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

Emerging safety concerns (thrombosis, cardiovascular events, tumor progression, reduced survival) have prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs). The initial scope of this national coverage analysis (NCA) was “non-renal” uses. Current non-renal indications for ESA use that are approved by the FDA are: cancer treatment related anemia (erythropoietin, darbepoetin), AZT-induced anemia in HIV-AIDS (erythropoietin only), and prophylactic use for select patients undergoing elective orthopedic procedures with significant expected blood loss (erythropoietin only) (Aranesp® drug label; Procrit® drug label). Because there is a preponderance of emerging data for ESA use in the oncology setting, the focus of the NCA will be ESA use in cancer and related conditions. The other non-renal uses may be addressed in future NCAs. We expect that our future reviews will also include the more adequately powered study of ESA use in spine surgery patients. In the interim, local Medicare contractors may continue to make reasonable and necessary determinations on all non-cancer and non-neoplastic conditions as well as other non-renal uses of ESAs.

CMS is seeking public comment on our proposed determination 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 of myelodysplasia
3. the anemia of myeloid cancers
4. the anemia associated with the treatment of myeloid cancers or erythroid cancers
5. the anemia of cancer not related to cancer treatment
6. any anemia associated with radiotherapy
7. prophylactic use to prevent chemotherapy-induced anemia
8. prophylactic use to reduce tumor hypoxia
9. patients with erythropoietin-type resistance due to neutralizing antibodies
10. patients with treatment regimens including anti-angiogenic drugs such as bevacizumab
11. patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor
12. anemia due to cancer treatment if patients have uncontrolled hypertension
13. patients with thrombotic episodes related to malignancy

We also propose that ESA treatment is only reasonable and necessary under specified conditions for the treatment of anemia in those types of cancer in which the presence of erythropoietin receptors on either normal tissue/cell lines or malignant tissue/cell lines has been reported in the literature. These cancer types include but are not necessarily limited to:

• bone (sarcoma),
• brain-neurologic,
• breast,
• cervical,
• colo-rectal,
• gastric,
• head-and-neck (squamous cell),
• hepatic,
• lung,
• lymphoma
• melanoma,
• multiple myeloma
• muscle including cardiac,
• ovarian,
• pancreatic (exocrine),
• prostate,
• retinal, and
• uterine.

For patients undergoing treatment for these cancers, we propose ESAs are reasonable and necessary with the following limitations:

1. the hemoglobin/hematocrit levels immediately prior to initiation of dosing for the month should be <9 g/dl/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 transfusion (The latter patients should be alerted to the increased potential for thrombosis and sequelae.) (We suggest that patients, especially those in the latter category, be alerted to the increased potential for thrombosis and sequelae.)
2. the maximum covered treatment duration is 12 weeks/year;
3. the maximum covered 4 week treatment dose is 126,000 units for erythropoietin and 630 μg for darbepoietin;
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;
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; and
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.

Local contractors may make reasonable and necessary determinations for all uses of ESA therapy for beneficiaries with cancer whose condition is not addressed above.

We are requesting public comments on this proposed determination pursuant to section 1862 as revised by 731 of the Medicare Modernization Act. In light of the issues discussed in our review of the evidence and serious safety concerns voiced in the May 10, 2007 FDA Oncologic Drugs Advisory Committee (ODAC) meeting we are also interested in public comment on whether coverage for ESA therapy for Medicare beneficiaries with cancer should occur only within appropriately designed clinical research studies where informed consent and safety monitoring can be assured. After considering the public comments and any additional evidence, we will make a final determination and issue a final decision memorandum.

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   
   
		LCDR Tara Turner, PharmD   
		Analyst   
   
		Elizabeth Koller, MD, FACE   
		Medical Officer   
   
		Shamiram Feinglass MD, MPH   
		Medical Officer   
   
Subject:		Proposed Coverage Decision Memorandum for the Use of Erythropoiesis Stimulating Agents in Cancer and Related Neoplastic Conditions   
   
Date:		May 14, 2007

I. Proposed Decision

Emerging safety concerns (thrombosis, cardiovascular events, tumor progression, reduced survival) have prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs). The initial scope of this national coverage analysis (NCA) was “non-renal” uses. Current non-renal indications for ESA use that are approved by the FDA are: cancer treatment related anemia (erythropoietin, darbepoetin), AZT-induced anemia in HIV-AIDS (erythropoietin only), and prophylactic use for select patients undergoing elective orthopedic procedures with significant expected blood loss (erythropoietin only) (Aranesp® drug label; Procrit® drug label). Because there is a preponderance of emerging data for ESA use in the oncology setting, the focus of the NCA will be ESA use in cancer and related conditions. The other non-renal uses may be addressed in future NCAs. We expect that our future reviews will also include the more adequately powered study of ESA use in spine surgery patients. In the interim, local Medicare contractors may continue to make reasonable and necessary determinations on all non-cancer and non-neoplastic conditions as well as other non-renal uses of ESAs.

CMS is seeking public comment on our proposed determination 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 of myelodysplasia
3. the anemia of myeloid cancers
4. the anemia associated with the treatment of myeloid cancers or erythroid cancers
5. the anemia of cancer not related to cancer treatment
6. any anemia associated with radiotherapy
7. prophylactic use to prevent chemotherapy-induced anemia
8. prophylactic use to reduce tumor hypoxia
9. patients with erythropoietin-type resistance due to neutralizing antibodies
10. patients with treatment regimens including anti-angiogenic drugs such as bevacizumab
11. patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor
12. anemia due to cancer treatment if patients have uncontrolled hypertension
13. patients with thrombotic episodes related to malignancy

We also propose that ESA treatment is only reasonable and necessary under specified conditions for the treatment of anemia in those types of cancer in which the presence of erythropoietin receptors on either normal tissue/cell lines or malignant tissue/cell lines has been reported in the literature. These cancer types include but are not necessarily limited to:

• bone (sarcoma),
• brain-neurologic,
• breast,
• cervical,
• colo-rectal,
• gastric,
• head-and-neck (squamous cell),
• hepatic,
• lung,
• lymphoma
• melanoma,
• multiple myeloma
• muscle including cardiac,
• ovarian,
• pancreatic (exocrine),
• prostate,
• retinal, and
• uterine.

For patients undergoing treatment for these cancers, we propose ESAs are reasonable and necessary with the following limitations:

1. the hemoglobin/hematocrit levels immediately prior to initiation of dosing for the month should be <9 g/dl/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 transfusion (The latter patients should be alerted to the increased potential for thrombosis and sequelae.) (We suggest that patients, especially those in the latter category, be alerted to the increased potential for thrombosis and sequelae.)
2. the maximum covered treatment duration is 12 weeks/year;
3. the maximum covered 4 week treatment dose is 126,000 units for erythropoietin and 630 μg for darbepoietin;
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;
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; and
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.

Local contractors may make reasonable and necessary determinations for all uses of ESA therapy for beneficiaries with cancer whose condition is not addressed above.

We are requesting public comments on this proposed determination pursuant to section 1862 as revised by 731 of the Medicare Modernization Act. In light of the issues discussed in our review of the evidence and serious safety concerns voiced in the May 10, 2007 FDA Oncologic Drugs Advisory Committee (ODAC) meeting we are also interested in public comment on whether coverage for ESA therapy for Medicare beneficiaries with cancer should occur only within appropriately designed clinical research studies where informed consent and safety monitoring can be assured. After considering the public comments and any additional evidence, we will make a final determination and issue a final decision memorandum.

