified conditions:

  1. The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is < 10 g/dL (or the hematocrit is < 30%).
  2. The starting dose for ESA treatment is the recommended FDA label starting dose, no more than 150 U/kg/three times weekly for epoetin and 2.25 mcg/kg/weekly for darbepoetin alpha. Equivalent doses may be given over other approved time periods.
  3. Maintenance of ESA therapy is the starting dose if the hemoglobin level remains below 10 g/dL (or hematocrit is < 30%) 4 weeks after initiation of therapy and the rise in hemoglobin is ≥ 1g/dL (hematocrit ≥ 3%).
  4. For patients whose hemoglobin rises <1 g/dl (hematocrit rise <3%) compared to pretreatment baseline over 4 weeks of treatment and whose hemoglobin level remains <10 g/dL after the 4 weeks of treatment (or the hematocrit is <30%), the recommended FDA label starting dose may be increased once by 25%. Continued use of the drug is not reasonable and necessary if the hemoglobin rises <1 g/dl (hematocrit rise <3 %) compared to pretreatment baseline by 8 weeks of treatment.
  5. Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin > 1 g/dl (hematocrit > 3%) over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to < 10 g/dL (or the hematocrit is < 30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose.
  6. ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen.

Local Medicare contractors may continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by NCD.

Decision Memo

To:		Administrative File: CAG #000383N   
		The Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions   
   
From:	Steve Phurrough, MD, MPA   
		Director, Coverage and Analysis Group   
   
		Louis Jacques, MD   
		Director, Division of Items and Devices   
   
		Maria Ciccanti, RN   
		Lead Analyst   
   
		Kimberly Long   
		Analyst   
   
		Elizabeth Koller, MD, FACE   
		Medical Officer   
   
		Shamiram Feinglass MD, MPH   
		Medical Officer   
   
Subject:		Coverage Decision Memorandum for the Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions   
   
Date:		July 30, 2007

I. Decision

Emerging safety concerns (thrombosis, cardiovascular events, tumor progression, and reduced survival) derived from clinical trials in several cancer and non-cancer populations prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs). We reviewed a large volume of scientific literature, including basic science research, to see if these safety signals seen in randomized controlled trials could be reasonably explained in whole or in part by the actions of ESAs on normal or cancerous cells. In doing so we proposed conditions of coverage based on expression of erythropoietin receptors. The scientific understanding of this mechanism is a subject of continuing debate among stakeholders, continues to evolve, and can only be resolved through additional studies. We also reviewed a large volume of comments on the use of ESAs in myelodysplastic syndrome (MDS), a pre-malignant syndrome that transforms into acute myeloid leukemia (AML) in many patients. Though we continue to be interested in these specific issues, this final decision does not differentiate ESA coverage by the erythropoietin receptor status of the underlying disease, and we have narrowed the scope of this final decision to make no national coverage determination (NCD) at this time on the use of ESAs in MDS.

CMS has determined that there is sufficient evidence to conclude that erythropoiesis stimulating agent (ESA) treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions include:

  1. any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis;
  2. the anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers;
  3. the anemia of cancer not related to cancer treatment;
  4. any anemia associated only with radiotherapy;
  5. prophylactic use to prevent chemotherapy-induced anemia;
  6. prophylactic use to reduce tumor hypoxia;
  7. patients with erythropoietin-type resistance due to neutralizing antibodies; and
  8. anemia due to cancer treatment if patients have uncontrolled hypertension.

We have also determined that ESA treatment for the anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia is only reasonable and necessary under the following specified conditions:

  1. The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is < 10 g/dL (or the hematocrit is < 30%).
  2. The starting dose for ESA treatment is the recommended FDA label starting dose, no more than 150 U/kg/three times weekly for epoetin and 2.25 mcg/kg/weekly for darbepoetin alpha. Equivalent doses may be given over other approved time periods.
  3. Maintenance of ESA therapy is the starting dose if the hemoglobin level remains below 10 g/dL (or hematocrit is < 30%) 4 weeks after initiation of therapy and the rise in hemoglobin is ≥ 1g/dL (hematocrit ≥ 3%).
  4. For patients whose hemoglobin rises <1 g/dl (hematocrit rise <3%) compared to pretreatment baseline over 4 weeks of treatment and whose hemoglobin level remains <10 g/dL after the 4 weeks of treatment (or the hematocrit is <30%), the recommended FDA label starting dose may be increased once by 25%. Continued use of the drug is not reasonable and necessary if the hemoglobin rises <1 g/dl (hematocrit rise <3 %) compared to pretreatment baseline by 8 weeks of treatment.
  5. Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin > 1 g/dl (hematocrit > 3%) over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to < 10 g/dL (or the hematocrit is < 30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose.
  6. ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen.

Local Medicare contractors may continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by NCD.

II. Background

In this section in our proposed decision memorandum, we described the technological developments that gave rise to the use of genetically engineered (recombinant) erythropoietin and related ESAs (see appendix A). We then described the anemias for which ESAs are prescribed in oncologic conditions, with an emphasis on solid tumors that constituted the majority of tumors in the studies upon which FDA approval was based. We refer the reader to Appendix A for a detailed discussion of the biochemical background of ESAs and their current usages. We will summarize these points here.

Erythropoietin is a glycoprotein produced primarily in the kidney and to a lesser extent in the liver. In the classic hormone pathway, erythropoietin regulates erythrocyte production by stimulating red cell production in the bone marrow. Suppression of erythropoietin production or suppression of the bone marrow response to erythropoietin has resulted in anemias in several disease processes to include renal disease, cancer treatment, other chronic diseases and use of certain drugs.

To combat these anemias, several forms of recombinant human erythropoietin have been developed. The two currently available in the US are epoetin and darbepoetin alpha. Recombinant erythropoietin was initially used as a replacement for missing hormone in select patients with anemia of end-stage renal disease. Use of ESAs has been extended to a variety of anemic conditions including the anemia of chronic renal disease (not yet on dialysis), anemia secondary to chemotherapy of solid tumors, anemia secondary to AZT therapy, anemia in myelodysplastic disorders and prophylactic use during the perioperative period to reduce the need for allogenic blood transfusions.

In cancer, anemia occurs with varying degrees of frequency and severity. It is most frequent in genitourinary, gynecologic, lung, and hematologic malignancies. Anemia may be directly related to cancer type or to its treatment.

Oncologic anemia occurs by a variety of mechanisms. Poor oral intake or altered metabolism may reduce nutrients (folate, iron, vitamin B-12) essential for the red cell production. Antibodies in certain tumor types may cause increased erythrocyte destruction through hemolysis. Tumors may cause blood loss via tissue invasion, e.g. gastrointestinal bleeding from colon cancer. Other neoplasms, particularly hematologic malignancies (leukemia, lymphoma, multiple myeloma) can invade the bone marrow and disrupt the erythropoietic microenvironment. In more advanced cases, there may be marrow replacement with tumor or amyloid. Marrow dysfunction can occur, however, even in the absence of frank invasion (Faquin 1992; Mikami 1998). Inflammatory proteins from interactions between the immune system and tumor cells are thought to cause inappropriately low erythropoietin production and poor iron utilization as well as a direct suppression of red cell production.

The treatment of cancer may also cause anemia. Radical cancer surgery can result in acute blood loss. Radiotherapy and many cytotoxic chemotherapeutic agents cause marrow suppression to some degree. Damage is due to a variety of mechanisms. For example, alkylating agents cause cumulative DNA damage, anti-metabolites damage DNA indirectly, and platinum-containing agents appear to damage erythropoietin-producing renal tubule cells.

Myelodysplastic disorders are a heterogenous group of pre-leukemic diseases characterized by cytopenias due to abnormal hematopoietic differentiation and maturation. The disease may be idiopathic or secondary to chemotherapy or radiation therapy for other disease. The primary defect resides in hematopoietic stem cells. New cases exceed 10,000/year. Transformation to acute non-lymphocytic leukemia occurs in 10 to 40% of patients with idiopathic MDS. Thrombocytopenic bleeding and neutropenic infections contribute to death. Survival at 3 years is approximately 40% for those over 50 (Ma 2007). Transfusion dependence and risk for leukemic transformation appear related to disease severity/diagnostic category. Therapeutic treatment of MDS related anemia requires treatment of the underlying marrow disorder. Treatment in younger patients is allogenic bone marrow transplantation. Treatment with cytotoxic agents has demonstrated limited utility. Supportive care includes transfusions and avoidance/treatment of iron overload. Readers interested in more information may wish to review the discussion of MDS by the National Cancer Institute (NCI) at http://www.cancer.gov/cancertopics.

In opening this NCD in March of this year, CMS stated that it would be reviewing the non-ESRD uses of ESAs. In our proposed decision in May of this year, we restricted our proposal to oncologic uses of ESAs. However, as pointed out to us, MDS is not an oncologic condition. Thus, we are making no decision on MDS in this final decision.

The level at which anemia requires intervention is not well established. By tradition, patients have been transfused at the hemoglobin level of 7 or 8 g/dl to avoid symptoms and physiologic complications. A transfusion of 2 or more units would result in an increase of at least 2 g/dl of hemoglobin (6 units of hematocrit). Indeed, one of the endpoints for pharmaceutical registration, need for transfusion, employed an 8 g/dl hemoglobin cut-off (FDA Medical Officer Review, Aranesp 2002). Most of these practices, however, are based on empiric observations and not clinical trials. In one of the few studies, Carson et al. found that hip-fracture patients transfused to hemoglobin levels in excess of 10 g/dl did not have more exercise tolerance than non-transfused patients who were transfused after hemoglobin levels dropped to below 8 g/dl or patients became symptomatic (Carson 1998).

The British Blood Transfusion Society has delineated the weaknesses in our knowledge base. Their guidelines state that transfusions are indicated in patients with hemoglobin levels less than 7 g/dl and that transfusion should not be undertaken for hemoglobin levels greater than 10 g/dl. They indicate that management of patients with hemoglobin levels between 7 and 10 remains unclear although the hemoglobin threshold for the treatment of patients with co-morbid conditions is probably higher than 7 g/dl. Although they have done so in the past, the College of American Pathologists (CAP) no longer issues transfusion practice guidelines.

Other groups have developed definitions for anemia and have been cited for these definitions, but these definitions cannot be extrapolated into guidelines for oncologic treatment. The World Health Organization (WHO) definitions for anemia were developed for surveillance of anemia due to nutritional deficiency and parasitic infections. The National Cancer Institute (NCI) has information on anemia, but does not issue treatment guidelines (Robin Bason 301-594-9051; NCI anemia information from web). Both the NCI and WHO consider hemoglobin levels less than 6.5 g/dl to be life-threatening.

III. History of Medicare Coverage

Prior to this National Coverage Analysis, there was no National Coverage Decision (NCD) concerning the use of ESAs for the indications discussed in this Decision Memorandum. Currently, the Medicare benefit for ESAs for end-stage renal disease (ESRD) related anemia is outlined in the Medicare Benefit Policy Manual, Chapter 11, Section 90 and Chapter 15, Section 50.5.2. For other indications, Medicare coverage of ESAs administered incident to a physician service for other indications under Part B is determined by local Medicare contractors.

Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage. § 1812 (Scope of Part A); § 1832 (Scope of Part B); § 1861(s) (Definition of Medical and Other Health Services). ESAs fall within the benefit categories specified in 1861(s)(2)(A) & 1861(s)(2)(B) of the Social Security Act.


IV. Timeline of Recent Activities

Date Action

March 14, 2007

CMS opened an internally generated National Coverage Decision (NCD) to evaluate coverage of uses of ESAs in non-renal disease applications. The initial 30-day comment period opened.

April 13, 2007

The initial public comment period closed; 69 timely comments were received.

May 14, 2007

CMS published the Proposed Decision Memorandum. The 30-day public comment period opened.

June 13, 2007

The public comment period on the proposed decision closed. 2641 timely comments were received.


V. FDA Status

A.    Erythropoietin-alpha was the first ESA approved by the FDA for use in renal failure (1989). Subsequently two ESAs were approved for the management of the anemia of cancer treatment (chemotherapy) of non-myeloid neoplastic disease: epoetin (1993) and darbepoetin alpha (2002).

B.    FDA reviewed results of the Breast Cancer Erythropoietin Trial (BEST) and Henke studies. Concerns regarding an increased rate of tumor progression and increased mortality were incorporated into the Precautions Section of product labeling in 2004.

C.    FDA convened a meeting of the Oncologic Drugs Advisory Committee 5/4/2004 to discuss safety issue for ESAs. The briefing information and transcript for the meeting is available at www.fda.gov/ohrms/dockets/ac/cder04.html#Oncologic.

D.    In conjunction with the FDA, Amgen issued a “Dear Doctor Letter” regarding the use of ESAs for anemia management in the absence of chemotherapy, which was sent 1/26/2007.(See www.fda.gov/medwatch/safety/2007/safety07.htm#Aranesp)

E.    Serial FDA ALERTS regarding ESA safety information were issued: 11/16/2006, 2/16/2007, and 3/09/2007.

F.    FDA strengthened its warning about cardiovascular and thrombotic events in a variety of populations via a BLACK BOX warning. A "black box" warning is the most serious warning placed in the labeling of a prescription medication. FDA included BLACK BOX warnings for tumor progression and decreased survival in cancer patients undergoing cancer treatment. FDA also warned that ESAs are not indicated for anemic cancer patients not undergoing treatment and that mortality is increased when ESAs are used by this population. Specific warnings on the use of ESAs included that they:

  • shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a hemoglobin of greater than 12 g/dL,
  • shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a hemoglobin of greater than 12 g/dL,
  • increased the risk of death when administered to target a hemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for this population.

G.    FDA convened a meeting of the Oncologic Drugs Advisory Committee (ODAC) on May 10, 2007 to discuss updated risk information on ESAs for the indication of cancer. The ODAC transcripts were recently posted at http://www.fda.gov/ohrms/dockets/ac/cder07.htm#OncologicDrugs .

VI. General Methodologic Principles

When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. Critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.

A detailed account of the methodological principles of study design that are used to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix B. In general, features of clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, the blinding of readers of the index test and reference test results.

Public comment sometimes cites the published clinical evidence and gives CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum.

VII. Evidence

1. Introduction

We are providing a summary of the evidence that we considered during our review. CMS extensively reviewed the body of literature on the use of ESAs in its proposed decision memorandum released on May 14, 2007. (http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=203). We will not review that evidence again in this final decision. We refer the reader to Appendix A for a full discussion.

This section presents the agency's evaluation of the evidence considered for the assessment questions:

1. Is the evidence sufficient to conclude that erythropoiesis stimulating agent therapy affects health outcomes when used by Medicare beneficiaries with cancer and related neoplastic conditions?

2. If the answer to Question 1 is affirmative, what characteristics of the patient, the disease, or the treatment regimen reliably predict a favorable or unfavorable health outcome?

We will review each of the questions in the context of our proposed individual coverage criteria separately, respond to comments on that recommendation, discuss any new evidence, and provide our response with any proposed changes. Our responses to comments on aspects of the proposed decision other than the proposed coverage criteria are summarized in the Comment Section.

Multiple studies have raised significant safety concerns about the potential for ESAs to increase tumor progression and decrease survival in cancer patients. Although some of these were studies of ESAs used during radiotherapy or for anemia of cancerboth off-label usesthe data nonetheless raises concerns about the use of ESAs for all cancer indications to include labeled indications.

Because tumor progression has now been seen in some cancer patients, we believe that to demonstrate improved health outcomes, all ESA indications need evidence demonstrating that they do not cause tumor progression and/or decrease survival even if they might decrease transfusions or improve quality of life. In concert with our general methodologic principles (Appendix B), we believe that in most instances, this evidence can only be obtained in randomized controlled trials.

Several commenters questioned CMS’ references in the proposed decision to basic science literature rather than solely to clinical trials. We emphasize that the safety signals came from randomized controlled clinical trials. Our review of other literature was to shed light on the possible underlying biological processes that may account for the trial findings. This was not a shift in CMS’ stated preference for methodologically robust clinical evidence in determining whether health outcomes are affected by various technologies.

We remain concerned that a number of trials have been terminated, suspended, or otherwise not completedpossibly due to signals of harmand that the existing fund of published evidence may reflect a bias toward ESA use. Transparent public access to clinical trial datasets, as opposed to data summaries, would enhance public confidence in this body of literature.

2. External Technology Assessments

Please refer to the Proposed Decision Memorandum for a review of this matter. (http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=203)

3. Internal Technology Assessment

Systematic reviews are based on a comprehensive search of published materials to answer a clearly defined and specific set of clinical questions. A well-defined strategy or protocol (established before the results of individual studies are known) is optimal.

CMS staff extensively searched Medline (1988 to present) for primary studies evaluating ESA therapy in cancer and related conditions. The emphasis was on studies structured to assess adverse events and mortality. CMS staff likewise searched the Cochrane collection, National Institute for Health and Clinical Excellence (UK) appraisals, and the Agency for Healthcare Research and Quality (AHRQ) library for systematic reviews and technology assessments. Systematic reviews were used to help locate some of the more obscure publications and abstracts. Preference was given to English publications.

Because much of the material remains outside the domain of the published medical literature, additional sources were used. CMS examined FDA reviews of the registration trials for epoetin and darbepoetin alpha as well as the FDA safety data for epoetin and darbepoetin alpha. CMS reviewed the transcripts and briefing documents (FDA and pharmaceutical sponsor) from the 2004 FDA Oncologic Drugs Advisory Committee (ODAC) meeting on ESA safety. CMS reviewed the FDA ESA drug safety alerts and label changes. CMS searched the National Institutes of Health (NIH) Clinical Trials.gov database for ongoing/completed trials of ESAs. CMS used internet searches to identify websites with clinical trial results, press releases for clinical trial termination, and U.S. government regulatory action. We catalogued these trials in our proposed decision (Appendix A).

Following the release of the proposed NCD on May 14, 2007, we received some additional references, primarily non-Medline publications. We also updated our search and broadened it to be more inclusive for MDS and multiple myeloma. We received over 300 additional citations as comments. Many of these addressed the blood supply, transfusion errors and erythropoietin receptors. We received many articles that duplicated items in our library. We also received numerous non-Medline abstracts. We did not receive any substantive raw data for analysis. The clinical trial tables have been updated to reflect the additional data.

Published Trials of ESA Use in Cancer
More than 100 papers or abstracts on ESA use in cancer have been published. Most studies have not been structured to assess survival, tumor progression and adverse events. Many studies enrolled patients with a variety of tumors. Others enrolled patients with a single disease, but were not stratified for tumor stage. Many studies included patients on a variety of treatment regimens. Many were not randomized, placebo-controlled trials. Many studies used another ESA as an active control. Most studies did not use fixed ESA doses, instead they titrated doses upward in poor responders without a statistical analysis that took this variability into account. Concomitant iron administration limited to patients in the ESA cohort was sometimes a confounding variable. Study endpoints were hemoglobin thresholds, changes in hemoglobin, transfusion requirements (without a priori definition), or quality of life. Frequently, the hematologic endpoint was a composite based on either a change in transfusion needs or hemoglobin level. Many studies did not declare a primary endpoint. Survival and/or tumor progression, if assessed, were secondary or add on endpoints. No studies presented a priori power calculations for patient number and study duration that would be required to demonstrate clinically significant survival differences for neoplastic diseases. No studies presented a priori methods for the assessment of tumor progression. Stratification of risk by tumor type, tumor stage, treatment modality, ESA dose, or ESA response to dose was not present in any of the studies reviewed. The additional data reviewed following the proposed decision did not change these conclusions (See Tables 2 and 3).

4. Medicare Evidence Development and Coverage Advisory Committee (MedCAC)

A MedCAC meeting was not convened for this issue.

5. Evidence Based Guidelines

There were no additional guidelines provided to CMS during the comment period. We describe guidelines in Appendix A.

6. Professional Society Position Published Statements

CMS received many comments from persons affiliated with various organizations. We distinguished bona fide position statements from professional organizations in part by determining if the author was identified as the president, executive vice president, executive director or equivalent of the society and if the comment was stated to be the position of the society rather than of an individual. All of these commenters disagreed with some provision of the proposed decision. In general, all thought that the decision was too restrictive. Some questioned CMS’ legal authority to make this decision. We have summarized their input in Table 4 of the appendices; the full texts of their comments are available on our website (http://www.cms.hhs.gov/mcd/viewpubliccomments.asp?nca_id=203). All of their comments focused on one of the proposed criteria and we respond to those below where we separately review each of our proposed determinations.

7. Industry comments

We received comments from both marketers of ESAs in this country. They presented similar recommendations that supported the following noncovered indications in the proposed decision:

  • Indication 1. Any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding or bone marrow fibrosis
  • Indication 3. Anemia of myeloid cancers (specifically AML/CML, not multiple myeloma)
  • Indication 6. Anemia associated with radiotherapy (primary treatment)
  • Indication 7. Prophylactic use to prevent chemotherapy-induced anemia (in patients who have never suffered from CIA)
  • Indication 8. Prophylactic use to reduce tumor hypoxia
  • Indication 9. Patients with erythropoietin-type resistance due to neutralizing antibodies
  • Indication 12. Anemia due to cancer treatment if patients have uncontrolled hypertension

They did not agree with the other proposed noncovered indications:

  • Indication 2. Anemia of myelodysplasia
  • Indication 10. Patients with treatment regimens including anti-angiogenic drugs such as bevacizumab
  • Indication 11. Patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor
  • Indication 13. Patients with thrombotic episodes related to malignancy

Furthermore, they recommended several changes to the restrictions on the covered indications:

  • The starting hemoglobin level should be 11 g/dL
  • There should be no maximum dose
  • For patients whose hemoglobin does not rise > 1 g/dL in the 4 weeks, two dose escalations should be allowed
  • Patients with a rapid rise in hemoglobin should have a dose reduction
  • ESA use should be discontinued when the hemoglobin level is 12 g/dL

We respond to these below where we separately review each of our proposed determinations.

8. Public Comments

Initial comment period: 3/14/2007 - 4/13/2007

We received 70 comments during the initial public comment period. Of the public commenters who furnished this information, 37 were from providers, 5 were from caregivers, 1 was from a patient, 13 were from professional organizations, 7 were from patient advocacy groups, 1 was from a national oncology policy consulting group and 2 were from pharmaceutical companies. Two comments regarding the use of ESAs for renal disease and two related to code assignments are included in the 70; both topics are outside the scope of this NCD.

The majority of commenters requested CMS to provide coverage of ESAs for all non-renal FDA approved indications. Several commenter included studies and scientific literature with their comments.

Comment period on the proposed decision: 5/14/2007 - 6/13/2007

CMS received 2641 comments on the proposed decision. Several individual commenters submitted multiple comments; in some cases the same comment was submitted more than once by the same commenter. It appears in quite a few instances that many clinical and/or administrative support staff members from a single medical practice submitted comments. Some commenters submitted identical comments.

Most commenters did not refer to or provide any scientific or medical evidence that had not already been reviewed in the proposed decision memorandum or that could definitively answer the outstanding safety questions surrounding ESAs. However, we received a comment from Michael Henke, MD, Professor of Medicine/Radio Oncology at the University of Freiburg, Germany, the principal investigator from one of the trials that demonstrated the safety concerns. He states, “I am convinced that ESA treatment negatively affects disease control and survival of head and neck cancer patients.” He further states that confirmed findings (RTOG 99 03 and DAHANCA 10) and his own research (Henke 2003) support this view. Dr. Henke indicated that comparable safety concerns can be assumed for other cancer sites as well, for example, Leyland Jones (2005) and Wright (2007) suggest breast and lung cancer.

Many commenters described their current clinical practice or current specialty guidelines. Of the physicians who commented, almost all were self-identified as hematologists and/or oncologists. CMS staff also received comments during meetings with representatives of Amgen, Ortho Biotech-Johnson & Johnson, Genentech, ASCO, US Oncology, Marti Nelson Cancer Foundation, Colorectal Cancer Coalition, and other institutions. Each organization used these meetings to emphasize their formal comments which are available online and summarized elsewhere in this document.

Almost all commenters disagreed with some provision of the proposed decision. Some commenters expressed agreement with some aspects of the proposed decision while disagreeing with other aspects. Some commenters did not express approval or disapproval. Thus, the count of commenters is a different number than the count of opinions of the commenters. Consequently, we will provide a summary of the different opinions and not the number of commenters supporting any specific opinions. Myelodysplasia was the subject of the largest number of comments about a specific clinical condition. Commenters also frequently speculated on the effect of the proposed decision on the need for transfusions and the adequacy of the blood supply to meet higher demands.

Subjects outside of the scope of this decision
Comment
Several commenters discussed the use of ESA therapy in the setting of anemia related to kidney disease or other uses that are beyond the scope of the proposed decision.

Response
We will not address those comments in this decision memorandum.

Personal or family member experience
Comment
Many commenters noted personal, friend, or family experience with ESA therapy. We heard from many cancer patients attesting to the benefit of ESAs regarding their quality of life. Beneficiaries submitted testimonies describing activities that were no longer difficult or impossible as a result of ESA therapy. Family members of beneficiaries receiving ESA therapy expressed concern over the costs of ESAs should CMS no long provider coverage. They expressed anger at Medicare for burdening them with the costs of ESAs. Beneficiaries and family members commented about their belief regarding the benefit and necessity of ESA therapy, adding that they would be forced to find a means to incur the costs.

Response
CMS carefully reviewed all the concerns submitted to us. We appreciate the comments received from the beneficiaries we serve and their families. We want our beneficiaries to have access to appropriate and quality care. While personal experiences are important and helpful to the Agency in understanding the impact of its decisions, CMS generally gives greater weight to published scientific evidence.

Lack of transparency/access regarding primary ESA data
Comment
Several commenters noted that it has been difficult if not impossible to obtain access to primary data from ESA clinical trials, and that this has made it problematic to have independent analyses of these data. They voiced support for measures that would increase public access to these data.

CMS received a comment from Marcia Angell, MD, Senior Lecturer in Social Medicine, Harvard Medical School, Former Editor in Chief, New England Journal of Medicine (NEJM.) who also expressed concern regarding the lack of transparency and access of primary ESA data. She states, “Medicare should have access to all the clinical trial information that the FDA has. Currently, companies seeking marketing approval must submit to the FDA all trials, not just the positive ones, but the agency generally does not share this information without the permission of the sponsoring company. That puts the proprietary interests of drug companies ahead of the public interest. Medicare should require full disclosure from the FDA as a condition of its support.”

Response
We agree with the need for greater access to these unpublished datasets.

Blood supply and transfusion demand
Comment
Several commenters asked CMS to consider the effect of ESA use on the blood supply, i.e. blood available for transfusion, if the final decision resulted in more transfusions. Commenters expressed concern that shortages in the blood supply commonly exist and is a particular problem in some minority populations.

Response
The concern about the adequacy of the nation’s blood supply is not a relevant factor for consideration in this national coverage determination. Our focus is whether the use of ESA is reasonable and necessary to treat a particular illness.

Financial considerations
Comment
Some commenters alleged that the specific provisions of the decision were prompted by CMS financial concerns. Some allege that we are trying to save money. Others suggest that the proposed decision would result in increased Medicare expenditures.

Response
The specific provisions of the proposed decision were derived from the regimens, including doses and durations of treatment, that were studied in clinical trials. We did not consider financial implications for these issues. Whether the decision ultimately affects Medicare expenditures is not a consideration in conducting national coverage analyses.

Quality of life as a research outcome
Comment
Many professional societies suggested that quality of life (QoL) outcomes should be a sufficient research endpoint. They urged CMS to use QoL outcomes as evidence to make a reasonable and necessary determination for coverage. For example, the American Society of Hematology (ASH) submitted a list of supporting evidence that included literature pertaining to QoL as an outcome measure for patients with cancer receiving ESA therapy.

Response
Wisloff et al. examined the impact of hemoglobin concentration on QoL scores in 745 patients with multiple myeloma. They had the following conclusion:

“When examining the effect of haemoglobin on QoL, it is essential to adjust for disease parameters and response to therapy in order not to overestimate the impact of haemoglobin on QoL. Our findings imply that uncontrolled studies on the effect of erythropoietin (EPO) in cancer patients may be making exaggerated claims for the effect of EPO on QoL” (Wisloff 2005).

We believe that there is currently insufficient evidence to postulate a QoL benefit to support ESA use. Such evidence of benefit, if one indeed exists, requires more robust research than we have reviewed to date. However, even if such evidence existed, it would need to be weighed against the new evidence suggesting tumor progression and increased mortality.

Pediatric populations
Comment
Some commenters suggested that the proposed decision would adversely effect pediatric populations.

Response
Infants and young children with cancer or leukemia are generally not Medicare beneficiaries. Any issues peculiar to the pediatric population are not generalizable to the Medicare population at large.

Coding
Comment
We were asked to provide ICD-9 codes with the policy.

Response
We do not provide coding instructions in NCDs. We do, however, consider coding in the instructions that are developed to direct our contractors who process claims for items and services billed to Medicare.

CMS authority to make the NCD
Comment
A commenter contested CMS’ authority to limit reimbursement for ESA therapy, claiming that toxicity is not relevant to decisions about medical reasonableness. Other commenters suggest that, under Section 1861(t)(2) of the Social Security Act, Medicare cannot establish coverage conditions for ESA use in the context of anticancer treatment.

Response
We disagree with these comments. CMS’ authority to develop and implement NCDs is clearly and unequivocally established in statute. In determining if a particular drug is reasonable and necessary, one of several considerations is whether the drug improves health outcomes. In this context, toxicity is relevant in determining if health outcomes are improved.

Section 1861(t)(1) of the Social Security Act defines the terms “drugs” and “biologicals.” The statute at § 1861(t)(2) defines a subset of “drugs,” those used in an anticancer chemotherapeutic regime for a medically accepted indication. ESAs may fall under either definition, depending on the use.

The definitions of drugs and biologics at § 1861(t)(1) & (t)(2) include listings in compendia. The United States Pharmacopoeia-Drug Information (USP-DI) is a compendium that lists accepted and unaccepted uses of drugs. Both epoetin and darbepoetin alpha are included in USP-DI and have listings that were changed after the FDA released its black box warning.

Prior to the changes made in March of 2007 in the USP-DI, both darbepoetin alpha and epoetin had accepted indications for the treatment of anemia in cancer patients when the anemia was due to chemotherapy. Epoetin had an off-label indication for treatment of chronic anemia associated with neoplastic diseases. Darbepoetin alpha had an unaccepted indication for treatment of anemia of cancer not due to chemotherapy.

Following the FDA black box warning, the darbepoetin alpha unaccepted indication was strengthened with additional data. The epoetin section also had additional language added that stated that epoetin improves anemia due to cancer in patients not receiving chemotherapy, but may compromise survival. Additional language in the cancer treatment section stated that epoetin has not demonstrated improvements in cancer outcomes and may compromise survival. In sum, the current US-PDI compendium listings provide unfavorable evaluations for these drugs.

Finally, we emphasize that Medicare NCDs instruct our contractors on the coverage of items or services for which claims are made. NCDs do not direct physicians regarding the provision of any particular item or service.

ESA overuse and revision of treatment guidelines
Comment
A commenter said in part that ESAs are overused and suggested that revised guidelines and a lower upper threshold could allow continued use of these agents in those patients who would benefit.

Response
We agree.

Preserving appropriate access
Comment
Y-ME National Breast Cancer Organization stated that breast cancer patients should have access to medications, including ESAs if appropriate, and noted that a significant portion of breast cancer patients are Medicare beneficiaries.

Response
We did not propose to eliminate coverage to ESA therapy for beneficiaries with breast cancer, though we did propose limitations on the dosing that would be covered by Medicare. We believe that our final decision preserves appropriate access with due attention to the serious concerns that are reflected in the FDA black box warnings, the discussions of the ODAC, and the evidence we reviewed.

ESAs are equivalent
Comment
Several commenters stated that ESAs have the same effects and should be treated similarly in this decision.

Response
We agree.

Need for more clinical trials
Comment
Several commenters pointed out that more clinical trials are needed to answer important outstanding questions.

Response
We agree.

ESAs as anti-tumor therapy
Comment
Commenters stated that current data do not support ESA use solely to potentiate the effectiveness of anti-tumor therapy.

Response
We agree.

CMS and FDA
Comment
A commenter said that FDA approved labeling indicates when treatment is “necessary.” Other commenters made various comments about FDA processes.

Response
The labeled indication for the treatment of anemia related to chemotherapy is to decrease the need for transfusions in patients who will be receiving concomitant chemotherapy. The FDA approved label does not identify a hemoglobin (or hematocrit) level at which ESA therapy may be indicated or necessary to treat anemia in patients who have cancer that is related to receiving chemotherapy. However, the FDA label does identify hemoglobin (or hematocrit) levels at which ESA therapy may be indicated, or necessary for the treatment anemia related to chronic renal failure, and for anemic patients scheduled to undergo elective, non-cardiac, nonvascular surgery. Some commenters were confused and believed that the FDA label did, in fact, identify a specific hemoglobin/hematocrit level at which ESA therapy may be indicated or necessary to treat anemia related to chemotherapy.

CMS is not changing the FDA indication for ESA therapy for cancer patients who have anemia related to chemotherapy. CMS’ coverage provision is the FDA label indication and ensures that cancer beneficiaries who have anemia related to chemotherapy can avoid transfusions by receiving ESA therapy “that will gradually increase the hemoglobin (or hematocrit)concentration to the lowest level sufficient to avoid the need for transfusion”, as stated in the FDA labeled Black Box Warning.

CMS and FDA are separate agencies with different statutory missions, and operate under distinct legal authorities. CMS cannot address these comments about FDA’s processes. They should be addressed to FDA directly.

FDA and ODAC
Comment
Several commenters requested that CMS delay rendering a proposed decision until after the FDA ODAC meeting scheduled for May 11, 2007. Other commenters suggested that we defer any final decision until the FDA has responded to the ODAC recommendations. Commenters suggested that CMS review the literature and data distributed at the ODAC meeting prior to rendering the proposed decision. Others asked if we have consulted with FDA or suggested that we consult with FDA.

Response
As stated above, CMS and FDA are separate agencies with different statutory missions, and operate under distinct legal authorities. CMS independently reviewed the evidence prior to the ODAC meeting, which was attended by CMS staff. The concerns raised and the evidence discussed at the ODAC are consistent with the body of evidence that we had already reviewed. We are encouraged that the separate and independent analyses of the FDA and CMS have raised similar serious concerns about the use of ESA treatment in patients with cancer and related neoplastic conditions. CMS' proposed decision was published after the ODAC meeting. FDA deliberations are not public and their timeline for making changes (if any are made) in the labeling for ESAs is unknown. We believe the safety concerns that we have identified in this document required CMS to act quickly to protect beneficiaries.

Acceptable risk
Comment
A number of commenters acknowledged risks associated with ESA use but said that among individual patients there will be different judgments made by patients about what risk is acceptable in light of their personal values, religious beliefs, disease severity, and other factors. They propose that patients and physicians should be allowed to make those decisions without CMS influence.

Response
We agree that treatment decisions regarding the use of ESAs shall be made by physicians and patients, making sound judgments about the risks associated with ESA therapy. In making national coverage determinations, we review the applicable evidence and may, as appropriate, make determinations wherein Medicare coverage for certain items and services is not reasonable and necessary. Thus, in this instance, CMS is making a determination as to those circumstances under which ESA use in patients with cancer and related neoplastic conditions is or is not reasonable and necessary.