II. Background

In this section, we describe the technological developments that gave rise to the use of genetically engineered (recombinant) erythropoietin and related ESAs. We then describe the anemia for which ESAs are prescribed in oncologic conditions, with an emphasis on solid tumors which constituted the majority of tumors in the studies upon which FDA approval was based. For purposes of this discussion, therapy for a medical condition includes treatment for the signs and symptoms of the underlying condition and treatment for the signs and symptoms of oncologic treatment. Though we have tried to simplify the discussion for the lay reader, the topic is scientifically complex and we believe that an overly simplistic treatment would ultimately be detrimental to the understanding of our review.

A. Biochemical Background

Erythropoietin is a 34-kDa glycoprotein produced primarily, but not exclusively, in the kidney and to a lesser extent in the liver (Dame 1998, Ebert 1999, Eckardt 1992, 2005, Jelkmann 2001, Koury 1991, Moritz 1997, Rankin 2007, Tam 2006, Zanjani 1981). The native protein is a 193 amino acid peptide sequence from which a 27 amino acid peptide leader sequence is removed from the N-terminus. An arginyl residue at the carboxyl terminus also appears to be cleaved during post-translation processing. The mature protein consists of a 165 amino acid backbone with 2 disulfide bonds, three N-linked carbohydrate chains, and one O-linked carbohydrate chain. The major side chains, sialated tetraantennary saccharides, contribute to in vivo stability (Elliott 1996, Faulds 1989, Narhi 1991, 1997, 2001, Sytkowski 1991, Toyoda 2000).

In the classic hormone pathway, erythropoietin regulates erythrocyte production by stimulating progenitor cell proliferation and differentiation in the bone marrow. Hypoxia plays a major role in the feedback loop (Ebert 1999). Erythropoietin activity is mediated through the erythropoietin receptor. The expression of erythropoietin receptors on erythroid progenitor cells is well known (Constantinescu 2003, D'Andrea 1989, 1991; Fraser 1988, Jones 1990; Winkelman 1990). Less well appreciated is the presence of erythropoietin receptors on other tissues including cardiac myocytes, macrophages, neurons, vascular endothelial cells (Anagnostou 1990, 1994; Digicaylioglu 1995; Haroon 2003; Lappin 2003, Masuda 1993; Wright 2004), and cancers/cancer cell lines (bone sarcoma, breast, cervical, colon, gastric, head-neck [squamous cell], hepatoblastoma, melanoma, ovarian, pediatric, renal, retinal, and uterine (Acs 2001, 2002, 2003; Arcasoy 2003, 2005; Batra 2003; Farrell 2004, Fraser 1989; Henke 2006, Jones 1990, Kumar 2006, Lappin 2003, Masuda 1993, Mioni 1992, Ogilvie 2000 Ribatti 2003; Selzer 2000; Westenfelder 2000; Yasuda 2001, 2006). Also less well understood is the role erythropoietin appears to play in angiogenesis (blood vessel formation) in wounds and the female reproductive tract (Haroon 2003; Yasuda 1998). Tumors differ in the extent of erythropoietin receptor and erythropoietin expression (Lai 2005). Metastatic tumors may express erythropoietin receptors and erythropoietin to a greater extent than primary tumor (Lai 2005). Erythropoietin, through its receptor, appears to activate several signaling pathways that are operational in cancer JAK-STAT (Janus kinase-Signal Transducer and Activator of Transcription), MAPK (mitogen-activated protein kinase), NFk B (nuclear factor-kappa B), and PI3K-Akt (phosphatidylinositol 3-kinase-Akt) (Barber 1994, 1997, Bittorf 2001, Constantinescu 2003, Kumar 2006, Lai 2005, Lester 2005, Linnekin 1992, Mohyeldin 2005, Xia 1996)

Several forms of recombinant human erythropoietin have been developed (Table 1). They differ in their carbohydrate structure. The most common species are erythropoietin-alpha and beta (Deechongkit 2006, MacDougall 2002). The pharmacokinetic half-life of these products is 6 to 8 hours after IV injection (Halstenson 1991). Because the pharmacodynamic response on the bone marrow is prolonged, dosing regimens vary from 3 times weekly to once weekly. Peak serum levels are higher with the weekly dosing regimens (Cheung 1998, 2001, FDA Procrit Clinical Pharmacology Review 2004, Kryzanski 2005, Ramakrishnan 2004). Dosing via the intravenous route may require 10 to 25% more drug for the same hematologic effect compared to subcutaneous administration (Kaufman 1998, McMahon 1990, Salmonson 1990). The erythropoietin molecule has been modified by the addition of 2 N-linked carbohydrate chains to form darbepoietin. The additional sialic acid residues decrease pharmacokinetic clearance by the body and permit weekly and semi-weekly dosing (MacDougall 1999). More recently, the erythropoietin molecule has been modified by the addition of a methoxy-poly-ethylene glycol polymer chain (pegylation) via a succinimidyl butanoic acid linker (MacDougall 2003, 2005). These changes further decrease pharmacokinetic clearance by the body and permit weekly and even monthly dosing (MacDougall 2005). Although the molecular modifications decrease the affinity of the compound for the erythropoietin receptor in vitro, the increased residence time results in increased exposure of the compound to the erythropoietin receptor and increased erythropoietin-type activity in vivo (MacDougall 2003).

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, and prophylactic use during the peri-operative period to reduce the need for allogenic blood transfusions (Aranesp label, Danna 1990, Fischl 1990, Laupacis 1993, Procit label). Exploratory work for ESA use treating the anemia of solid tumors and the chemotherapy-induced anemia of hematologic cancers has been undertaken (Dammacco 2002, Gagnon 2003, Patrick 1996, Quirt 2001, Straus 2003)

Table 1: Erythropoiesis Stimulating Agents

B. Disease Summary

Anemia occurs with varying degrees of frequency and severity in cancer. It is most frequent in genitourinary, gynecologic, lung, and hematologic malignancies (Barrett-Lee 2006, Groopman 1999, Ludwig 2004, Moullet 1998, Tas 2002). Anemia may be directly related to cancer (type, stage) or to its treatment (type, dose). Co-morbid conditions as well as age can aggravate the anemia (Lipschitz 1995).

Oncologic anemia occurs by a variety of mechanisms (Birgegard 2005, Mercadante 2000). Poor oral intake or altered metabolism may reduce nutrients (folate, iron, vitamin B-12) essential for the proliferation and differentiation of erythroid progenitor cells (Borelli 2007). Antibodies in chronic lymphocytic leukemia (CLL), lymphoma, and some solid tumors may cause increased erythrocyte destruction through hemolysis (Rytting 1996). 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 (Munker 1995, Skilling 1995). In more advanced cases, there is marrow replacement with tumor or amyloid. Marrow dysfunction can occur, however, even in the absence of frank invasion (Faquin 1992, Mikami 1998). Inflammatory cytokines 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 erythroid progenitor proliferation (Faquin 1992, Miller 1990, Spivak 2002, Ward 1971).

The treatment of cancer may also cause anemia (Barrett-Lee 2000, 2006, Coiffier 2001, Harrison 2000, Ludwig 2004, Skilling 1999). 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 (Girdwood 1976, Horiguchi 2000).

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% 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 (Murphy 2001). 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 with probably higher than 7 g/dl. The College of American Pathologists (CAP) no longer issues transfusion practice guidelines although they have done so in the past (CAP 2002).

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 (WHO 1994, 2001). 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 Proposed Decision Memorandum. Currently, Medicare payment for ESAs for end-stage renal disease (ESRD) related anemia is outlined in the Medicare Benefit Policy Manual, 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. ESAs fall within the benefits categories specified in 1861(s)(2)(A) & 1861(s)(2)(B) of the Social Security Act.

IV. Timeline of Recent Activities

March 14, 2007
CMS opened an internally generated National Coverage Decision (NCD) to to evaluate coverage of uses of ESAs in non-renal disease applications.

The initial 30-day comment period began.

April 13, 2007
The public comment period closed; 69 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 2 ESAs were approved for the management of the anemia of cancer treatment (chemotherapy) of non-myeloid neoplastic disease: erythropoietin (1993) and darbepoietin (2002).

B.     The 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.    The 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 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.     The FDA strengthened its warning about cardiovascular and thrombotic events in a variety of populations via a BLACK BOX warning. The FDA included BLACK BOX warnings for tumor progression and decreased survival in cancer patients undergoing cancer treatment. The 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.

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

A. Introduction

We are providing a summary of the evidence that we considered during our review. We will, of course, consider additional evidence submitted through the public comment period.

Emerging data suggest that ESAs are associated with increased mortality and morbidity despite the alleviation of anemia. The evidence reviewed in this NCA includes the literature on ESA therapy in cancer and focuses on the safety considerations. Most of the studies address the use of ESAs for the treatment or prophylactic management of cancer therapy-related anemia. Select studies address the use of ESAs to treat tissue hypoxia in cancer and thereby attempt to improve response to cancer treatment. Still other studies addressed the use of ESAs in cancer patients without clinically significant anemia. Because of the nature of the findings, literature sources other than the standard medical journals were used when necessary.

B. Discussion of evidence reviewed

1. Questions

Outcomes

We preface our consideration of the questions with a discussion of the evidence regarding appropriate outcomes (endpoints) for trials of ESA treatment. Because of concern about serious adverse effects including death, we are focusing on evidence of morbidity and mortality. Most trials have enrolled subjects with a variety of underlying diseases, especially in the trials of cancer where multiple cancer types are represented by the subjects. In light of evidence that the ESA effect may vary by cancer type, it is possible that trials may dilute and thereby underestimate the effect of ESA usage in some cancers.

We are concerned that a number of trials have been terminated, suspended, or otherwise not completed, possibly due to signals of harm, and that the existing fund of published evidence may reflect a bias toward ESA use. For example, the Securities and Exchange Commission (Atlanta bureau) is reported to be investigating Amgen for failure to disclose to investors until 2/2007 that a Danish study of darbepoietin use in head-and-neck cancer was terminated in 10/2006 for safety reasons. The SEC request was disclosed in the annual report recently filed with the Agency (NY Times 3/1/07; USA Today 3/11/07).

CMS, as a public health agency, is aware that many clinical trials are statistically powered for efficacy and not for safety. The absence of adverse events in a setting of potential harm with an absence of adequate safety data cannot be interpreted as proof of no harm.

ESA use may impact a beneficiary in many ways. Thus, we believe that the broad questions above are appropriately addressed by reviewing the evidence for the following questions:

1. Do ESAs (individually or as a class) cause morbidity and mortality?
2. Do ESAs contribute to morbidity and mortality?
3. Are morbidity and mortality related to baseline hemoglobin/hematocrit levels, achieved hemoglobin/hematocrit levels, rate of change in hemoglobin/hematocrit levels, dose levels, or stratified hematologic response to dosages?
4. Are morbidity and mortality with ESAs associated with certain cancers?
5. Do ESAs negatively interact with certain cancer treatments?
6. Do comorbidities common in the Medicare population, such as ischemic disease and congestive heart failure, contribute to this putative morbidity and mortality?

2. External Technology Assessments

We are aware of several external assessments of ESAs and describe them below briefly.

National Institute for Health and Clinical Excellence (NICE)

In 3/2006, the National Institute for Health and Clinical Excellence in the United Kingdom issued a final appraisal determination for “Erythropoietin for Anemia Induced by Cancer Therapy” (Nice, 2006 ). This was followed by an Appeals Panel that convened in 6/2006 (Nice, 2006 B). The Cochrane Collaboration, an independent, international, not-for-profit organization that prepares and disseminates systematic reviews of healthcare interventions and promotes the search for evidence, prepared an analysis for NICE (Bohlius, 2007). NICE concluded that “Erythropoietin is recommended for use in the management of anaemia only as part of ongoing or new clinical trials that are constructed to generate robust and relevant data in order to address the gaps in the currently available evidence as outlined in Section 5.” Research is needed to confirm the benefits and risks associated with erythropoietin in the management of anaemia induced by cancer treatment (specifically mortality benefits and risks) and to identify patient subgroups (including those with different tumour types) in whom the possible risks are acceptable.”

Cochrane Collaboration

(See above.)

Agency for Healthcare Research and Quality (AHRQ)

The AHRQ analysis was structured to assess comparative efficacy for the two FDA approved ESAs, erythropoietin and darbepoetin (BC-BS contract #29020026). The authors concluded that there were not definitive data to indicate that ESA use improved tumor response to treatment and that enhancement of tumor progression was uncertain. The authors indicated that none of the studies, including the unpublished work presented by pharmaceutical sponsors at the 2004 ODAC meeting were designed to test survival.

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. 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 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 erythropoietin and darbepoetin as well as the FDA safety data for erythropoietin and darbepoetin. CMS reviewed the transcripts and briefing documents (FDA and pharmaceutical sponsor) from the 2004 FDA Oncologic Drug Advisory Committee meeting on ESA safety. CMS reviewed the FDA ESA drug safety alerts and label changes. CMS searched the National Institutes of Health 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.

Keywords used in the searches included: erythropoietin and survival, darbepoietin and survival, epoetin and survival, erythropoietin and mortality, darbepoietin and mortality, epoetin and mortality, erythropoietin and thrombosis, darbepoietin and thrombosis, epoetin and thrombosis, erythropoietin and tumor progression, darbepoietin and tumor progression, epoetin and tumor progression, erythropoietin and cardiovascular, darbepoietin and cardiovascular, and epoetin and cardiovascular.

Despite an exhaustive search, we identified no high quality, randomized clinical trials that were of sufficient duration and powered to definitely determine the risk of adverse events including death, tumor progression, and cardiovascular-thromboembolic events in cancer patients, particularly geriatric cancer patients, using ESAs. No trials were structured to assess these hard endpoints in patients with different cancers, cancers at various stages, cancers treated with different modalities or drugs, variable ESA dose responses, and variable comorbidities. We did identify one high quality published trial that was structured to assess locoregional progression (Henke 2003). It did adjust for baseline tumor stage, but was not powered to assess risk for the various tumor stages. Also, in this study, erythropoietin was employed to putatively enhance radiotherapy through a reduction in hypoxia and not to just alleviate anemia. We did identify multiple studies that were terminated for safety reasons. Most of these were never published as full-length articles in Medline journals.

A. Registration Trials

The clinical trials of ESAs that were submitted for FDA approval (registration) were of relatively short duration (12-16 weeks) and focused on non-survival endpoints, specifically reduction of the need for transfusion, change in hemoglobin, and quality-of-life. [Table 2A and 2B in Appendix B]. Many were very small and assessed heterogenous patient populations, primarily those with solid tumors. Indeed the initial erythropoietin approval was based on a composite of 72 non-platinum chemotherapy treated patients from 3 studies and a composite of 59 platinum chemotherapy treated patients from 3 studies in which the primary endpoint, transfusions, was not attained. In a post hoc analysis, transfusions were reduced during the 2nd and 3rd months of treatment. Furthermore, the data from the most extensive blinded, placebo controlled studies of lymphoproliferative disease (darbepoetin #20000161) submitted to the FDA was not included in the FDA label. In addition, the inclusion critieria for most studies included an expected lifespan of at least 3-6 months or an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or less (ECOG website, Aranesp Medical Officer Review 2002, 2006, Procrit 1993 FDA Summary basis of approval, Procrit 2004 Medical Officer Review). Significant cardiac disease and hypertension were generally excluded. As such, these studies were not structured to assess mortality and more chronic morbidity. Of note, however, a FDA integrated summary of safety for darbepoetin performed with pooled data from 7 studies suggested that fluid overload is more common in oncologic patients on either darbepoetin (n=975) or erythropoietin (n=115) than placebo (n=221) and that a rapid rise in hemoglobin may be associated with fluid overload, hypertension, and thrombosis.