9. Expert Opinion

CMS received numerous responses from individuals and organizations that could be classified as “expert.” Due to the large number of these comments, we will not separately include those here. We will limit discussion under this heading to a summary of the FDA Oncologic Drugs Advisory committee (ODAC).

FDA convened the ODAC on 5/10/07 to consider ESA use in cancer. Background materials are available at: fda.gov/OHRMS/DOCKETS/ac/07/briefing/2007-4301b2-02-FDA.pdf (accessed 05/25/07). The ODAC transcripts are available at fda.gov/ohrms/dockets/ac/cder07.htm#OncologicDrugs (accessed 07/03/07).

Included among the recommendations made by the ODAC to FDA are:

  • further marketing authorization be contingent upon additional restriction in product labeling;
  • further marketing authorization be contingent upon additional trials;
  • labeling should specifically state that ESAs are not indicated for use in specific tumor types that may include breast cancer, head and neck cancer, and non small-cell lung cancer (NSCLC);
  • the current evidence is insufficient to determine a lower limit different from the current level of 10 g/dl;
  • the current evidence is insufficient to determine an upper limit different from the current level of 12 g/dl; and
  • product labeling should recommend discontinuation of the ESA following completion of a chemotherapy regimen and re-evaluation of the degree of anemia with subsequent chemotherapy regimen.

VIII. CMS Analysis

National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally under title XVIII of the Social Security Act, § 1869(f)(1)(B). In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage. Moreover, with limited exceptions, the expenses incurred for items or services must be “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member” (§ 1862(a)(1)(A)). This section presents the agency's evaluation of the evidence considered and conclusions reached for the assessment questions:

1. Is the evidence sufficient to conclude that erythropoiesis stimulating agent therapy affects health outcomes when used by Medicare beneficiaries with cancer and related neoplastic conditions?

2. If the answer to Question 1 is affirmative, what characteristics of the patient, the disease, or the treatment regimen reliably predicts a favorable or unfavorable health outcome?

As discussed above, CMS considers improved health outcomes in its reasonable and necessary determinations. Because multiple studies have demonstrated increased tumor progression and decreased survival in certain cancer patients, there may be the potential that the ESA stimulated tumor progression and increased mortality seen in these few cancers may be seen in other cancers. Thus, we believe that in order to demonstrate improved health outcomes, we need to review evidence that demonstrates that ESAs do not cause tumor progression and/or decrease survival in these other cancers even if they might decrease transfusions or improve quality of life.

Thus, in order to assess the evidence for questions 1 and 2, we consider whether the evidence is robust and demonstrates that the use of ESAs in any cancer patient decreases transfusion requirements and/or improves survival and, if so, does the evidence demonstrate that the use of ESAs does not increase tumor progression or decrease survival?

For the convenience of the reader we have organized our analysis by the coverage criteria in our proposed decision. Following a general discussion, we will in each case:

  • review public comments;
  • discuss any additional evidence presented during the comment period;
  • annotate the FDA labeling for that criteria;
  • annotate the recommendation in the United States Pharmacopoeia-Drug Information (USP-DI), a compendium that lists accepted and unaccepted uses of drugs;
  • evaluate the assessment questions above (see Section VII.1);
  • respond to the comments and evidence; and
  • summarize our decision.

General Discussion

In a typical setting, physiologic replacement of a missing hormone should result in normalization caused by that deficit. Indeed many, albeit not all, patients with ESRD are deficient in erythropoietin because of damage to the renal parenchyma. Their anemia is secondary to and highly responsive to low doses of ESAs. In other settings, a hormone is used at higher than physiologic levels because of hormone resistance or to supplement endogenous pathways to achieve superphysiologic or accelerated physiologic responses.

Early ESA drug development was based on the typical setting of a deficit in erythropoietin action. The endpoints in the clinical trials were reduction in the transfusion rate, quality of life, absolute hemoglobin level, and change in hemoglobin level. The hemoglobin parameters were surrogate endpoints. Because anemia portended poor clinical outcome (Dunphy 1989; Fein 1995; Obralic 1990; Oehler 1990; Reed 1994), it was hypothesized that reversal of anemia itself would improve long-term clinical status. It was presumed that the primary risk was thromboembolic vascular events, and that these were related to hemoglobin level rather than to drug dose and/or response to drug dose. As such, most of the registration trials for FDA approval were relatively small and conducted in heterogeneous patient populations with a mixture of primarily solid tumors at various stages who were undergoing treatment with a variety of regimens. (See Proposed Decision Memorandum-drug registration section (http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=203))

At the time of initial drug approvals for cancer-treatment associated anemia, the FDA had concerns about ESA mediated tumor initiation or promotion. The FDA requested post-approval Phase IV commitments in 1993 and 2002 to explore this putative risk promotion because the registration studies were not structured to assess overall survival, cause-specific mortality, cause-specific morbidity, tumor-free survival, and tumor progression. The post approval studies permitted heterogeneous patient populations because it was presumed that the risk benefit ratio would be similar for all tumors at all stages, for all treatment modalities, and in all adult patient populations. For a listing of Phase IV commitments, see Proposed Decision Memorandum sections on terminated trials and ongoing studies (http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?id=203).

In many of the terminated trials, there was a signal suggesting decreased survival. Attribution for the precise determination of mortality cause was often not done or not done rigorously. Nonetheless, results from studies that attempted to assess cancer disease-free survival or changes in locoregional tumor control, suggest that tumor progression plays a more significant role than vascular-thrombotic events in the apparent decreased survival observed with ESA use for the anemia secondary to cancer chemotherapy, an FDA approved indication. A signal for decreased survival was also observed with ESA use for the anemia of cancer (in patients not undergoing chemotherapy) and to reduce tissue hypoxia during radiation treatments, neither of which are FDA approved indications. These observations have resulted in FDA Black Box warnings, the most serious warning placed in the labeling of a prescription medication (see section III (V) F).

Tumor progression might occur via a number of avenues. Malignant cells could be transformed, or their milieu enriched. The first mechanistic pathway includes the ability of malignant cells to survive via decreased programmed cell death (apoptosis), the ability to survive through resistance to chemo/immuno/radiotherapy, increased proliferation leading to greater tumor burden, enhanced invasiveness, and improved migratory or metastatic travel capacity. Another mechanistic pathway includes decreased tissue hypoxia and increased nutrient supply via a more extensive vascular network (angiogenesis) and increased erythrocyte number.

In the absence of definitive clinical data we have reviewed significant amount of in vitro work to support the first pathway (Acs 2001, 2002, 2003; Anagnostou 1990, 1994; Arcasoy 2003, 2005; Batra 2003; D’Andrea 1989; Digicaylioglu 1995; Farrell 2004; Fraser 1989; Haroon 2003; Henke 2006, Jones 1990; Kumar 2006; Lai 2005; Lappin 2003; Masuda 1993; Mioni 1992; Ogilvie 2000; Ribatti 2003; Rossert 2005; Selzer 2000; Westenfelder 2000; Wright 2004; Winkelman 1990; Yasuda 1998, 2001, 2006). Indeed, elements of the erythrocyte receptor signaling cascade are similar to those of epidermal growth factor (EGF) receptor, a target against which immunotherapeutic agents are being developed (Wakao 1997; Zhang 2006). Locoregional progression of head-and-neck cancer was increased in patients with tumors positive for erythropoietin receptors and who were treated with erythropoietin (Henke 2006). There is a trend for such progression even in the patients with erythropoietin receptors who did not receive erythropoietin, suggesting that endogenous erythropoietin might be variable and able to impact clinical outcome (Henke 2006). Cultured cells (cervical cancer line HT100 and glioma line U87) developed resistance to ionizing radiation and cis-platinum after exposure to erythropoietin (Belenkov 2004; Yasuda 2003). Incubation with an inhibitor to the erythropoietin receptor’s JAK-STAT pathway, typhostin (AG490), could reverse this resistance (Belenkov 2004).

The picture, however, is not straightforward. As such, universal statements about how ESA use results in the outcomes seen in oncology cannot be made. Erythropoietin receptor number may change with the cell cycle (Acs 2001; Broudy 1991). The number may increase with the stage of the tumor (Acs 2001). Some cell lines do not exhibit proliferation in response to erythropoietin exposure (Wesphal 2002). Indeed, Henke et al. found that locoregional progression of head-and-neck cancer was not increased in erythropoietin-treated patients lacking erythropoietin receptors (Henke 2006). Mittelmann et al. even found myeloma regression in mice after ESA treatment (Mittelmann 2001). Tovari et al. found that ESA treatment might enhance sensitivity to 5-fluorouracil chemotherapy (Tovari 2005).

There is also a significant amount of in vitro work that supports the second mechanistic pathway. Microvascular density and tumor stage (for neuroblastomas and hepatocellular carcinomas) have been found to correlate with both erythropoietin and erythropoietin receptor expression (Ribatti 2007 A&B). This suggests that there is tumor secretion of erythropoietin that binds to erythropoietin receptors on vasculature which, in turn, proliferates and further promotes tumor growth (Ribatti 2007 A&B). Secretion of pro-angiogenic factors and recruitment of vascular endothelium has also been observed with human mesenchymal stem cells which, like cancer cells, are less differentiated than normal cells (Zwezdaryk 2007). There has even been a report of the conversion of myelodysplastic syndrome (MDS) to leukemia attributed to erythropoietin’s angiogenic effects on the bone marrow (Bunworasate 2001; Ribatti 2002). Indeed anti-angiogenic monoclonal antibody therapy has been approved for colon cancer and is under development for other tumors (Panares 2007). Nonetheless, erythropoietin-induced angiogenesis has not been found in all cancers or test models (Hardee 2005).

Oncology patients may be exposed to supraphysiologic ESA doses. Many cancer patients manifest erythropoietin resistance, i.e., they have an inappropriately low endogenous erythropoietin response to anemia (Ward 1977) and do not respond to low exogenous dose levels (Miller 1990). This is likely to be compounded in geriatric patients who are known to have reduced hematopoietic reserve (Miller 1990). Less frequent dosing regimens, although equivalent to more frequent dosing regimens on the basis of a hematologic response, result in higher peak blood levels of hormone (Chung 1998, 2001; Kryzunski 2005; Ramakrishnan 2004). It is not known whether supraphysiologic ESA blood levels would increase the likelihood of spill-over from the classic high affinity erythropoietin receptor binding sites in the bone marrow to non-marrow receptors with different binding constants where it can act as a growth factor (Fraser 1988, 1989; Masuda 1993; Hardee 2006) or whether excess hormone is bound by the soluble erythropoietin receptors secreted by some tumors (Harris 1996; Maeda 2001; Wesphal 2002).

Regardless of the cause(s), careful prospective trials controlled for the tumor, tumor stage and perhaps tumor cell cycle, cancer treatment, and perhaps endogenous systemic or paracrine/autocrine erythropoietin production and the presence of erythropoietin receptor on tumors and as soluble elements in the blood are needed to inform practitioners as to whether ESAs provide a meaningful clinical benefit for the various oncologic populations. Careful trials would also assess the effects of dose including doses in patients who exhibit a poor hematologic response to low doses as well as the effects of long-term dosing and repeated dosing.

We cannot be sure of the completeness of the evidentiary database because of the question of unpublished data. Negative studies were frequently not available as full published reports on Medline. The early termination of studies by data safety monitoring boards, investigators, and/or pharmaceutical sponsors because of a safety concern does not permit complete appraisal of the magnitude of safety risk. Early termination may reduce the statistical power of a safety finding. Nonetheless, evidence of harm is apparent despite these limitations. ESA treatment has been associated with an increased risk of thrombotic-vascular disease, tumor progression, and decreased survival. Furthermore, there are potential mechanisms that could explain the etiology of the harm.

Although the evidence is less robust than we would like, particularly for geriatric patients, it is sufficient to identify certain patient characteristics and treatment practices that have a high likelihood of unfavorable clinical outcomes. In our proposed decision, we identified several instances in which this high likelihood occurred. Additionally, we proposed that for other indications, we limit use of ESAs to tumors with erythropoietin receptors and to specific targets that we felt the evidence supported. Use of ESAs in other tumors was left to contractor discretion.

The following subsections will discuss each indication separately and any changes to what we proposed.

Analysis by Specific Indications

Proposed Noncovered Indication #1: Any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis

Public Comments
Commenters on this issue supported the CMS proposed decision. A majority of commenters agreed that use of ESAs for these indications was not supported by evidence. Two societies suggested that this indication be covered in the case of marrow fibrosis, but agreed with the rest of the restrictions.

Additional Evidence
We received no new evidence supporting the use of ESAs in the treatment of anemia in cancer patients due to the conditions listed.

We note that the current FDA labels for Epogen (epoetin) and Aranesp (darbepoetin alpha) respectively include the following relevant language.

EPOGEN (epoetin) is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding, which should be managed appropriately.

A lack of response or failure to maintain a hemoglobin response with Aranesp (darbepoetin alpha) doses within the recommended dosing range should prompt a search for causative factors. Deficiencies of folic acid, iron or vitamin B12 should be excluded or corrected. Depending on the clinical setting, intercurrent infections, inflammatory or malignant processes, osteofibrosis cystica, occult blood loss, hemolysis, severe aluminum toxicity and bone marrow fibrosis may compromise an erythropoietic response.

We note that the USP-DI has similar language for both epoetin and darbepoetin alpha.

Response
We agree with the majority of the commenters who supported this decision. We were not presented evidence, nor did we find any evidence that would support the use of ESAs in marrow fibrosis. We are finalizing our decision of noncoverage for this indication.

Summary
We have determined that ESAs are not reasonable and necessary for any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis.

Proposed Noncovered Indication #2: Anemia of myelodysplasia (MDS)

Public Comments
Commenters on this issue strongly opposed the CMS proposed decision. Many commenters referred to current clinical practice and longitudinal experience to support the use of ESAs in MDS. Others suggested that these data could be sufficiently inferred from existing published trials. Others expressed concern that continuing this noncoverage would markedly increase the transfusion rate and exhaust the available blood supply

Additional Evidence
Data was presented demonstrating that MDS patients on ESAs had fewer transfusions than had been historically needed for MDS patients prior to ESAs.

FDA: This is an off-label use.

USP-DI describes MDS as an “Acceptance not established” indication. MDS is not explicitly addressed in the USP-DI listing for darbepoetin alpha.

Response
We continue to believe that there is insufficient robust clinical evidence to support the coverage of ESAs for treatment of MDS. When we opened this NCD, we committed to looking at all non-ESRD uses of ESAs. However, in the proposed decision, we narrowed the scope of the NCD to cancer and related neoplastic conditions. MDS is not an oncologic disease; it is a premalignant condition. We note what is still lacking in this clinical field, are randomized clinical trials of appropriate duration, examining safety as a primary endpoint and powered sufficiently to determine whether use of ESAs in this population is ultimately beneficial or harmful; and if so, whether for all patients with MDS or only to specified subpopulations. While data does suggest that ESAs lower the number of transfusions in MDS patients, it is unclear if some or much of this decrease is from the general decrease in transfusions that occurred in a similar time frame to the introduction of ESAs.

Summary
MDS is not an oncologic disease; it is a premalignant condition. Thus, we believe it appropriate to not include this indication in this decision.

Proposed Noncovered Indications #3: Anemia of myeloid cancers

This indication is a subset of #5: Anemia of cancer not related to cancer treatment. We are collapsing this indication into that one.

Proposed Noncovered Indications #4: Anemia associated with the treatment of myeloid cancers or erythroid cancers

Public Comments
Commenters were most concerned about how CMS defined myeloid cancer. They requested that multiple myeloma be specifically excluded from this definition. They supported the CMS proposed decision to noncover use in acute and chronic myelogenous leukemias (AML and CML) and erythroid cancers.

Additional Evidence
We received no new published evidence that supports the use of ESAs during the treatment of CML, AML, or erythroid cancers.

The FDA approved label for Epogen (epoetin) includes the following language.

EPOGEN (epoetin) is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy.

Aranesp (darbepoetin alpha) is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis and for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy.

The USP-DI has similar language for both epoetin and darbepoetin alpha.

Response
We agree that multiple myeloma is not included in the definition of myeloid cancer. We also agree with the commenters that the noncoverage for myeloid cancers be specifically linked to CML and AML. We clearly listed it among the solid tumors for which we proposed restricted coverage.

Summary
We will modify our proposed decision and define the specific myeloid cancers that are noncovered. We have determined that ESAs are not reasonable and necessary for any anemia associated with the treatment of CML, AML, or erythroid cancers.

Proposed Noncovered Indication #5: Anemia of cancer not related to cancer treatment

Public Comments
Most commenters were in support of this noncoverage, stating that this was the setting in which much of the adverse outcomes were reported. Some commenters suggested that in spite of the evidence, physicians should make individual decisions about the use of ESAs in this setting. Some beneficiaries with cancer stated that they received ESA therapy continuously for years. Others stated that they continue to receive ESA therapy, though their cancer is in remission. Some commenters suggested Coverage with Evidence Development (CED) for this indication.

Additional Evidence
We received no additional published evidence supporting the use of ESAs for the treatment of anemia not related to cancer. We were provided with observational data on the improvement in QoL scores in some patients who received ESAs while not under treatment. No data supported any improvement in other measures of morbidity or survival.

FDA: This is an off-label use. We note that the labels for Epogen/Procrit (epoetin) and Aranesp (darbepoetin alpha) include the following language in their black box warnings.

  • increased the risk of death when administered to target a hemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for this population.

In the USP-DI, epoetin is listed under the section ‘Acceptance not established’ with the language:

Epoetin improves anemia due to cancer in patients not receiving chemotherapy, but may compromise survival.

USP-DI lists darbepoetin alpha as not indicated (“unaccepted”) for the treatment of anemia associated with neoplastic diseases.

Response
Use of ESAs in cancer not associated with treatment is the specific indication in which much of the reports of adverse events have occurred. While we agree that physicians and patients have the freedom to make independent treatment choices, this Agency must evaluate the relevant evidence and make determinations to ensure that Medicare coverage is provided only for items and services that are reasonable and necessary. In this case, we have determined that the use of ESAs for this indication is not reasonable and necessary. Moreover, this determination is supported by the strong FDA black box warning.

CMS uses coverage with evidence development when we believe there is some evidence of benefit but not to the point of national coverage. In this case, there is evidence of harm and thus we do not believe that CED is appropriate for ESA use for this indication.

Summary
The evidence we reviewed and the public comments support the determination that ESAs are not reasonable and necessary for any anemia in cancer that is not related to cancer treatment.

Proposed Noncovered Indication #6: Anemia associated with radiotherapy

Public Comments
The majority of commenters on this issue supported the CMS proposed decision. Those few that disagreed noted that in some cases (especially colorectal cancer) chemotherapy is given in concert with radiotherapy. They did not disagree with radiotherapy alone as being a limitation to coverage.

Additional Evidence
We received no additional evidence supporting the use of ESAs in the treatment of anemia associated with radiotherapy.

FDA: This is an off label use. We note that the labels for Epogen/Procrit (epoetin) and Aranesp (darbepoetin alpha) include the following language in their black box warnings.

  • shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a hemoglobin of greater than 12 g/dL.

The USP-DI has strong warnings for the use of ESAs for this indication.

The following language is included in the ‘Unaccepted’ section of the indications.

A non-significant trend towards reduced 1-year overall survival was reported in an additional abstract in patients with squamous cell carcinoma of the head and neck who received definitive radiotherapy with epoetin alfa (70%) versus those who did not receive epoetin alfa. In addition, the class of erythropoiesis-stimulating agents (ESA) has been noted in other clinical trials to have an increase in serious/life-threatening side effects and/or a detrimental effect on survival

We note the following language in ‘Side/Adverse Effects’

The use of darbepoetin alpha in cancer patients when administered to target of greater than 12g/dL

  • shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy

Response
There is agreement on this issue by all commenters and CMS. To clarify, we are referring only to radiotherapy and not to concomitant chemotherapy.

Summary
The evidence reviewed and the comments received support the determination that ESAs are not reasonable and necessary for the treatment of anemia associated only with radiotherapy.

Proposed Indication #7: Prophylactic use to prevent chemotherapy-induced anemia

Public Comments
The majority of commenters on this issue supported the CMS proposed decision. A few commenters did advocate for prophylactic use in patients who were about to receive chemotherapy.

Additional Evidence
We received no additional evidence supporting the use of ESAs to prevent chemotherapy-induced anemia.

FDA: This is an off-label use.

USP-DI: This indication is not listed nor discussed in the USP-DI for epoetin or darbepoetin alpha.

Response
Given the evidence surrounding this and the public comments on this issue, this indication will remain non-covered.

Summary
The evidence reviewed and the comments received support the determination that ESAs are not reasonable and necessary for prophylactic use to prevent anemia in beneficiaries who have cancer.

Proposed Noncovered Indication #8: Prophylactic use to reduce tumor hypoxia

Public Comments
All commenters on this issue supported the CMS proposed decision.

Additional Evidence
We received no additional evidence supporting the use of ESAs to reduce tumor hypoxia.

FDA: This is an off-label use.

The USP-DI does not address this indication.

Response
We agree with the public comments received regarding this proposed decision.

Summary
The evidence reviewed and the comments received support the determination that ESAs are not reasonable and necessary for prophylactic use to reduce tumor hypoxia.

Proposed Noncovered Indication #9: Patients with erythropoietin-type resistance due to neutralizing antibodies

Public Comments
Most commenters on this issue supported the CMS proposed decision. One dissenting argument was that this provision was unrealistic since the assay is not clinically available and serves as a research tool.

Additional Evidence
We received no additional evidence supporting the use of ESAs in patients with erythropoietin-type resistance due to neutralizing antibodies.

FDA: We note the following language in the labels for Epogen (epoetin) and Aranesp (darbepoetin alpha).

EPOGEN (epoetin) should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).

If anti-erythropoietin antibody-associated anemia is suspected, withhold Aranesp (darbepoetin alpha) and other erythropoietic proteins...Aranesp (darbepoetin alpha) should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).

The USP-DI does not address erythropoietin resistance due to neutralizing antibodies.

Response
We recognize that this is not a commonly performed test. However, there is broad evidence to indicate that the use of ESAs in patients who, for any reason, have had this test performed with a positive result, may lead to negative outcomes. Given the favorable comments and the fact that we received no new evidence, this indication will remain noncovered.

Summary
The evidence reviewed and the comments received support the continuing determination that ESAs are not reasonable and necessary in beneficiaries with erythropoietin-type resistance due to neutralizing antibodies.

Proposed Noncovered Indication #10: Patients with treatment regimens including anti-angiogenic drugs such as bevacizumab

Public Comments
Commenters on this issue generally opposed the CMS proposed decision restricting the use of ESAs in patients receiving anti-angiogenic drugs. Commenters also contested our assumptions about the angiogenic effects of ESAs. Several commenters have noted that concomitant use with anti-angiogenic therapy is contraindicated. Several commenters noted that many chemotherapy drugs have some anti-angiogenic properties. Also, commenters suggested that the concern about the interaction of ESAs with anti-angiogenic drugs are only theoretical and have not been demonstrated in practice. Many supported CED in lieu of noncoverage when anti-angiogenic drugs are used alone. A manufacturer of an anti-angiogenic drug expressed concern that a specific drug was cited as an example, rather than referring to the class of drugs alone.

Additional Evidence
Published data evaluating the addition of ESAs to chemotherapy regimens including anti-angiogenic drugs were not available. One company presented an analysis of data from trials involving bevacizumab. In that analysis it separately evaluated outcomes on patients receiving ESAs and those not receiving ESAs and found no differences in outcomes.

FDA: This is a labeled indication.

The USP-DI does not list nor include any indication/discussion regarding treatment regimens including anti-angiogenic drugs for either epoetin or darbepoetin alpha.

Response
Angiogenesis appears to be important for both tumor growth and metastasis formation. Until neoplasms acquire the potential to induce vessel formation that can ensure adequate nutrition and oxygen, their growth is effectively held in check. Targeting angiogenesis is more focused than generalized cytotoxic or cytostatic therapy which targets all rapidly growing cells (Seimann 2005). Anti-angiogenesis can be achieved in several ways. Repeated small doses of chemotherapy can be given to semi-selectively poison the vascular epithelium (metronomic therapy). Other drugs do this by targeting growth factors (e.g. basic fibroblast growth factor [bFGF], platelet derive growth factor [PDGF], transforming growth factor [TGF], and vascular endothelial growth factor [VEGF]), their receptors, matrix metalloproteinases, and tumor suppressor gene activity (Bouis 2006; Svensson 2003; Zhong 2006).

Hardee et al. have provided some of the most compelling data for angiogenesis. Breast cancer cells injected into a window chamber imbedded in living mice showed evidence of vessel formation (angiogenesis) and tumor size progression that was greater than controls when the cells were exposed to erythropoietin (Hardee 2007). These changes occurred in the absence of differences in hematocrit levels. These findings could be blunted by any one of three inhibitors: recombinant soluble erythropoietin receptor, neutralizing monoclonal erythropoietin antibody, or mutant erythropoietin (competitive inhibition). There were similar findings of vessel proliferation and tumor progression, when breast cancer cells were genetically altered to include a mutant and constitutively active (always on) erythropoietin receptor. The findings from the window chamber assay were replicated in an assay using the mouse mammary fat pad.

Folkman has stated that the benefits of anti-angiogenic therapy might be limited by the redundancy or multiplicity of pathways for angiogenesis (Folkman 2006). Vascular endothelial growth factor (VEGF) is not the sole regulator of angiogenesis. Farrell and Lee state “…Ribatti and colleagues recently provided evidence that erythropoietin can also elicit an angiogenic response in endothelial cells in vitro and in vivo, and, thus, like VEGF, is an effective angiogenic factor…In agreement with the previous studies in human umbilical vein endothelial cells and bovine adrenal capillary endothelial cells, recombinant human erythropoietin substantially increased EA.hy926 cell proliferation. Furthermore, recombinant human erythropoietin exposure resulted in a three-fold greater matrix metalloproteinase 2 activity in treated EA.hy926 cultures compared with cell cultures grown in untreated media” (Farrell 2004). The first author of this paper is a Johnson & Johnson scientist.

It is not known whether the anti-angiogenic activity (efficacy) of these drugs are significantly diminished by the angiogenic activity of ESAs since prospective drug interaction studies have not been done. For the same reason, it is also not known whether 1) the cardiovascular complications, fluid retention, thrombosis, and hypertension observed with the anti-angiogenic monoclonal antibody, bevacizumab, are unique to the drug or are class effect and 2) the likelihood of these adverse effects, which also occur with ESAs, would be increased by combination use (Dear Doctor Letter with FDA warning 2004, 2006; USA Today 8/13/04). As we are modifying our proposed decision, CED is not an option.

Summary
Some evidence supports the pathophysiologic construct that ESAs can stimulate certain growth factors (VEGF, EGFR) that are the targets of chemotherapy. The appropriate evidence would be randomized trials that evaluate the addition of ESAs to standard treatment regimens. That evidence is not available. We have strongly considered, as many commenters suggested, whether this indication would be appropriate for CED. However, CED restricts coverage to within research studies. Coverage would not be available to any patients outside the study. We have considered options that would enroll beneficiaries initially into observational studies that could be used to assist in designing the appropriate randomized trial. However, the complexities of this option exceed the Agency’s current ability to manage those vastly differing studies. In addition, as some of the data presented indicated, some patients do appear to have an improved QoL with appropriate ESA dosing. Thus, we will remove the proposed noncoverage from the final decision. However, since the tumor types for which these drugs are indicated are included below, the use of ESAs with these agents must meet the restrictions outlined below.

Proposed Noncovered Indication #11: Patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor

Public Comments
All commenters on this issue disagreed with noncoverage. However, many supported CED in lieu of noncoverage.

Additional Evidence
Specific evidence evaluating the addition of ESAs to chemotherapy regimens including these drugs was not available. Commenters presented data evaluating the differences in outcomes in patients in trials that included these drugs and found no differences in outcomes between those patients that received ESAs and those that did not.

FDA: This is a labeled indication.

The USP-DI does not list nor include any indication/discussion regarding treatment regimens including these drugs for either epoetin or darbepoetin alpha.

Response
The recognition of the epidermal growth factor receptor (EGFR) as an oncogene has resulted in the development of pharmacologic agents directed against the growth factor or its receptor. These agents have numerous targets including the external domain of the receptor, phosphorylation sites, and the DNA itself (anti-sense gene therapy) (Lai 2007; Paez 2004). These agents include cetuximab, erlotinib, gefitinib, and panitumumab. The signaling cascades for the epidermal growth factor and erythropoietin receptors are complex, but appear to have some overlap in pathways or targets (Oda 2005; Witthun 1993). For example, STAT-3 activation appears to occur with both (Grandis 1998; Kirito 2002). This overlap suggests that the efficacy of anti-EGFR therapy could be diminished by concomitant ESA use. Definitive answers are not available as prospective drug interaction studies have not been performed. The recent termination of the PAACE trial which assessed chemotherapy with avastin +/- panitumumab for decreased survival and pulmonary thrombosis in the experimental treatment arm suggests that these interactions cannot be predicted (Amgen press release).

Summary
Some evidence supports the pathophysiologic construct that ESAs can stimulate certain growth factors (VEGF, EGFR) that are the targets of chemotherapy. The appropriate evidence would be randomized trials that evaluate the addition of ESAs to standard treatment regimens. That evidence is not available. We have strongly considered, as many commenters suggested, whether this indication would be appropriate for CED. However, CED restricts coverage to within research studies. Coverage would not be available to any patients outside the study. We have considered options that would enroll beneficiaries initially into observational studies that could be used to assist in designing the appropriate randomized trial. However, the complexities of this option exceed the Agency’s current ability to manage those vastly differing studies. In addition, as some of the data presented indicated, some patients do appear to have an improved QoL with appropriate ESA dosing. Thus, we will remove the proposed noncoverage from the final decision. However, since the tumor types for which these drugs are indicated are included below, the use of ESAs with these agents must meet the restrictions outlined below.

Proposed Noncovered Indication #12: Anemia due to cancer treatment if patients have uncontrolled hypertension

Public Comments
All commenters on this issue supported the CMS proposed decision.

Additional Evidence
We received no additional evidence supporting the use of ESAs in cancer patients with uncontrolled hypertension.

FDA: Uncontrolled hypertension is a contraindicated use in both the Epogen (epoetin) and Aranesp (darbepoetin alpha) labels. We also note the following language in the labeling for Aranesp (darbepoetin alpha).

Patients with uncontrolled hypertension should not be treated with Aranesp (darbepoetin alpha); blood pressure should be controlled adequately before initiation of therapy. Blood pressure may rise during treatment of anemia with Aranesp (darbepoetin alpha) or epoetin. In Aranesp (darbepoetin alpha) clinical trials, approximately 40% of patients with chronic renal failure (CRF) required initiation or intensification of antihypertensive therapy during the early phase of treatment when the hemoglobin was increasing. Hypertensive encephalopathy and seizures have been observed in patients with CRF treated with Aranesp (darbepoetin alpha) or epoetin.

The USP-DI has similar language.

Response
Hypertension is a well-recognized complication of ESA therapy. Patients with uncontrolled hypertension are at greater risk of complications. The FDA label specifically lists this as a contraindication for ESA therapy.

Summary
The evidence reviewed and the comments received support the determination that ESAs are not reasonable and necessary in beneficiaries with cancer who have uncontrolled hypertension.

Proposed Noncovered Indication #13: Patients with thrombotic episodes related to malignancy

Public Comments
Some commenters agreed with CMS. However, some commenters suggested that with proper evaluation, certain patients might be successfully placed on ESAs and an anticoagulant and managed. Commenters noted that clinical guidelines include precautions about thrombotic adverse effects. Also, commenters expressed concern that there are many other potential causes of thrombotic events in cancer patients that may not be related to the malignancy.

Additional Evidence
We received no additional evidence on the use of ESAs in cancer patients with thrombotic episodes.

The FDA approved labeling for both Aranesp (darbepoetin alpha) and Procrit/Epogen (epoetin) lists the following:

Thrombotic and Cardiovascular Events
Overall, the incidence of thrombotic events was 6.2% for Aranesp (darbepoetin alpha) and 4.1 % for placebo. However, the following events were reported more frequently in Aranesp (darbepoetin alpha) -treated patients than in placebo controls: pulmonary embolism, thromboembolism, thrombosis, and thrombophlebitis (deep and/or superficial). In addition, edema of any type was more frequently reported in Aranesp (darbepoetin alpha)-treated patients (21%) than in patients who received placebo (10%).

Increased Mortality, Serious Cardiovascular and Thromboembolic Events
EPOGEN (epoetin) and other erythropoiesis-stimulating agents (ESAs) increased the risk for death and for serious cardiovascular events in controlled clinical trials when administered to target a hemoglobin of greater than 12 g/dL. There was an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure, and hemodialysis graft occlusion. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may also contribute to these risks.

To reduce cardiovascular risks, use the lowest dose of EPOGEN (epoetin) that will gradually increase the hemoglobin concentration to a level sufficient to avoid the need for red blood cell (RBC) transfusion. The hemoglobin concentration should not exceed 12 g/dL, the rate of hemoglobin increase should not exceed 1 g/d L in any two week period (see DOSAGE AND ADMINISTRATION).

The USP-DI has similar language.

Response
We remain concerned that ESAs may precipitate lethal thrombosis. However, thrombotic events may be unrelated to the episode of chemotherapy and unrelated to the use of ESAs. While we remain concerned about this potential adverse event, commenters clearly outlined the various regimens that are available to physicians in treating these episodes. Since it will not be clear in many cases that ESAs are the causative factor in thrombotic events, we are removing this restriction in coverage.

Summary
We have not included this proposed limitation in the final decision.

B. Indications covered with restrictions in proposed decision

Receptor Status in patients with cancer undergoing chemotherapy:

CMS proposed to use ESA receptor status of tumors as a selection criterion for those tumors that were more likely to have an adverse response to ESAs. While the data are preliminary, we believe that they do provide a plausible explanation for the tumor progression seen in the two trials.

Public Comments
Some commenters debated the relevance, the clinical significance, or even the existence of erythropoietin receptors on malignant or normal cells, and stated that CMS should not develop coverage criteria that are based on the putative role of these receptors in the development or progression of cancer or related conditions. Others criticized the currently available assays as being nonspecific. Others said that CMS should not extrapolate from basic science or in vitro studies in its discussion of a possible mechanism for the adverse outcomes associated with ESAs.

Additional Evidence
We have received no evidence or proposal for an alternative explanation for the tumor progression.

The FDA label and the USP-DI do not address the use of erythropoietin receptor status as a criterion for determining use of ESAs.

Response
We are aware that there is spirited discussion about erythropoietin receptors. We proposed a mechanism to explain the cancer progression that has been seen with the use of ESAs in clinical trials and which has been highlighted in the black box warning. Though various commenters have objected to our proposal, they have not offered alternative explanations.

The presence of erythropoietin receptors on nonmalignant cells does not exclude an effect of ESAs on malignant cells at physiologic or supraphysiologic levels. Similarly, erythropoietin may exert additional effects beyond its usual physiologic pathway.

Farrell and Lee have stated, “Given the potentially wide range of functions of erythropoietin and the erythropoietin receptor, the mechanisms underlying these functions must be determined. Interestingly, Lappin and colleagues, repeating some work done by Acs et al. found that erythropoietin receptors were present in tumor cells, but absent from surrounding normal breast tissue (Maxwell, unpublished data). This, Lappin noted, is significant because it suggests the potential use of erythropoietin receptors of a tumor to target an erythropoietin-attached drug to the tumor and not damage the surrounding healthy tissue (Farrell 2004).

Indeed, it is possible that erythropoietin as a ligand may be interacting with cells through other receptors as well as erythropoietin receptors. Regardless of the route, evidence of a biologic effect after exposure is paramount. Although some of the in vitro data are conflicting (Rosti 1993), these contradictions might be explained by the cell lines or tissues that were used. Erythropoietin might have its most important effects in certain tissue subsets. Indeed, Phillips et al. have recently shown that the stem cells that reside within a tissue are such an important subset (Phillips 2007). Breast cancer initiating cell (stem cells) exposed to erythropoietin increased both their population size and capacity for self-renewal.

Summary
We agree with the commenters on the lack of maturity of this data. However, in response to the commenters we will not use this distinction in the final policy. We will consider all solid tumor types, multiple myeloma, lymphoma, and lymphocytic leukemia, regardless of ESA receptor status, to fall under the restrictions defined below.

Proposed Restrictions

1. The hemoglobin/hematocrit levels immediately prior to initiation of dosing for the month should be < 9 g/dl (hematocrit < 27%) in patients without known cardiovascular disease and <10 g/dl/30% in patients with documented symptomatic ischemic disease that cannot be treated with blood. (We suggest that patients, especially those in the latter category, be alerted to the increased potential for thrombosis and sequelae.)

Public Comments
Many commenters stated that CMS arbitrarily selected the proposed maximum hemoglobin level at which ESA therapy could be initiated. Those who opposed this restriction suggested higher levels. ASH suggested that instead of identifying a hemoglobin level when ESA therapy is covered by Medicare, CMS should identify a level when the physician should evaluate the possible need for ESA therapy. Others commented that ESAs should be considered when the hemoglobin drops below 11 g/dL and should be stopped at a hemoglobin of 12 g/dL (hematocrit of 36%).

Additional Evidence
We received no additional published information regarding the threshold for intervention for transfusions/ESAs, the timing of anemia onset with chemotherapy and the rate of anemia onset with chemotherapy. Per Dr. Henry Chang, National Institutes of Health/National Heart/Lung Institute/Extramural (NIH-NHLBI-Extramural), there is a large on-going study that may address transfusion thresholds, albeit in a perioperative population.

The FDA label states that ESAs are indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. ESAs are indicated to decrease the need for transfusions in patients who will be receiving chemotherapy. The dose should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion and not to exceed 12 g/dL. Prior to the Black Box warning, some labels included a suggested hemoglobin target range of 10 -12 g/dL.

The USP-DI lists the treatment of anemia in adults with nonmyeloid malignancies in which the anemia is due to the effect of concomitantly administered chemotherapy in order to decrease the need for transfusion as an accepted indication. The General Dosing section includes the following language, “To reduce cardiovascular and thromboembolic risks, the lowest dose of epoetin alfa should be used. The dose administered should gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red blood cell transfusion. The hemoglobin concentration should not exceed 12 g per dL. However, in the Dose Adjustment/Therapeutic Goal section, the following language is included, “The dosage of epoetin must be individualized to maintain the hemoglobin within the suggested target range, 10 to 12 g per dL. At the physician's discretion, the suggested target hemoglobin range may be expanded to achieve maximal patient benefit.”

For darbepoetin alpha, the following language is in ‘General Dosing Information.’

To reduce cardiovascular risks, the lowest dose of darbepoetin alpha should be used. The dose administered should gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red blood cell transfusion. The hemoglobin concentration should not exceed 12g/dL.

ASCO and ASH guidelines recommended evaluating patients for the need for ESA therapy when the hemoglobin is at or below 10 g/dL.

Response
The current label for ESAs indicates that there is increased risk for death and serious cardiovascular events when the hemoglobin is greater than 12g/dL. The label does not identify a specific hemoglobin level for treatment initiation or treatment target in patients with anemia induced by chemotherapy. The goal is to avoid transfusions. Transfusions are not required for hemoglobin levels 10.0g/dL or greater. There are no definitive data regarding transfusion need, and by extension ESA need for patients with hemoglobin levels between 7 and 10 g/dL. We proposed that patients who have hemoglobin levels less than 9g/dL are potential candidates for initiation or continuation of ESA therapy. Many commenters recommended that we raise that to 11g/dL.

Removal of the hemoglobin target range of 10 – 12 g/dl indicates that treatment of chemotherapy induced anemia should no longer focus on keeping the hemoglobin above 10 g/dL but at the lowest level that will prevent transfusions while still remaining below 12 g/dL. Although transfusion guidelines no longer provide hemoglobin initiation levels, it is a common practice for physicians to only transfuse patients when the hemoglobin approaches or drops below 8 g/dL. Thus, use of ESAs should begin at a hemoglobin level most likely to prevent the hemoglobin from dropping to 8 g/dL.

The ODAC did not identify specific a hemoglobin target at which ESA therapy should begin, but recommended that FDA establish one.

We proposed that initiating ESAs at a hemoglobin of 9 g/dL would be a sufficient starting point to prevent transfusions. The commenters disagreed and recommended 11 g/dL but with the outcome of keeping the hemoglobin above 10 g/dL. They argued that ESAs may take several weeks to reach peak activity and that if not started earlier, the hemoglobin was likely to drop to transfusion levels. Evidence to support that was lacking.

Summary
Because changes in hemoglobin after chemotherapy do not appear to be precipitous and because a response to ESAs can be seen as early as 2 weeks, we do not believe that early intervention at a hemoglobin of 11 g/dL with ESAs is reasonable and necessary (Barrett-Lee 2000, 2006; Birgegard 2005, 2006, 2007; Coiffier 2001; Tas 2002). However, we do agree that a starting level of 9 g/dL has the potential to result in more hemoglobins dropping to transfusion levels and will thus modify our proposed decision and find that the use of ESAs is reasonable and necessary in beneficiaries with cancer undergoing myelosuppressive therapy when their hemoglobin levels immediately prior to initiation or maintenance of ESA treatment are < 10 g/dL (or the hematocrit < 30%).

2. The maximum covered treatment duration is 12 weeks/year.

Comment
Many commenters disagreed with the proposed overall 12-week limit on ESA coverage and noted that many chemotherapeutic regimens are longer than 12 weeks. Several commenters supported ESA therapy for 4 weeks to 12 weeks after cessation of myelosuppressive chemotherapy. Still others supported ongoing ESA therapy that could last for years. A commenter asked us to clarify the timeframe to distinguish anemia resulting from chemotherapy from anemia due to other causes. Some commenters suggested specific timeframes, such as six weeks, 90 days, and one year. Others were unclear if this meant a total of 12 weeks/year of 12 weeks after completion of chemotherapy.

Additional Evidence
No additional published data regarding the duration of anemia after myelosuppressive chemotherapy and the cessation of such therapies was presented except for studies describing residual post therapy tissue platinum levels (Stewart 1982, 1994; Tothill 1992; Vermorkem 1986). No additional substantive data discriminating between the anemia due to chemotherapy after cessation of therapy and the anemia of cancer were provided.

FDA and USP-DI do not address maximum doses in its recommended dosing.

Response
Our intent for this restriction was not clearly understood. The controlled segments of the registration trials were 12-16 weeks long. We do not have substantive information for longer treatment cycles and for repeat treatment cycles. There are limited data on the temporal aspects of marrow recovery and the duration of anemia after myelosuppressive chemotherapy (Barrett-Lee 2000, 2006; Birgegard 2005, 2006, 2007; Coiffier 2001; Tas 2002). The ODAC voted overwhelmingly (16-1) against the continuation of ESA therapy after the completion of chemotherapy, but did not define the time period beyond which persisting anemia could no longer be attributed to the chemotherapy. The public comments were varied. Thus, we have modified our initial proposal and have determined that treatment of anemia due to myelosuppressive chemotherapy is reasonable and necessary up to 8 weeks following the last dose of myelosuppressive chemotherapy.

Summary
We have determined that continued use of ESAs for beneficiaries with cancer whose anemia is related to chemotherapy is not reasonable and necessary after 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen. There are no restrictions on chemotherapy regimen frequency or duration in this decision.

3. The maximum covered 4 week treatment dose is 126,000 units for erythropoietin and 630 μg for darbepoetin alpha.

Public Comments
Commenters on this topic generally opposed the maximum doses that we proposed. A commenter supported the implementation of maximum ESA dosage ranges, with the possibility for individual case consideration as an exception. Many felt that the other restrictions imposed would limit the overall dose. Some commented that the maximums were not therapeutically equal for the two drugs. Many recommended that we specify the starting and maintenance dose and not have a maximum dose. They questioned why CMS would impose dose limitations when the drug label does not.

Additional Evidence
No additional published information regarding the long term safety in cancer and cancer related conditions were provided. No additional published information comparing long term safety of ESAs for those who responded to low doses versus those who required high doses for any hemoglobin response versus non responders was provided.

The current FDA labels and USP-DI recommend a starting dose of 150U/kg/three times weekly for epoetin and 2.25 mcg/kg/week for darbepoetin alpha.

Response
We agree with the commenters that a fixed maximum covered dose may interfere with appropriate patient management. Labeled dosing is based upon weight and thus maximum doses will vary by weight. Although fixed dose studies have been conducted by the sponsors, are discussed in FDA labeling, and reported to be therapeutically equivalent, most of the labeled dosing is based on weight. Also, a more important issue is to begin at the lowest dose necessary to prevent transfusion. Thus, we will not continue with a fixed maximum dose limitation as imposed in the proposed decision, recognizing that the clinically appropriate number may vary with the beneficiary’s weight and response to therapy. However, we will apply a limitation to the starting dose as indicated by the label. For epoetin, the recommended starting dose is no more than 150U/kg/TIW. For darbepoetin alpha, the recommended starting dose is no more than 2.25 mcg/kg/week. Maintenance of these doses may continue if the hemoglobin level has not risen about the initiation level of 10 g/dL (hematocrit 30%) 4 weeks after the initiation of treatment and the hemoglobin rise is ≥ 1 g/dL (hematocrit ≥ 3%).

Summary
We have determined that the starting dose for ESA treatment is the recommended FDA label starting dose, no more than 150 U/kg/three times weekly for epoetin and 2.25 mcg/kg/weekly for darbepoetin alpha. Equivalent doses may be given over other approved time periods. Maintenance of ESA therapy is the starting dose if the hemoglobin level remains below 10 g/dL (or hematocrit is < 30%) 4 weeks after initiation of therapy and the rise in hemoglobin is ≥ 1g/dL (hematocrit ≥ 3%).

4. Continued use of the drug is not reasonable and necessary if there is evidence of poor drug response (hemoglobin/hematocrit rise <1 g/dl/<3%) after 4 weeks of treatment.

Public Comment
Many commenters stated that non-response should result in the administration of a higher dose. Most recommended that at least one dose escalation be allowed to better identify non-responders. ASH suggested that ESAs should not be continued after eight weeks in the absence of response, assuming the appropriate dose increase has been attempted in low-responders. US Oncology supported discontinuation after six weeks if the hemoglobin did not rise 1 g/dl or greater. All commenters supported discontinuation of ESA therapy in the face of non-response. A few commenters proposed that no change in the hemoglobin level after ESA therapy was initiated, that is, no increase or decrease, should be accepted as evidence of response to ESA therapy.

Additional Evidence
No groups supplied published data on safety outcomes in poor responders. The change in transfusion need for poor responders after ESA dose increases is not well characterized because of the use of composite endpoints and the lack of stratification by response.

The FDA label recommends that epoetin be increased to 300U/kg/TIW if there is no rise in hemoglobin after 8 weeks. The label recommends that darbepoetin alpha dose be adjusted to prevent transfusions and keep Hgb < 12 g/dL.

Dosing recommendations listed in the USP-DI are confusing, and at times, contradictory. Under the “Three Times a Week Dosing,’ it states, “If response is not satisfactory (no reduction in transfusion requirements or no rise in hemoglobin after 8 weeks), increase dose to 300 Units per kg of body weight three times a week to achieve the suggested target hemoglobin range, 10 to 12 g per dL. And, the ‘Weekly Dosing’ section states, “If after 4 weeks of therapy, the hemoglobin has not increased by 1 g per dL, in the absence of RBC transfusion, the epoetin dose should be increased to 60,000 Units weekly. If the patient has not responded after 4 weeks of additional therapy at 60,000 Units weekly, it is unlikely the patient will respond to higher doses of epoetin”.

We note the following language in ‘General Dosing Information (usual adult dose, anemia associated with chemotherapy in cancer patients)’

For patients receiving weekly administration, if there is less than a 1g/dL increase in hemoglobin after 6 weeks of therapy, the dose of darbepoetin alpha should be increased up to 4.5 mcg/kg of body weight.

Response
There is insufficient evidence to define specific regimens for treatment of nonresponders. However based upon the comments from the public, we are modifying this restriction to allow one dose escalation of 25% and increasing the total time period for assessment of response to 8 weeks. We will also clarify that the increase in dose shall only occur if the hemoglobin remains < 10g/dL (or the hematocrit < 30%).

Summary
We have determined that it is reasonable and necessary to increase the covered dose once by 25% in patients whose hemoglobin rise is < 1 g/dl (hematocrit rise < 3%) compared to pretreatment baseline over 4 weeks of treatment and the hemoglobin level has remained < 10 g/dL (hematocrit < 30%) after the 4 weeks of treatment. Continued use of the drug is not reasonable and necessary if the hemoglobin rise is < 1 g/dl (hematocrit rise <3 %) compared to pretreatment baseline after 8 weeks of treatment.

5. Continued administration of the drug is not reasonable and necessary if there is an increase in fluid retention or weight (5 kg) after 2 weeks of treatment.

Public Comments
We had very few commenters addressing this specific proposal. Of those who did, some commenters opposed this restriction citing lack of clinical evidence. Another comment suggested this be clarified to distinguish between fluid retention or weight gain not associated with cancer.

Additional Evidence
No additional data were submitted. The FDA approved labeling for both Aranesp (darbepoetin alpha) and Procrit/Epogen (epoetin) respectively reflect these concerns.

Thrombotic and Cardiovascular Events
Overall, the incidence of thrombotic events was 6.2% for Aranesp (darbepoetin alpha) and 4.1 % for placebo. However, the following events were reported more frequently in Aranesp (darbepoetin alpha)-treated patients than in placebo controls: pulmonary embolism, thromboembolism, thrombosis, and thrombophlebitis (deep and/or superficial). In addition, edema of any type was more frequently reported in Aranesp (darbepoetin alpha)-treated patients (21%) than in patients who received placebo (10%).

Increased Mortality, Serious Cardiovascular and Thromboembolic Events
EPOGEN (epoetin) and other erythropoiesis-stimulating agents (ESAs) increased the risk for death and for serious cardiovascular events in controlled clinical trials when administered to target a hemoglobin of greater than 12 g/dL. There was an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure, and hemodialysis graft occlusion. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may also contribute to these risks.

To reduce cardiovascular risks, use the lowest dose of EPOGEN (epoetin) that will gradually increase the hemoglobin concentration to a level sufficient to avoid the need for RBC transfusion. The hemoglobin concentration should not exceed 12 g/dL, the rate of hemoglobin increase should not exceed 1 g/d L in any two week period (see DOSAGE AND ADMINISTRATION).

The USP-DI has similar language.

Response
We remain concerned that ESAs may precipitate edema and heart failure. However, weight changes in cancer patents may have a multitude of causes. As discussed above in thrombotic events, it is typically not clear to practitioners that edema and heart failure would be due to the ESA versus other causes. Thus, we will not continue this restriction.

Summary
We are not including this proposed limitation in the final decision.

6. Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin/hematocrit >1 g/dl/>3% after 2 weeks of treatment.

Public Comments
Some public commenters suggested that the ESA dose be lowered rather than discontinuing ESA therapy. Others suggested that there was not enough clinical evidence to allow CMS to make this decision. Commenters cited the FDA label to decrease the dose, not discontinue ESA therapy.

Additional Evidence
No additional substantive published data were provided.

The FDA approved labeling as well as the USP-DI dosing recommendation for EPOGEN/Procrit (epoetin) and Aranesp (darbepoetin alpha) include the following:

If the hemoglobin increases by more than 1.0 g/dL in a 2-week period, the dose should be decreased by approximately 25%.

Response
In several clinical trials, patients with brisk hemoglobin responses were excluded from further dosing and follow-up. Brisk hemoglobin response has been linked to thrombosis.

Summary
We have determined that continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin > 1 g/dl (hematocrit > 3%) in 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to < 10 g/dL (or the hematocrit is < 30%) and there has been a dose reduction of 25% from the previously administered dose.

Summary of restrictions for covered indications:

For patients with anemia secondary to anticancer chemotherapy, ESAs are appropriate when the hemoglobin is < 10g/dL (hematocrit < 30%). The maximum dose for the first 4 weeks is 1800 U/kg for epoetin and 9 mcg/kg for darbepoetin alpha. If after the first 4 weeks the hemoglobin is > 10g/dL (hematocrit > 30%), ESA treatment is not covered. ESA treatment may resume if the hemoglobin again drops below 10g/dL (hematocrit below 30%). If after any 4 week ESA treatment cycle, the hemoglobin remains below 10 g/dL (hematocrit below 30%), ESA treatment may continue at the same dose. If after the first 4 week ESA treatment cycle, the hemoglobin rise is less than 1 g/dL (hematocrit < 3%) and the hemoglobin level remains < 10 g/dL (hematocrit < 30%), the dose may be increased by 25% one time. If the rise in hemoglobin is < 1g/dL (hematocrit < 3%) for 8 weeks in spite of a 25% increase in dose, ESA treatment should be discontinued. If after any 2 week period of time, the hemoglobin rise is > 1g/dL (hematocrit > 3%), then ESA treatment should be discontinued unless the hemoglobin is < 10 g/dL (hematocrit <3 0%) at which time ESA treatment may be reinstituted at a dose reduction of 25%. ESA treatment meeting the above requirements may be continued for 8 weeks following the completion of the final dose of myelosuppressive chemotherapy in a chemotherapy regimen.

IX. Conclusion

Emerging safety concerns (thrombosis, cardiovascular events, tumor progression, and reduced survival) derived from clinical trials in several cancer and non-cancer populations prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs). We reviewed a large volume of scientific literature, including basic science research, to see if these safety signals seen in randomized controlled trials could be reasonably explained in whole or in part by the actions of ESAs on normal or cancerous cells. In doing so we proposed conditions of coverage based on expression of erythropoietin receptors. The scientific understanding of this mechanism is a subject of continuing debate among stakeholders, continues to evolve, and can only be resolved through additional studies. We also reviewed a large volume of comments on the use of ESAs in myelodysplastic syndrome (MDS), a premalignant syndrome that transforms into acute myeloid leukemia (AML) in many patients. Though we continue to be interested in these specific issues, this final decision does not differentiate ESA coverage by the erythropoietin receptor status of the underlying disease, and we have narrowed the scope of this final decision to make no NCD at this time on the use of ESAs in MDS.

CMS has determined that there is sufficient evidence to conclude that erythropoiesis stimulating agent (ESA) treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions include:

  1. any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis;
  2. the anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers;
  3. the anemia of cancer not related to cancer treatment;
  4. any anemia associated only with radiotherapy;
  5. prophylactic use to prevent chemotherapy-induced anemia;
  6. prophylactic use to reduce tumor hypoxia;
  7. patients with erythropoietin-type resistance due to neutralizing antibodies; and
  8. anemia due to cancer treatment if patients have uncontrolled hypertension.

We have also determined that ESA treatment for anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia is only reasonable and necessary under the following specified conditions:

  1. The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is < 10 g/dL (or the hematocrit is < 30%).
  2. The starting dose for ESA treatment is the recommended FDA label starting dose, no more than 150 U/kg/three times weekly for epoetin and 2.25 mcg/kg/weekly for darbepoetin alpha. Equivalent doses may be given over other approved time periods.
  3. Maintenance of ESA therapy is the starting dose if the hemoglobin level remains below 10 g/dL (or hematocrit is < 30%) 4 weeks after initiation of therapy and the rise in hemoglobin is ≥ 1g/dL (hematocrit ≥ 3%).
  4. For patients whose hemoglobin rises < 1 g/dl (hematocrit rise < 3%) compared to pretreatment baseline over 4 weeks of treatment and whose hemoglobin level remains < 10 g/dL after the 4 weeks of treatment (or the hematocrit is < 30%), the recommended FDA label starting dose may be increased once by 25%. Continued use of the drug is not reasonable and necessary if the hemoglobin rises < 1 g/dl (hematocrit rise < 3 %) compared to pretreatment baseline by 8 weeks of treatment.
  5. Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin > 1 g/dl (hematocrit > 3%) over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to < 10 g/dL (or the hematocrit is < 30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose.
  6. ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen.

Local Medicare contractors may continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by NCD.



Appendices [PDF, 4MB]

Bibliography

Abbrederis K, Bassermann F, Schuhmacher C, Voelter V, Busch R, Roethling N, Siewert JR, Peschel C, Lordick F. Erythropoietin-alfa during neoadjuvant platin-based chemotherapy for locally advanced esophagogastric adenocarcinoma: results of a phase II trial. 2006 Gastrointestinal Cancers Symposium:44.

Abels R. Use of recombinant human erythropoietin in the treatment of anemia in patients who have cancer. Seminars in Oncology. 1992;19 (No 3 Suppl 8):29-35.

Abel R. Erythropoietin for anaemia in cancer patients. Eur J Cancer. 1993;29A(Suppl 2):S2-8.

Acs G, Acs P, Beckwith SM, et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res. 2001;61:3561–5.

Acs G, Zhang PJ, Rebbeck TR, Acs P, Verma A. Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma. Cancer. 2002;95:969–81.

Acs G, Zhang PJ, McGrath CM, et al. Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression. Am J Pathol. 2003;162:1789–806.

Adamson JW, Ludwig H. Predicting the hematopoietic response to recombinant human erythropoietin (epoetin alfa) in the treatment of the anemia of cancer. Oncology. 1999;56:46-53.

Akizawa T, Kinugasa E, Kitaoka T, Koshikawa S. Effects of recombinant human erythropoietin and correction of anemia on platelet function in hemodialysis patients. Nephron. 1991;58:400–6.

Albertsson M. Assessment of quality of life and hemoglobin values in breast-cancer patients treated with epoetin beta. Proc Am Soc Clin Oncol. 2002;21:1981.

Alcay A, Wun T, Khatri V, Chew HK, Harvey D, Zhou H, White RH. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol. 2006;24:1112-8.

Alexopoulos CG, Ka A. A randomized comparison of rHuEPO with darbepoetin for cancer related anemia. Ann Oncol. 2004;15 (Suppl 3):page and abstract number not known.

American Journal of Kidney Diseases, 37(1)(suppl 1). 2001:p:S210-238.

American Society for Clinical Oncology. www.asco.org/portal/site/ASCO. Accessed 4/5/07.

American Society of Hematology website. www.hematology.org. Accessed 4/5/07.

Amgen press release. Available at: http://www.amgen.com/media/pr.jsp?year=2006. Accessed 3/19/07.

Amgen press release. Available at: http:// www.amgen.com/media/pr.jsp?year=2007. 1/25/07 and 2/16/07. Accessed 3/19/07.

Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A. 1990;87:5978-82.

Anagnostou A, Liu Z, Steiner M, et al. Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci U S A. 1994;91:3974–8.

Ando M, Iwata A, Ozeki Y, Tsuchiya K, Akiba T, Nihei H. Circulating platelet-derived microparticles with procoagulant activity may be a potential cause of thrombosis in uremic patients. Kidney Int. 2002;62:1757–64.

Ang KK, Berkely B, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relative patients with advanced head and neck carcinoma. Caner Research. 2002;62:7350-6.

Antonadou D, Cardamakis E, Puglisi M, Malamos N, Throuvalas N. Erythrpoietin enhances radiation treatment efficacy in patients with pelvic malignancies. Final results of a randomized phase III study. European Journal of Cancer. 2001;37 (Suppl 6):S144.

Aoki I, Nishijima K, Homori M, Nakahara K, Higashi K, Ishikawa K. Responsiveness of bone marrow erythroid progenitors (CFU-E and BFU-E) to recombinant human erythropoietin (rh-Ep) in vitro in multiple myeloma. British Journal of Haematology. 1992;81:463-9.

Aranesp™ package insert. Available at: http://www.fda.gov/cder/foi/label/2002/darbamg071902LB.pdf.

Aravantinos G, Linardou H, Makridaki D, Laiou E, Zafiropoulos A, Janninis J, Sofos G, Gikas D, Samantas E, Markantoni-Kyroudi S. Recombinant human erythropoietin for platinum-based chemotherapy-induced anaemia: a single-centre randomized study. Journal of BUON. 2003;8:127-32.

Arcasoy M, Harris KW, Forget BG. A human erythropoietin receptor gene mutant causing familial erythrocytosis is associated with deregulation of the rates of Jak2 and Stat5 inactivation. Exp Hematol. 1999;27(1):63-74.

Arcasoy M, Jiang X, Haroon Z. Expression of erythropoietin receptor splice variants in human cancer. Biochem Biophys Res Commun. 2003;307:999–1007.

Arcasoy M, Amin K, Chou S-C, Haroon Z, Varia M, Raleigh JA. Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Clin Cancer Res. 2005;11:20-27.

Arslan M, Kurt E, Evrensel T, Gonullu G, Demiray M, Kanat O, Manavoglu O. Efficacy of different usage strategies of recombinant human erythropoietin (rHuEPO) in platinum containing chemotherapy. Proc Am Soc Clin Oncol;2002;21:2884.

Arslan M, Evrensel T, Kurt E, Demiray M, Gonullu G, Kanat O, Manavoglu O. Comparison of clinical outcomes of different erythropoietin usage strategies. Tumori. 2004;90:394-8.

AuBuchon JP. Managing change to improve transfusion safety. Transfusion. 2004;44:1377-83.

Auerbach M, Ballard H, Trout J, McIlwain M, Ackerman A, Bahrain H. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multi-center, open-labeled, randomized trial. Journal of Clinical Oncology. 2004;22:1301-07.

Ault P, Kantarjian H, O’Brien S, Garcia-Manero G, Rios MB, Cortes JE. Use of darbepoetin alfa for the treatment of anemia occurring during imatinib therapy for CML: preliminary evidence of safety and efficacy. Proc Am Soc Clin Oncol. 2003;22:2467.

Ayash LJ, Elias A, Hunt M, Demetri G, Wheeler C, Tepler I, Schwartz G, Mazanet R, Reich E, McCauley M, Antman K, Anderson KC. Recombinant human erythropoietin for the treatment of the anaemia associated with autologous bone marrow transplantation. British Journal of Haematology. 1994;87:153-61.

Aziz K, Hashem T, Mobarek N, Bary N, Ghoneimy I, Haddad S. Does recombinant human erythropoietin improve the outcome of radiation in head and neck cancer patients? Proceedings of American Society for Therapeutic Radiology And Oncology (ASTRO). 2001;vol.unknown:#2274.

Balleari E, Gatti A, Mareni C, Massa G, Marmont A M, Ghio R.. Recombinant Human Erythropoietin for Long-Term Treatment of Anemia in Paroxysmal Nocturnal Hemoglobinuria. Haematologica 1996; 81:143-147.

Balleari E, Mareni C, Marmont AM, Ghio R. Therapy with recombinant erythropoietin in paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1996;94(2):424.

Balleari E, Rossi E, Clavio M, Congiu A, Gobbi M, Grosso M, Secondo V, Spriano M, Timitilli S, Ghio R. Erythropoietin plus granulocyte colony-stimulating factor is better than erythropoietin alone to treat anemia in low-risk myelodysplastic syndromes: results from a randomized single-centre study. Annals of Hematology. 2006; 85:174-80.

Baltz B, Gregory SA, Ehmann WC, Williams D. Initial dosing of epoetin alfa 60,000 U QW followed by Q2W maintenance for anemic patients with cancer receiving chemotherapy. Journal of Clinical Oncology. 2004;22(14S):8212.

Bamias A, Aravantinos G, Kalofonos C, Timotheadou N, Siafaka V, Vlahou I, Janinis D, Pectasides D, Pavlidis N, Fountzilas G. Prevention of anemia in patients with solid tumors receiving platinum based chemotherapy by recombinant human erythropoietin (rHuEpo): a prospective, open label, randomized trial by the Hellenic Cooperative Oncology Group. Oncology. 2003;64:102-10.

Barber D, D’Andrea D. Erythropoietin and interleukin-2 activate distinct JAK kinase family members. Mol Cell Biol. 1994;14:6506-14.

Barber D, Corless C, Xia K, Roberts T, D’Andrea D. Erythropoietin activates Raf1 by an Shc-independent pathway in CTLL-EPO-R cells. Blood. 1997;89:55-64.

Barbone FP, Middleton SA, Johnson DL, McMahon FJ, Tullai J, Gruninger RH, Schilling AE, Jolliffe LK, Mulcahy LS. Mutagenesis studies of the human erythropoietin receptor. The Journal of Biological Chemistry. 1997;272(8):4985-92.

Baron F, Sautois B, Baudoux E, Matus G, Fillet G, Beguin Y. Optimization of recombinant human erythropoietin therapy after allogenic hematopoietic stem cell transplantation. International Society for Experimental Hematology. 2002; 30:546-554.

Baron F, Frere P, Fillet G, Bequin Y. Tandem high-dose therapy (HDT) for multiple myeloma: recombinant human erythropoietin therapy given between first and second HDT allows second peripheral blood stem cell transplantation without red blood cell transfusion. British Journal of Haematology. 20003;123:103-5.

Baron F, Frere P, Fillet G, Beguin Y. Recombinant human erythropoietin therapy is very effective after an autologous peripheral blood stem cell transplant when started soon after engraftment. Clinical Cancer Research. 2003;9:5566-72.

Barrett-Lee P, Bailey N, O’Brien M, Wager E. Large-scale UK audit of blood transfusion requirements and anaemia in patients receiving cytotoxic chemotherapy. Br J Cancer. 2000;82:93-7.

Barrett-Lee P, Ludwig H, Birgegård G, Bokemeyer C, Gascón P, Kosmidis P, Kongable G, Krzakowski M, Schneider M, Schrijvers D, Van Belle S for the European Cancer Anaemia Survey Advisory Board and Participating Centers. Independent risk factors for anemia in cancer patients receiving chemotherapy: results from the European Cancer Anaemia Survey. Oncology. 2006;70:34-48.

Barrios M, Alliot C. IgA multiple myeloma responding to erythropoietin monotherapy. Am J Hematol. 2005 Oct;80(2):165-6.

Barton CM, Hall PA, Hughes CM, Gullick WJ, Lemoine NR. Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer. Journal of Pathology. 1991;163:111-6.

Batra S, Perelman N, Luck L, Shimada H, Malik P. Pediatric tumor cells express erythropoietin and a functional erythropoietin receptor that promotes angiogenesis and tumor cell survival. Lab Invest. 2003;83:1477–87.

Battaglia A, Fattorossi A, Pierelli L, Bonanno G, Marone M, Ranelletti FO, Coscarella A, De Santis R, Bach S, Mancuso S, Scambia G. The fusion protein MEN 11303 (granulocyte-macrophage colony stimulating factor/erythropoietin) acts as a potent inducer of erythropoiesis. Experimental Hematology. 2000;28:490-8.

Baz R, Brand C, McGowan Y, Hussein A. High dose recombinant human erythropoietin use is associated with increased overall survival in patients with multiple myeloma. Journal of Clinical Oncology. 2005;23(16S):6621.

Beer TM, Higano CS. Darbepoetin administered every 4 weeks for anemia in advanced prostate cancer patients. 2006 Prostate Cancer Symposium. Abstract#2948.

Begg T, Hearns J. Components in blood viscosity. The relative contribution of haematocrit, plasma fibrinogen and other proteins. Clin Sci. 1966;31:87–93.

Beggs VL, Disalvo WM, Meyer LP, Dragnev KH, Gibson JJ, Hoopes PJ, Strawbridge RR, Hammond S, Van Dyk O, Rigas JR. Fatigue and plasma cytokines in a randomized double-blind placebo-controlled trial of epoetin alfa in patients undergoing combined modality therapy for unrespectable non-small cell lung cancer (NSCLC). The Journal of Supportive Oncology. 2003;1(Suppl 1):2948.

Belenkov A, Shenouda G, Rizhevskaya E, et al. Erythropoietin induces cancer cell resistance to ionizing radiation and to cisplatin. Mol Cancer Ther. 2004;3:1525-32.

Bennett CL, Nathan DP, Adams JR. Epoetin alfa use for cancer patients in the United States and Europe: review of vignette and clinical data. Proc Am Soc Clin Oncol. 2002;21:1026.

Bennett CL, Luminari S, Nissenson AR, Klinge SA, McWilliams N, McKoy J, Raisch DW, Kim B, Casadevall N, Tallman MS. Re-importation of pharmaceuticals may be unsafe: lessons learned from the RADAR assessment of erythropoietin (EPO)-associated pure red cell aplasia (PRCA). Journal of Clinical Oncology. 2004:22(14S):2512.

Bennett CL, Cournoyer D, Carson KR, et al. Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on adverse drug events and reports (RADAR) project. Blood. 2006;106(10):3343-7.

Bergsagel DE, Phil D, Fitzgerald B, Quirt I, Meharchand J, Hasselback R. Treatment of anemia associated with multiple myeloma[Letter to the editor]. The New England Journal of Medicine. 1991;324(1):62.

Bern M, Lokich J, Wallach S, Bothe A Jr, Benotti P, Arkin C, Greco F, Huberman M, Moore C. Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Intern Med. 1990;112:423-8.

Bernell P, Stenke L, Wallvik J, Hippe E, Hast R. A sequential erythropoietin and gm-csf schedule offers clinical benefits in the treatment of anaemia in myelodsyplastic syndromes. Leukemia Research. 1996;20(8):693-9.

Besa EC, Kunselman S, Nowell PC. A pilot trial of 13-cis-retinoic acid and alpha-tocopherol with recombinant human erythropoietin in myelodysplastic syndrome patients with progressive or transfusion-dependent anemias. Leukemia Research. 1998; 22:741-9.

Bessho M, Jinnai I, Matsude A, Saito M, Hirashima K. Improvement of Anemia by Recombinant Erythropoietin in Patients with Myelodysplastic Syndromes and Aplastic Anemia. International Journal of Cell Cloning. 1990; 8:445-458.

Bessho M, Jinnai I, Hirashima K, Saito M, Murohashi I, Ino H, Tsuji M, Fukuda M, Maruyama M, Kusumoto S, Tominaga K, Matsuda A, Kawai N, Itoh K, Sakata T, Handa A, Endo K, Toyoda A, Kobayashi Y, Kashimura T, Kawano N, Minanihisamatsu M. Trilineage recovery by combination therapy with recombinant human granulocyte colony-stimulating factor and erythropoietin in patients with aplastic anemia and refractory anemia. Stem Cells. 1994;12:604-15.