B. Early Promising Studies

Three early studies by Glaser et al. and Littlewood et al. and Antonadou et al. suggested that ESA therapy might contribute to improved survival and tumor control (Antonadou et al., Glaser 2001, Littlewood 2001). The first was a retrospective review of a small population (n=191) of head-and-neck cancer patients who underwent surgical resection after external beam radiation and adjuvant chemotherapy (mitomycin and 5-flourouracil) (Glaser 2001). Patients were stratified by tumor stage, baseline hemoglobin, and use of erythropoietin. A pre-treatment hemoglobin level of 14 g/dl or greater portended a better prognosis than lower levels. Patients with hemoglobin levels under 14.5 g/dl who were treated with erythropoietin (150 U/kg TIW) had greater likelihood of survival (50/57) than those who did not receive erythropoietin (52/87; p=0.001). Loco-regional control was also better (p=0.001). This study was complicated by the lack of randomization.

The second study was a prospective, blinded study in 375 patients with a variety of cancers who were randomized to erythropoietin (150 U/kg TIW) or placebo for up to 28 weeks (Littlewood 2001). The dose could be doubled in poor responders. The primary endpoint was the fraction of patients who received transfusions after 4 weeks of ESA treatment. The study was later amended to include survival. The follow-up period was 12 months after the last patient completed the study. There was a trend towards improved survival in the erythropoietin group: 37% vs 33%; p=0.13. The median survival was 17 months in the erythropoietin group vs 11 months in the placebo group. The study was complicated by a high drop-out rate (159 of 375), the absence of a treatment protocol for patients with iron deficiency, variable doses, variable duration of follow-up, and the admixture of tumors. The solid tumors were comprised primary of breast and gastrointestinal tumors whereas the hematologic tumors included chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and multiple myeloma. Survival was greater in patients with hematologic cancers.

The third study was a prospective study in 385 patients with pelvic malignancies treated with radation (Antonadou 2001). Patients were randomized to erythropoietin or placebo. The primary endpoints were changes in hemoglobin and local tumor control. The secondary endpoints included disease-free survival and overall survival. Reportedly disease-free survival at 4 years was better in the erythropoietin group. Unfortunately, this study has only been published as an abstract despite its completion in 2000 or 2001. As such there are many outstanding questions about the study’s design, e.g., inclusion-exclusion criteria, blind status, drug dose escalation, stratification by disease and stage, treatment duration, follow-up strategy, power calculations, and statistical plan, as well as study results, e.g. baseline characteristics, drop-out rate, and intent-to-treat analyses.

A fourth study, by Vansteenkiste et al., was constructed to assess a 50% reduction in the proportion of patients with at least 1 transfusion during week 5 until the end of the 12 week double-blind, placebo-controlled, treatment phase in anemic patients (hemoglobin ≤ 11 g/dl) randomized to darbepoetin (2.25 mcg/kg/wk initial dose; 4.5 mcg/kg/wk in poor responders) or placebo (Vansteenkiste 2002). Patients were followed for another 4 weeks and then for another unspecified duration. The manuscript reports that survival and tumor progression did not differ by treatment cohort as of 8/2001, a mean duration of follow-up of 1 year. Criteria for follow-up and drop-out rates during this phase of the trial were not reported. Publications of future planned analyses could not be located.

C. Other Published Trials

More than 100 papers on ESA use in cancer and related disorders 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 variety of tumor stages. Many studies included patients on a variety of chemotherapy or radiation treatment regimens. Many of the studies were not randomized, double-blind placebo controlled trials. Active control with another ESA was common. Most studies did not employ fixed ESA doses; instead doses could be titrated upwards in poor responders. Concomitant iron administration was sometimes limited to patients in the ESA cohort. Study endpoints were generally hemoglobin thresholds, changes in hemoglobin, transfusion requirements (without a protocol defining transfusion requirement), or quality-of-life. Many studies did not declare a primary endpoint. Survival and/or tumor progression were secondary or add-on endpoints. No studies presented a priori power calculations for the numbers of patients and the study duration required to show a clinically significant survival difference for the specified neoplastic disease. No studies presented a priori methods for assessment of tumor progression. Any putative risk was presumed not to vary by tumor type or stage, treatment modality, ESA dose, or ESA response to dose. (See Table 3 in Appendix)

D. Terminated Trials

Emerging data suggest that ESA use may be associated with increased morbidity and mortality. The events are not limited to any single pharmacologic agent, to any specific tumor, or to concomitant use with any single therapeutic regimen (Table 4). Complete data from these studies are lacking. Several of these studies were initiated in response to phase 4 commitments to the FDA because of concerns about tumor progression and mortality. Available data are delineated below.

Table 4: Terminated Trials

Non-small Cell Lung Cancer, Receiving Chemotherapy, Pegylated Erythropoietin β
(Hoffmann-LaRoche Funding) (FDA Alert)

A prospective, 4-arm, dose-finding trial was conducted in anemic Stage III or IV non-small cell lung cancer patients undergoing first-line chemotherapy. Pegylated erythropoietin was titrated to achieve hemoglobin levels between 11 and 13 g/dl. The study was terminated after enrollment of 153 patients because of increased mortality in the experimental treatment arms.

Breast Cancer, Receiving Chemotherapy, Erythropoietin α
(Ortho Biotech/Johnson & Johnson Funding)

(Published letter and paper- Leyland-Jones 2003 and 2005) (FDA review-2004)

This prospective, placebo-controlled, randomized, non-U.S. study (Breast Cancer Erythropoietin Trial [BEST] [EPO-INT-76]) (n=939) in minimally anemic (hemoglobin ≤ 13 g/dl) metastatic breast cancer patients, who were on first line chemotherapy/hormone (but not homogeneous) therapy and whose disease was stratified for metastasis location, was structured for survival analysis. These patients with ECOG scores ≤ 2 received erythropoietin (40,000-60,000 U/week) or placebo for 12 to 24 weeks to achieve target hemoglobin levels 12-14 g/dl (Oken 1982). Enrollment began in 2000. The treatment arms were well balanced with regard to baseline demographic features, tumor-related characteristics, and hematologic values. (Only 21% of the study population was 66 or older; 4% 76 or older, and 2% from minority groups.) A data safety monitoring board was instituted 1/2002 at the behest of German and British ethics committees. An unplanned interim analysis and eventually trial termination resulted. 59% of hemoglobin values in erythropoietin treated patients were within target vs 45% in placebo treated patients. The erythropoietin cohort experience decreased survival at 12 months: 70% vs 76% (p= 0.012) (Table 5). The increased mortality occurred primarily during the first 4 months. Most of the early deaths were attributable to early disease progression: 6% vs 3%. Others were attributable to vascular and thrombotic events: 1% vs 0.2%. Persistently low hemoglobin levels portended reduced survival regardless of treatment cohort. Reportedly, an analysis of cardiovascular/thrombotic events and absolute hemoglobin levels could not be undertaken because of insufficient data. The principal investigator criticized the study for its inability to collect data on potential prognostic variables (Leyland-Jones 2003). More complete study results were published in 2005 (Leyland-Jones 2005). Its results prompted the FDA 2004 ODAC meeting.