Bessho M, Hirashima K, Asano S, Ikeda Y, Ogawa N, Tomonaga M, Toyama K, Nakahata T, Nomura T, Mizoguchi H, Yoshida Y, Niitsu Y, Kohgo Y and the Multicenter Study Group. Treatment of the anemia of aplastic anemia patients with recombinant human erythropoietin in combination with granulocyte colony-stimulating factor: a multicenter randomized controlled study. European Journal of Haematology. 1997;58:265-72.

Bick R. Cancer-associated thrombosis. N Engl J Med. 2003;349:109-11.

Bindi M, Montemaggi M, Sabatino M, Paolelli L, Morelli R, Piazza D, Cigno A, Carreca I. Reticulocytes can represent and early indicator of the erythropoietic response to darbepoietin alfa in the anemia by chemotherapy. Journal of Clinical Oncology. 2004;22:14S #8245.

Birgegård G, Pere Gascón P, Ludwig H. Evaluation of anaemia in patients with multiple myeloma and lymphoma:findings of the European Cancer Anaemia Survey. Eur J Haematol. 2006;77:378–86.

Birgegård G, Aapro M, Bokemeyer C, Dicato M, Drings P, Hornedo J, Krzakowski M, Ludwig H, Pecorelli S, Schmoll H, Schneider M, Schrijvers D, Shasha D, Van Belle S. Cancer-related anemia: pathogenesis, prevalence, and treatment. Oncology. 2005;68 (Suppl 1):3-11.

Bittorf T, Buchse T, Sasse T. Activation of the transcription factor NF-kappa B by the erythropoietin receptor:structural requirements and biological significance. Cell Signal. 2001;13:673-681.

Blau AC. Erythropoietin in Cancer: Presumption of Innocence? Stem Cells. 2007;10:1-5.

Blayney D, Fesen M, Mirtsching B, Katz D, Tomita D. Every-2-week darbepoetin alfa improves hemoglobin in anemic patients with cancer undergoing chemotherapy: a stratified analysis by tumor type. Blood. 2003;102 Issue 11. Unknown page.

Blayney DW, Spiridonidis H, Fesen MR, McGuire WP, Bhatia AW, Hellman RM, Terry D, Tomita D. Darbepoetin alfa every 2 weeks to treat chemotherapy-induced anemia: experience in a randomized, open-label study. Proc Am Soc Clin Oncol. 2003;22:3003.

Blohmer JU, Wurschmidt F, Petry U, Weise G, Sehouli J, Kimmig R. 6th interim analysis of a prospective, randomized, open and controlled AGO- and NOGGO-intergroup study: sequential adjuvant chemo-radiotherapy with vs without epoetin alfa for pts with high-risk cervical cancer. Proc Am Soc Clin Oncol. 2003;22:1798.

Blohmer J, Wuerschmidt J, Petry K, Weise G, Sehouli J, Kimming R, Dressler P, Kentenich H, Kohls A. Results with sequential adjuvant chemo-radiotherapy with vs without epoietin for patients with high-risk cervical cancer: results of a prospective, randomized, open and controlled AGO and NOGGO-intergroup study. Annals of Oncology. 2004;15 (Suppl 3):Page Unknown.

Blohmer JU, Dunst J, Harrison L, Johnston P, Khayat D, Ludwig H, O’Brien M, Van Belle S, Vaupel P. Cancer-related anemia: biological findings, clinical implications and impact on quality of life. Oncology. 2005;68(suppl 1):12-21.

Blue Cross and Blue Shield Association Technology Evaluation Center (EPC)-Chicago, IL. Seidenfeld J, Piper M, Bohlius J, Weingart O, Trelle S, Engert A, Skoetz N, Schwarzer G, Wilson J, Brunskill S, Hyde C, Bonnell C, Ziegler KM, Aronson N. Comparative effectiveness review number 3. Comparative effectiveness of epoetin and darbepoetin for managing anemia in cancer patients undergoing cancer treatments. Contract No. 290-02-0026. (www.effectivehealthcare.ahrq.gov. Accessed 4/4/07. Copies of the executive summary available via phone call (800) 358-9295 or e-mail ahrqpubs@ahrq.hhs.gov.)

Boccia R, Liu D, Silberstein P, Tchekmedyian NS, Holladay C, Tomita D, Rossi G, Otterson G. Evaluating the effectiveness of darbepoetin alfa 300 mcg Q3W for the treatment of chemotherapy-induced anemia. Journal of Clinical Oncology. 2005;23(16S):8129.

Boccia R, Malik I, Raja V, Kahanic S, Liu R, Lillie T, Tomita D, Clowney B, Silberstein P. Darbepoetin alfa administered every three weeks is effective for the treatment of chemotherapy induced anemia. The Oncologist. 2006;11:409-17.

Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennett C, Engert A. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. Journal of the National Cancer Institute. 2005;97(7):489-98.

Bohlius J, Weingart O, Trelle S, Engert A. Cancer-related anemia and recombinant human erythropoietin-an updated overview. Nature Clinical Practice Oncology. 2006;3:152-64.

Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B, Bennett CL, Langensiepen S, Hyde C, Engert A. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 2006;98:708-14.

Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwartzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Brunskill S, Djulbegovic B, Langensiepen S, Hyde S, Engert E. Erythropoietin or darbepoetin for patients with cancer: Review. Cochrane Library. John Wiley and Sons. 2007;1-228. www.thecochranelibrary.com

Boissel J, Lee W, Presnell SR, Cohen FE, Bunn HF. Erythropoietin structure-function relationships. The Journal of Biological Chemistry. 1993;268(21):15983-93.

Bokemeyer C, Oechsle K, Hartmann J.-T. Anaemia in cancer patients: pathophysiology, incidence and treatment. European Journal of Clinical Investigation. 2005;35(suppl 3):26-31.

Bokemeyer C, Aapro M, Courdi A, Foubert J, Link H, Österborg A, Repetto L, Soubeyran P. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer. 2007 Jan;43:258-70. Epub 2006 Dec 19.

Bona R. Thrombotic complications of central venous catheters in cancer patients. Semin Thromb Hemost. 1999;25:147-55.

Boogaerts M, Coiffier B, Kainz C, and the Epoietin B QOL Working Group. Impact of epoietin B on quality of life in patients with malignant disease. British Journal of Cancer. 2003;88:988-95.

Boogaerts M, Oberhoff C, Ten Bokkel Huinink W, Nowrousian MR, Hayward CRW, Burger HU. Epoetin beta (NeoRecormon®) therapy in patients with solid tumours receiving platinum and non-platinum chemotherapy: a meta-analysis. Anticancer Research. 2006;26:479-84.

Borelli P, Blatt S, Pereira J, de Maurino B, Tsujita M, de Souza A, Xavier J, Fock R. Reduction of erythroid progenitors in protein-energy malnutrition. Br J Nutr. 2007;97:307-14.

Boschetti, C, Fermo E, Bianchi P, Vercellati C, Barraco F, Zanella A. Clinical and Molecular Aspects of 23 Patients Affected by Paroxysmal Nocturnal Hemoglobinuria. American Journal of Hematology. 2004; 77:36-44.

Bosi A, Vannucchi AM, Grossi A, Guidi S, Saccardi R, Rafanelli D, Longo G, Ferrini PR. Inadequate erythropoietin production in allogeneic bone marrow transplant patients. Haematologica. 1991;76:280-4.

Boven K, Stryker S, Knight J, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney International. 2005;67:2346-53.

Bowen D, Hyslop A, Keenan N, Groves M, Culligan D, Johnson P, Shaw A, Geddes F, Evans P, Porter J, Cavill I. Predicting erythroid response to recombinant erythropoietin plus granulocytes colony-stimulating factor therapy following a single subcutaneous bolus in patients with myelodysplasia. Haematologica. 2006;91:5:709-10.

Boyle P, Robertson C, Kerr DJ. Anemia and neutropenia in cancer patients receiving chemotherapy. Journal of Clinical Oncology. 2004;22(14S):9706.

Brocke-Heidrich K, Kretzschmar AK, Pfeifer G, Henze C,Löffler D, Koczan D, Thiesen HJ, Burger R, Gramatzki M, Horn F. Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation. Blood. 2004 Jan 1;103(1):242-51. Epub 2003 Sep 11.

Broudy V, Lin N, Brice M, Nakmoto B, Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells. Blood. 1991;77:2583-90.

Bunworasate U, Arnouk H, Minderman H, O'Loughlin K, Sait S, Barcos M, Stewart C, Baer M. Erythropoietin-dependent transformation of myelodysplastic syndrome to acute monoblastic leukemia. Blood. 2001;98:3492-4.

Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, et al. Efficacy of peglilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. Journal of Clinical Oncology. 2005;33:20-3.

Buyukpamukcu M, Varan A, Kutluk T, Akyuz C. Is epoetin alfa a treatment option for chemotherapy related anemia in children? Medical Pediatric Oncology. 2002;39:455-58.

Caillette A, Barreto S, Gimenez E, Labeeuw M, Zech P. Is erythropoietin treatment safe and effective in myeloma patients receiving haemodialysis? Clin Nephrol. 1993;40:176-8.

Canadian Orthopedic Perioperative Erythropoietin Study Group. Effectiveness of perioperative recombinant human erythropoietin in elective hip replacement. The Lancet. 1993;341:1227-32.

Canon, Vansteenkiste J, Bodoky G, Mateos M, Bastit L, Ferreira I, Rossi G. Final results of a randomized, double-blind, active-controlled trial of darbepoetin alfa administered once every 3 weeks (Q3W) for the treatment of anemia in patients receiving multicycle chemotherapy. Journal of Clinical Oncology. 2005, 23(16S):8284.

Carabantes FJ, Benavides M, Trujillo R, Cobo M, Hebrero ML, Garcia S, Gomez D, Reche P, Breton JJ, Marquez A, Paredes G, Juarez C. Epoetin alfa in the prevention of anemia in cancer patients undergoing platinum-based chemotherapy (CT). A prospective randomized study. 1999 ASCO Annual Meeting:2303.

Carlisle R, Hind D, McCabe C, Jones R, Ryan A. Norcom commissioning policy on recombinant human erythropoietin for the treatment of anaemia in people with multiple myeloma and myelodysplastic syndromes. 2004.

Carson J, Terrin M, Barton F, Aaron R, Greenburg A, Heck D, Magazinger J, Merlino F, Bunce G, McClelland B, Duff A, Noveck H. A pilot randomized trial comparing symptomatic vs. hemoglobin-level-driven red blood cell transfusions following hip fracture. Transfusion. 1998;38:522-9.

Casadevall N, Belanger C, Goy A, Varet B, Lang J, Poisson D. High-dose recombinant human erythropoietin administered intravenously for the treatment of anaemia in myelodysplastic syndromes. Acta Haematologica. 1992;87(suppl 1):25-7.

Casadevall N. Pure red cell aplasia and anti-erythropoietin antibodies in patients treated with epoetin. Nephrol Dial Transplantation. 2003;18(suppl 8):viii37-41.

Casadevall N, Durieux P, Dubois S, Hemery F, Lepage E, Quarre’MC, Damai G, Giraudier S, Guerci A, Laurent G, Dombret H, Chomienne C, Ribrag V, Stamatoullas A, Marie JP, Vekhoff A, Maloisel F, Navarro R, Dreyfus F, Fenaux P, for the group Myelodysplasies F. Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial. Blood. 2004;104:(2):321-27.

Cascinu S, Fedeli A, Del Ferro E, Fedeli S, Catalano G. Recombinant human erythropoietin treatment in cisplatin associated anemia: a randomized double blind trial with placebo. Journal of Clinical Oncology. 1994;12(5):1058-62.

Case D, Carey R, Fishkin E, Henry D, Jacobson R, Jones S, Keller A, Craig I, Salmotl R, Silver R, Storniolo AM, Wampler GL, Doole-i CM, Larholt KM, Nelson RA, Abels R. Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. Journal of the National Cancer Institute. 1993;85(10):801-06.

Case AS, Rocconi RP, Barnes MN, Kilgore LC. Comparison of transfusion rates between erythropoietic stimulating agents in gynecologic oncology patients with chemotherapy induced anemia. Journal of Clinical Oncology. 2005;23(16S):5092.

Cazzola M, Ponchio L, Beguin Y, Rosti V, Bergamaschi G, Liberato NL, Fregoni V, Nalli G, Barosi G, Ascari E. Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial. Blood. 1992;79(1):29-37.

Cazzola M, Messinger D, Battistel V, Bron D, Cimino R, Enller-Zie L, Essers U, Greil R, Grossi A, Jager G, LeMevel A, Najan A, Silingardi V, Spriano M, van Hoof A, Ehmer B. Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-hodgkin’s lymphoma: dose finding and identification of predictors of response. Blood. 1995;86(12):4446-53.

Cazzola M, Ponchio L, Pedrotti C, Farina G, Cerani P, Lucotti C, Novella A, Rovati A, Bergamaschi G, Beguin Y. Prediction of Response to Recombinant Human Erythropoietin (rHuEpo) in Anemia of Malignancy. Haemotolgica. 1996;81-434-41.

Cazzola M. Use of recombinant human erythropoietin in anemia of malignancy. Med Oncol. 1998;15 Suppl 1:S1-2.

Cazzola M. Haematopoietic growth factors in the treatment of myelodysplastic syndromes. Forum. 1999;1:49-57.

Cazzola M. Mechanisms of anaemia in patients with malignancy: implications for the clinical use of recombinant human erythropoietin. Medical Oncology. 2000;17(suppl 1):S11-16.

Cazzola M, Bequin Y, Kloczko J, Spicka I, Coiffier B. Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. British Journal of Haematology. 2003; 122:386-93.

Cella D, Evans W, Wallace J, Kallich J, Blayney D, Vadjan-Raj S. The relationships between FACT-fatigue (FACT-f) scores and physical function (PF) in patients (pts) with chemotherapy-induced anemia treated with darbepoetin alfa (DA). Journal of Clinical Oncology. 2004;22(14S):8062.

Cermák J. Erythropoietin administration may potentiate mobilization of storage iron in patients on oral iron chelation therapy. Hemoglobin. 2006;30:105-12.

Chakraborty A, Natarajan J, Guilfoyle M, Morgan N, Vercammen E, Cheung W. Population pharmacokinetics of erythropoietin in critically ill subjects. J Clin Pharmacol. 2005;45(2):193-202.

Chan A, Leung W, Lin J, Yeo W, Johnson P. Recominant human erythropoietin for anemia in Chinese cancer patients on chemotherapy. The Royal College of Radiologists. 1995;7:272.

Chan EM, Comer EM, Brown FC, Richkind KE, Holmes ML, Chong BH, Shiffman R, Zhang D, Slovak ML, Willman CL, Noguchi CT, Li Y, Heiber DJ, Kwan L, Chan RJ, Vance GH, Ramsey HC, Hromas RA. AML1-FOG2 fusion protein in myelodysplasia. Blood. 2005;105:4523-6.

Chang J, Couture F. A randomized study to evaluate the effects of maintaining hemoglobin levels with epoetin alfa (Eprex) on anemia and quality of life in breast cancer patients receiving myelotoxic chemotherapy. Proc Am Soc Clin Oncol. 2002;21:1502.

Chang J, Couture F. Once weekly epoetin alfa maintains hemoglobin, improves quality of life and reduces transfusion in breast cancer patients receiving chemotherapy. Proc Am Soc Clin Oncol. 2003;22:2923.

Chang J, Couture F, Young S, McWatters K, Lau C. Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol. 2005;23:2597-2605.

Chang J, Phippard L, Sharma D, Lau CY. A phase II randomized trial of three loading doses of epoetin alfa followed by every three-week (q3w) dosing in cancer patients receiving chemotherapy. Journal of Clinical Oncology. 2005;23(16S):8219.

Chap L, George M, Glaspy JA. Evaluation of epoetin alfa (Procrit®) 60,000 U once weekly in anemic cancer patients receiving chemotherapy. Proc Am Soc Clin Oncol. 2002;21:2873.

Charu V, Belani CP, Gill AN, Bhatt M, Ben-Jacob A, Tomita D, Katz D. A controlled, randomized, open-label study to evaluate the effect of every-2-week darbepoetin alfa for anemia of cancer. Journal of Clinical Oncology. 2004;22(14S):8084.

Chester JF, Gaissert HA, Ross JS, Malt RA. Pancreatic cancer in the Syrian hamster induced by N-Nitrosobis (2-oxyopropylO-amine: cocarginogenic effect of epidermal growth factor. Cancer Research. 1986;46:2954-7.

Cheung W, Goon B, Guilfoyle M, Wacholtz M. Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects. Clin Pharmacol Ther. 1998;64:412-23.

Cheung W, Natarajan J, Sanders M, Vercammen E. Comparative pharmacokinetics, safety, and tolerability after subcutaneous administration of recombinant human erythropoietin formulated with different stabilizers. Biopharm Drug Dispos. 2000;21(6):211-9.

Cheung W, Minton N, Gunawardena K. Pharmacokinetics and pharmacodynamics of epoetin alfa once weekly and three times weekly. Eur J Clin Pharmacol. 2001;57:411-8.

Chew H, Wun T, Harvey D, Zhou H, White R. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166:458-64.

Chew H, Wun T, Harvey D, Zhou H, White R. Incidence of venous thromboembolism and the impact on survival in breast cancer patients. J Clin Oncol. 2007;25:70-6.

Chiba T, Nagata Y, Kishi A, Sakamaki K, Miyajima A, Yamamoto M, Engel JD, Todokoro K. Induction of erythroid-specific gene expression in lymphoid cells. Proc Natl Acad Sci. 1993;90(24):11593-7.

Clahsen PC, van de Velde CJ, Julien J, Floiras J, Mignolet FY. Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: a European organization for research and treatment of cancer breast cancer cooperative group study. Journal of Clinical Oncology. 1994;12(6):1266-71.

Clark RE, Smith SA, Jacobs A. Myeloid surface antigen abnormalities in myelodysplasia: relation to prognosis and modification by 13-cis retinoic acid. Journal of Clinical Pathology. 1987;40:652-6.

Clavio M, Nobili F, Balleari E, Girtler N, Ballerini F, Vitali P, Rosati P, Venturino C, Varaldo R, Gobbi M, Ghio R, Rodgriquez G. Quality of life and brain function following high-dose recombinant human erythropoietin in low-risk myelodysplastic syndromes: a preliminary report. European Journal of Haematology. 2004;72:113-20.

Cleary SP, Gryfe R, Guindi M, Greig P, Smith L, Mackenzie R, Strasberg S, Hanna S, Taylor B, Langer B, Gallinger S. Prognostic factors in resected pancreatic adenocarcinoma: analysis of actual 5-year survivors. J Am Coll Surg. 2004;198(5):722-31.

Cleeland D, Crawford J, Lubeck D, Tomita D. Using the MD Anderson Symptom Inventory (MDASI) to assess symptom burden and interference: interim results of an open-label study of darbepoetin alfa 200 mcg every 2 weeks (Q2W) for the treatment of chemotherapy-induced anemia (CIA). Journal of Clinical Oncology. 2004;22(14S):8065.

Cloutier S, Tetu FA, Poulin J, Lau CY, Cantin G. Evaluation of recombinant human erythropoietin (epoetin alfa) and autologous blood donation in breast reconstruction with transverse rectus abdominus myocutaneous (TRAM) flap after mastectomy for breast cancer. Proc Am Soc Clin Oncol. 2003;22:3106.

Coiffier B, Boogaerts M, Kainz C. Impact of epoetin beta versus standard of care on quality of life in patients with malignant disease. 6th Congress of the European Haematology Association. 2001. Abstract #194.

Coiffier B, Guastalla J, Pujade-Lauraine E, Bastit T, Anemia Study Group. Predicting cancer-associated anaemia in patients receiving non-platinum chemotherapy: results of a retrospective survey. Eur J Cancer. 2001;37:1617-23.

Coiffier B. Epoetin once weekly in anaemic patients with cancer. British Journal of Haematology. 2004;125:90-102.

College of American Pathologists. Special announcement. Notification to all users of practice guidelines. Arch Pathol Lab Med. 2002;126:401.

Constantinescu S, Ghaffari S, Lodish F. The erythropoietin receptor: structure, activation and intracellular signal transduction. Trends Endocrinol Metab. 1999;10:18-23.

Cortelezzi A, Moia M, Falanga A, Pogliani EM, Agnelli G, Bonizzoni E, Gussoni G, Barbui T, Mannucci PM. Incidence of the thrombotic complications with patients with haematological malignancies with entral venous catherters: a prospective multicentre study. British Journal of Haematology. 2005; 129, 811-17.

Cortesi E, Gascon P, Henry D, Littlewood T, Milroy R, Pronzato P, Reinhardt U, Shasha D, Thatcher N, Wilkinson P. Standard of care for cancer-related anemia: improving hemoglobin levels and quality of life. Oncology. 2005;68(suppl 1):22-32.

Cortesi E, Ricci S, Ucci G, Cruciani G, de Marinis F, Orecchia S. Randomized phase III study comparing standard TIW and weekly dosage of epoetin alfa with 2 weeks loading dose: preliminary results. Journal of Clinical Oncology. 2005;23(16S):8215.

Crawford J, Blackwell S, Shoemaker D, Pupa M, Sparrow T, Herndon J, Winer E, Flynn J, Dempsey H. Prevention of chemotherapy-related anemia by recombinant human erythropoietin (EPO) in patients with small cell lung cancer receiving cyclophosphamide, doxorubicin, and etoposide (CAE) chemotherapy with G-CSF support. Lung Cancer. 1997;18(1):205.

Crawford J, Blackwell S. Erythropoietin and the management of anemia in patients with lung cancer. Cancer Control Journal (supplement);5(2).

Crawford J, Robert F, Perry M, Belani C, Sarokhan B. Epoetin alfa 40,000 U once weekly maintains hemoglobin in advanced non-small cell lung cancer patients receiving first-line chemotherapy. Proc Am Soc Clin Oncol. 2003;22:628.

Crawford J. Erythropoiesis-stimulating protein support and survival. Oncology. 2006;20(8):39-43.

Curt GA, Breitbart W, Cella D, Groopman JR, Horning SJ, Itri LM, Johnson DH, Miaskowski C, Scherr SL, Portenov RK, Vogelzang NJ. Impact of cancer-related fatigue on the lives of patients: new findings from the fatigue coalition. The Oncologist. 2000;5:353-60.

D’Ambra M, Gray R, Hillman R, Jones J, Kim H, Rawitscher R, Schnaper H, Szymanski I, Vlahakes G, Kaplan D, Lynch K, Guilfoyle M, Abels R. Effect of recombinant human erythropoietin on transfusion risk in coronary bypass patients. Ann Thorac Surg. 1997;64:1686-93.

D’Antonadou D, Varveris P, Karageorgis P, Papadopoulos V, Georgakopoulos G, Kyprianou C, Panousaki A, Athanasiou H, Beroukas C, Skarlatos J, Misailidou D. Darbepoetin alfa improves quality of life in cancer patients undergoing radiation, final results of a multicenter, open study. Journal of Clinical Oncology. 2006;24(18S):18531.

Dalton WS. Anemia in multiple myeloma and its management. www.moffitt.org/moffittapps/ccj/v5ns/article9.html. Accessed 5/24/07.

Dame C, Fahnenstich H, Freitag P, Hofmann D, Abdul-Nour T, Bartmann P, Fandrey J. Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood. 1998;92:3218–25.

Dammacco F, Silvestris F, Castoldi G, Grassi B, Bernasconi C, Nadali G, Perona G, De Laurenzi A, Torelli U, Ascari E, Rossi Ferrini P, Caligaris-Cappio F, Pileri A, Resegotti L. The effectiveness and tolerability of epoetin alfa in patients with multiple myeloma refractory to chemotherapy. International Journal Clinical Lab Resources. 1998;28:127-34.

Dammacco F, Castoldi G, Rodjer S. Efficacy of epoetin alfa in the treatment of anemia of multiple myeloma. British Journal of Haematology. 2001;113:172-79.

Dammacco F, Lucarrelli G, Prete M, Sivlestris F. The role of recombinant human erythropoietin alpha in the treatment of chronic anemia in multiple myeloma. 2002;Suppl 1:32-8.

D'Andrea A, Lodish H, Wong G. Expression cloning of the murine erythropoietin receptor. Cell. 1989;57:277–85.

D'Andrea A, Jones S. Activation of the erythropoietin receptor in stable lymphoid and myeloid transfectants. Semin Hematol. 1991;28:152-7.

Dainiak N, Kulkarni V, Howard D, Kalmanti M, Dewey MC, Hoffman R. Mechanisms of abnormal erythropoiesis in malignancy. Cancer. 1983;51:1101-6.

Dainiak K, Kreczko S. Interactions of insulin, insulinlike growth factor II, and platelet-derived growth factor in erythropoietic culture. J. Clin. Invest. 1985;76:1237-42.

Daneryd P, Svanberg E, Korner U, Lindholm E, Sandstrom R, Brevinge H, Pettersson C, Bosneus I, Lundholm K. Protection of metabolic and exercise capacity in unselected weight losing cancer patients following treatment with recombinant erythropoietin: a randomized prospective study. Cancer Research. 1998;58:5374-79.

Daneryd P. Epoetin alfa for protection of metabolic and exercise capacity in cancer patients. Seminars in Oncology. 2002;29(suppl 8):69-74.

Dang C, Hudis C. Can Granulocyte-Colony Stimulating Factor Worsen Anemia? Journal of Clinical Oncology. 2006;24:2985-6.

Danish Head and Neck Cancer Group website publication: www. conman.au.dk/dahanca. Accessed 3/20/07. ECOG website: www.ecog.org/general/perf_stat.html. Accessed 4/13/07.

Danna R, Rudnick S, Abels R. Erythropoietin therapy for anemia associated with AIDS and AIDS therapy and cancer. In MB Garick, Ed. Erythropoietin in clinical applications: An international perspective. New York, NY: Marcel Decker; 1990:301-24.

Darbepoetin (Aranesp): 2002 FDA approval letter, phase 4 commitment for study regarding stimulatory effects on metastatic breast cancer.

Darbepoetin (Aranesp): 2002 FDA clinical (medical officer) review (redacted).

Darbepoetin (Aranesp): 2002 FDA statistical review (redacted).

Darbepoetin (Aranesp): 2006 FDA clinical (medical officer) review q3 week dosing (redacted).

Darbepoetin (Aranesp): 2006 FDA clinical pharmacology review q3 week dosing (redacted).

Darbepoetin (Aranesp): 2006 FDA statistical review (redacted).

Davis HP. Erythropoietin for patient refusing blood transfusion. Lancet. 1990;336(8711):384-5.

De Andrade JR, Jove M, Landon G, Frei D, Guilfoyle M, Young DC. Baseline hemoglobin as a predictor of risk of transfusion and response to epoetin alfa in orthopedic surgery patients. The American Journal of Orthopedics. 1996:533-42.

De Campos E, Radford J, Steward W, Milray R, Dougal M, Swindell R, Testa N, Thatcher N. Clinical and in vitro effects of recombinant human erythropoietin in patients receiving intensive chemotherapy for small cell lung cancer. J Clin Oncol. 1995;13(7):1623-31

De Cicco M, Matovic M, Balestreri L, Panarello G, Fantin D, Morassut S, Testa V. Central venous thrombosis: an early and frequent complication in cancer patients bearing long-term silastic catheter. A prospective study. Thromb Res. 1997;86:101-13.

De Cicco M. The prothrombotic state in cancer: pathogenic mechanisms. Crit Rev Oncol Hematol. 2004;50:187-96.

De La Chapelle A, Traskelin A, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc. Natl. Acad. Sci. 1993;90:4495-99.

De Los Santos. Anemia correction in malignancy management: threat or opportunity? Gynecologic Oncology. 2007; 105( 2):517-529.

Deechongkit S, Aoki K, Park S, Kerwin B. Biophysical comparability of the same protein from different manufacturers: a case study using Epoetin alfa from Epogen and Eprex. J Pharm Sci. 2006;95:1931-43.

Del Mastro L, Venturini M, Lionetto R, Garrone O, Melioli G, Pasquetti W, Sertoli M, Bertelli G, Canavesa G, Costantini M, Rosso R. Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy induced anemia. J Clin Oncol. 1997;15 (Vol 15) 7:2715-21.

Del Mastro L, Gennari A, Donati S. Chemotherapy of non-small-cell lung cancer: role of erythropoietin in the management of anemia. Annals of Oncology. 1999;10(suppl 5).

Delarue R, Mounier N, Haioun C, Coiffier B, Gisselbrecht C, Ghesquieres H, Lederlin P, Blanc M, Recher C, Hermine O, Reyes F, Tilly H, Bosly A. Safety of phophylactic use of darbepoetin alfa in patients with diffuse large b-cell lymphoma (DLBCL) treated with R-CHOP 14 or R-CHOP 21: preliminary results of the LNH03-6B randomized GELA study. Blood. 2006;108(11):abstract#2436.

Dember LM. Anemia in patients with chronic kidney disease: defining the optimal hemoglobin target (commentary). Nature Clinical Practice Nephrology. 2007;3(5):244-5.

Demetri G, Kris M, Wade J, Degas L, Cella D for the Procrit Study Group. Quality of life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. J Clin Oncol. 1998;16:3412-25.

Depaoli L, Levis A, Isabella N, Ficara F, Priotto C, Lista P, Foá R, Resegotti L. Serum Erythropoietin level and marrow erythroid infiltration predict response to recombinant human erythropoietin in myelodysplastic syndromes. Haematologica. 1993;78:118-22.

Deshmukh N, Tripathi S. Thrombosis of tibial arteries in a patient receiving tamoxifen therapy. Cancer. 1995;76:1006-8.

Dessypris E, Graber SE, Krantz SB, Stone WJ. Effects of recombinant erythropoietin on the concentration and cycling status of human marrow hematopoietic progenitor cells in vivo. Blood. 1988;72:2060-2.

Di Raimondo F, Longo G, Cacciola EJR, Milone G, Palumbo GA, Cacciola RR, Alessi M, Giustolisi R. A good response rate to recombinant erythropoietin alone may be expected in selected myelodysplastic patients. A preliminary clinical study. European Journal of Haemotology. 1996;56:7-11.

Di Raimondo F, Azzaro M, Palumbo G, Bagnato S, Giustolisi G, Floridia P, Sortino G, Giustolisi R. Angiogenic factors in multiple myeloma: higher levels in bone marrow than in peripheral blood. Haematologica. 2000;85:800-5.

Dicato M, Vercammen E, Liu K, Xiu P, Bowers P. The relationship of body weight and efficacy of fixed dose epoetin alfa vs placebo. Journal of Clinical Oncology. 2005;23(16S):8192.

Digicaylioglu M, Bichet S, Marti H. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci USA. 1995;92:3717–20.

Dmoszyska A, Kloczko J, Rokicka M, Hellman A, Spicka I, Eid JE. A dose exploration, phase I/II study of administration of continuous erythropoietin receptor activator once every 3 weeks in anemic patients with multiple myeloma receiving chemotherapy. The Hematology Journal. 2007;92(04):493-501.

Donati M, Semeraro N. Cancer cell procoagulants and their pharmacological modulation. Haemostasis. 1984;14:422-9.

Dong X, Han CZ, Yang R. Angiogenesis and antiangiogenic therapy in hematologic malignancies. Critical Reviews in Oncology/Hematology.2007; 62:105-118.

Duffy JP, Eibl G, Reber HA, Hines OJ. Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. Molecular Cancer. 2003;2:12.

Dunphy EP, Petersen IA, Cox RS, Bagshaw MA. The influence of initial hemoglobin and blood pressure levels on results of radiation therapy for carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 1989;16(5):1173-8.

Dunphy FR, Dunleavy TL, Harrison BR, Boyd JH, Varvares MA, Dunphy CH, Rodgriquez JJ, McDonough EM, Minster JR, McGrady MD. Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin. Cancer. 1997;79(8):1623-8.

Dunphy F, Harrison B, Dunleavy T, Rodriguez J, Hilton J, Boyd J. Erythropoietin reduces anemia and transfusions: a randomized trial with or without erythropoietin during chemotherapy. American Cancer Society. 1999;1362-67.

Dupont S, Masse A, James C, Teyssandier I, et al. The JAK2 V617F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. Blood. Pre-published online; March 27, 2007.

Dusenbery K, McGuire W, Holt P, Carson L, Fowler J, Twiggs L, Potish R. Erythropoietin increases hemoglobin during radiation therapy for cervical cancer. Int J Radiat Oncol Biol Phys. 1994;29(5):1079-84.

Eastern Oncology Group. www.ecog.org/general/perf_stat.html. Accessed 4/13/07.

Eckardt K, Ratcliffe P, Tan C, Bauer C, Kurtz A. Age-dependent expression of the erythropoietin gene in rat liver and kidneys. J Clin Invest. 1992;89:753–60.

Eckardt K, Kurtz A. Regulation of erythropoietin production. Eur J Clin Invest. 2005;35(Suppl. 3):13–9.

Economopoulos T, Mellou S, Papageorgiou E, Pappa V, Kokkinou V, Stathopoulou E, Pappa M, Raptis S. Treatment of anemia in low risk myelodysplastic syndromes with granulocyte-macrophage colony-stimulating factor plus recombinant human erythropoietin. Leukemia. 1999;13:1009-12.

Edwards R, Rickles F, Cronlund M. Abnormalities of blood coagulation in patients with cancer. Mononuclear cell tissue factor generation. J Lab Clin Med. 1981;98:917-28.

Elandt K, Horak P, Schieder KC, Leikermoser R, Altmann R, Albrecht A, Reisenberger K, Tomek S, Fischer H, Zielinski CC, Krainer M. Early vs. late treatment with darbepoetin alfa in patients with genitourinary tumors during chemotherapy. Journal of Clinical Oncology. 2006;24(18S):18583.

Elbert B, Bunn H. Regulation of the erythropoietin gene. Blood. 1999;94:1864–77.

El-Rayes BF , LoRusso PM. Targeting the Epidermal growth Factor Receptor. British Journal of Cancer. 2004;91:418-424.

Elliott S, Chang D, Delorme E, Dunn C, Egrie J, Griffin J, Lorenzini T, Talbot C, Hesterberg L. Isolation and characterization of conformation sensitive anti-erythropoietin monoclonal antibodies: effect of disulfide bonds and carbohydrate on recombinant human erythropoietin structure. Blood. 1996;87:2714-22.

Erythropoeitin (Procrit): 1993 FDA approval letter, approved labeling, phase 4 commitment for study regarding stimulatory effects on solid tumors.

Erythropoeitin (Procrit): 1993 FDA statistical review (redacted).

Erythropoeitin (Procrit): 1993 FDA summary basis of approval review (redacted). (No clinical/medical officer review).

Erythropoeitin (Procrit): 2004 FDA statistical review of Phase 4 commitment studies for tumor stimulation (redacted).

Erythropoeitin (Procrit): 2004 FDA letter indicating completion of phase 4 commitment and Dear Doctor Letter.

Erythropoeitin (Procrit): 2004 FDA clinical (medical officer) review (redacted).

Erythropoeitin (Procrit): 2004 FDA statistical review (redacted).

Erythropoeitin (Procrit): 2004 FDA clinical pharmacology review (redacted).

Erythropoeitin (Procrit): 2004 FDA review of BEST (redacted).

Erythropoeitin (Procrit): 2004 FDA label after review of BEST, Grote, and Henke studies.

Erythropoeitin (Procrit): 2004 FDA memo for ODAC meeting.

Evens AM, Bennett CL, Luminari S. Epoetin-induced pure red-cell aplasia (PRCA): preliminary results from the research on adverse drug events and reports (RADAR) group. Best Practice & Research Clinical Haematology. 2005;18(3):481-9.

Falanga A, Gordon SG. Isolation and characterization of cancer procoagulant: a cysteine proteinase from malignant tissue. Biochemistry. 1985;24:5558-67.

Falanga A, Shaw E, Donati MB, Consonni R, Barbui T, Gordon S. Inhibition of cancer procoagulant by peptidyl diazomethyl ketones and peptidyl sulfonium salts. Thrombosis Research. 1989;54:389-98.

Falanga A, Levine MN, Consonni R, Gritti G, Delaini F, Oldani E, Julian JA, Barbui T. The effect of very-low-dose warfarin on markers of hypercoagulation in metastatic breast cancer: results from a randomized trial. Thromb Haemot. 1998;79(1):23-7.

Falanga A, Domati M. Pathogenesis of thrombosis in patients with malignancy. Int J Hematol. 2001;73:137-44.

Falanga A. Clotting mechanisms and cancer: implications in thrombus formation and tumor progression. Clinical Advances in Hematology & Oncology. 2003;1(11):673-8.

Falanga A. Thrombosis and malignancy: an underestimated problem. Journal of Hematology. 2003;88(06):607-10.

Falanga A. The effect of anticoagulant drugs on cancer. Journal of Thrombosis and Haemostasis. 2004;2:1263-5.

Falanga A, Vignoli A. Venous thromboembolism in oncology. Exp Oncology. 2004;26:11-14.

Falanga A, Zacharski L. Deep vein thrombosis in cancer: the scale of the problem and approaches to management. Annals of Oncology. 2005; 16:696-701.

Fallowfield L, Gagnon D, Zagari M, Cella D, Bresnahan B, Littlewood TJ, McNulty P, Gorzegno G, Freund M. Multivariate regression analyses of data from a randomized, double-blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy. British Journal of Cancer. 2002;87:1341-53.

Fandrey J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am J Physiol Regul Integr Comp Physiol. 2004;286:R977-R988.

Faquin W, Schneider T, Golderberg M. Effect of inflammatory cyokines on hypoxia-induced erythropoietin production. Blood. 1992;79:1987.

Faris PM, Ritter MA, Abels RI. The effects of recombinant human erythropoietin on perioperative transfusion requirements in patients having a major orthopaedic operation. The Journal of Bone and Joint Surgery. 1996;78(1):62-72.

Farrell F, Lee A. The erythropoietin receptor and its expression in tumor cells and other tissues. Oncologist. 2004;9 (Suppl 5):18-30.

Faulds D, Sorkin E. Epoietin (recombinant human erythropoietin). A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in anemia and the stimulation of erythropoiesis. Drugs. 1989;38:863-99.

Fastenau J, Lefebvre P, Duh MS, Buteau S, McKenzie RS, Piech CT. Evaluation of the relationship between early hemoglobin rise during epoetin alfa treatment and improved patient-reported quality of life. Journal of Clinical Oncology. 2004;22(14S):8124.

Faust E. A phase III, double-blind, placebo-controlled, randomized study of novel erythropoiesis stimulating protein (Aranesp™) in patients undergoing platinum-treatment for lung cancer. Proc Am Soc Clin Oncol. 2001;20:1293.

Fastenau J, Memisoglu A, Peake C, Salva C, Howell J, McKenzie S. Dosing and outcomes study of erythropoiesis-stimulating therapies-D.O.S.E. Journal of Clinical Oncology. 2005;23(16S):6092.

FDA alert. www.fda.gov/medwatch/safety/2007/safety07.htm#ESA. Accessed 3/10/07.

FDA 5/4/04 ODAC meeting. www.fda.gov/ohrms/dockets/ac/cder04.html#Oncologic. Accessed 3/29/07.

Feagan BG, Wong CJ, Kirkley A, Johnston DWC, Smith FC, Whitsitt P, Wheeler SL, Lau CY. Erythropoietin with iron supplementation to prevent allogeneic blood transfusion in total hip joint arthroplasty. Annals of Internal Medicine. 2000;133:845-54.

Feffer S, Carmosino L, Fox R. Acquired protein C deficiency in patients with breast cancer receiving cyclophosphamide, methotrexate, and 5-fluorouracil. Cancer. 1989;63:1303-7.

Fein D, Lee W, Hanlon A, Ridge J, Langer C, Curran W Jr, Coia L. Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol. 1995;13:2077-83.

Feldman L, Wang Y, Rhim JS, Bhattacharya N, Loda M, Sytkowski AJ. Erythropoietin stimulates growth and STAT5 phosphorylation in human prostate epithelial and prostate cancer cells. The Prostate. 2006;66:135-45.

Finelli EV, Bosi C, El-Cheikh J, Martinelli G, Malagola M, Rondoni M, Baccarani M. High doses of recombinant erythropoietin alfa for myelodysplastic syndromes: high incidence of responses in patients with low pre-treatment serum erythropoietin concentrations. Journal of Clinical Oncology. 2004;22(14S):6683.

Fischl M, Galpin J, Levine J, Groopman J, Henry D, Kennedy P, Miles S, Robbins W, Starrett B, Zalusky R. Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med. 1990;322:1488-93.

Fisher B, Redmond C, Legault-Poisson S, Dimitrov V, Brown M, Wickerham D, Wolmark N, Margolese R, Bowman D, Glass A. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol. 1990;8:1005-18.

Fraser J, Lin F, Berridge M. Expression of high affinity receptors for erythropoietin on human bone marrow cells and on the human erythroleukemic cell line, Exp Hematol. 1988;16:836-42.

Fraser J, Tan A, Lin F, Berridge M. Expression of specific high-affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol. 1989;17:10-6.

Fried W, Ward HP, Hopeman AR. Leiomyoma and erythrocytosis: a tumor producing a factor which increases erythropoietin production. Report of case. Blood. 1968;31(6):813-6.

Frolove A, Schuller K, Tzeng CD, Cannon EE, et al. ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib. Cancer Biol Ther. 2007 Apr 13;6(4). PMID: 17457047.

Fujisaka Y, Tamura T, Ohe Y, Kunitoh H, Sekine I, et al. Pharmacokinetics and pharmacodynamics of weekly epoetin chemotherapy-induced anemia. Journal of Clinical Oncology. 2004;22(15S): 8206.

Fujisaka Y, Tamura T, Ohe Y, Kunitoh H, Sekine I, Yamamoto N, Nokihara H, Horiike A, Kodama T, Saijo N. Pharmacokinetics and pharmacodynamics of weekly epoetin beta in lung cancer patients. J Clin Oncol. 2006;36(8):477-82.

Gabrilove J, Cleeland C, Livingston R, Sarokhan B, Winer E, Einhorn L. Clinical evaluation of once weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three times weekly dosing. J Clin Oncol. 2001;19(11):2875-82.

Gabrilove JL, Cleeland C, Perez E, Mendes E, Tomita D, Colowick A. Assessment of symptom burden using the MD Anderson Symptom Inventory (MDASI) in subjects with nonmyeloid malignancies receiving multicycle chemotherapy and darbepoetin alfa every two weeks (Q2W). Proc Am Soc Clin Oncol. 2003;22:3161.

Gabrilove J, Paquette R, Lyons R, Mushtag C, Sekeres M, Lam H, Dreiling L. The efficacy and safety of darbepoetin alfa for testing anemia in low-risk myelodysplastic syndrome patients: results after 53/55 weeks. Blood. 2006;108(11):abstract#2671.

Gabrilove J, Paquette R, Lyons R, Mushtag C, Sekeres M, Lam H, Dreiling L. Darbepoetin alfa for treatment anemia in patients with low-risk myelodysplastic syndromes: exploratory analysis of baseline predictors of response. Journal of Clinical Oncology. 2006;24:20(18S):6579.

Gagnon D, Zagari M. Assessing the clinical significance of health-related quality of life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa. Eur J Cancer 2003;39:335–345.

Galli M, Elice F, Crippa C, Comotti B, Rodeghiero F, Barbui T. Recombinant human erythropoietin and the risk of thrombosis in patients receiving thalidomide for multiple myeloma. Haematologica. 2004;89(Letters to the Editor)1141-2.

Gamucci T, Thorel M, Frasca A, Giannarell D, Callabresi F. Erythropoietin for the prevention of anaemia in neoplastic patients treated with cisplatin. Eur J Cancer. 1993; Vol 29A (Suppl 2):S13-14.

Ganser A, Ottmann OG, Hoelzer D. Interleukin-3 in the treatment of myelodysplastic syndromes. International Journal of Clinical & Laboratory Research. 1992;22:125-8.

Ganser A, Hoelzer D. Clinical use of hematopoietic growth factors in the myelodysplastic syndromes. Seminars in Hematology. 1996;33(3):186-95.

Garton J, Gertz M, Witzig T, Greipp P, Lust J, Schroeder G, Kyle R. Epoetin alfa for the treatment of the anemia of multiple myeloma: a prospective, randomized placebo-controlled, double-blind trial. Archives Internal Medicine. 1995;155:2069-74.

Gascon P, Barrett-Lee PJ. Prevalence of anemia in cancer patients not receiving antineoplastic treatment (ANT): data from the European cancer anaemia survey (ECAs). Journal of Clinical Oncology. 2006; 24(18S):8565.

Gascon B, Ludwig H. Evaluation of anaemia in patients with multiple myeloma and lymphoma: findings of the European Cancer Anaemia Survey. European Journal of Haematology. 2006;77:378-86.

Ghio R, Balleari E, Ballestrero A, Gatti AM, et al. Subcutaneous recombinant human erythropoietin for the treatment of anemia in myelodysplastic syndromes. Acta Haematol. 1993;90:58-64.

Giraldo P, Nomdedeu B, Loscertales J, Requena C, De Paz R, Tormo M, Navarro P, Benedit P, Gasquet JA. Darbepoetin a for the treatment of anemia in patients with myelodysplastic syndromes. Cancer. 2006;107:2807-15.

Girdwood R. Drug-induced anaemias. Drugs. 1976;11:394-404.

Glaspy JA, Jadeja J, Justice G, Kessler J, Richards D, Schwartzberg L, O’Byrne J, Armstrong S, Colowick A. Randomized, active-controlled, phase ½, dose-escalation study of NESP administered weekly and every 2 weeks in patients with solid tumors. Proc Am Soc Clin Oncol. 2001;20:1546.

Glaspy J, Jadeja J, Justice G, Darbepoetin alfa 2000174 Study Group, Fleishman A, Armstrong S, Colowick A. Optimizing the management of anemia in patients with cancer: a randomized, active-controlled study investigating the dosing of darbepoetin alfa. Proc Am Soc Clin Oncol. 2002;21:1446.

Glaspy J, Tchekmedyian NS, Erder MH, Isitt J, Kallich J. Early and sustained improvement in health-related quality of life (HRQOL) was observed with frontloaded darbepoetin alfa compared to conventional therapy. Proc Am Soc Clin Oncol. 2003;22:3063.

Glaspy J, Berg R, Tomita D, Rossi G, Vadhan-Raj S. Final results of a phase 3, randomized, open-label study of darbepoetin alfa 200 mcg every 2 weeks (Q2W) versus epoetin alfa 40,000 U weekly (QW) in patients with chemotherapy-induced anemia (CIA). Journal of Clinical Oncology. 2005 ASCO Annual Meeting Proceedings, 23(16S):8125.

Glaspy J, Henry D, Canon J, Lam H, Lillie T. Darbepoetin alfa administered at varying intervals compared with weekly epoetin alfa for treating chemotherapy-induced anemia: a pooled analysis of 20 clinical trials. Journal of Clinical Oncology. 2006;24(18S):18508.

Glaser C, Millesi W, Wanschitz F, Schull B, Lang S, Leitha T. R-Hu Erythropoeitin treatment increases efficacy of neo-adjuvant radiochemotherapy and improves cancer free survival of patient with oral squamous cell carcinoma: a 17 months follow-up. 1999 ASCO Annual Meeting:abstract #1543.

Glaser C, Millesi W, Kornek G, Lang S, Schull B, Watzinger, Christoph F, Lang S, Selzer E, Lavey R. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of pre-operative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharyyx. Int J Rad Oncol Biol Physics. 2001;50:705-15.

Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedyion S, Vadhan-Raj S for the Procrit Study Group. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Journal of Clinical Oncology. 1997;15:1218-34.

Glaspy J, Singh J, Justice G, Kessler J, Richards D, Schwartzberg L, Rigas J, Kuter D, Harmon D, Prow D, Demetri G, Gordon D, Arseneau J, Saven A, Hynes H, Boccia R, O’Byrne J, Colowick A. A dose-finding and safety study of novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia in patients receiving multicycle chemotherapy. British Journal of Cancer. 2001;84 (1):17–23.

Glaspy J, Degos L, Dicato M, Demetri G. Comparable efficacy of epoetin alfa for anemic cancer patients receiving platinum and nonplatinum-based chemotherapy: a retrospective subanalysis of two large, community-based trials. The Oncologist. 2002;7:126-35.

Glaspy J, Jadeja J, Justice G, Kessler J, Richards D, Schwartzberg L, Tchekmedyian N, Armstrong S, O’Byrne J, Rossi G, Colowick A. Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy. British Journal of Cancer. 2002;87:268-76.

Glaspy J, Jadeja J, Justice G, Fleishman A, Rossi G, Colowick A. A randomized, active-control, pilot trial of front-loaded dosing regimens of darbepoetin-alfa for the treatment of patients with anemia during chemotherapy for malignant disease. Cancer. 2003;97 (5):1312-20.

This is the webcast presentation of the terminated darbpoetin study:

Glaspy J. Results from a Phase III, randomized, double-blind, placebo-controlled study of darbepoetin alfa (DA) for the treatment of anemia in patients not receiving chemotherapy or radiotherapy. Phase III Clinical Plenary Session: Breakthroughs in Clinical Research (Clinical Research Track: Special Session 1) American Association for Cancer Research Annual Meeting 2007 4/16/07 8:15 AM-10:15 AM www.acr.org/home/scientists/meetingsworkshops/annual-meeting-2007/webcast-sessions.aspx. Accessed 4/18/07.

Glimelius B, Linne T, Hoffman K, Larsson L, Svensson J, Nasman P, Svensson B, Helmers C. Epoetin beta in the treatment of anemia in patients with advanced gastrointestinal cancer. J Clin Oncol. 1998;16(2):434-40.

Glossmann J, Engert A, Wassmer G, Flechtner H, Ko Y, Rudolph C, Metzner B, Dorken B, Wiedenmann S, Diehl V, Josting A. Recombinant human erythropoietin, epoetin beta, in patients with relapsed lymphoma treated with aggressive sequential salvage chemotherapy—results of a randomized trial. Ann Hematol. 2003;82:469–75.

Goldberg M, Schneider T. Similarities between the Oxygen-sensing Mechanisms Regulating the Expression of Vascular Endothelial Growth factor and Erythropoietin. The Journal of Biological Chemistry. 1994; 269:4355-4359.

Goldberg M, McCutchen JW, Jove M, DiCesare P, Friedman RJ, Poss R, Guilfoyle M, Frei D, Young D. A safety and efficacy comparison study of two dosing regimens of epoetin alfa in patients undergoing major orthopedic surgery. The American Journal of Orthopedics. 1996;544-52.

Goldberg P. Study finds more deaths on Aranesp arm in cancer anemia study, no benefit seen [newsletter]. The Cancer Letter. 2007;33:1.

Goldstein D, Carroll S, Apte M, Keogh G. Modern management of pancreatic carcinoma. Intern Med J. 2004;34(8):475-81.

Goodnough LT. Risks of Blood Transfusion. Anesthesiology Clin N Am. 2005;23:241-52.

Goy A, Belanger C, Casadevall N, Picard F, Guesnu M, Jaulmes D, Poisson D, Varet B. High doses of intravenous recombinant erythropoietin for the treatment of anaemia in myelodysplastic syndrome. British Journal of Haematology. 1993;84:232-7.

Grandis JR, Drenning S, Xhakraborty A, Zhou M, Zeng QPitt A, Tweadry D.

Requirement of Sta3 but not Stat 1 Activation for Epidermal Growth Factor Receptor-mediated Cell Growth In Vitro. Journal of Clinical Investigation. 1998;102:1385-1392.

Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y, Kim JD. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. PNAS. 2000;97(8):4227-32.

Granetto C, Ricci S, Martoni A, Pezzella G, Testore F, Mattiol R, Lampignan M, Tacconi F, Porrozzi S, Gasparini G, Matovani G. Comparing the efficacy and safety of fixed versus weight-based dosing of epoetin in anemic cancer patients receiving platinum-based chemotherapy. Oncology Reports. 2003;10:1289-96.

Greenspan E. Treatment of anemia associated with multiple myeloma[Letter to the editor]. The New England Journal of Medicine. 1991;324(1):62.

Grignani G, Falanga A, Pacchiarini L, Alessio MG, Zucchella M, Fratino P, Donati MB. Human breast and colon carcinomas express cysteine proteinase activities with pro-aggregating and pro-coagulant properties. Int. J. Cancer. 1988;42:554-7.

Groopman J, Itri L. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst. 1999;91:1616–34.

Grosbach A, Langer CJ, Montoya V, Williams D. Epoetin alfa 60,000 U QW followed by 80,000 U Q3W maintenance in patients with anemia and cancer receiving chemotherapy. Journal of Clinical Oncology. 2004;22(14S):8215.

Gross J, Moller R, Henke W, Hoesel W. Detection of anti-EPO antibodies in human sera by a bridging ELISA is much more sensitive when coating biotinylated rhEPO to streptavidin rather than using direct coating of rhEPO. Journal of Immunological Methods. 2006;313:176-82.

Grossi A, Vannucchi AM, Bacci P, Caporale R, Cappelli G, Visconti G, Pagliai G, Ferrini PR. Erythropoietin upregulates the expression of its own receptor in tf-1 cell line. Leukemia Research. 1998;22(2):145-51.

Grossi A, Fabbri A, Santini V, Leoni F, Nozzoli C, Longo G, Pagliai G, Ciolli S, Ferrini PR. Amifostine in the treatment of low-risk myelodysplastic syndromes. Haematologica. 2000;85:367-71.

Grote T, Yeilding A, Castillo R, Fishkin E, Henry D, DeLeo M, Fink K, Sullivan D. Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2005;23:9377-86.

Grudeva-Popova J. Cancer and venous thromboembolism. J BUON. 2005;10:483-9.

Gulbrandsen WF, Hjorth N, Lenhoff M, Fayers SP. Quality of life may be affected more by disease parameters and response to therapy than by haemoglobin changes. Eur J Haematol. 2005;75:293-8.

Gussetis ES, Peristeri J, Kitra V, Liakopoulou T, Kattamis A, Graphakos S. Clinical value of bone marrow cultures in childhood pure red cell aplasia. Journal of Pediatric Hematology/Oncology. 1998; 20(2):120-124.

Haematoloica. Editorial, comments & news. 2003;88(06):601-5.

Hallahan D, Chen A, Teng M, Cmelac A. Drug-radiation interactions in tumor blood vessels. Oncology (Williston Park). 1999 Oct;13(Suppl 5):71-7.

Halstenson C, Macres M, Katz S, Schneiders J, Watanabe M, Sobota J, Abraham P. Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin Pharmacol Ther. 1991;50:702-12.

Hansen PB, Johnsen HE, Hippe E, Hellstrom-Lindberg E, Ralfkiaer E. Recombinant human granulocyte-macrophage colony-stimulating factor plus recombinant human erythropoietin may improve anemia in selected patients with myelodysplastic syndromes. American Journal of Hematology. 1993;44:229-36.

Hansen O, Baekke J, Hansen KH, Peter S. The need of transfusion of packed red blood cells in pallitative chemotherapy for advanced NSCLC when no erythropoietin is used. Proc Am Soc Clin Oncol. 2003;22:2817.

Hardee M, Arcsoy M, Blackwell K, Kirkpatrick J, Dewhurst M. Erythropoietin biology in cancer. Clin Cancer Res. 2006;12:332-9.

Hardee M, Kirkpatrick J, Shan S, Snyder S, Vujaskovic Z, Rabanni Z, Dewhirst M, Blackwell K. Human recombinant erythropoietin (rEpo) has no effect on tumor growth or angiogenesis. Br J Cancer. 2005;93:1350-5.

Harman C. What new drugs can nephrologists look forward to in the next year or two? Nature Clinical Practice Nephrology. 2007;3(5):235.

Harris K, Winkelmann J. Enzyme-linked immunosorbent assay detects a potential soluble form of the erythropoietin receptor in human plasma. Am J Hematol. 1996;52:8-13.

Haroon Z, Amin K, Jiang X, Arcasoy M. A novel role for erythropoietin during fibrin-induced wound-healing response. Am J Pathol. 2003;163:993–1000.

Harrison L, Shasha D, Horel P. Prevalence of anemia in cancer patients undergoing radiotherapy:prognostic significance and treatment. Oncology. 2002;63(Suppl 2):11-8.

Hast R, Wallvik J, Folin A, Bernell P, Stenke L. Long-term follow-up of 18 patients with myelodysplastic syndromes responding to recombinant erythropoietin treatment. Leukemia Research. 2001;25:13-18.

Heaney ML, Golde DW. Myelodysplasia. New England Journal of Medicine. 1999;340:1649-1660.

Hedenus M, Hansen S, Taylor K, Arthur C, Emmerich B, Dewey C, Watson D, Rossi G and Osterborg O on behalf of the Darbepoetin alfa 990114 Study Group. Randomized, dose-finding study of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies. British Journal of Haematology. 2002;119:79–86.

Hedenus M, Adriansson M, San Miguel J, Kramer M, Schipperus M, Juvonen E, Taylor K, Belch A, Alte´s A, Martinelli G, Watson D, Matcham J, Rossi G and Littlewood T on behalf of the Darbepoetin alfa 20000161 Study Group. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. British Journal of Haematology. 2003;122:394–403.

Hedenus M, Vansteenkiste J, Kotasek D, Austin M, Amado RG. Darbepoetin alfa for the treatment of chemotherapy-induced anemia: disease progression and survival analysis from four randomized, double-blind, placebo-controlled trials. Journal of Clinical Oncology. 2005;23:6941-8

Heit JA, O’Fallon M, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton III J. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2002;162:1245-8.

Hellstrom-Lindberg E, Birgegard G, Lockner D, Helmers C, Ost A, Wide L. Treatment of myelodysplastic syndromes with recombinant human erythropoietin. Eur J Haematol. 1991;47:355-60.

Hellstrom-Lindberg E, Birgegard G, Carlsson M, Carneskog J, Dahl I, Dybedal I, Grimfors G, Merk K, Tangen J, Winqvist I, Ost A. A combination of granulocyte colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes. Leukemia and Lymphoma. 1993;11:221-8.

Hellstorn-Lindberg E. Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. British Journal of Haematology. 1995;89:67-71.

Hellström-Lindberg E, Kanter-Lewensohn L, Öst A. Morphological changes and apoptosis in bone marrow from patients with myelodysplastic syndromes treated with granulocyte-csf and erythropoietin. Leukemia Research. 1997;21:415-425.

Hellstrom-Lindberg E, Negrin R, Stein R, Krantz S, Lindberg G, Vardiman J, Ost A, Greenberg P. Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive mode. British Journal of Haematology. 1997;99:344-51.

Hellstrom-Lindberg E, Ahlgren T, Beguin Y, Carlsson M, Carneskog J, Dahl I, Dybedal I, Grimfors G, Kanter-Lewensohn L, Linder O, Luthman M, Lofvenberg E, Nilsson-Ehle H, Samuelsson J, Tangen J, Winqvist I, Oberg G, Osterborg A, Ost A. Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. American Society of Hematology. 1998;92(11):68-75.

Hellström-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl I, Dybedal I, Grimfors G, Hesse-Sundin E, Hjorth M, Kanter-Lewensohn L, Linder O, Luthman M, Löfvenberg E, Öberg G, Porwit-MacDonald A, Rådlund A, Samuelsson J, Tangen JM, Winquist I, Wisloff F. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. British Journal of Haematology. 2003;120:1037-46.

Henke M, Guttenberger R, Barke A, Pajonk F, Potter R, Frömmhold H. Erythropoietin for patients undergoing radiotherapy: a pilot study. Radiotherapy and Oncology. 1999;50:185-90.

Henke M, Lazig R, Rube C, Schafer U, Haase K, Schilcher B, Mose S, Beer K, Burger U, Dougherty C, Frommhold H. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255-60.

Henke M, Mattern D, Pepe M, Bezay C, Weissenberger C, Werner M, Pajonk F. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol. 2006;24:4708-13.

Henry D, Abels R. Prediction of response to recombinant human erythropoietin therapy in cancer patients. 1994; 21(2 Supp 3):21-8.

Henry D, Brooks B, Case D, Fishkin E, Jacobson R, Keller A, Kugler J, Moore J, Silver R, Storniolo A, Abels R, Gordon D, Nelson R, Larholt K, Bryant E, Rudnick S. Recombinant human erythropoietin therapy for anemic cancer patients receiving cisplatin chemotherapy. The Cancer Journal from Scientific American. 1995; April:252-60.

Henry D, Patel R, Tchekmedyian S, Jumbe N, Austin M, Berg R, Allen C, Glaspy J. A phase 2 randomized study evaluating the timing of darbepoetin alfa administration relative to chemotherapy. Proc Am Soc Clin Oncol. 2003;22:3162.

Henry DH, Kamin M, Wilhelm F, Williams D, Xie J, Woodman RJ. Final results of a randomized study comparing two dosing regimens of epoetin alfa in patients with chemotherapy-induced anemia: 80,000 U every two weeks vs 40,000 U weekly. Journal of Clinical Oncology. 2006;24(18S):8624.

Henze G, Michon J, Morland B, Perek D, Rizzazi C, Zoubek A. Phase III randomized study: efficacy of epoetin alfa in reducing blood transfusions in newly diagnosed pediatric cancer patients receiving chemotherapy. Proc Am Soc Clin Oncol. 2002;21:1547.

Heras P, Hatzopoulos A, Karagiannis S. Efficacy and safety of epoetin beta 30,000 IU once weekly in patients with solid tumors and chemotherapy-induced anemia. Journal of Clinical Oncology. 2006;24(18S):18620.

Herrmann F, Mertelsmann R, Lindemann A, Ottman OG, Seipelt G, Oster W, Hoelzer D, Ganser A. Clinical use of recombinant human hematopoietic growth factors (GM-CSF, IL-3, EPO) in patients with myelodysplastic syndrome. Biotechnology Therapeutics. 1991;2(3&4):299-311.

Herrington J, Davidson S, Tomita D, Green L, Smith R, Boccia R. Utilization of darbepoetin alfa and epoetin alfa for chemotherapy-induced anemia. Am J Health Syst Pharm. 2005;62(1):54-62.

Hesketh PJ, Arena F, Patel D, Poulsen E, D’Avirro P, Rossi G, Schwartzberg L. Front-loaded darbepoetin alfa with Q3W maintenance administered as a fixed or weight-based dose in anemic cancer patients results in similar efficacy profiles. Proc Am Soc Clin Oncol. 2003;22:2941.

Hesketh J, Arena F, Patel D, Austin M, D’Avirro P, Rossi G, Colowick A, Schwartzberg L. A Randomized controlled trial of Darbepoetin Alfa administered as a fixed or weight-based dose using a front-loading schedule in patients with anemia who have nonmyeloid malignancies. American Cancer Society. 2004;100(4):859-68.

Hirashima K, Bessho M, Jinnai I. Improvement in anemia by recombinant human erythropoietin in patients with myelodysplastic syndrome and aplastic anemia. Contributions to Nephrology. 1991;88:254-65.

Hitomi K, Fujita K, Sasaki R, Chiba H, Okuno Y, Ichiba S, Takahashi T, Imura H. Erythropoietin receptor of a human leukemic cell line with erythroid characteristics. Biochemical and Biophysical Research Communications. 1988;154(3):902-9.

Hoefsloot LH, van Amelsvoort MP, Broeders L, van der Plas DC, van Lom K, Hoogerbrugge H, Touw IP, L öwenberg B. Erythropoietin-induced activation of STAT5 is impaired in the myelodysplastic syndrome. Blood. 1997;89(5):1690-1700.

Homoncik M, Jilma-Stohlawetz P, Schmid M, Ferlitsch A, Peck-Radosavljevic M. Erythropoietin increases platelet reactivity and platelet counts in patients with alcoholic liver cirrhosis: a randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2004;20(4):437-43.

Horiguchi H, Kayama F, Oguma E, Willmore W, Hradecky P, Bunn HF. Cadmium and platinum suppression of erythropoietin production in cell culture: Clinical implications. Blood. 2000;96:3743-7.

Hoshino S, Teramura M, Takahashi M, Motoji T, Oshimi K, Ueda M, Mizoguchi H. Expression and characterization of erythropoietin receptor s on normal human bone marrow cells. International Journal of Cell Cloning. 1989;7:156-7.

Huddart R, Welch R, Chan S, Perren T, Atkinson R. A prospective, randomised trial comparative-group evaluation of epoetin alfa for the treatment of anaemia in UK in cancer patients receiving platinum-based chemotherapy. Annals of Oncology. 2002;23:177.

Hudis C, Williams D, Gralow J. Epoetin alfa maintains hemoglobin levels and quality of life in breast cancer patients during adjuvant chemotherapy. Proc Am Soc Clin Oncol. 2002;21:1518.

Hudis C, Williams D, Gralow JR. Epoetin alfa maintains hemoglobin and quality of life in breast cancer patients receiving conventional adjuvant chemotherapy: final report. Proc Am Soc Clin Oncol. 2003;22:3084.

Hunault-Berger M, Tanguy-Schmidt A, Rachieru P, Levy V, Truchan-Graczyk M, Francois S, Gardembas-Pain M, Dib M, Foussard C, Piard N, Godon A, Solal-Celigny P, Ifrah N. rHuEpo before high-dose therapy allows autologous peripheral stem-cell transplantation without red blood cell transfusion: a pilot study. Bone Marrow Transplantation. 2005;35:903-7.

Hussein MM, Mooij JMV, Roujouleh H. Use of recombinant erythropoietin in the treatment of anaemia associated with multiple myeloma in a haemodialysis patient. Nephrology Dialysis Transplantation 1994;9(7):876-7.

Iconomou G, Koutras A, Rigopoulos A, Vagenakis A, Kalofonos H. Effects of recombinant human erythropoietin on quality of life in cancer patients receiving chemotherapy: results of a randomized, controlled trial. Journal of Pain and Symptom Management. 2003;(Vol 25);6:512-18.

Ikegaya N, Yamamoto T, Takeshita A, Watanabe T, Yonemura K, Miyaji T, Ohishi K, Furuhashi M, Maruyama Y, Hishida A. Elevated erythropoietin receptor and transforming growth factor-ß1 expression in stenotic arteriovenous fistulae used for hemodialysis. J Am Soc Nephrol. 2000;11:928-35.

Imamura M, Kobayashi M, Kobayashi S, Yoshida K, Mikuni C, Ishikawa Y, Matsumoto S, Sakamaki S, Niitsu Y, Hinoda Y, Yachi A, Kudoh T, Chiba S, Kasai M, Oka T, Okuno A, Maekawa I, Sakurada K, Miyazaki T. Failure of combination therapy with recombinant granulocyte colony-stimulating factor and erythropoietin in myelodsyplastic syndromes. Annals of Hematology. 1994;68:163-6.

Imamura M, Kobayashi M, Kobayashi S, Yoshida K, Mikuni C, Ishikawa Y, Matsumoto S, Sakamaki S, Niitsu Y, Hinoda Y, Yachi A, Kudoh T, Chiba S, Kasai M, Oka T, Okuno A, Maekawa I, Sakurada K, Miyazaki T. Combination therapy with recombinant human granulocyte colony-stimulating factor and erythropoietin in aplastic anemia. American Journal of Hematology. 1995;48:29-33.

Iniesta CB, Carpeño JD, Saenz EC, Batlle JF, Bernabeu F, Alves J, Cejas P, Sereno M, Perona R, Baron MG. Erythropoietin receptor expression in bladder cancer. Journal of Clinical Oncology. 2006;24(18S):4584.

Inomata Y, Hirata A, Takahashi E, Kawaji T, Fukushima M, Tanihara H. Elevated erythropoietin in vitreous with ischemic retinal diseases. Clinical Neuroscience and Neuropathology. 2004;15(5):877-9.

Isnard F, Najman A, Jaar B, Fenaux P, Baillou C, Khoury E, Labopin M, Laporte J, Woler M, Gorin N, Bauters F. Efficacy of recombinant human erythropoietin in the treatment of refractory anemias without excess of blasts in myelodysplastic syndromes. Leukemia and Lymphoma. 1994;12:307-14.

Italian Cooperative Study Group. A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. British Journal of Haematology. 1998;103:1070-74.

Jacubowski AA, Hurria A. Head-to-head comparison of epoetin alfa 40,000 U QW vs darbepoetin alfa 200 mcg Q2W in anemic patients with cancer receiving chemotherapy: preliminary results. Blood. 2003;102(11):4391.

Jädersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellström-Lindberg. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood. 2005;106:803-11.

James C, Ugo V, Casadevall N, Constantinescu SN, Vainchecker W. A JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects. Trends in molecular medicine. 2005;11(112):546-54.

Janinis J, Dafni U, Aravantinos G, Kalofonos H, Papakostas P, Tsavdaridis D, Fountzilas G. Qaulity of life (QOL) outcome of epoietin-alpha (EPO-A) in anemia cancer patients undergoing platinum or non-platinum-based chemotherapy: a randomized study conducted by the Hellenic Cooperative Oncology Group. Proc Am Soc Clin Oncol. 2003;22:789.

.Jelic S. Management of hematological complications of malignancy and chemotherapy: the role of hematopoietic growth factors. Arch Oncol. 2004;12(3):177-8.

Jelkmann A. The role of the liver in the production of thrombopoietin compared with erythropoietin. Eur J Gastroenterol Hepatol. 2001;13:791-801.

Jitnuyanont A. Impact of therapy with recombinant human erythropoietin (r-HuEPO) and quality-of-life in anemic cancer patients. Intern Med J Thai. 2001;17:283-290.

Johansson J, Wersa P, Brandberg Y, Andersson S, Nordstrom L and the EPO-Study Group. Efficacy of epoetin beta on hemoglobin, quality of life, and transfusion needs in patients with anemia due to hormone-refractory prostate ancer: a randomized study. Scand J Urol Nephrol. 2001;35:288–94.

Jones S, D'Andrea A, Haines L, Wong G. Human erythropoietin receptor: cloning, expression, and biologic characterization. Blood. 1990;76:31–5.

Jumbe NL, Heatherington AC. Darbepoetin alfa rational dose/schedule evaluation based on quantitative understanding of erythropoiesis for early and sustained alleviation of anemia. Proc Am Soc Clin Oncol. 2003;22:abstract 3077.

Justice G, Kessler J, Jadeja J, Campos L, Weick J, Poulsen E, Jumbe N. Subcutaneous and intravenous darbepoetin alfa in patients with chemotherapy-induced anemia. Proc Am Soc Clin Oncol. 2003;22:3118.