Table 5: Death Profile in BEST

Breast Cancer, Receiving Chemotherapy, Erythropoietin α
(Ortho Biotech/Johnson & Johnson Funding) (Published article-Rosenzweig et al. 2004)

Mildly anemic (hemoglobin <12 g/dl) metastatic breast cancer patients were randomized to usual care or usual care plus open-label subcutaneous erythropoietin for a 12 week study. The initial dosing was 40,000 U per week. At week 4, if the hemoglobin had not increased by at least 1 g/dl, the dose was increased by 50%. If patients continued to be unresponsive to erythropoietin at week 8, the drug was discontinued. The trial was terminated by the investigators after recruitment of only 27 patients when 4 thrombotic events (deep vein thrombosis, pulmonary embolism with deep vein thrombosis, pulmonary embolism with deep vein thrombosis 1 month after drug discontinuation, and brachial vein thrombosis with an infected Mediport) occurred in the experimental arm. In addition, hypertension contributed to the discontinuation by 1 patient in the erythropoietin cohort. Disease progression was similar for the 2 treatment arms (Rosenzweig 2004).

Colon Cancer, Receiving Immunotherapy, Darbepoietin α
(Amgen Funding) (Press release)

Colon cancer patients treated with Vectibix (panitumumab, the human monoclonal antibody directed against epidermal growth factor receptor) (but not chemotherapy or radiotherapy) and darbepoetin-alfa) experienced decreased survival within 16 weeks. The need for transfusion did not differ between those who received darbepoietin and those who did not.

Head-and-neck Cancer, Receiving Radiotherapy, Darbepoietin α
(Amgen Funding)
(Danish Head and Neck Cancer Group website publication:conman.au.dk/dahanca)

Advanced stage head-neck cancer patients treated with radiotherapy and randomized to open-label darbepoietin (vs placebo) in the Danish Head and Neck Cancer 10 Study (N=600 planned, 522 randomized, 516 eligible, 484 with sufficient study time for interim analysis) experienced worse clinical outcomes despite target hemoglobin levels of 14.0 to 15.5 g/dl during radiation therapy. Loco-regional disease progression was greater at 3 years (p=0.01). Overall mortality also tended to be greater (p=0.08). The findings were thought to be significant enough to result in trial termination. Studies on erythropoietin receptor tissues numbers will be undertaken 5/2007. It should be noted that this study was conducted to fulfill a phase 4 commitment to the FDA for the study of tumor progression and survival. Before the trial was terminated, a report to the FDA was originally due 9/2008.

Head-and-neck Cancer, Receiving Radiotherapy, Erythropoietin α
Drug supplied by Ortho Biotech)
(Non-Medline published abstract-Machtay et al. 2004; RTOG 99-03 website)

The study was an international, prospective, randomized, phase III NCI study (PR99-03-046) to assess the role of erythropoietin (40,000 U/wk SQ x 8-9 weeks) in anemic patients (hemoglobin <12.5 g/dl in women and ,13.5 g/dl in men) with Stage I-IV head-and-neck cancer treated with radiotherapy. The hypothesis was that reduction of hypoxia with an erythrocyte stimulating agent would enhance radiosensitivity. Concomitant platin therapy was not mandated, but permitted. The endpoint was death or local-regional failure (persistent or recurrent disease in the primary tumor or regional nodes). An interim analysis was prompted by the Henke study (Henke 2003). There was a trend towards a less favorable outcome in patients in the erythropoietin arm, but statistical significance was not reached. The investigators, the Radiation Therapy Oncology Group, suspended study enrollment in 11/2003 after entering 148 of 372 planned patients. Erythropoietin dosing was immediately discontinued. The investigators recognized the statistical power losses introduced by the early termination.

Head-and-neck Cancer, Receiving Radiotherapy, Erythropoietin β
(Hoffman LaRoche Funding) (Published article- Henke et al. 2003)

Three hundred fifty-one advanced head-neck squamous cell cancer patients with mild anemia (hemoglobin <12 g/dl [women]; <13 g/dl [men]) were randomized to erythropoietin-beta (300 U/kg TIW) or placebo prior to and during radiotherapy (60 or 70 Gy) in a prospective, blinded, randomized, placebo controlled study (MF-4449; ENHANCE) (n=351) by Henke et al. The erythropoietin group experienced more local progression over time (relative risk: 1.69; p=0.007) and reduced survival (relative risk: 1.39; p=0.02) than those who did not receive erythropoietin. This pattern was present regardless of tumor resection status, and occurred despite anemia correction. Eighty-two percent of patients on erythropoietin vs only 26% of patients on placebo achieved hemoglobin levels >15 g/dl (men) or >14 g/dl (women). Prognosis was in part related to hemoglobin concentration at baseline and response to fixed dose therapy, i.e., 300 u/kg/TIW during radiation. Patients on erythropoietin also appear to experience more vascular disorders (hypertension, hemorrhage, venous thrombosis and pulmonary embolism, and cerebrovascular disease) (11% vs 5%). Of the 15 cardiac deaths, 10 occurred in the erythropoietin treatment arm.

Gastric/Rectal Cancer, Receiving Chemo-radiotherapy then Surgery, Erythropoeitin α
(Johnson & Johnson Funding)
(Published Non-Medline Abstract-Vadhan-Raj et al. 2004)
(Johnson & Johnson FDA briefing document)

Patients with rectal or gastric cancer with hemoglobin levels 10 to <15 g/dl were randomized to erythropoietin 40,000 U/wk or placebo in a double-blind, prospective, double-blind study in which patients underwent chemo (fluoropyramide)-radiotherapy prior to surgical resection. If the hemoglobin remained below 13 after 4 weeks, the dose was increased by 50%. The study was terminated because of increased thrombo-embolic-vascular events. Data were reportedly available for 59 of the planned 184 patients. Eleven percent (6/53) of the events occurred in patients with rectal cancer; 33% (2/6) occurred in patients with gastric cancer. Twenty-one percent (6/28) of events (primarily serious deep vein thromboses) occurred in patients on epoetin; 6% (2/31) occurred in patients on placebo. Twenty-one percent (7/35) of patients with hemoglobin levels in excess of 13 g/dl experienced; 4% (1/24) occurred in patients with lower levels. The small numbers preclude more extensive analysis.

Lung Cancer, Receiving Chemo-radiotherapy, Erythropoeitin α
(Johnson & Johnson Funding) (Briefing document for FDA meeting)

This study was a double-blind, randomized, placebo-controlled study (EPO-CAN-15) in which patients with limited small cell lung cancer treated with combined chemo- radiotherapy were randomized 1:1 to erythropoietin (40,000 U/wk). The initial treatment target was hemoglobin levels 14-16 g/dl. This was later lowered to 13-14 g/dl. The study appears to have been terminated following thrombo-embolic-vascular events and related deaths. Data were reportedly available for 106 of the planned 620 patients. Nineteen events occurred in the epoetin arm (albeit 2 prior to treatment); 3 occurred in the placebo arm. Four of the epoetin patients with thrombo-embolic-vascular events died. Fourteen of sixteen patients with thrombo-embolic-vascular events were randomized when the hemoglobin target level was 14-16 g/dl. The small numbers preclude more extensive analysis.