Justice G. Kessler JF, Jadeja J, Campos L, Weick J, Chen CF, Heatherington AC, Amado RG. A randomized multicenter study of subcutaneous and intravenous darbepoetin alfa for the treatment of chemotherapy –induce anemia. Annals of Oncology.2005;16:1192-1198.

Kagan A, Sinay-Trieman L, Bar-Khayim Y. Recombinant human erythropoietin for anaemia in thalassaemia minor patients on dialysis[Letter to the editor]. Nephrology Dialysis Transplantation. 1995;10(12):2375-6..

Kajikawa M, Nonami T, Kurokawa T, Hashimoto S, Harada A, Nakao A, Takagi H. Autologous Blood Transfusion for Hepatectomy in Patients with Cirrhosis and Hepatocellular Carcinoma: Use of Recombinant Human Erythropoietin. Surgery. 1994;115:727-34.

Kakkar A, DeRuvo N, Chinswangwatanakul V, Tebbutt S, Williamson R. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet. 1995 ;346:1004-5.

Kallich J, Erder H, Glaspy JA, Tchekmedyian S. Darbepoetin alfa has higher observed improvements in fatigue and physical well-being than epoetin alfa. Proc Am Soc Clin Oncol. 2002;21:1466.

Kalyankrishna S, Grandis R. Epidermal growth factor receptor biology in head and neck cancer. Journal of Clinical Oncology. 2006;24(17):2666-72.

Kanoh T, Fujii H. Phagocytic myeloma cells. Report of a case and review of the literature. Am J Clin Pathol. 1985;84(1):121-4.

Kasper C, Terhaar A, Fossä A, Welt A, Seeber S, Nowrousian MR. Recombinant human erythropoietin in the treatment of cancer-related anaemia. European Journal of Heamotology. 1997;58:251-6.

Kasper C, Zahner J, Sayer HG. Recombinant human erythropoietin in combined treatment with granulocyte- or granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. Journal of Cancer Research and Clinical Oncology. 2002;128:497-502.

Kasselberg AG, Orth DN, Gray ME, Stahlman MT. Immunocytochemical localization of human epidermal growth factor/urogastrone in several human tissues. The Journal of Histochemistry and Cytochemistry. 1985;33(4):315-22.

Katodritou E, Speletas M, Zervas K, Kapetanos D, Georgiou E, Christoforidou A, Pavlitou A, Sion M, Christakis J. Evaluation of hypochromic erythrocytes in combination with s TfR-F index for predicting response to r-HuEPO in anemic patients with multiple myeloma. Laboratory Hematology. 2006;12:47-54.

Kaufman S, Reda J, Fye C, Goldfarb D, Henderson W, Kleinman J, Vamone C. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med. 1998;339:578-83.

Kessler C. Anticoagulation and thrombolytic therapy. Practical considerations. Chest. 1989;95(5 Suppl):245S-56S.

Kirito K, Nakajima K, Watanabe T, Uchida M, Tanaka M, Ozawa K, Komatsu N. Identification of the human erythropoietin receptor region for Stat1 and Stat3 activation. Blood, 1 January 2002, Vol. 99, No. 1, pp. 102-110.

Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med. 2006 May 11;354(19):2079-80.

Kobrin MS, Funatomi H, Friess H, Buchler MW, Stathis P, Korc M. Induction and expression of heparin-binding egf-like growth factor in human pancreatic cancer. 1994;202(3):1705-9.

Kokhaei P, Abdalla A, Hansson L, Mikaelsson E, Kubbies M, Haselbeck A, Jernberg-Wiklund H, Mellstedt H, Österborg A. Expression of erythropoietin receptor and In vitro functional effects of epoetins in B-cell malignancies. Clin Cancer Res. 2007;13(12):3536-44.

Konigsberg W, Kirchhofer D, Riederer MA, Nemerson Y. The TF: Vlla complex: clinical significance, structure-function relationships and its role in signaling and metastasis. Thromb Haemost. 2001;86:757-71.

Kontor JT. Erythropoietin for total hip joint arthroplasty. Annals of Internal Medicine. 2001;135(6):471.

Konturek JW, Bielanski W, Konturek SJ, Bogdal J, Oleksy J. Distribution and release of epidermal growth factor in man. Gut. 1989:30;1194-1200.

Kooistra M, van Es A, Marx J, Hertsig M, Struyvenberg A. Low-dose aspirin does not prevent thrombovascular accidents in low-risk haemodialysis patients during treatment with recombinant human erythropoietin. Nephrol Dial Transplant. 1994;9:1115–20.

Korc M, Chandrasekar B, Yamanaka Y, Friess H, Buchler M, Beger HG. Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J. Clin. Invest. 1992;90:1352-60.

Kotasek D, Albertsson M, Mackey J. Randomized, double-blind, placebo-controlled, dose-finding study of darbepoetin alfa administered once every 3 (Q3W) or 4 (Q4W) weeks in patients with solid tumors. Proc Am Soc Clin Oncol. 2002;21:1421.

Kotasek D, Stegerb G, Faught W, Underhill C, Poulsen E, Colowick A, Rossi G, Mackey J for the Aranesp 980291 Study Group. Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumors receiving chemotherapy: Results of a double-blind, placebo-controlled, randomized study. Eur J Cancer. 2003;39:2026–34.

Kotasek D, Canon, J, Mateos M, Hedenus M, Rossi G, Taylor K. A randomized controlled trial comparing darbepoetin Alfa/correction maintenance dosing with weekly dosing for treating chemotherapy –induced anemia.. MD promotions. 2007; 23:1387-1401.

Kotsori AA, Alexopoulos CG. A randomized comparison of Darbepoetin alfa with epoetin for chemotherapy induced anemia in nonhematological tumors. Journal of Clinical Oncology. 2006. 24(18S):18554.

Kotsori A, Alexopoulos C. A randomized comparison of darbepoetin alfa with epoetin for chemotherapy induced anemia in nonhematological tumors. Journal of Clinical Oncology. 2006:24(20 June Suppl):18S Abstract No: 18554.

Koury S, Bondurant M, Koury M, Semenza G. Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood. 1991;77:2497–2503.

Krzyzanski W, Jusko W, Wacholtz M, Minton N, Cheung W. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects. Eur J Pharm Sci. 2005;26:295-306.

Kumar S, Yu H, Fong D. Erythropoietin activates the phosphoinositide 3-kinase/Akt pathway in human melanoma cells. Melanoma Res. 2006;16:275-83.

Kunikane H, Watanabe K, Fukuoka M, Saijo N, Furuse K, Ikegami H, Ariyoshi Y, Kishimoto S. Double-blind randomized control trial of the effect of recombinant human erythropoietin on chemotherapy-induced anemia in patients with non-small cell lung cancer. Int J Clin Oncol. 2001;6:296–301.

Kurz C, Marth C, Windbichler G, Lahousen M, Medl M, Vavra N, Sevelda P. Erythropoietin treatment under polychemotherapy in patients with gynecologic malignancies: A prospective, randomized, double-blind placebo-controlled multicenter study. Gynecologic Oncology. 1997;65:461–66.

Kurzrock R, Talpaz M, Estey E, O’Brien S, Estrov Z, Gutterman JU. Erythropoietin treatment in patients with myelodysplastic syndrome and anemia. Leukemia. 1991;5(11):985-90.

Kurzrock R, Cortes J, Thomas DA, Jeha S, Pilat S, Talpaz M. Pilot study of low-dose interleukin-11 in patients with bone marrow failure. Journal of Clinical Oncology. 2001;19:4165-4172.

Kuzel T, Esparaz B, Green D, Kies M. Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer. 1990;65:885-9.

Kwak EL, Jankowski J, Thayer SP, Lauwers GY, Brannigan BW, Harris PL, Okimoto RA, Haserlat SM, Driscoll DR, Ferry D, Muir B, Settleman J, Fuchs CS, Kulke MH, et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clinical Cancer Research. 2006;12:4283-7.

LaMontagne KR, Butler J, Marshall DJ, Tullai J, Gechtman Z, Hall C, Meshaw A, Farrell FX, Recombinant epoetins do not stimulate tumor growth in erythropoietin receptor-positive breast carcinoma models. Mol Cancer Ther. 2006;5(2):347-55.

Lage J, Panizo C, Masdeu J, Rocha E. Cyclist’s doping associated with cerebral sinus thrombosis. Neurology. 2002;58:665.

Lai S, Childs E, Xi S, Coppelli F, Gooding W, Well A, Ferris R, Grandis J. Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma. Oncogene. 2005;24:4442–9.

Lai SY, Lui VW, Koppikar J, Thomas SM, Gooding WE, Seethala RR, Bransletter BF, Argiris A, Grandis JR. Intratumoral Epidermal Growth Factor Receptor (EGFR) Antisense (AS) DNA in recurrent squamous cell carcinoma (SCCHN) of the head and neck: A phase 1 trial. Journal of Clinical Oncology. 2007; 25:1-2.

Laporte JPH, Isnard F, Fenaux P, Woler M, Najman A. Recombinant human erythropoietin at high dose is effective for the treatment of the anemia of myelodysplastic syndromes. Contributions to Nephrology. 1991;88:271-2; discussion 273-5.

Lappin T. The cellular biology of erythropoietin receptors. Oncologist. 2003;8 (Suppl 1):15-8.

Lappin T, Maxwell AP, Johnson PG. Warning flags for erythropoiesis-stimulation agents and cancer-associated anemia. The Oncologist. 2007;12:362-5.

Laupacis A. Effectiveness of perioperative recombinant human erythropoietin in elective hip replacement. COPES Study Group.Lancet. 1993;342:378.

Lavey R, Dempsey W. Erythropoietin increases hemoglobin in cancer patients during radiation therapy. International Journal of Radiation Oncology. 1993;27(5):1147-52.

Lavey R. Clinical trial experience using erythropoietin during radiation therapy. Strahlentherapie und Onkologie. 1998;174(Suppl IV):24-30.

Lavey R, Liub P, Greerc B, Robinson W IIId, Change P, Wynnf R, Conradg M, Jiangb C, Markmanh M, Albertsi D. Recombinant human erythropoietin as an adjunct to radiation therapy and cisplatin for stage IIB–IVA carcinoma of the cervix: a Southwest Oncology Group study. Gynecologic Oncology. 2004;95:145-51.

Lee A, Levine M. The thrombophilic state induced by therapeutic agents in the cancer patient. Semin Thromb Hemost. 1999;25:137-45.

Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. Journal of Clinical Oncology. 2005;23(10):2123-29.

Lee A. Thrombosis and cancer: the role of screening for occult cancer and recognizing the underlying biological mechanisms. Hematology Am Soc Hematol Educ Program. 2006:438-43.

Leitgeb C, Pecherstorfer M, Fritz E, Ludwig H. Quality of life in chronic anemia of cancer during treatment with recombinant human erythropoietin. CANCER. 1994;73(10):2535-42.

Leon P, Jiménez M, Barona P, Sierrasesúmaga L. Recombinant human erythropoietin for the treatment of anemia in children with solid malignant tumors. Medical and Pediatric Oncology. 1998;30:110-16.

Lester J, Jo M, Campana W, Gonias S. Erythropoietin promotes MCF-7 breast cancer cell migration by an ERK/mitogen-activated protein kinase-dependent pathway and is primarily responsible for the increase in migration observed in hypoxia. J Biol Chem. 2005;280(47):39273-7. Epub 2005 Oct 5.

Levin I, Cohen J, Supino-Rosin L, Yoshimura A, Watowich SS, Neumann D. Identification of a cytoplasmic motif in the erythropoietin receptor required for receptor internalization. FEBS Letters. 1998;427:164-70.

Levine E, Laborde C, Hambrick E, McKnight CA, Vijayakumar S. Influence of Erythropoietin on Transfusion Requirements in Patients Receiving Preoperative Chemoradiotherapy for Rectal Cancer. Dis Colon Rectum. 1999;42(8):1065-71.

Levine M, Gent M, Hirsh J, Arnold A, Goodyear M, Hyrniuk W, De Pauw S. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med. 1988;318:404-7.

Levine M. Cancer patients in Goldhaber SZ, Ed. Prevention of venous thromboembolism. New York: Marcel Dekker. 1993:463-83.

Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, Samosh M, Bramwell V, Pritchard K, Stewart D, Goodwin P. Double-blind randomized trial of very low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet. 1994;343:886-89.

Leyland-Jones B, BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol. 2003;4:459-60.

Leyland Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, Makhson A, Roth A, Dodwell D, Baselga J, Biakhov M, Valuckas K, Voznyi E, Liu X, Vercammen E. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. 2005;23:5960-72. Epub 2005 Aug 8.

Libretto S, Barrett-Lee P, Branson K, Gorst D, Kaczmarski R, McAdam K, Stevenson P, Thomas R. Improvement in quality of life for cancer patients treated with epoetin alfa. European Journal of Cancer. 2001;10:183-91.

Libutti MPF. Darbepoetin a, quality of life and fatigue in outpatients in chemo-radiotherapy. Journal of Clinical Oncology. 2004;22(14S):8190.

Lin AY, Ryu JK, Harvey D, Sieracki B, Scudder SA, Wun T, Davis UC. Incidence of symptomatic venous thrombosis in cervical and vulvo-vaginal carcinoma treated with concurrent chemoradiation, erythropoietin, and coumadin. Journal of Clinical Oncology. 2004;22(14S):8101.

Lin A, Ryu J, Harvey D, Sieracki B, Scudder S, Wun T. Low-dose warfarin does not decrease the rate of thrombosis in patients with cervix and vulvo-vaginal cancer treated with chemotherapy, radiation, and erythropoietin. Gynecologic Oncology. 2006;102:98-102.

Lin F, Suggs S, Lin C, Browne JK, Smalling R, et al. Cloning and expression of the human erythropoietin gene. Proc. Natl. Acad. Sci. 1985;82:7580-4.

Lindholm E, Daneryd P, Ko¨rner U, Hyltander A, Fouladiun M, Lundholm K. Effects of recombinant erythropoietin in palliative treatment of unselected cancer patients. Clinical Cancer Research. 2004;10:6855-64.

Link H, Arseniev L, Bähre, Kada JG, Diedrich H, Poliwoda H. Transplantation of allogeneic CD34+ blood cells. Blood. 1996;87:4903-9.

Linnekin D, Evans G, D’Andrea D, Farrar W. Association of the erythropoietin receptor with protein tyrosine kinase activity. Proc Natl Acad Sci U S A. 1992;89:6237-41.

Lipschitz D. Age-related declines in haematopoietic reserve capacity. Semin Oncol. 1995;22 (Suppl 1):3-5.

Lipton A, Harvey H, Hamilton R. Venous thrombosis as a side effect of tamoxifen treatment. Cancer Treat Rep. 1984;68:887-9.

List A. Vascular Endothelial Growth factor Signaling Pathway as an Emerging Target in Hematologic Malignancies. The Oncologist. 2001;6:24-31.

List AF. New approaches to the treatment of myelodysplasia. The Oncologist. 2002;7(suppl 1):39-49.

List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. The New England Journal of Medicine. 2005;352:549-57.

Littlewood TJ. Erythropoietin for the treatment of anemia associated with hematological malignancy. Hematology & Oncology. 2001;19:19-30.

Littlewood T, Bajetta E, Nortier J, Vercammen E, Rapoport B, Epoetin Alpha Study Group. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2001;19:2865-74.

Littlewood T, Kallich J, San Miguel J, Hendricks L, Hedenus M. Efficacy of darbepoetin alfa in alleviating fatigue and the effect of fatigue on quality of life in anemic patients with lymphoproliferative malignancies. Journal of Pain and Symptom Management. 2006;31(4):317-325.

Livnah O, Stura EA, Middleton SA, Johnson DL, Jolliffe LK, Wilson IA. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science. 1999;283(12):987-91.

Lockich J, Becker B. Subclavian vein thrombosis in patients treated with infusion chemotherapy for advanced malignancy. Cancer. 1983;52:1586-9.

Lokich JJ, Becker B. Subclavian vein thrombosis in patients treated with infusion chemotherapy for advanced malignancy. Cancer. 1983;52:1586-9.

Luban NL. Transfusion Safety: Where are we today? Annals New York Academy of Sciences. 2005;1054:325-41.

Ludwig H, Fritz E, Kotzmann H, Hocker P, Gisslinger H, Barnas U. Erythropoietin Treatment of Anemia Associated With Multiple Myeloma. The New England Journal of Medicine. 1990;322(24):1693-99.

Ludwig H, Fritz E, Kotzmann H, Gisslinger H. Erythropoietin treatment of tumor-associated anemia. Onkologie. 1990;13(1):46-9.

Ludwig H, Fritz E, Kotzmann H, Hocker P, Gisslinger H, Barnas U. Treatment of anemia associated with multiple myeloma[Letter to the editor]. The New England Journal of Medicine. 1991;324(1):62-3.

Ludwig H, Leitgeb C, Fritz E, Krainer M, Kuhrer I, Kornek G, Sagaster P, Weibmann A. Erythropoietin treatment of chronic anaemia of cancer. European Journal of Cancer. 1993;29A(Suppl 2):S8-S12.

Ludwig H, Fritz E, Leitgeb C, Krainer M, Kuhrer I, Sagaster P, Umek H. Erythropoietin treatment for chronic anemia of selected hematological malignancies and solid tumors. Annals Oncology. 1993;4:161-7.

Ludwig H, Pecherstorfer M, Leitgeb C, Fritz E. Recombinant human erythropoietin for the treatment of chronic anemia in multiple myeloma and squamous cell carcinoma. Stem Cells. 1993;11:348-55.

Ludwig H, Fritz E, Leitgeb C, Pecherstorfer M, Samonigg H, Schuster J. Prediction of response to erythropoietin treatment in chronic anemia of cancer. Blood. 1994;84(4):1056-63.

Ludwig H, Chott A, Fritz E, Krainer M. Increase of bone marrow cellularity during erythropoietin treatment in myeloma. Stem Cells. 1995; 13(suppl 2):77-87.

Ludwig H, Sundal E, Pecherstorfer M, Leitgeb C, Bauernhofer T, Beinhauer A, Samonigg H, Kappeler AW, Fritz E. Recombinant Human Erythropoietin for the Correction of Cancer Associated Anemia with and without Concomitant Cytotoxic Chemotherapy. Cancer. 1995;76(11):2319-2329.

Ludwig H. rHuEPO and treatment outcomes: the preclinical experience. The Oncologist. 2004;9(suppl 5):48-54.

Ludwig H, Van Belle S, Barrett-Lee P. The European cancer anaemia survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence and treatment of anaemia in cancer patients. Eur J Cancer. 2004;40:2293–2306.

Ma X, Does M, Raza A, Mayne S. Myleodysplastic Syndromes Incident and Survival in the United States. Wiley Intersciecne. 2007: 10: 1536-1542.

Macdougall I, Davies M, Hallett I, Cohlin D, Hutton R, Coles G, Williams J. Coagulation in studies and fistula blood flow during erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant. 1991;6:862–7.

Macdougall I, Roberts DE, Coles GA, Williams JD. Clinical pharmacokinetics of epoetin (recombinant human erythropoietin). Clin Pharmacokinet. 1991;20(2):99-113.-

Macdougall IC. Poor response to erythropoietin. British Medical Journal. 1995;310:1424-5.

MacDougall I, Gray S, Elston O, Breen C, Jenkins B, Browne J, Egrie J. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:2392-5.

MacDougall I. Optimizing the use of erythropoietic agents—pharmacokinetic and pharmacodynamic considerations. Nephrol Dial Transplant. 2002;17(Suppl 5):66-70.

MacDougall J, Bailon P, Tare N. CERA (Continuous Erythropoiesis Receptor Activator) for the treatment of renal anemia: an innovative agent with unique receptor binding characteristics and prolonged serum half-life. J Am Soc Nephrol. 2003;14:769A.

MacDougall I. CERA (Continuous Erythropoietin Receptor Activator): a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep. 2005;4:436-40.

MacLennan S, Williamson LM. Risks of fresh frozen plasma and platelets. The Journal of Trauma Injury, Infection, and Critical Care. 2006;50(6):S46-50.

Machtay M, Pajak T, Suntharalingam M, Hershock D, Stripp D, Cmelak. Definitive radiotherapy +/- erythropoietin for squamous cell carcinoma of the head and neck: Preliminary report of RTOG 99-03. Int J Rad Oncol Biol Physics. 2004;60(Suppl 1):S132. RTOG 99-03 website. www.rtog.org/members/protocols/99-03/9903. www.rtog.org/members/protocols/99-03/revision. Accessed 3/20/97.

Maeda Y, Sakaguchi M, Naiki Y, Sumimoto Y, Miyatake J, Matsuda M, Hasegawa H, Kanamaru A. Possible involvement of soluble erythropoietin receptor in resistance to erythropoietin in patients with renal anemia. Am J Nephrol. 2001;21:426.

Maisnar V, Chroust K. Treatment of associated anemia in different hematological disorders with epoetin alpha. Neoplasma. 2004;51:375-84.

Malik I, Khan Z, Hakimali A, Sabih M, Rehman G. The effect of subcutaneous recombinant human erythropoietin (r-HuEPO) on anemia in cancer patients receiving platinum-based chemotherapy. Journal of the Pakistan Medical Association. 1998;48(5):127-31.

Malik I, Kahanic S, Liu R, Tchekmedyian S, Tomita D, Lillie T, Boccia R. Effectiveness of darbepoetin alfa administered every 3 weeks on clinical outcomes in patients with gastrointestinal cancer and chemotherapy-induced anemia. 2006 Gastrointestinal Cancers Symposium. Abstract #382.

Malmstrom H, Karlsson T. Cognitive functions in patients with ovarian cancer receiving chemotherapy. Proc Am Soc Clin. 2003;22:1855.

A-Malyszko J, Malyszko J, Borawski J, Rydzewski A, Kalinowski M, Azzadin A, Mysliwiec C, Buczko W. A study of platelet functions, some hemostatic and fibrinolytic parameters in relation to serotonin in hemodialyzed patients under erythropoietin therapy. Thromb Res. 1995;77:133–43.

B-Malyszko J, Maschio G. Erythropoietin and systemic hypertension. Nephrol Dial Transplant. 1995;10 (Suppl 2):74–9.

Malyszko J, Malyszko J, Pawlak K, Mysliwiec M. Erythropoietin and uremic platelet aggregation in vivo and in vitro. Int J Clin Lab Res. 1996;26:199-202.

Mannone L, Gardin C, Quarre MC, Bernard JF, Giraudier S, et al. High response rate to darbepoetin alfa in “low risk” results of a phase II study. Blood. 2004;104:abstract 69.

Mannone L, Gardin C, Quarre MC, Bernard JF, Vassilieff D, Ades L, Park S, Vaultier S, Hamza F, Beyne-rauzy MO, Cheze S, Giraudier S, Agape P, Legros L, Voillat L, Dreyfus F, Fenaux P. High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. British Journal of Haematology. 2006;133:513-19.

Mantovani L, Lentini G, Hentschel B, Wickramanayake P, Loeffler M, Diehl V, Tesch H. Treatment of anaemia in myelodysplastic syndromes with prolonged administration of recombinant human granulocyte colony-stimulating factor and erythropoietin. British Journal of Haematology. 2000;109:367-75.

Marinaccio M, Mele E, Giotta F, Cantinieri C, Cocca M. Pretreatment normalization of mild anemia with epoetin alfa: impact on the outcome in epithelial ovarian cancer patients. Proc Am Soc Clin Oncol. 2003;22:1952.

Marinaccio M, Mele E, Poma S, Cantinieri C, Cocca M, Latiano T. Pretreatment normalization of mild anemia with epoetin alfa predicts long-term outcome for women with epithelial ovarian cancer. Journal of Clinical Oncology. 2004;22(14S):5132.

Markman M, Reichman B, Hakes T, Rubin S, Jones W, Lewis J Jr, Barakat R, Curtin J, Almadrones L, Hoskins W. The use of recombinant human erythropoietin to prevent carboplatin-induced anemia. Gynecologic Oncology. 1993;49:172-76.

Markman M. The prophylactic administration of recombinant erythropoietin in the management of ovarian cancer: time for a definitive Phase 3 randomized trial. Gynecologic Oncology. 2002;86:237-8.

Markman M. Use of progression-free survival as a valid endpoint in phase II cancer clinical trials. Current Oncology Reports. 2007;9:159-60.

Marques da Costa R. Current use of recombinant human erythropoietin (r-huEPO) in the management of symptomatic anaemia in patients with myelodysplastic syndromes (MDS). Sangre. 1994;39:105-10.

Maruyama Fumio, Ezaki K, Okamoto M, Hirano M. Increased blood cell destruction during vigorous regeneration of bone marrow after intensive chemotherapy for non-hodgkin lymphoma. European Journal of Haematology. 1993;29A(10):1499.

Maschio G. Erythropoietin and systemic hypertension. Nephrol Dial Transplant. 1995;10(Suppl 2):74-9.

Masinar V, Khroust K. Treatment of associated anemia in different hematological disorders with epoetin alfa. Neoplasma. 2004;51:5.

Masuda S, Nagao M, Takahata K, Konishi Y, Gallyas F Jr, Tabira T, Sasaki R. Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem. 1993;268:11208-16.

Matsuda A, Kishimoto K, Yoshida K, Yagasaki F, Ito Y, Sakata T, Kawai N, Ino H, Hirashima K, Bessho M. Long-term follow-up of patients with aplastic anemia and refractory anemia responding to combination therapy with recombinant human granulocyte colony-stimulating factor and erythropoietin. International Journal of Hematology. 2002;76:244-50.

Matsuda K, Idezawa T, You XJ, Kothari NH, Fan H, Korc M. Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor. Cancer Research. 2002;62:5611-7.

Maurer AB, Ganser A, Seipelt G, Ottmann OG, Mentzel U, Geissler GR, Hoelzer D. Changes in erythroid progenitor cell and accessory cell compartments in patients with myelodysplastic syndromes during treatment with all-trans retinoic acid and haemopoietic growth factors. British Journal of Haematology. 1995;89(3):449-51..

McKenzie RS. Use of erythropoietic agents in anemic lung cancer patients receiving chemotherapy. Proc Am Soc Clin Oncol. 2003;22:3145.

McMahon F, Vargas R, Ryan M, Jain A, Abels R, Perry B, Smith I. Pharmacokinetics and effects of recombinant human erythropoietin after intravenous and subcutaneous injections in healthy volunteers. Blood. 1990;76:1718-22.

Medical News Today. EGFr targeted drugs: vectibix setback, EGFr testing. April 4, 2007.

Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. Journal of Clinical Oncology. 2003;21(14):2787-99.

Mercadante S, Gebbia V, Marrazzo A, Filosto S. Anaemia in cancer: pathophysiology and treatment. Cancer Treat Rev. 2000;26:303-11.

Michael U, Jackisch C, Lenhard MS, DuBois A, Lueck HJ, Thomssen C, Kuhn W, Kurbacher C, Nitz U, Kreienberg R, Mobüs, VJ. Epoetin-alpha reduces red blood cell transfusions (RBC) in high-risk breast cancer patients with adjuvant dose-dense, sequential chemotherapy with epirubicin (E) paclitaxel (T) and cyclophosphamide (C) (ETC). Journal of Clinical Oncology. 2005;23(16S):613.

Migliorino MR, De Petris L, Martelli O, Mancuso A, DiSalvia R, Demarinis F. Hemoglobin increase in advanced/metastatic lung cancer patients receiving multicycle chemotherapy and weekly darbepoetin alfa: an initial ongoing experience. Journal of Clinical Oncology. 2004;22(14S):8250.

Mikami Y, Mikami M, Nannmoku H, Kawashima H, Sasaki T, Hada R, Inoue S. Anemia-inducing factor expressed in gastric cancer is homologous with complement regulatory factor CD59? J Exp Clin Cancer Res. 1998;17:355-60.

Miller AM, Noyes WE, Taetle R, List AF. Limited erythropoietic response to combined treatment with recombinant human interleukin 3 and erythropoietin in myelodysplastic syndrome. Leukemia Research. 1999;23:77-83.

Miller B, Jones J, Piantadosi S, Abeloff M, Spivak J. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med. 1990;322:1689-92.

Miller CP, Liu ZY, Noguchhi CT, Wojchowski DM. A minimal cytoplasmic subdomain of the erythropoietin receptor mediates erythroid and megakaryocytic cell development. Blood. 1999;94(10):3381-87.

Minamoto S, Treisman J, Hankins WD, Sugamura K, Rosenberg SA. Acquired erythropoietin responsiveness of interleukin-2-dependent T lymphocytes retrovirally transduced with genes encoding chimeric erythropoietin/interleukin-2 receptors. Blood. 1995;86(6):2281-7.

Mioni R, Gottardello F, Bordon P, Montini G, Forestqa C. Evidence for specific binding and stimulatory effects of recombinant human erythropoietin on isolated adult rat Leydig cells. Acta Endocrinol (Copenh). 1992;127:459-65.

Mirtsching B, Charu V, Vadhan-raj S, Colowick A, Rossi G, Tomita D, McGuire W. III. Every-2-week darbepoetin alfa is comparable to rHuEPO in treating chemotherapy-induced anemia. Oncology. 2002;16(Suppl):31-36.

Mirtsching BC, Beck JT, Charu V, Nazha NT, Tchekmedyian NS, et al. Darbepoetin alfa administered every two weeks (Q2W) reduces chemotherapy-induced anemia (CIA) to the same extent as recombinant human erythropoietin (rHuEPO) but with less-frequent dosing. Proc Am Soc Clin Oncol. 2003;22:2944.

Mittelman M, Neumann D, Peled A. Erythropoietin induces tumor regression and anti tumor immune responses in murine myeloma models. Proc Natl Acad Sci USA. 2001; 98:5181-6.

Mittelman M, Zeidman A, Fradin Z, Magazanik A, Lewinski UH, Cohen A. Recombinant human erythropoietin in the treatment of multiple myeloma-associated anemia. Acta Haematologica. 1997;98:204-10.

Mittelman M, Zeidman A, Kanter P, Katz O, Oster H, Rund D, Neumann D. Erythropoietin has an anti-myeloma effect-a hypothesis based on a clinical observation supported by animal studies. European Journal of Haematology. 2004;72:155-65.

Moebus V, Bastert G, Kreienberg R, Eidtmann H, Cierna M, Untch M, Jackish C, Kliniken S. Epoetin alpha prevents anemia and transfusions of Rbcs in patients (pts) receiving dose-dense sequential chemotherapy. Proc Am Soc Clin Oncol. 2001;20:abstract 36.

Moebus VJ, Untch M, DuBois A, Lueck HJ, Thomssen C, Kuhn W, Kurbacher C, Nitz U, Kreienberg R, Jackisch C. Dose-dense sequential chemotherapy with epirubicin (E), paclitaxel (T) and cyclophosphamide (C) (ETC) is superior to conventional dosed chemotherapy in high-risk breast cancer patients (=4+LN). First results of an AGO-trial. Journal of Clinical Oncology. 2004;22(14S):513.

Moertel CG, Frytak S, Hahn RG, O’Connell MJ, Reitmeir RJ, Rubin J, et al. Therapy of locally unrespectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads+5-fluorouracil), and high-dose radiation + 5-fluorouracil: the gastrointestinal tumor study group. Cancer. 1981;48(8):1705-10.

Mohr B, Herrmann, Huhn D. Recombinant human erythropoietin in patients with myelodysplastic syndrome and myelofibrosis. Acta Haematol. 1993;90:65-70.

Mohyeldin A, Lu H, Dalgard C. Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma. Neoplasia 2005;7:536-43.

Molica S. Erythropoietin Treatment of Anaemia Associated with Lymphoproliferative Disorders. Eur J Cancer. 1993;29A(Letters):1499-50.

Monreal M, Lafoz E, Ruiz J, Valls R, Alastrue A. Upper-extremity deep venous thrombosis and pulmonary embolism. A prospective study. Chest. 1991;99:280-3.

Moritz K, Lim G, Wintour E. Developmental regulation of erythropoietin and erythropoiesis. Am. J. Physiol. 1997;273:R1829–44.

Mortimer J, Bardwell W, Blair S, Podbelewicz-Schuller Y. Correlation between hemoglobin and quality of life in women undergoing adjuvant chemotherapy for breast cancer. Journal of Clinical Oncology. 2005;23(16S):590.

Moullet I, Salles G, Ketterer N, Dumontet C, Buoafia F, Niedhardt-Berard E, Thieblemont C, Feldman P, Coiffier B. Frequency and significance of anemia in non-Hodgkin's lymphoma patients. Ann Oncol. 1998;9:1109-15.

Mundle S, Lefebvre P, Duh MS, Bourezak A, Yektashenas B, Moyo V. Erythroid response (ER) rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa (EPO) or darbepoetin alfa (DARB) using international working group response criteria (IWGc): comparative meta-analysis. Blood. 2006;108(11):abstract#2672.

Munker R, Hasenclever D, Brosteanu O, Hiller E, Diehl V. Bone marrow involvement in Hodgkin’s disease: an analysis of 135 consecutive cases. German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 1995;13:403-9.

Muñoz-Langa J, Juan O, Olmos S, Albert A, Molins C, Caranana V, Almenar D, Campos JM, Bosch C, Alberola V. Once-weekly dosing of epoetin alfa are similar to three-times-weekly dosing to improve hemoglobin levels in chemotherapy patients: results from multicenter prospective cohort study. Journal of Clinical Oncology. 2005;23(16S):8161.

Murphy L, Cluck MW, Lovas S, Otvos F, Murphy R, Schally AV, Permert J, Larsson J, Knezetic JA, Adrian TE. Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions. British Journal of Cancer. 2001;84(7):926-35.

Murphy M, Wallington T, Kelsey P, Boulton F, Bruce M, Cohen H, Duguid J, Knowles S, Poole G, Williamson L, British Committee for Standards in Hematology. Guidelines for the clinical use of red cell transfusions. British Journal of Haematology. 2001;113:24–31.

Musto P, Falcone A, Carotenuto M. Granulocyte Colony-Stimulating Factor and Erythropoietin for the Anemia of Myelodysplastic Syndromes: A Real Improvement With Respect to Erythropoietin Alone? Blood. 1994;84(5):1687-8.

Musto P, Matera R, Minervini MM, Checchia-de Ambrosio C, Bodenizza C, Falcone A, Carotenuto M. Low serum levels of tumor necrosis factor and interleukin-1 ß in myelodysplastic syndromes responsive to recombinant erythropoietin. Haematologica. 1994;79:265-8.

Musto P, Modoni S, Alicino G, Savino A, Longo A, Bodenizza C, Falcone A, D’Arena G, Scalzulli P, Perla G, Casparrini G, and Carotenuto M. Modifications of Erythropoiesis in Myelodysplastic Syndromes Treated With Recombinant Erythropoietin As Evaluated By Soluble Transferrin Receptor, High Fluorescence Reticulocytes and Hypochromic Erythrocytes. Haematologica. 1994; 79;493-9.

Musto P, Scalzulli P, Carotenuto M. Recombinant Erythropoitin for Myelodysplastic Syndromes. British Journal of Haematology. 1995;91:256-7.

Musto P, Falcone A, D’Arena G, Scalzulli PR, Matera R, Minervini MM, Lombardi GF, Modoni S, Longo A, Carotenuto M. Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis. European Journal of Haematology. 1997;58:314-319.

Musto P, Sanpaolo G, D’Arena G, Scalzulli R, Matera R, Galcone A, Bodenizza C, Perla G, and Carotenuto M. Adding growth factors or interleukin-3 to erythropoietin has limited effects on anemia of transfusion-dependent patients with meylodysplastic syndromes unresponsive to erythropoietin alone. Haematologica. 2001;86:44-51.

Musto P, Falcone A, Sanpaolo G, Bodenizza C, LaSala A, Perla G, Carella AM. Efficacy of a single, weekly dose of recombinant erythropoietin in myelodysplastic syndromes. British Journal of Haematology. 2003;122:269-71.

Musto P, Lanza F, Balleari E, Grossi A, Falcone A, Sanpaolo G, Bodenizza C, Scalzulli PR, La Sala A, Campioni D, Ghio R, Cascavilla N, Carella AM. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. British Journal of Haematology. 2005;128:204-9.

Musto P, Falcone A, Sanpaolo G, Bodenizza C. Combination of erythropoietin and thalidomide for the treatment of anemia in patients with myelodysplastic syndromes. Leukemia Research. 2006;30:385-8.

Mystakidou K, Kalaidopoulou O, Katsouda E, Parpa E, Kouskouni E, Chondros C, Tsiastas ML, Vlahos L. Evaluation of epoetin supplemented with oral iron in patients with solid malignancies and chronic anemia not receiving anticancer treatment. Anticancer Research. 2005;25:3495-3500.

Nakamura Y, Komatsu N, Nakauchi H. A truncated erythropoietin receptor that fails to prevent programmed cell death of erythroid cells. Science. 1992;257:1138-41.

Nakamura N, Chin H, Miyasaka N, Muira O. An Epidermal Growth factor Receptor/Jak2 Tyrosine Kinase Domain Chimera Induces Tyrosine Phosphorylation of Stat5 and Transduces a growth Signal in Hematopoietic Cells. The Journal of Biological Chemistry. 2001;271:19483-19488.

Narhi L, Arakawa T, Aoki K, Elmore R, Rohde M, Boone T, Strickland T. The effect of carbohydrate on the structure and stability of erythropoietin. J Biol Chem. 1991;266:23022-6.

Narhi L, Aoki K, Philo J, Arakawa T. Changes in conformation and stability upon formation of complexes of erythropoietin (EPO) and soluble EPO receptor. J Protein Chem. 1997;16:213-25.

Narhi L, Arakawa T, Aoki K, Wen J, Elliot S, Boone T, Cheetham J. Asn to Lys mutations at three sites which are N-glycosylated in the mammalian protein that decrease the aggregation of Escherichia coli-derived erythropoietin. Protein Eng. 2001;14:135-40.

National Cancer Institute. http://ctep.cancer.gov/forms/ctcaed3.pdf [page 5]; accessed 4/9/07.

National Comprehensive Cancer Network www.nccn.org. www.nccn.org/professionals/physicians_gls/PDF/anemia.pdf. Accessed 4/5/07

A - National Institute for Health and Clinical Excellence (NICE). Final appraisal determination: Erythropoietin for anaemia induced by cancer treatment. 2006;March:1-23. www.guidance.nice.org.uk. Accessed 3/18/07.

B - National Institute for Health and Clinical Excellence (NICE). Appraisal of erythropoietin for anaemia induced by cancer treatment. Decision of the panel. 2006;September:1-31. www.guidance.nice.org.uk. Accessed 3/18/07.

Natori T, Sata M, Washida M, Hirata Y, Nagai R, Makuuchi M. G-CSF stimulates angiogenesis and promotes tumor growth: potential contribution of bone marrow-derived endothelial progenitor cell. Biochem Biophys Res Commun. 2002 Oct 4;297(4):1058-61.

Negrin R, Stein R, Vardiman J, Doherty K, Cornwell J, Krantz S, Greenberg P. Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin. Blood. 1993;82(3):737-43.

Negrin R, Stein R, Doherty K, Cornwell J, Vardiman J, Krantz S, Greenberg P. Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy. Blood. 1996;87(10):4076-81.

Nestel P, Davidsson L. Anemia, iron deficiency, and iron deficiency anemia. Reviewed by INACG Steering Committee. 2002.

Neumeister P, Jaeger G, Eibl M, Sormann S, Zinke W, Linkesch W. Amifostine in Combination with erythropoietin and G-CSF promotes multilineage hematopoiesis in patients with myelodysplastic syndrome. Leukemia and Lymphoma. 2001;40:345-9.

New York Times – Business Section. Sec asks Amgen about anemia drugs. 3/1/07. Accessed 3/2/07.

Nilsson KR, Berenholtz SM, Garrett-Mayer E, Dorman T, Klag MJ, Pronovost PJ. Association between venous thromboembolism and perioperative allogeneic transfusion. Arch Surg. 2007;142:126-32.

Norda R, Tynell E, Åkerblom O. Cumulative risks of early fresh frozen plasma, cryoprecipitate and platelet transfusion in Europe. The Journal of Trauma Injury, Infection, and Critical Care. 2006;60(6):S41-45.

Nordyke RJ, Chang C, Chiou C, Wallace JF, Yao B, Schwartzberg LS. Validation of a patient satisfaction questionnaire for anemia treatment, the PSQ-An. Health and Quality of Life Outcomes. 2006;4:28.

Notification to all users of practice guidelines (special announcement). Arch Pathol Lab Med. 2002;126:401.

Oberhoff C, Neri B, Amadori D, Petry K, Gamucci T, Rebmann U, Nowrousian M, Voigtmann R, Monfardini S, Armand J, Herrmann R, Netter-Pinon J, Tubiana-Mathieu N, Zwierzina H. Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study. Annals of Oncology. 1998;9:255-60.

Oberhoff C. Speed of haemoglobin response in patients with cancer: a review of the erythropoietic proteins. Support Care Cancer. 2006;15(6):603-11.

Obralic N, Bilenjki D, Bilbija Z. Prognostic importance of anemia related parameters in patients with carcinoma of the cervix uteri. Acta Oncol. 1990;29:199-201.

Oda K, Matsuoka Y, Funahashi A, Hiroaki K. A comprehensive pathway map of epidermal growth factor receptor signaling. MSB journal.2007; 1:1-2.

Oehler W, Fisher J, Merkle K. Does the initial hemoglobin value modify the primary tumor reaction? A study of 264 irradiated brochial cancers. Radiobiol Radiother (Berl). 1990;31:325-31.

Ogilvie M, Yu X, Nicolas-Metral V, Pulido S, Liu C, Ruegg U, Noguchi C. Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. J Biol Chem. 2000;275:39754-61.

Ohashi H, Maruyama K, Liu Y, Yoshimura A. Ligand-induced activation of chimeric receptors between the erythropoietin receptor and receptor tyrosine kinases. Proc Natl Acad Sci. 1994;91:158-62.

Oken M, Creech R, Tormey D, Horton J , Davis T, McFadden E, Carbone P. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.

Okuno Y, Takahashi T, Suzuki A, Ichiba S, Nakamura K, Hitomi K, Sasaki R, Imuro H. Expression of the erythropoietin receptor on a human myeloma cell line. Biochemical and Biophysical Research Communications. 1990;170(3):1128-34.

Olivieri A, Scortechini I, Capelli D, Montanari M, Lucesole M, Gini G, Troiani M, Offidani M, Poloni A, Masia MC, Raggetti GM, Leoni P. Combined administration of alpha-erythropoietin and filgrastim can improve the outcome and cost balance of autologous stem cell transplantation in patients with lymphoproliferative disorders. Bone Marrow Transplantation. 2004;34:693-702.

Olsson A, Svensson J, Sundström J, Bergström S, Edekling T, Carlsson G, Hansen J, Svensson B, Albertsson M. Erythropoietin treatment in metastatic breast cancer: Effects on hb, quality of life and need for transfusion. Acta Oncologica. 2002;41:517-24.

Olujohungbe A, Handa S, Holmes J. Does erythropoietin accelerate malignant transformation in multiple myeloma? Postgrad Med J. 1997;73:163-4.

O’Shaughnessy J. Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy. Clinical Breast Cancer. 2002;3(Suppl 3):S116-20.

O’Shaughnessy J, Vukelja S, Holmes F, Savin M, Jones M, Royall D, Geroge M, Von Hoff D. Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. Clinical Breast Cancer. 2005;5:439-46.

Oster HS, Hoffman M, Prutchi-Sagiv S, Katz O, Neumann D, Mittelman M. Erythropoietin in clinical practice: current use, effect on survival, and future directions. Isr Med Assoc J. 2006;8(10):703-6.

Ordóñez A, González-Barón M, Isla D, Sanchez A, Arrivi A, Manzano J. Epoetin beta treatment to prevent anemia in solid tumor patients receiving platinum-based chemotherapy. Journal of Clinical Oncology. 2005;23(16S):8230.

Österborg A, Boogaerts M, Cimino R, Essers U, Holowiecki J, Juliusson G, Jäger G, Najman A, Peest D for the European Study Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myeloma and Non-Hodgkin’s Lymphoma. Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-hodgkin’s lymphoma – a randomized multicenter study. Blood. 1996;87:2675-82.

Österborg A, Brandberg Y, Molostova V, Iosava G, Abdulkadyrov K, Hedenus M, Messinger D for the Epoetin Beta Hematology Study Group. Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin beta, in hematologic malignancies. J Clin Oncol. 2002;20:2486-94.

Österborg A, Brandberg Y, Hedenus M. Impact of epoetin-ß on survival of patients with lymphoproliferative malignancies: long-term follow up of a large randomized study. British Journal of Haematology. 2005;129:206-9.

Österborg AC, De Boer R, Clemens M, Renczes G, Kotasek D, Prausova J, Marschner N, Hedenus M, Hendricks L, Amado R. A novel erythropoiesis-stimulating agent (AMG114) with 131-hour half-life effectively treats chemotherapy-induced anemia when administered as 200 mcg every 3 weeks. Journal of Clinical Oncology. 2006;24(18S):8626.

Österborg A, Steegmann J, Hellmann A, Couban S, Mayer J, Eid J. Phase II study of three dose levels of continuous erythropoietin receptor activator (C.E.R.A.) in anaemic patients with aggressive non-Hodgkin’s lymphoma receiving combination chemotherapy. British Journal of Haematology. 2007;136:736-44.

Österborg A, Aapro M, Cornes P, Haselbeck A, Hayward CRW, Jelkmann W. Preclinical studies of erythropoietin receptor expression in tumour cells: impact on clinical use of erythropoietic proteins to correct cancer-related anaemia. European Journal of Cancer. 2007;43:510-9.

Pajonk F, Weil A, Sommer A, Suwinski R, Henke M. The erythropoietin-receptor pathway modulates survival of cancer cells. Oncogene. 2004;23:8987-91.

Panares R, Garcia A. Bevacizumab in the management of solid tumors. Expert Rev Anticancer Ther. 2007;7:433-45.

Pancreatic Cancer Research. Newsletter. “Pancreatic cancer, pancreas and cancer treatment. Accessed 2/21/07.

Papaldo P, Ferretti G, Di Cosimo S, Giannarelli D, Marolla P, Lopez M, Cortesi E, Antimi M, Terzoli E, Carlini P, Vici P, Botti C, Di Lauro L, Naso G, Nistico C, Mottolese M, Di Filippo F, Ruggeri E, Ceribelli A, and Cognetti F. Does Granuloctye Colony-Stimulating Factor Worsen Anemia in early Breast Cancer Patients Treated With Epirubicin any Cyclophosphamide? Journal of Clinical Oncology. 2006;24:3048-55.

Papatheofanis F, Fahrbach K, Mark TL, Chiang T, Frame D, Suruki Y, Scheye R, Drielick M, Nalysnyk L. A pooled analysis of observational data evaluating usage and clinical outcomes of erythropoietic agents. Journal of Clinical Oncology. 2004;22(14S):6144.

Pappalardo A, Giuffrida D, Castorina S, Russo A, Ponzio R, Rosario C, Marino O, Failla G. Epoetin alfa (100,000 U in 8 consecutive days) in treatment of anemic “home care” patients with advanced cancer. Proc Am Soc Clin Oncol. 2003;22:3160.

Paquette R, Gabrilove J, Lyons R, Mushtag C, Sekeres M, Lam H, Dreiling L. Darbepoetin alfa for treating anemia in low-risk myelodysplastic syndrome patients: interim results after 27/28 weeks. American Society of Clinical Oncology. 2006;24(18S):6564.

Pasqualetti P, Collacciani A, Casale R. Circadian rhythm of serum erythropoietin in myelodysplastic syndromes. European Review for Medical and Pharmacological Sciences. 2000;4:111-5.

Patrick D, Abels R, Larholt K, Krantz. Recombinant human erythropoietin (rHuEPO) for the treatment of the anemia of cancer. The Oncologist. 1996;1:140–50.

Patrick DL, Gagnon MJ, Mathijs R, Sweetenham J. European Journal of Cancer. 2003;

39:335-345. Assessing the clinical significance of health-related quality of Life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa. 2003; 39;335-345.

Patton J, Camp M, Kuzur M, Liggett W, Miranda F, Varsos H, Porter L. Epoetin alfa (Procrit) 60,000 U once-weekly followed by 120,000 U every three weeks to maintain hemoglobin levels in anemic cancer patients receiving chemotherapy. Proc Am Soc Clin Oncol. 2002;21:1469.

Patton J, Kuzur M, Liggett W, Miranda F, Varsos H, Porter L. Epoetin alfa 60,000 u once weekly followed by 120,000 u every three weeks maintains hemoglobin levels in anemic cancer patients receiving chemotherapy: final report. Proc Am Soc Clin Oncol. 2003;22:3033.

Patton JF, Sullivan T, Mun Y, Reeves T, Rossi G, Wallace JF. A retrospective cohort study to assess the impact of therapeutic substitution of darbepoetin alfa for epoetin alfa in anemic patients with myelodysplastic syndrome. Support Oncology. 2005;3(6):419-26.

Perillo A, Pierelli L, Scambia G, Serafini R, Paladini U, Salerno M, Bonanno G, Fattorossi A, Leone G, Mancuso S, Menichella G. Peripheral blood progenitor cell collection after epirubicin, paclitaxel, and cisplatin combination chemotherapy using EPO-based cytokine regimens: a randomized comparison of G-CSF and sequential GM-/G-CSF. Transfusion. 2001;41:674-80.

Perillo A, Ferrandina G, Pierelli L, Rutella S, Mancuso S, Scambia G. Cytokines alone for PBPC collection in patients with advanced gynecological malignancies: G-CSF vs G-CSF plus EPO. Bone Marrow Transplantation. 2004;34:743-44.

Peterson M, Mao Q, Schwartzberg LS, Fortner BV. Higher rates of early response needed with epoetin alpha (epo) and darbepoetin alpha in the community setting. Proc Am Soc Clin Oncol. 2003;22:3149.

Petti MC, Aloe-Spiriti MA, Latagliata R, Bertelletti DS, Jazlouk G, De Filice L, Valentini T, Villa RS, Mandelli F. Treatment of Myelodysplastic Syndromes (MDS) With Recombinant Human Erythropoietin (rHuEPO): Preliminary Clinical Results reported at the Second International Conference on Myelodysplastic Syndromes. April 90 to March 91, Page 33.

Phillips T, Li Y, Kim K, McBride WH, Pajonk F. Erythropoietin affects the number of CD24-/low/CD44+ breast cancer initiating cells. American Association for Cancer Research. 2007;Los Angeles: April14-18.

Pierelli L. Perillo A, Greggi S, Salerno G, Panici P, Menichella G, Fattorossi A, Leone G, Mancuso S, Scambia G. Erythropoietin addition to granulocyte colony-stimulating factor abrogates life-threatening neutropenia and increases peripheral-blood progenitor-cell mobilization after epirubicin, paclitaxel, and cisplatin combination chemotherapy: results of a randomized comparison. Journal of Clinical Oncology. 1999;17:1288-95.

Pierelli L, Menichella G, Scambia G, Teofili L, Iovino S, Serafini R, Panici P, Salerno G, Rumi C, Zini G, d’Onofrio G, Leone G, Mancuso S, Bizzi B. In vitro and in vivo effects of recombinant human erythropoietin plus recombinant human G-CSF on human haemopoietic progenitor cells. Bone Marrow Transplantation. 1994;14:23-30.

Pineo G, Regoeczi E, Hatton M, Brian M. The activation of coagulation by extracts of mucus: a possible pathway of intravascular coagulation accompanying adenocarcinomas. J Lab Clin Med. 1973;82:255-66.

Pirisi M, Fabris C, Soardo G, Cecchin E, Toniutto P, Bartoli E. Thrombocytopenia of chronic liver disease corrected by erythropoietin treatment. J Hepatol. 1994;21:376–80.

Pirker R, Vansteenkiste J, Gately J, Yates P, Colowick A, Musil J. A Phase 3, Double-blind, placebo-controlled, randomized study of novel erythropoiesis stimulating protein (NESP) in patients undergoing platinum treatment for lung cancer. Proc Am Soc Clin Oncol. 2001;20:1572.

Platanias L, Miller C, Mick R, Hart R, Ozer H, McEvilly J, Jones R, Ratain M. Treatment of chemotherapy-induced anemia with recombinant human erythropoietin in cancer patients. J Clin Oncol. 1991;9:2021-26.

Porter J, Leahey A, Polise K, Bunin G, Manno, C. Recombinant human erythropoietin reduces the need for erythrocyte and platelet transfusions in pediatric patients with sarcoma: a randomized, double-blind, placebo-controlled trial. Journal of Pediatrics. 1996;129:656-60.

Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol. 2005;6:401-10.

Pritchard K, Paterson A, Paul N, Zee B, Fine S, Pater J. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol. 1996;14:2731-7.

Pruneri G, Bertolini F, Soligo D, Carboni n, Cortelezzi A, Ferrucci PF, Buffa R, Lambertenghi-Deli G , Pezzella F. Angiogenesis in myeledysplastic syndromes. British Journal of Cancer. 1999;81: 1398-1401.

Prunier F, Pfister O, Hadri L, Liang L, del Monte F, Liao R, Hajjar RJ. Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells. Am J Physiol Heart Cir Physiol. 2007;292:H522-9.

The Pure Red Cell Aplasia Global Scientific Advisory Board (GSAB). Erythropoietin-induced, antibody-mediated pure red cell aplasia. Eur J Clin Invest. 2005;35(suppl 3):95-9.

Quirt I, Micucci S, Moran L, Pater J, Browman G. The role of recombinant human erythropoietin (EPO) in reducing blood transfusions and maintaining the quality of life (QOL) in patients with lymphoma and solid tumors requiring cytotoxic chemotherapy. Results of a randomized, double-blind, placebo-controlled clinical trial. Blood. 1996;88(10 Suppl 1):347A.

Quirt I, Robeson C, Lau C. Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. J Clin Oncol. 2001;19:4126–34.

Quirt I, Kovacs M, Couture F, Turner A, Noble M, Burkes R, Dolan S, Plante R, Lau C, Chang J, Camacho F. Patients previously transfused or treated with epoetin alfa at low baseline hemoglobin are at higher risk for subsequent transfusion: an integrated analysis of the Canadian experience. The Oncologist. 2006;11:73-82.

Rafanelli D, Grossi A, Longo G, Vannucchi AM, Bacci P, Ferrini PR. Recombinant human erythropoietin for treatment of myelodysplastic syndromes. Leukemia. 1992;6:323-7.

Ramakrishnan R, Cheung W, Wacholtz M, Minton N, Jusko W. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers. J Clin Pharmacol. 2004;44:991-1002.

Rankin E, Biju M, Liu Q, Unger T, Rha J, Johnson R, Simon M, Keith B, Haase V. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest. 2007;117:1068-77.

Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma[Letter to the editor]. New England Journal of Medicine. 2006;354(19):2079-80.

Razzano M, Caslini C, Cortelazzo S, Battistel V, Rambaldi A, Barbui T. Therapy With Human Recombinant Erythropoietin in Patients With Myelodysplastic Syndromes. British Journal of Haematology. 1992;81:628-30.

Razzano M, Caslini C, Cortelasso S, Battistel V, Rambaldi A, and Barbui T. Clinical and Biological Effects of Erythropoietin treatment of Myelodysplastic Syndrome. Leukemia and Lymphoma. 1993;10:127-34.

Razzouk BI, Hockenberry M, Hinds PS, Rackoff W, Hord JD. A double-blind, placebo-controlled study of once-weekly epoetin alfa in children with cancer undergoing myelosuppressive chemotherapy. Journal of Clinical Oncology. 2004;22(14S):8527.

Razzouk B, Hord J, Hockenberry M, Hinds P, Feusner J, Williams D, Rackoff W. Double-blind, placebo-controlled study of quality of life, hematologic end points, and safety of weekly epoetin alfa in children with cancer receiving myelosuppressive chemotherapy. J Clin Oncol. 2006;24:3583-89.

Rearden TP, Charu V, Saidman B, Ben-Jacob A, Justice GR. Results of a randomized study of every three-week dosing (Q3W) of chemotherapy-induced anemia (CIA). Journal of Clinical Oncology. 2004;22(14S):8064.

Reed W, Hussey D, DeGowin R. Implications of anemia of chronic disorders in patients anticipating radiotherapy. Am J Med Sci. 1994;308:9-15. Erratum in Am J Med Sci. 1994;308:288.

Reed N, Chan S, Hayward C, Burger H, Huinink WTB. Impact of epoetin beta on the survival of anemic patients with ovarian cancer receiving platinum-based chemotherapy. Journal of Clinical Oncology. 2005;23(16S):5102.

Reinhardt U, Tulusan A, Angermund R, Lutz H. Increased Hemoglobin Levels and Improved Quality–of-Life Assessments During Epoetin Alfa treatment in Anemic Cancer Patients :Results of a prospective, Multicenter German Trial. The Oncologist .2005; 10:225-237.

Rella C, Coviello M, Giotta F, Maiello E, Colavito P, Colangelo D, Quarenta M, Colucci G, Schittulli F. A prothrombotic state in breast cancer patients treated with adjuvant chemotherapy. Breast Cancer Res Treat. 1996;40:151-9.

Remacha AF, Arrizabalaga B, Villegas A, Mantiega R, Calvo T, Juliá A, Fuertes M, González FA, Font L, Juncá J, Del Arco A, Malcorra JJ, Equiza EP, Pérez de Mendiguren B, Romero M. Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification of a subgroup of responders. Haematologica. 1999;84:1058-64.

Remacha AF, Nomdedéu JF, Puget G, Estivilli C, Sarda MP, Canals C, Aventin A. Occurrence of the JAK2 V617F mutation in the WHO provisional entity: myelodysplastic myeloproliferative disease, unclassifiable refractory anemia with ringed sideroblasts associated with marked thrombocytosis. The Hematology Journal. 2006,91:719-20.

Reuters. ImClone soars after setback to rival Amgen drug. March 23, 2007.

Ribatti D. A potential role of Leukemia. 2002;16:1890-1.

Ribati D, Polimeno G, Vacca A Marzollo A, Crivellato E, Nico B, Lucarelli G, Dammacco F. Correlation of bone marrow angiogenesis and mast cells with tryptase in myelodysplastic syndromes. Leukemia..2002;16:1680-1684.

Ribatti D, Marzullo A, Nico B, Crivellato E, Ria R, Vacca A. Erythropoietin as an angiogenic factor in gastric carcinoma. Histopathology. 2003;42:246–50.

A-Ribatti D, Poliani P, Longo V, Mangieri D, Nico B, Vacca A. Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastoma. Histopathology. 2007;50:636-41.

B-Ribatti D, Marzullo A, Gentilli A, Longo V, Nico B, Vacca A, Dammacco F. Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma. Histopathology. 2007;50:591-6.

Richards S, Gibbs RA. A truncated erythropoietin receptor and cell death: a reanalysis. Science. 1994;264:588-9.

Rickles F, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res. 2001;102:V215-24.

Riely GJ, Politi KA, Miller VA, Pao W. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res. 2006;12(24):7232-41.

Rigolin GM, Porta MD, Ciccone M, Bugli AM, Bragotti LZ, Mauro E, Fraulini C, Rossi AR, Bardi A, Cuneo A, Castoldi G. British Journal of Haematology. 2004;126:501-7.

Rivkin S, Green S, Metch B, Cruz A, Abeloff M, Jewell W, Costanzi J, Farrar W, Minton J, Osborne C. Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a southwest oncology group study. J Clin Oncol. 1994;12:2078-85.

Rizzo J, Lichtin A, Woolf S, Seidenfeld J, Bennett C, Cella D, Djulbegovic B, Goode M, Jakubowski A, Lee S, Miller C, Rarick M, Regan D, Browman G, Gordon M. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol. 2002;20:4083-107.

Rizzo J, Lichtin A, Woolf S, Seidenfeld J, Bennett C, Cella D, Djulbegovic B, Goode M, Jakubowski A, Lee S, Miller C, Rarick M, Regan D, Browman G, Gordon M. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. Blood. 2002;100:2303-20.

Rodgriques JN, Dieguez JC, Prados D. Erythopoietin in the myelodysplastic syndromes: meta-analytical study. British Journal of Haematology. 1995;91:253-8.

Roger R, Fluck R, McMahon A, Raine A. Recombinant erythropoietin increases blood pressure in experimental hypertension and uraemia without change in vascular cytosolic calcium. Nephron.1996;73:212–8.

Roger S, Piper J, Tucker B, Raine A, Baker L, Kovacs I. Enhanced platelet reactivity with erythropoietin but not following transfusion in dialysis patients. Nephrol Dial Transplan. 1993;8:213–7.

Rogers J, Murgo A, Fontana J, Raich P. Chemotherapy for breast cancer decreases plasma protein C and protein S. J Clin Oncol. 1988;6:276.

Rogers S, Russell NH, Morgan AG. Effect of erythropoietin in patients with myeloma. Br J Med. 1990;301:667.

Rose E, Abels R, Nelson R, McCullough D, Lessin L. The use of r-HuEpo in the treatment of anaemia related to myelodysplasia (MDS). British Journal of Haematology. 1995;89:831-7.

Rosen F, Haraf D, Kies M, Stenson K, Portugal L, List M, Brockstein B, Mittal B, Rademaker A, Witt M, Pelzer H, Weichselbaum R, Vokes E. Multicenter randomized phase II study of paclitaxel (1-hour infusion), fluorouracil, hydroxyurea, and concomitant twice daily radiation with or without erythropoietin for advanced head and neck cancer. Clinical Cancer Research. 2003;9:1689-97.

Rosenzweig M, Bender CM, Lucke JP, Yasko JM, Brufsky AM. Increased thrombotic events in a clinical trial of erythropoietin (EPO) in metastatic breast cancer. Proc Am Soc Clin Oncol. 2002;21:1522.

Rosenzweig M, Bender C, Lucke J, Yasko J, Brufsky A. The decision to prematurely terminate a trial of R-HuEPO due to thrombotic events. J Pain Symp Manage. 2004;27:185-90.

Ross SD, Allen E, Henry DH, Seaman C, Sercus B, Goodnough LT. Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced anemia: a systematic review of the literature. Clinical Therapeutics. 2006;28:801-31.

Rossert J, Eckardt K. Erythropoietin receptors: their role beyond erythropoiesis. Nephrol Dial Transplan. 2005;20:1025-28.

Runde V, Aul C, Ebert A, Grabenhorst U, Schneider W. Sequential administration of recombinant human granulocyte-macrophage colony-stimulating factor and human erythropoietin for treatment of myelodysplastic syndromes. European Journal of Haematology. 1995;54:39-45.

Rushing DA, Einhorn LH, Wildgust M. Epoetin alfa 40,000 u once weekly significantly improves hemoglobin and quality of life in anemic colorectal cancer patients. Proc Am Soc Clin Oncol. 2003;22:3098.

Rytting M, Worth L, Jaffe N. Hemolytic disorders associated with cancer. Hematol Oncol Clin North Am. 1996;10:365-76.

Sakai H, Ohashi Y, Hirashima K, Saijo N. Once weekly epoetin beta to increase hemoglobin and improve quality of life in anemic cancer patients receiving chemotherapy: a randomized, double-blind, dose-finding study. Journal of Clinical Oncology. 2004;22(14S):8169.

Salmonson T, Danielson B, Wikstrom B. The pharmacokinetics of recombinant human erythropoietin after intravenous and subcutaneous administration to healthy subjects. Br J Clin Pharmacol. 1990;29:709-13.

Samantas E, Rigatos SK, Konstantinopoulou A, Vourli G, Siganaki M, Pectasides D, Pectasides M, Papakostas E, Karagianidis G, Aravantinos G. Darbepoetin alfa assessment in chemotherapy induced anemia. Journal of Clinical Oncology. 2006;24(18S):18617.

Sanders M, Sorba S, Dainiak N. Insulin-like growth factors stimulate erythropoiesis in serum-substituted umbilical cord blood cultures. Experimental Hematology. 1993;21:25-30.

Sanders MR, Lu H, Walker F, Sorba S, Dainiak N. The Raf-1 protein mediates insulin-like growth factor-induced proliferation of erythroid progenitor cells. Stem Cells. 1998;16:200-7.

Saphner T, Tormey D, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol. 1991;9:286-94.

Savonije J, Van Groeningen C, Van Bochove A, Pinedo H, Giaccone G. Early intervention with epoetin-alfa during platinum-based chemotherapy. Journal of Clinical Oncology. 2004;22(14S):8111.

Savonije J, van Groeningen C, van Bochove A, Honkoop A, van Felius C, Wormhoudt L, Giaccone G. Effects of early intervention with epoetin alfa on transfusion requirement, hemoglobin level and survival during platinum-based chemotherapy: Results of a multicenter randomized controlled trial. Eur J Cancer. 2005;41(11):1560-9.

Savonije J, van Groeningen C, Wormhoudt L, Giaccone G. Early intervention with epoetin alfa during platinum-based chemotherapy: an analysis of the results of a multicenter, randomized, controlled trial based on initial hemoglobin level. The Oncologist. 2006;11(2):206-16.

Savonije J, van Groeningen C, Wormhoudt L, Giaccone G. Early Intervention with epoetin alfa during platinum-based chemotherapy: an analysis of quality-of-life results of a multicenter, randomized, controlled trial compared with population normative data. The Oncologist. 2006;11:197-205.

Schiffer CA. Clinical issues in the management of patients with myelodysplasia. Hematology. 2006;205-10.

Schipper J, Henke M. Erythropoietin bei Karzinomen im Kopf-/Halsbereich? Laryngo-Rhino-Otol. 2004;83:292-7.

Schouten HC, Vellenga E, van Rhenen DJ, de Wolf J, Coppens P, Blijham GH. Recombinant human erythropoietin in patients with myelodysplastic syndromes. Leukemia. 1991;5(5):432-6.

Schreiber D, Kapp D. Axillary-subclavian vein thrombosis following combination chemotherapy and radiation therapy in lymphoma. Int J Radiat Oncol Bio Phys.1986;12:391-5.

Schwartz B, Edgington T. Immune complex-induced human monocyte procoagulant activity: a rapid unidirectional lymphocyte-instructed pathway. J Exp Med. 1981;154:892-906.

Schwartzberg L, Hesketh P, Rossi G, Tomita D, Colowick A, Glaspy J. Optimizing management of chemotherapy-induced anemia: a combined analysis of data using a darbepoetin alfa frontloading/maintenance approach. Proc Am Soc Clin Oncol. 2003;22:2945.

Schwartzberg L, Shiffman R, Tomita D, Stolshek B, Rossi G, Adamson R. A multicenter retrospective cohort study of practice patterns and clinical outcomes of the use of darbepoetin alfa and epoetin alfa for chemotherapy-induced anemia. Clinical Therapeutics. 2003;25:2781-96.

Schwartzberg L, Yee L, Senecal F, Charu V, Tomita D, Wallace J, Rossi G. A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. The Oncologist. 2004;9:696-707.

Schwartzberg L, Yee L, Senecal F, Charu V, Tomita D, Rossi G. Darbepoetin alfa (DA) 200 mcg every 2 weeks (Q2W) vs epoetin alfa (Epo) 40,000 U weekly (QW) in anemia patients (pts) receiving chemotherapy (ctx). Journal of Clinical Oncology. 2004;22(14S):8063.

Scott S, Boeve T, McCulloch T, Fitzpatrick K, Karnell L. The effects of epoetin alfa on transfusion requirements in head and neck cancer patients: a prospective, randomized, placebo-controlled study. The Laryngoscope. 2002;112:1221-29.

Seipelt G, Ottmann OG, Hoelzer D. Cytokine therapy for myelodysplastic syndrome. Hematology. 2000;7:156-60.

Selzer E, Wacheck V, Kodym R. Erythropoietin receptor expression in human melanoma cells. Melanoma Res. 2000;10:421–6.

Semrad T, O’Donnell R, Wun T, Chew H, Harvey D, Zhou H, White R. Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg. 2007;10:601-8.

Senecal F, Yee L, Gabrail N, Charu V, Tomita D, Rossi G, Schwartzberg L. Treatment of chemotherapy-induced anemia in breast cancer: results of a randomized controlled trial of darbepoetin alfa 200µg every 2 weeks versus epoetin alfa 40,000U weekly. Clinical Breast Cancer. 2005;6:446-54.

Shaib YH, Davila JA, El-Serag HB. The epidemiology of pancreatic cancer in the united states: changes below the surface. Aliment Pharmacol Ther. 2006;24(1):87-94.

Shapiro S, Gerson H, Rosenbaum H, and Merchav S. Characterization of Circulating Erythrocytes from Myelodysplastic Patients Treated with Recombinant Human Erythropoietin. Leukemia. 1993;7:1328-33.

Sharpe P, Desai Z, Morris T. Increase in mean platelet volume in patients with chronic renal failure treated with erythropoietin. J Clin Pathol. 1994;47:159–61.

Shasha D. The negative impact of anemia on radiotherapy and chemoradiation outcomes. Seminars in Hematology. 2001;38(3):8-15.

Shasha D, Harrison LB. Anemia treatment and the radiation oncologist: optimizing patient outcomes. Oncology. 2001;15(11):1486-96.

Shasha D, George M, Harrison L. Once-weekly dosing of epoetin-a increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy. Cancer. 2003;98:1072-79.

Shasha D, Homel P, Harrison LB. The additive effect of chemotherapy (CT) on the prevalence and severity of anemia of in cancer patients (pts) receiving curative-intent radiation therapy (RT). Proc Am Soc Clin Oncol. 2003;22:3188.

Shasha D, Henry DH. Hematopoietic response to extended dosing of epoetin alfa 60,000 U every 2 weeks in anemic cancer patients not receiving therapy: final results. Blood. 2006;108(11):3764.

Shasha D, Williams D. Weekly epoetin alfa treatment of anemia in patients with cancer not undergoing therapy. Journal of Supportive Oncology. 2006;4:129-35.

Shepherd J, Currie C, Sparling T, Krystal G, Eaves A. Erythropoietin Therapy of Myelodysplastic Syndromes. Blood. 1992;79:1891-3.

Shinjo K, Takeshita A, Higuchi M, Ohnishi K, Ohno R. Erythropoietin receptor expression on human bone marrow erythroid precursor cells by a newly-devised quantitative flow-cytometric assay. British Journal of Haematology. 1997;96:551-8.

Siemann DW, Bibby M, Dark g, Dicker A, Eskens F, Horsman M, Marme D, LoRusso P.

Differentiation and Definition of Vascular-Targeted Therapies. Clinical Cancer Research. 2005;11: 416-420.