Breast Cancer, Receiving Chemotherapy & Later Radiation, Erythropoietin α
(Ortho Biotech/Johnson & Johnson Funding)
(Published paper- Grote et al. 2005)

A prospective, double-blind trial (N93-004) was conducted in small cell lung cancer patients who were to receive up to 12 cycles of chemotherapy; at least 3 of these being etoposide/cis-platinum. Radiation therapy could be added after the third chemotherapy cycle. Patients were randomized to placebo or erythropoietin α 150 U/kg TIW during and for 3 weeks after the completion of chemotherapy. Because the study was to fulfill a 1993 phase 4 safety commitment to the FDA, patients were to be followed for an additional 3 years. The study was structured as a non-inferiority trial. Tumor responses were categorized as complete remission, partial remission, no response, or disease progression. The study was reportedly terminated at 224 of 400 because of slow enrollment. It should be noted that a divergence in survival, in favor of placebo, could be noted at 16-20 months and persisted. With the truncated enrollment, this finding did not reach statistical significance.

The 2004 ODAC Briefing Document and transpscripts were initially available as an internal pharmacologic industry document: Vercammen E, Sullivan D, Matone P. The effect of r-HuEPO in patients with small cell lung cancer (SCLC): A randomized, double-blind, placebo-controlled trial. Protocol N93-004; Phase 4. Document ID No. EDMS-USRA-8057829:4.0. Sept. 26, 2002. This information was later presented in the 2004 J&J ODAC briefing document and at the meeting (2004 ODAC briefing document & transcript). There was no subsequently published study by this author in Medline (Accessed 4/9/07). There is a publication by Grote et al. that describes this study (Grote 2005).

Non-small Cell Lung Cancer, Not Receiving Chemotherapy, Erythropoietin α
(Funded by Ortho Biotech/Johnson & Johnson Funding)
(Briefing document for FDA meeting) (FDA Alert)

A prospective, double-blind, placebo controlled trial (EPO-CAN-20) was conducted in anemic non-small cell lung cancer patients not undergoing chemotherapy. Erythropoietin was titrated to achieve hemoglobin levels between 12 and 14 g/dl. The endpoint was quality of life. Planned enrollment was 300 patients. Study enrollment was terminated after 70 patients because of increased mortality in the experimental treatment arm. The median time-to-death was shorter in the erythropoietin cohort: 68 days vs 131 days; p=0.04. The increased mortality was attributed primarily to disease progression. Quality of life and the need for transfusion were not better in the erythropoietin arm. Reportedly enrollment was terminated in 12/2003. Preliminary results were included in the briefing document, but apparently FDA was not notified of additional study analyses until 2/2007.

Assorted Cancers, Not Receiving Chemotherapy, Darbepoietin
(Funded by Amgen)
(Press release; American Association for Cancer Research Annual Meeting Webcast)

Patients (N=989) with a variety of active cancers, including hematologic cancers, who were anemic (hemoglobin <11 g/dl), but were not undergoing myelosuppressive chemotherapy or radiotherapy, were randomized to darberpoietin or placebo in a 16 week, double-blind trial with follow-up. Patients were to have a life expectancy greater than 4 months and an ECOG score of 2 or less. There was stratification by entry hemoglobin (<10 g/dl or ≥10 g/dl). The primary endpoint was transfusion rate between weeks 5 to 17. Other endpoints included hemoglobin change and quality of life. The patients receiving darbepoietin did not receive fewer transfusions (18% vs 24%; p=0.15, although reportedly fewer patients on darbepoetin would have met the protocol criteria for transfusions. Patients experienced more mortality (136/515 vs 94/470; p<0.05 CI1.04-1.51). The statistical significance in the preliminary analysis reportedly decreased with adjustments for baseline and prognostic characteristics, but still did not favor the ESA. Subgroup analysis suggested that the results varied by tumor. Reportedly the rate of hemoglobin increase, whether induced by drug or not, did not correlate with survival outcome. Poor response rate may have some predictive value. Thrombotic events were somewhat greater in the darbepoetin group (9.7% vs 7.7%). It should be noted that this study was conducted to fulfill a phase 4 commitment to the FDA for the study of tumor progression and survival. A report to the FDA is due 10/2007.

Cervical Cancer, Receiving Chemotherapy & Radiotherapy, Erythropoeitin α
(Funded by Johnson & Johnson) (Briefing document for FDA meeting)

An open-label randomized study (PR01-04-005/GOG-0191) in which patients with cervical cancer treated with concomitant radiotherapy and cisplatin and with hemoglobin levels <14 g/dl were randomized to receive erythropoietin (40,000 U/wk). The dose was increased 50% in poor responders after 4 weeks. The study appears to have been terminated because of excess numbers of thrombo-embolic-vascular events. Data were reportedly available for 79 of the planned 460 patients. 17% (10/58) of events (primarily venous thromboses) occurred in patients on epoetin; 9% (5/55) occurred in patients on placebo. The small numbers preclude more extensive analysis.

E. Ongoing Studies

We identified 17 reportedly ongoing studies in patients with non-myeloid cell line tumors (16 solid tumors, 1 large B cell lymphoma, 1 chronic lymphocytic leukemia) (Table 5). Despite the antiquated start dates for many of the studies, we were unable to locate Medline publications as of 3/28/07. One study investigator, however, has published a discussion paper on the subject. Several studies were initiated as phase 4 commitments to the FDA. Several studies, but not all, are registered with Clinical Trials.gov.

Table 6: Ongoing Studies

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

A MEDCAC meeting was not convened for this issue.

5. Evidence Based Guidelines/Professional Society Position Published Statements

a. American Society of Hematology (ASH)
Guidelines for ESA use in cancer patients were issued in conjunction with the American Society for Clinical Oncology. They are available as a 2002 publication by Rizzo et al. (Rizzo 2002). The Society has indicated that “Since the publication of this guideline, the product labeling for erythropoiesis stimulating agents has been significantly revised based on emerging safety data.” The Society directs site users to the 3/9/ 2007 FDA alert via a web link.

b. American Society for Clinical Oncology (ASCO)
Guidelines for ESA use in cancer patients were issued in conjunction with the American Society of Hematology. They are available as a 2002 publication by Rizzo et al. via request from the Society (Rizzo 2002). The Society has indicated that “Since the publication of this guideline, the product labeling for erythropoiesis stimulating agents has been significantly revised based on emerging safety data.” The Society directs website users to the FDA website.

c. National Comprehensive Cancer Network (NCCN)
The National Comprehensive Cancer Network issued updated guidelines from 2/2006 in 1/2007 and 2/2007. Additional revisions are underway. Identification of non-cancer related causes of anemia and appropriate treatment is promoted. It states that cancer-related fatigue is multifactorial, that anemia is only one of the causes, and that this is an active area of investigation. It states that the relationship between anemia and treatment outcome is poorly characterized. It recommends assessment of clinical risk before initiating treatment and determining treatment targets. It acknowledges that “high risk” patients are poorly characterized and that there is a paucity of prospective data regarding their management. It encourages ESA discontinuation in poor responders and dose lowering in brisk responders. Most recently, it has strengthened its warnings about ESA-associated thrombosis based on the meta-analysis by Bohlius et al. and noted the paper’s identification of a trend towards reduced survival (Bohlius 2006). It also recommended that physicians not use ESAs in cancer patients with anemia not due to concurrent chemotherapy if the patients are similar to those enrolled in the Amgen trial. The NCCN “believes that the best management of any patient is in a clinical trial. Participation in clinical trials is especially encouraged.”

d. European Organization for Research and Treatment of Cancer (EORTC)
The European Organisation for Research and Treatment of Cancer last prepared an update for ESA use in 2006 prior to the emergence of new data (Bokemeyer 2006/7).