Silberstein PT, Witzig TE, Sloan JA, Mailliard JA, Rowland Jr KM, Krook JE, Ghosh C, Steen PD, Loprinzi CL. Weekly erythropoietin for patients with chemotherapy induced anemia: a randomized, placebo-controlled trial in the North Central Cancer Treatment Group. Proc Am Soc Clin Oncol. 2002;21:1422.

Singh AK, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-98.

Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton J. Trends in the incidence of deep vein thrombosis and pulmonary embolism. Arch Intern Med. 1998;158:585-93.

Silvestris F, Salvino L, Tucci M, Vacca A, Dammacco F. Immunomodulation of T and B cell functions in multiple myeloma patients treated with combined erythropoietin and a-interferon therapy. International Journal of Clinical & Laboratory Research. 1995;25(2):79-83.

Silvestris F, Romito A, Fanelli P, Vacca A, Dammacco F. Long-term therapy with recombinant human erythropoietin (rHu-EPO) in progressing multiple myeloma. Annals of Hematology. 1995;70:313-18.

Sinclair AM, Todd MD, Forsythe K, Knox SJ, Elliott S, Begley CG. Expression and function of erythropoietin receptors in tumors. Cancer. 2007;110(3):477-488.

Skilling J, Rogers-Melamed I, Nabholtz, J. An epidemiologic review of anaemia in cancer chemotherapy in Canada. Proc European Conference Clin Oncol Cancer Nurs. (Paris) 1995;S813.

Skillings J, Rogers-Melamed I, Nabholtz J, Sawka C, Gwadry-Sridhar F, Moquin J, Rubinger M, Ganguly P, Burnell M, Shustik C, Dryer D, McLaughlin M, White D. An epidemiological review of red cell transfusions in cancer chemotherapy. Cancer Prev Control. 1999;3:207-12.

Smith RE, Meza L, Tchekmadyian S, Chan D, Jaiyesimi I, Fleishman A, Gayko U, Colowick A, Glaspy J. Open-label, phase I/II dose escalation study of NESP in patients with chronic anemia of cancer. Proc Am Soc Clin Oncol. 2001;20:1574.

Smith RE, Tchekmedyian S, Richards D, Klarnet J, Fleishman A, Gayko U, Heatherington A, Glaspy JA. Darbepoetin alfa effectively alleviates anemia in patients with chronic anemia of cancer: efficacy and pharmacokinetic results of a dose-escalation study. Proc Am Soc Clin Oncol. 2002;21:1465.

Smith KJ, Bleyer AJ, Little WC, Sane DC. The cardiovascular effects of erythropoietin. Cardiovascular Research. 2003;59:538-48.

Smith Jr R, Tchekmedyian N, Chan D, Meza L, Northfelt D, Patel R, Austin M, Colowick A, Rossi G, Glaspy J for the Aranesp 990111 Study Group. A dose- and schedule-finding study of darbepoetin alpha for the treatment of chronic anaemia of cancer. British Journal of Cancer. 2003;88;1851-58.

Snady H, Bruckner H, Cooperman A, Paradiso J,Kiefer L. Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma. An outcomes trial. Cancer. 2000;89(2):314-27.

Spiridonidis H, Brinkmann K, Gore K, Tannous RE, Gupta S. Evaluating the “effectiveness” of epoetin alfa in oncology. Proc Am Soc Clin Oncol. 2002;21:1482.

Spiriti MA, Latagliata R, Niscola P, Cortelezzi A, Francesconi M, Ferrari D, Volpe E, Clavio M, Grossi A, Reyes MT, Musto P, Mitra ME, Azzará A, Pagnini D, D’Arena G, Spadano A, Balleari E, Pecorari P, Capochiani E, De Biasi E, Perego D, Monarca B, Pisani F, Scaramella G, Petti MC. Impact of a new dosing regimen of epoetin alfa on quality of life and anemia in patients with low-risk myelodysplastic syndrome. Annals of Hematology. 2005;84:167-76.

Spivak J. Iron and the anemia of chronic disease. Oncology (Williston Park). 2002;16(9 Suppl 10):25-33.

Sriuranpong V, Park JI, Amornphimoltham P, Patel V, Nelkin BD, Gutkind JS. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracine stimulation of the interleukin 6/gp130 cytokine system. Cancer Research. 2003;63:2948-56.

Stasi R, Brunetti M, Bussa S, Conforti M, Di Giulio C, Crescenzi A, Terzoli E, Vecchione A, Pagano A. Response to recombinant human erythropoietin in patients with myelodysplastic syndromes. Clinical Cancer Research. 1997;3:733-9.

Stasi R, Brunetti M, Bussa S, Conforti M, Martin LS, La Presa M, Bianchi M, Parma A, Pagano A. Serum levels of tumour necrosis factor-a predict response to recombinant human erythropoietin in patients with myelodysplastic syndrome. Clinical and Laboratory Haematology. 1997;19:197-201.

Stasi R, Pagano A, Terzoli E, Amadori S. Recombinant human granulocyte-macrophage colony-stimulating factor plus erythropoietin for the treatment of cytopenias in patients with myelodysplastic syndromes. British Journal of Haematology. 1999;105:141-8.

Stasi R, Brunetti M, Terzoli E, Amadori S. Sustained response to recombinant human erythropoietin and intermittent all-trans retrinoic acid in patients with myelodysplastic syndromes. Blood. 2002;99:1578-84.

Stasi R, Amadori S. The Role of Angiogenesis in Hematologic Malignancies. Pathology Internationall. 2004;54: 2-3.

Stasi R, Brunetti M, Terzoli E, Abruzzese E, Amadori S. Once-weekly dosing of recombinant human erythropoietin alpha in patients with myelodysplastic syndromes unresponsive to conventional dosing. Annals of Oncology. 2004;15:1684-90.

Stasi R, Abruzzese E, Lanzetta G, Terzoli E, Amadori S. Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes. Annals of Oncology. 2005;16:1921-27.

Stasi R, Amadori S, Littlewood TJ, Terzoli E, Newland AC, Provan D. Management of cancer-related anemia with erythropoietic agents: doubts, certainties, and concerns. The Oncologist. 2005;10:539-54.

Stebler C, Tichelli A, Dazzi H, Gratwohl A, Nissen C, Speck B. High-dose recombinant human erythropoietin for treatment of anemia in myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria: a pilot study. Experimental Hematology. 1990;18:1204-8.

Steensma D, Witzig TE. Does treatment with recombinant human erythropoietin affect the survival of anemic patients with cancer? (commentary). Nature Clinical Practice Oncology. 2005;2(9):444-5.

Steensma D, Molina R, Sloan J, Nikecevich D, Schaefer P, Rowland Jr, K, Dentchev T, Novotny P, Tschetter L, Alberts S, Hogan T, Law A, Loprinzi C. Phase III Study of Two Different Dosing Schedules of Erythropoietin in Anemic Patients with Cancer. Journal of Clinical Oncology. 2006; 24: 1079-1089.

Stein R, Abels R, Krantz S. Pharmacologic doses of recombinant human erythropoietin in the treatment of myelodysplastic syndromes. Blood. 1991;78:1658-63.

Steinmetz HT, Fandel F, Hellmich M, Neise M, Aldaud A, Lerchenmüller C, Tsamaloukas A, Weiligmann C, Schmitz S. Evaluation of predictive factors for response to Darbepoetin Alfa (DA): A prospective study. Journal of Clinical Oncology. 2006;24(18S):18514.

Stenke L, Wallvik J, Celsing F, Hast R. Prediction of response to treatment with human recombinant erythropoietin in myelodysplastic syndromes. Leukemia. 1993;7(9):1324-7.

Steurer M, Sudmeier I, Stauder R, Gastl G. Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with darbepoietin-alpha. British Journal of Haematology. 2003;121:101-3.

Stohlawetz P, Dzirio L, Hergovich N. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood. 2000;95:2983–9.

Stone RM, Bernstein SH, Demetri G, Facklam DP, Arthur K, Andersen J, Aster JC, Kufe D. Therapy with recombinant human erythropoietin in patients with myelodysplastic syndromes. Leukemia Research. 1994;18:769-76.

Straus D. Epoeitin Alfa as a Supportive Measure in Hematologic Malignancies. Seminars in Hematology. 2002;39(suppl 3):25-31.

Straus D. Epoetin alfa therapy for patients with hematologic malignancies and mild anemia. Clin Lymphoma. 2003;4 (Suppl 1):S13-7.

Straus D, Testa M, Sarokhan B, Czuczman M, Tulpule A, Turner R, Riggs S. Quality-of-life and health benefits of early treatment of mild anemia. Cancer. 2006;107:1909-17.

Strauss H, Haensgen G, Dunst J, Hayward C, Koelbl H. Effects of anaemia correction with epoetin beta in patients with advanced cervical cancer and radiochemotherapy. Journal of Clinical Oncology. 2005;23(16S):5121.

Sue-Ling H, Johnston D, McMahon M, Philips P. Pre-operative identification of patients at high risk of deep venous thrombosis after elective major abdominal surgery. Lancet. 1986;1:1173-6.

Supino-Rosin L, Yoshimura A, Altaratz H, Neumann D. A cytosolic domain of the erythropoietin receptor contributes to endoplasmic reticulum-associated degradation. Eur. J. Biochem. 1999;263:410-9.

Svára F, Spicka I, Sulková S, Zabka J. Erythopoietin (r-HuEPO) for the treatment of anaemia in patients with multiple myeloma and end-stage renal disease[Letter to the editor]. Nephrology Dialysis Transplantation. 1995;10(12):2374-2375.

Svensson A. Application of a New Logic to Old Drugs; Angiogenesis Inhibition in Neuroblastoma. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine. 2003:1-33.

Sweeney P, Nicolae D, Ignacio L, Chen L, Roach III M, Wara W, Marcus K, Vijayakumar S. Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: final report of a randomized, open-labeled, phase II trial. British Journal of Cancer. 1998;77:1996-2002.

Sytkowski A, Feldman L, Zurbuch D. Biological activity and structural stability of N-deglycosylated recombinant human erythropoietin. Biochem Biophys Res Commun. 1991;176:698-704.

Takeshita A, Shinjo K, Higuchi M, Miyawaki S, et al. Quantitative expression of erythropoietin receptor (EPO-R) on acute leukaemia cells: relationships between the amount of EPO-R and CD phenotypes, in vitro proliferative response, the amount of other cytokine receptors and clinical programs. British Journal of Haematology. 2000;108:55-63.

Takeshita A, Shinjo K, Naito K, Ohnishi K, Higuchi M, Ohno R. Erythopoietin receptor in myelodysplastic syndromes and leukemia. Leukemia & Lymphoma. 2002;43(2):261-4.

Tam B, Wei K, Rudge J, Hoffman J, Holash J, Park S, Yuan J, Hefner C, Chartier C, Lee J, Jiang S, Niyak N, Kuypers F, Ma L, Sundram U, Wu G, Garcia J, Schrier S, Maher J, Johnson R, Yancopoulos G, Mulligan R, Kuo C. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nat Med. 200612:793-800. Epub 2006 Jun 25.

Tarabay G, Braly P, Baker JJ, Williams D, Waltzman RJ. Treatment of anemia with epoetin alfa 80,000 U QW in cancer patients receiving chemotherapy. Journal of Clinical Oncology. 2004;22(14S):8205.

Tarantolo S, Bouda DW. Early results from a novel treatment strategy for chemotherapy-related anemia: epoetin alfa 60,000 U SC QW induction followed by 60,000 U SC Q2W. Journal of Clinical Oncology. 2004;22(14S):8204.

Tas F, Eralp Y, Basaran M, Sakar B, Alici S, Argon A, Bulutiar G, Camlica H, Aydiner A, Topuz E. Anemia in oncology practice: relation to diseases and their therapies. Am J Clin Oncol. 2002;25:371-9.

Taylor J, McLaren M, Henderson I, Belch J, Stewart W. Prothrombotic effect of erythropoietin in dialysis patients. Nephrol Dial Transplant. 1992;7:235–9.

Taylor D, Yoka B, Kusumanto H, Meijer C, Mulder NH, Hospers G. A review on pro-and-antioangiogenic factors as targets of clinical intervention. Pharmacol Res. 2006;53(2):89-103.

Ten Bokkel Huinink WW, de Swart C, van Toom D, Morack G, Breed W, Hillen H, van der Hoeven J, Reed N, Fairlamb D, Chan S, Godfrey K, Kristensen G, van Tinteren H, Ehmer B. Controlled multicentre study of the influence of subcutaneous recombinant human erythropoietin on anaemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based chemotherapy. Medical Oncology. 1998;15:174-82.

Terpos E, Mougiou A, Kouraklis A, Chatzivassili A, Michalis E, Giannakoulas N, Manioudaki E, Lazaridou A, Bakaloudi V, Protopappa M, Liapi D, Grouzi E, Parharidou A, Symeonidis A, Kokkini G, Laoutaris NP, Vaipoulos G, Anagnostopoulos NI, Christakis JI, Meletis J, Bourantas KL, Zoumbos NC, Yataganas X, Viniou N. Prolonged administration of erythropoietin increases erythroid response rate in myelodysplastic syndromes: a phase II trial in 281 patients. British Journal of Haematology. 2002;118:174-80.

Thames W, Yao B, Scheifele A, Alley JL. Drug use evaluation (DUE) of darbepoetin alfa in anemic patients undergoing chemotherapy supports a fixed dose of 200 mcg Q2W given every 2 weeks (Q2W). Proc Am Clin Oncol. 2003;22:2196.

Thatcher N, De Campos E, Bell D, Steward W, Varghese G, Morant R, Vansteenkiste J, Rosso R, Ewers S, Sundal E, Schatzmann E, Stocker H. Epoetin alpha prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. British Journal of Cancer. 1999;80(3/4):396-402.

Thomas GM. Raising hemoglobin: an opportunity for increasing survival? Oncology. 2002;63(suppl 2):19-28.

Thomas H, McAdam K, Thomas R, Joffe J, Sugden E, Awwad S. Early intervention with epoetin alpha for treatment of anaemia and improvement of quality of life in cancer patients undergoing myelotoxic chemotherapy. Annals of Oncology. 2002;Vol 13 (Suppl 5):177#653P.

Thompson J, Gilliland D, Prchal J, Bennett J, Larholt K, Nelson R, Rose E, Dugan M, GM/EPO MDS Study Group. Effect of recombinant human erythropoietin combined with granulocyte/macrophage colony-stimulating factor in the treatment of patients with myelodysplastic syndrome. Blood. 2000;95(4):1175-9.

Throuvalas N, Antonadou D, Boufi M, Lavey R, Malamos N. Erythropoietin decreases transfusion requirements during radiochemotherapy. Proc Am Soc Clin Oncol. 2000;19:1558.

Throuvalas N, Antonadou D, Lavey R, Boufi M, Malamos N. Final results of a randomized phase II study evaluating the role of erythropoietin during radiochemotherapy for pelvic tumors. I.J. Radiation Oncology Biology Physics. 2004;60(1):S300.

Tilbrook PA, Bittorf T, Callus BA, Busfield SJ, Ingley E, Klinken SP. Regulation of the erythropoietin receptor and involvement of JAK2 in differentiation of J2E erythroid cells. Cell Growth & Differentation. 1996;7(4):511-20.

Tobu M, Iqbal O, Fareed D, Chatha M, Hoppensteadt D, Bansal V, Fareed J. Erythropoietin-induced thrombosis as a result of increased inflammation and thrombin activatable fibrinolytic inhibitor. Clinical and Applied Thrombosis/Hemostasis. 2004;10:225-32.

Tovari J, Gilly R, Raso E. Recombinant human erythropoietin alpha targets intratumoral blood vessels, improving chemotherapy in human xenograft models. Cancer Res. 2005;65:7186-93.

Toyoda T, Itai T, Arakawa T, Aoki K, Yamaguchi H. Stabilization of human recombinant erythropoietin through interactions with the highly branched N-glycans. J Biochem (Tokyo). 2000;128:731-7.

Trzonkowski P, Mysliwska J, Debska-Slizien A, Bryl E, Rachon D, Mysliwski A, Rutkowski B. Long-term therapy with recombinant human erythropoietin decreases percentage of CD152+ lymphocytes in primary glomerulonephritis haemodialysis patients. Nephrol Dial Transplant. 2002;17:1070-80.

Tsiara SN, Kapsali HD, Panteli K, Christou L, Bourantas KL. Preliminary results of amifostine administration in combination with recombinant human erythropoietin in patients with myelodysplastic syndromes. Journal of Experimental and Clinical Cancer Research. 2001;20:35-8.

Tsukuda M, Mochimatsu I, Nagahara T, Kokatsu T, Sawaki S, Kubota A, Furkawa M, Arai Y. Clinical application of recombinant human erythropoietin for treatments in patients with head and neck cancer. Cancer Immunol Immunother. 1993;36:52-56.

Tsukuda M, Yuyama S, Kohno H, Itoh K, Kokatsu T, Kokatsu S. Effectiveness of weekly subcutaneous recombinant human erythropoietin administration for chemotherapy-induced anemia. Biotherapy. 1998;11:21-25.

Turitto V, Weiss H. Red blood cells: their dual role in thrombus formation. Science. 1980;207:541–43.

Turitto VT, Weiss HJ, Baumgartner HR. The effect of shear rate of platelet interaction with subendothelium exposed to citrated human blood. Microvascular Research. 1980;19:352-65.

Urabe A, Mizoguchi H, Takaka F, Miyazaki T, Yachi A, Niitsu Y, Miura Y, Mutoh Y, Fujioka S, Nomura T, Toyama K, Kawato M, Kurokawa K, Yazaki Y, Onozawa Y, Togawa A, Mori M, Enomoto H, Ogawa M, Ikeda Y, Ohshima T, Aoki I, Shionoya S, Arimori S, Chiba S, Omine M, Saito H, Ohno R, Kodera Y, Hirabayashi N, Nakagawa M, Kasuga M, Niho Y, Etoh S, Takatsuki K, Araki K. Phase II clinical study of recombinant human erythropoietin on the anemia associated with multiple myeloma. Japan Society of Clinical Hematology. 1993;34(8):919-27.

Uppal NP, Griggs J. Incidence, timing and severity of anemia with dose dense breast cancer adjuvant chemotherapy. Journal of Clinical Oncology. 2005;23(16S):8264.

Urra JM, de la Torre M, Alcazar R, Peces R. Rapid method for detection of anti-recombinant human erythropoietin antibodies as a new form of erythropoietin resistance. Clinical Chemistry. 1997;43:848-9.

USA Today. Cancer Drug Avastin increases risk of stroke, heart attack. 2003.

USA Today. 3/11/07. Accessed 3/12/07.

Vadhan-Raj S. Recombinant human erythropoietin in combination with other hematopoietic cytokines in attenuating chemotherapy-induced multilineage myelosuppression: brief communication. Seminars in Hematology. 1996;33(1):16-8.

Vadhan-Raj S, Mirtsching B, Charu V, Terry D, Rossi G, Tomita D, McGuire W. Assessment of hematologic effects and fatigue in cancer patients with chemotherapy-induced anemia given darbepoetin alfa every two weeks. The Journal of Supportive Oncology. 2003;1(2):131-38.

Vadhan-Raj S, Schreiber F, Thomas LC, Gandhi J, Hong JJ, Gregory SA, Tomita D, Colowick A. Every-2-week darbepoetin alfa improves fatigue and energy rating scores in cancer patients (pts) undergoing chemotherapy. Proc Am Clin Oncol. 2003;22:2942.

Vadhan-Raj S, Skibber J, Crane C, Buesos-Ramos C, Rodriguez-Bigas , Feig B. Randomized, double-blind, placebo-controlled trial of epoetin alpha (Procrit) in patients with rectal and gastric cancer undergoing chemo-radiotherapy (CT/RT) followed by surgery: Early termination of the trial due to increased thrombo-embolic events (TEE). Blood. 2004;104(11):#2915.

Valera ET, Do Rosário Dias Latorre M, Mendes WL, Seber A, De Martino Lee ML, De Paula MJA, Loggetto SR, Velloso E, Niero-Melo L, Lopes LF. Treatment of pediatric myelodysplastic syndromes and juvenile myelomonocytic leukemia: the Brazilian experience in the past decade. Leukemia Research. 2004;28:933-9.

Van den Bosch J, van de werf P, Sleeboom H, Biesma B, Kerkhofs L, Mol J, Ten Velde G, Melissant C. Improvements in anemia management with epoetin alfa-a dutch survey. Journal of Clinical Oncology. 2005;23(16S):8126.

Van der Niepen P, Sennesael J, Verbeelen D. r-HuEPO treatment of anemia associated with multiple myeloma and ESRD[Letter to the editor]. Clinical Nephrology. 1993;39(2):113.

Van Kamp H, Prinsze-Postema T, Kluin P, Den Ottolander G, Veverstock G, Willemze R, and Fibbe W. Effect of subcutaneously administered human recombinant erythropoietin on erythropoiesis in patients with myelodysplasia. British Journal of Haematology. 1991;78:488-93.

Vannucchi AM, Grossi A, Bosi A, Rafanelli D, Statello M, Guidi S, Saccardi R, Rossi-Ferrini P. Effects of cyclosporine A on erythropoietin production by the human Hep3B hepatoma cell line. Blood. 1993;82(3):978-84.

Vannucchi AM, Grossi A, Rafanelli D, Statello M, Cinotti S, Rossi-Ferrini P. Inhibition of erythropoietin production in vitro by human interferon gamma. British Journal of Haematology. 1994;87:18-23.

Vansteenkiste J, Pirker R, Massuti B, Barata F, Font A, Fiegl M, Siena S, Gateley J, Tomita D, Colowick A, Musil J. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. Journal of the National Cancer Institute. 2002;94(16):1211-20.

Vansteenkiste J, Poulsen E, Rossi G, Glaspy J. Darbepoetin alfa: impact on treatment for chemotherapy-induced anemia and considerations in special populations. Oncology. 2002;16(10) (suppl):45-55.

Vansteenkiste J, Rossi G, Foote M. Darbepoetin alfa: a new approach to the treatment of chemotherapy-induced anemia. Expert Opin Biol Ther. 2003;3(3):501-8.

Vansteenkiste J, Tomita D, Rossi G, Pirker R. Darbepoetin alfa in lung cancer patients on chemotherapy: a retrospective comparison of outcomes in patients with mild versus moderate-to-severe anaemia at baseline. Support Care Cancer. 2004;12:253-62.

Varan A, Buyukpamukcu M, Kutluk T, Akyuz C. Recombinant human erythropoietin treatment for chemotherapy-related anemia in children. Pediatrics. 1999;103(2):pg # unknown.

Varricchio CG, Sloan JA. The need for and characteristics of randomized, phase III trials to evaluate symptom management in patients with cancer. Journal of National Cancer Institute. 2002;94(16):1184-5.

Vasu S, Seidler C, Field T, Emani S. Tumor-specific response rates to erythropoietin in chemotherapy-induced anemia in a community practice setting. Journal of Clinical Oncology. 2006;24(18S):18528.

Vekeman F, McKenzie RS, Watson S, Mody S, Lefebvre P, Piech CT, Duh MS. Comparison of red blood cell transfusion rates of epoetin alfa and darbepoetin alfa in an inpatient oncology setting. Journal of Clinical Oncology. 2006;24(18S):16002.

Vercammen E, Ludwig H, Liu K, Xiu L, Bowers P. Analysis of the effect of body weight on the efficacy and safety of epoetin alfa. Journal of Clinical Oncology. 2005;23(16S):8184.

Verhoef G, Zachee P, Ferrant A, Demuynch H. Selleslag D, and Boogaerts M. Recombinant Human Erythropoietin for the Treatment of Anaemia in the Myelodysplastic Syndromes. Second International Conference on Myelodysplastic Syndromes.

Verhoef GEG, Zachee P, Ferrant A, Demuynck H, Sellaslag D, Van Hove L, Deckers F, Boogaerts MA. Recombinant human erythropoietin for the treatment of anemia in the myelodysplastic syndromes: a clinical and erythrokinetic assessment. Annals of Hematology. 1992;64:16-21.

Verhoef GE, Demuynck H, Zachee P, Boogaerts MA. Myelodysplastic syndrome evolving into a myeloproliferative disorder: one disease or two? [Letter to the editor]. Leukemia. 1994;8(4):714-715.

Verma M. Pancreatic cancer epidemiology. Technology in Cancer Research & Treatment. 2005;4(3):295-301.

Vijayakumar S, Roach III M, Wara W, Chan S, Ewing C, Rubin S, Sutton H, Halpern H, Awan A, Houghton A, Quiet C, Weichselbaum R. Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: preliminary results of a randomized, open-labeled, phase II trial. International Journal of Radiation Oncology, Biology, Physics. 1993;26(4):721-29.

Villar A, Martinez J, Fuentes C, Cabezon M, Perez M, Espineira M, Hernandez R, Borque C, Martin J. The use of erythropoietin instead of transfusions to correct anemia in hyperfractioned chemoradiation of advanced head and neck cancer. Proceedings of the 43rd Annual ASTRO Meeting:367.

Vinh TT, Lewis BH, Yao B, Yim J. Initial experience with darbepoetin alfa in patients with myelodysplastic syndrome (MDS). Proc Am Soc Clin Oncol. 2003;22:2464.

Wagner L, Billups C, Furman W, Rao B, Santana V. Combined use of erythropoietin and granulocyte colony-stimulating factor does not decrease blood transfusion requirements during induction therapy for high-risk neuroblastoma: a randomized controlled trial. J Clin Oncol. 2004;22(10):1886-93.

Wagner W, Granetzny A, Hilejan L, Marra A, Koch OM, Krukemeyer MG, Wiedemann GJ. Hb-level stabilization with epoetin alfa in patients with advanced NSCLC undergoing concurrent neoadjuvant chemo-radiation therapy (phase III study). Journal of Clinical Oncology. 2006;24(18S):17110.

Wakao H, Chida D, Damen J, Krystal G, Miyajima A. A possible involvement of Stat5 in erythropoietin-induced hemoglobin synthesis. Biochem Biophys Res Commun. 1997;234:198-205.

Wallvik J, Stenke L, Bernell P, Nordahl G, Hippe E, Hast R. Serum erythropoietin (EPO) levels correlate with survival and independently predict response to EPO treatment in patients with myelodysplastic syndromes. European Journal of Haematology. 2002;68:180-6.

Walsh J, Bonnar J, Wright F. Study of pulmonary embolism and deep leg vein thrombosis after major gynecological surgery using labeled fibrinogen-phlebography and lung scanning. J Obstet Gynaecol Br Commonw. 1974;81:311-6.

Waltzman R. A randomized, active-control pilot trial of front-loaded dosing regimens of darbepoetin-alfa for the treatment of patients with anemia during chemotherapy for malignant disease (Correspondence). Cancer. 2004;100(7)1545-6.

Waltzman RJ, Fesen M, Justice GR, Croot C, Williams D. Epoetin alfa 40,000 U QW vs darbepoetin alfa 200 mcg Q2W in anemic cancer patients receiving chemotherapy: preliminary results of a comparative trial. Journal of Clinical Oncology. 2004;22(14S):8153.

Waltzman R, Croot C, Justice G, Fesen M, Charu V, Williams D. Randomized comparison of epoetin alfa (40,000 U Weekly) and darbepoetin alfa (200 µg Every 2 Weeks) in anemic patients with cancer receiving chemotherapy. Oncologist. 2005;10 (8):642-50.

Ward H, Kurnick J, Pisarczyk M. Serum levels of erythropoietin in anemias associated with chronic infection, malignancies, and primary hematopoietic disease. J Clin Investig. 1971;50:332-5.

Ward HP, Vautrin R, Swasdikul D. Effect of serum from myeloproliferative disorders. The Journal of Laboratory and Clinical Medicine. 1971;78(5):849.

Weitz I, Israel V, Liebman H. Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden. Cancer. 1997;79:2024-7.

Welch R, James R, Wilkinson P, Belli F, Cowan R. Recombinent human erythropoietin and platinum-based chemotherapy in advanced ovarian cancer. The Cancer Journal from Scientific American. 1995;1:261-66.

Weiss L, Rougier N, Blouin J, Kazatchkine MD, Lhotta K, König P. Hypocomplementaemia in a newborn caused by transplacental passage of maternal autoantibody with C3 nephritic factor (C3 NeF) activity[Letter to the editor]. Nephrology Dialysis Transplantation. 1995;10(12):2374.

Westenfelder C, Baranowski L. Erythropoietin stimulates proliferation of human renal carcinoma cells. Kidney Int. 2000;58:647–57.

Wesphal G, Niederberger E, Blum C. Erythropoietin and G-CSF receptors in human tumor cells: expression and aspects regarding functionality. Tumori. 2002;88:150-9.

Westphal G, Braun K, Debus J. Detection and quantification of the soluble form of the human erythropoietin receptor (sEpoR) in the growth medium of tumor cell lines and in the plasma of blood samples. Clin Exp Med. 2002;2:45-52.

Westphal G, Niederberger E, Blum C, Wollman Y, Knoch TA, Rebel W, Debus J, Friedrich E. Erythropoietin and G-CSF receptors in human tumor cells: expression and aspects regarding functionality. Tumori. 2002;88(2):150-9.

Whitaker BI, Sullivan M. The 2005 Nationwide Blood Collection and Utilization Survey Report. http://www.aabb.org/apps/docs/05nbcusrpt.pdf.

White R, Chew H, Zhou H, Parikh-Patel A, Harris D, Harvey D, Wun T. Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch Intern Med. 2005;165:1782-7.

Wilson C, Lambert H, Scott R. Subclavian and axillary vein thrombosis following radiotherapy for carcinoma of the breast. Clin Radiol. 1987;38:95-6.

Wimazal F, Jordan JH, Sperr W, Chott A, Dabbass S, Lechner K, Horny H, Valent P. Increased Angiogenesis in the Bone Marrow of Patients with Systemic Mastocytosis. American Journal of Pathology. 2002; 160:1639-1645.

Winearls C, Oliver D, Pippard M, Reid C, Downing M, Cotes P. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic dialysis. Lancet. 1986;2:1175-8.

Winkelmann J, Penny L, Deaven L, Forget B, Jenkins R. The gene for the human erythropoietin receptor: analysis of the coding sequence and assignment to chromosome 19p. Blood. 1990;76:24–30.

Witthuim B, Quelle F, Silvermoine O, Taolin Y, Tang B, Osamu M, Ihle J. F.JAK2 Associates with the Erythropoietin Receptor and is Tyrosine Phosphorylated and Activated following Simulation with Erythropoietin. 1993; 74:227-236.

Witzig T, Silberstein P, Loprinzi C, Sloan J, Novotny P, Mailliard J, Rowland K, ALberts S, Krook J, Levitt R, Morton R. Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol. 2005;23:2606-17.

World Health Organization (1994). Indicators and strategies for iron deficiency and anemia programs. Report of the WHO/UNICEF/UNU Consultation. Geneva, Switzerland, 6–10 December, 1993.

World Health Organization/United Nations University/UNICEF. Iron deficiency anemia, assessment prevention, and control: a guide for program managers. Geneva. WHO. 2001.

Wright G, Hanlon P, Amin K, Steenbergen C, Murphy E, Arcasoy M. Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB J. 2004;18:1031–3.

Wright J, Ung Y, Julian J, Pritchard K, Whelan T, Smith C, Szechtman R, Roa W, Mulrroy L, Rudinskina L, Gagnon B, Okawara G, Levine M. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007;25:1027-32. Epub 2007 Feb 20

Wun T, Law L, Harvey D, Sieracki B, Scudder S, Ryu J. Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin. Cancer. 2003;98:1514-20.

Wurnig C, Windhager R, Schwameis E, Kotz R, Zoubek A, Stockenhuber F, Kurz R. Prevention of chemotherapy-induced anemia by the use of erythropoietin in patients with primary malignant bone tumors (A double-blind, randomized, phase III study). Transfusion. 1996;36:155-59.

Xia K, Mukhopadhyay N, Inhorn R, Barber D, Rose P, Lee R, Narsimhan R, D’Andrea A, Griffin J, Roberts T. The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner. Proc Natl Acad Sci U S A. 1996;93:11681-6.

Yamada K, Murakami M, Okamoto Y, Okuno Y, Nakajima T, Kusumi F, Takakuwa H, Matsusue S. Treatment results of chemo-radiotherapy for clinical stage I (T1N0M0) esphogael carcinoma. I.J. Radiation Oncology Biology Physics. 2004;60(1):S300.

Yasuda Y, Masuda S, Chikuma M, Inoue K, Nagao M, Sasaki R. Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol Chem. 1998;273:25381–7.

Yasuda Y, Musha T, Tanaka H. Inhibition of erythropoietin signaling destroys xenografts of ovarian and uterine cancers in nude mice. Br J Cancer. 2001;84:836–43.

Yasuda Y, Fujita Y, Masuda S, Musha T, Ueda K, Tanaka H, Fujita H, Matsuo T, Nagao M, Sasaki R, Nakamura Y. Erythropoietin is involved in growth and angiogenesis in malignant tumors of female reproductive organs. Carcinogenesis. 2002;23:1797-805.

Yasuda Y, Fujita Y, Matsuo T. Erythropoietin regulates tumor growth of human malignancies. Carcinogenesis. 2003;24:1021-9. Erratum in: Carcinogenesis. 2003;24:1567.

Yilmaz D, Cetingul N, Kantar M, Oniz H, Kansoy S, Kavakli K. A single institutional experience: is epoetin alfa effective in anemic children with cancer? Pediatric Hematology and Oncology. 2004;21:1-8.

Yoshida Y, Anzai N, Kawabata H. Kohsaka Y, and Okuma M. Serial changes in endogenous erythropoietin levels in patients with myelodysplastic syndromes and aplastic anemia undergoing erythropoietin treatment. Annals of Hematology. 1993;66:175-80.

Zallinger-Thurn M, Krainer M, Budinsky AC, Brodowicz T, Sliutz G, Kainz C, Leodolter S, Zielinski CC. Initial hemoglobin levels as predictor for platinum-associated anemia. Proc Am Soc Clin Oncol. 2002;21:2539.

Zanjani E, Ascensao J, McGlave P, Banisadre M, Ash R. Studies on the liver to kidney switch of erythropoietin production. J. Clin. Invest. 1981;67:1183–8.

Zeigler ZR, Jones D, Rosenfeld CS, Shadduck RK. Recombinant human erythropoietin (rHuEPO) for treatment of myelodysplastic syndrome. Stem Cells. 1993;11:49-55.

Zhang W, Gordon M, Lenz H. Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies. Ann Med. 2006;38:545-51.

Zhu Y, D’Andrea AD. The molecular physiology of erythropoietin and the erythropoietin receptor. Curr Opin Hematol. 1994;1(2):113-8.

Zou S, Fujii K, Johnson S, Spencer B, Washington N, Iv EN, Musavi F, Newman B, Cable R, Rios J, Hillyer KL, Hillyer CD, Dodd RY. Prevalence of selected viral infections among blood donors deferred for potential risk to blood safety. Transfusion. 2006;46:1997-2003.

Zwezdaryk K, Coffelt S, Figueroa Y, Liu J, Phinney D, LaMarca H, Florez L, Morris C, Hoyle G, Scandurro A. Erythropoietin, a hypoxia-regulated factor, elicits a pro-angiogenic program in human mesenchymal stem cells. Exp Hematol. 2007;35:640-52.