7. Public Comments

We received 66 topical 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.

Finally, several commenters requested that CMS delay rendering a proposed decision until after the FDA Oncology Drug Advisory Committee (ODAC) meeting scheduled for May 11, 2007. Commenters suggested that CMS review the literature and data distributed at the ODAC meeting prior to rendering the proposed decision. CMS' final decision will be published after the ODAC meeting. CMS will as usual consider additional timely evidence furnished after the publication of the proposed decision.

8. Expert Opinion

CMS has solicited external expert opinion and anticipates receiving responses before the publication of the final decision memorandum.

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:

In the classic paradigm, physiologic replacement of a missing hormone should result in normalization. Indeed many, albeit not all, patients with end-stage renal disease 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 the non-classic paradigm, 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 classic paradigm of 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 thrombo-embolic-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 patient heterogeneous populations with a mixture of primarily solid tumors at various stages and undergoing treatment with a variety of regimens. (See tables 2A and 2B.) The relative risks and benefits for patients with lymphoproliferative disease are not addressed in the drug label and anecdotal evidence suggest that ESA use in hematologic disease may increase the risk for transformation to plasma leukemia, increased light chain excretion, and decrease the remission interval (Caillette 1993, Olujohungbe 1996, Rogers 1990). The studies were of relatively short duration (12-16 weeks). In addition, entry criteria excluded patients who were sicker because of their oncologic disease or their co-morbidities. Typically life expectancy was to be at least 6 months and/or an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or lower (Oken 1982; ECOG website). In general, patients with New York Heart Association (NYHA) classifications 3 and 4 were excluded. Geriatric patients constituted a relatively small proportion of patients in the registration trials.

Emerging data suggest that ESA use may be associated with increased morbidity and mortality in a variety of patient populations despite the alleviation of anemia. Although the features and exact mechanisms of the increased mortality require better delineation, both thrombo-embolic-vascular disease and tumor progression appear to be involved.

Indeed thrombosis was observed in the early trials in renal patients (the first approved indication for ESAs (Winearls 1986). It was also observed retrospectively (adjusted odds ratio 15.3) in cervical cancer patients. (Wun 2003) More recently thrombosis was observed in patients who received ESAs for spinal and cardiac surgery (D’Ambra 1997, FDA Alert 2007, Procrit label). These data suggest that the thrombotic phenomenon is related to the pharmacologic agent and cannot be entirely attributed to the underlying disease condition.

Etiologic attribution of thrombotic-vascular disease in oncology and cancer treatment, however, is particularly challenging in the absence of randomized clinical trials stratified for a variety of variables because cancer is a hypercoagulable state (Alacay 2006, Chew 2006, 2007, De Cicco 2004, Grudeva-Popova 2005, Semrad 2007, White 2005). Typically the venous system is involved, but arterial thrombosis does occur. Tumor cells release cysteine proteases that activate coagulation cascade factor X and tissue factor (TF) that activates factor VII (Kakkar1995). Sialic chains on the mucin from adenocarcinomas activate factor X (Donati 1984, Pineo 1973). Cancer cells interacting with monocytes and macrophages induce the release of interleukins (IL)(1,6) and tumor necrosis factor (TNF) (De Cicco 2004, Edwards 1981, Rickles 2001, Schwartz 1981). Furthermore, cancer treatment, including radiotherapy and surgery, can also contribute to thrombosis (Hallahan 1999, Schreiber 1986, Wilson 1987). Growth-factors, high dose fluorouracil, L-asparaginase, mitomycin, platinum compounds, and tamoxifen have all been implicated (Deshmukh 1995, Falanga 2001, Feffer 1989, Fisher 1990, Kuzel 1990, Lee 1999, 2006, Levine 1988, Lipton 1984, Pritchard 1996, Rella 1996, Rivkin 1994, Rogers 1988, Saphner 1991, Weitz 1997). Central line catheter surfaces can activate platelets and factors X and XII (Bern 1990, Bona 1999, De Cicco 124, Lockich 1983, Monreal 1991). Infections of such catheters can result in the release of mucopolysaccharides (gram positive organisms) and endotoxins (gram negative organisms) that activate factor XII, IL-1, TF, and TNF. Venous stasis due to immobility and drug therapy also contributes to thrombosis (De Cicco 2004, Kessler 1989, Levine 1993, Sue-Ling 1986, Walsh 1974).

Several studies in cancer patients were terminated because of thrombo-embolic-vascular events. The FDA has strengthened its warnings for these types of events in the ESA drug labels. The mechanism(s) by which ESAs might cause or aggravate thrombosis are not known. ESA-induced hyperviscosity has been postulated as a cause in patients with high hematocrit levels (Begg 1966; Lage 2002; Turito 1980). Hematocrit elevation, however, cannot be the sole cause of thrombosis because platelet number is increased, function altered, and bleeding time shortened even prior to the erythrocytic rise (Akizawa 1991; Ando 2002; Aranesp™ package insert; Homonchick 2004, Kooistra 1994; Malyszko 1995, 1996; Pirisi 1994; Roger 1993, Sharpe 1994; Stohlawetz 2000). Alterations in other coagulation factors (decreased proteins C and S; increased Factor VIII, thrombin-antithrombin (TAT) III complex, thrombin activatable fibrinolytic inhibitor, and von Willenbrand factor) have been reported (Akizawa 1991; Macdougall 1991, Malyszko-A 1995, Taylor 1992, Tobu 2004). It is known that ESAs cause fluid retention and hypertension (Malyszko –B 1995, Maschio 1995, Roger 1996, Winearls 1986). Both of these can precipitate congestive heart failure and resulting venous stasis. Regardless of the cause(s), only careful prospective trials controlled for the various thrombotic risk factors associated with vascular-thrombotic-embolic disease of cancer will delineate the magnitude of risk attributable to ESAs for the various oncologic populations. Medicare beneficiaries may be at increased risk for such events because of increased cardiovascular disease, increased co-morbidity, and decreased mobility.

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 4 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.

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 (but no therapy) and to reduce tissue hypoxia during radiation treatments, neither of which are FDA approved indications. These observations have resulted in FDA Black Box warnings.

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.

There is a significant amount of in vitro work to support the first pathway, and this might inform CMS in its coverage decision in the absence of definitive clinical data (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 ESA use 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 that 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 CMS determinations 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.

Summary

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 is 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 data are less robust than we would like, particularly for geriatric patients, they are sufficient to identify patient characteristics and treatment practices that increase the likelihood of unfavorable clinical outcomes. Increased thrombotic-vascular disease, tumor progression, and/or decreased survival occurred with ESA use to prevent or treat anemia secondary to cancer, cancer chemotherapy, or radiotherapy or to improve tissue hypoxia in an attempt to enhance tumor sensitivity to therapy.

From the evidence reviewed, we believe that:

• cancers with erythropoietin receptors-especially when coupled with extensive exogenous ESA exposure may predict increased risk for tumor progression and/or decreased survival.
• the risk:benefit profile is less defined for hematologic cancers because FDA reviewed studies are lacking and patients with myelogenous cancers were excluded from studies.
• a variety of factors including a rapid rise in hemoglobin, a normalized hemoglobin, and a high ESA dose requirement may contribute to or portend increased risk for thrombotic-vascular events
• patients with poorly controlled hypertension, fluid retention, congestive heart failure, and prior thrombo-embolic events are at increased risk for future thrombotic-vascular events with ESA use.
• ESAs may negate the therapeutic utility of anti-angiogenesis and anti-EGF receptor agents.
• bone marrow or progenitor cells within the bone marrow damaged by proliferative or scarring disease have not been adequately shown to respond to low ESA doses without sequelae.

Especially in the setting of potential harm, we believe ESA treatment is not a reasonable substitute for targeted therapy addressing the underlying cause(s) of the anemia. Anemia due to vitamin or mineral deficiency should be addressed by supplementation of those nutritional deficiencies. We believe that ESA use is reasonable and necessary only in clinically significant anemias due to chemotherapy when used at low doses for short durations. In particular, appropriate limitations should be applied to ESA use by beneficiaries with tumors with erythropoietin receptors. ESA use is not reasonable and necessary in beneficiaries with a poor hemoglobin response.

IX. Conclusion

CMS is seeking public comment on our proposed determination 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 of myelodysplasia
3. the anemia of myeloid cancers
4. the anemia associated with the treatment of myeloid cancers or erythroid cancers
5. the anemia of cancer not related to cancer treatment
6. any anemia associated with radiotherapy
7. prophylactic use to prevent chemotherapy-induced anemia
8. prophylactic use to reduce tumor hypoxia
9. patients with erythropoietin-type resistance due to neutralizing antibodies
10. patients with treatment regimens including anti-angiogenic drugs such as bevacizumab
11. patients with treatment regimens including monoclonal/polyclonal antibodies directed against the epidermal growth factor (EGF) receptor
12. anemia due to cancer treatment if patients have uncontrolled hypertension
13. patients with thrombotic episodes related to malignancy

We also propose that ESA treatment is only reasonable and necessary under specified conditions for the treatment of anemia those types of cancer in which the presence of erythropoeitin receptors on either normal tissue/cell lines or malignant tissue/cell lines has been reported in the literature. These cancer types include but are not necessarily limited to:

• bone (sarcoma),
• brain-neurologic,
• breast,
• cervical,
• colo-rectal,
• gastric,
• head-and-neck (squamous cell),
• hepatic,
• lung,
• lymphoma
• melanoma,
• multiple myeloma
• muscle including cardiac,
• ovarian,
• pancreatic (exocrine),
• prostate,
• retinal, and
• uterine.

For patients undergoing treatment for these cancers, we propose that ESA use is reasonable and necessary with the following limitations:

1. the hemoglobin/hematocrit levels immediately prior to initiation of dosing for the month should be < 9 g/dl/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 transfusion (We suggest that patients, especially those in the latter category, be alerted to the increased potential for thrombosis and sequelae).
2. the maximum covered treatment duration is 12 weeks/year;
3. the maximum covered 4 week treatment dose is 126,000 units for erythropoietin and 630 μg for darbepoietin;
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;
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; and
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.

Local contractors may continue to make reasonable and necessary determinations for all uses of ESA therapy for beneficiaries with cancer whose condition is not addressed above.

We are requesting public comments on this proposed determination pursuant to section 1862 as revised by 731 of the Medicare Modernization Act. In light of the issues discussed in our review of the evidence and serious safety concerns voiced in the May 10, 2007 FDA Oncologic Drugs Advisory Committee (ODAC) meeting we are also interested in public comment on whether coverage for ESA therapy for Medicare beneficiaries with cancer should occur only within appropriately designed clinical research studies where informed consent and safety monitoring can be assured. After considering the public comments and any additional evidence, we will make a final determination and issue a final decision memorandum.

Abel 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.

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.

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 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.

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.

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, 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, 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.

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.

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.

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.

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. 2006;70:34-48.

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.

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.

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 V, Disalvo W, Meyer L, Gragnev K, Gibson J, Hoopes P, Strawbridge R, Hammond S, Van Dyk E, Rigas J. Fatigue and plasma cytokines in a randomized double-blind placebo-controlled trial of epoetin alfa in patients undergoing combined modality therapy for unresectable non-small cell lung cancer (NSCLC). Proceedings of the American Society of Clincal Oncologists (ASCO). 2003;22:733.

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.

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.

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.

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.

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.

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.

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, 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, 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

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.

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.

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.

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.

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.

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, 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.

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.

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.

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.

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, 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.

Coiffier B, Boogaerts M, Kainz C. Impact of epoetin beta versus standard of care on quality of life in patients with malignant disease. 6^th 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.

College of American Pathologists. Special announcement. Notifiction to all users of proactice 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.

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, 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.

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.

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 Maematolgy. 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 transfectant. Semin Hematol. 1991;28:152-7.

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.

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).

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.

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.

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.

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

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.

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

Dunphy P, Petersen A, Cox R, Bagshaw M. 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;16:1173-8.

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.

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.

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.

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

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.

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

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

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

Faults 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.

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.

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. J Clin Oncol. 1995;13:2077-83.

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.

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.

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.

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.

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.

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

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. ACSO. 1999.

Glaser C, Millesi W, Kornek G, Lang S, Schull B, Watzinger, Christoph F, Lang S, Selzer E, Lavey R. Impact 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.

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.

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

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 Ocol. 2005;23:9377-86.

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

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.

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.

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.

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.

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. 1995;92(11):68-75.

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.

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.

Henze G, Michon J, Morland B, Perek D, Rizzari C, Zoubek A, EPO INT51 Study Group. Phase III randomized study: efficacy of epoietin alfa in reducing blood transfusions in newly diagnosed pediatric cancer patients receiving chemotherapy. American Society for Clinical Oncolgy (ASCO) Annual Meeting. 2002.

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 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.

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.

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.

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.

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 A, Hurria A, Williams D. 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;Vol.102:11.

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.

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.

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.

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.

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.

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.

Kotsori A, Alexopoulos C. Abstract No: 18554 from ASCO Annual Meeting Proceedings Part I. Journal of Clinical Oncology. 2006:24(20 June Suppl):18S.

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.

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

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.

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

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 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.

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.

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.

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.

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.

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

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, 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, 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, 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.

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

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.

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.

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.

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.

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.

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.

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

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.

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.

Mercadante S, Gebbia V, Marrazzo A, Filosto S. Anaemia in cancer: pathophysiology and treatment. Cancer Treat Rev. 2000;26:303-11.

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 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.

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.

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.

Mohyeldin A, Lu H, Dalgard C. Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma. Neoplasia 2005;7:536-43.

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.

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.

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.

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.

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.

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.

New York Times – Business Section. Sec asks Amgen about anemia drugs. 3/1/07. Accessed 3/2/07.

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.

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.

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.

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.

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.

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;129:206-09.

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.

Panares R, Garcia A. Bevacizumab in the management of solid tumors. Expert Rev Anticancer Ther. 2007;7:433-45.

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.

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.

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.

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.

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.

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;14:2731-7.81.

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.

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.

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.

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.

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.

Ribatti D. A potential role of erythropoietin in angiogenesis associated with myelodysplastic syndromes. 2002;16:1890-1.

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.

Rickles F, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res. 2001;102:V215-24.

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.

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;89:831-37.

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 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.

Rossert J, Eckardt K. Erythropoietin receptors: their role beyond erythropoiesis. Nephrol Dial Transplan. 2005;20:1025-28.

Rytting M, Worth L, Jaffe N. Hemolytic disorders associated with cancer. Hematol Oncol Clin North Am. 1996;10:365-76.

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.

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, 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.

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, 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.

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.

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.

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, 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, Williams D. Weekly epoetin alfa treatment of anemia in patients with cancer not undergoing therapy. Journal of Supportive Oncology. 2006;4:129-35.

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.

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 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.

Spivak J. Iron and the anemia of chronic disease. Oncology (Williston Park). 2002;16(9 Suppl 10):25-33.

Stein R, Abels R, Krantz S. Pharmacologic doses of recombinant human erythropoietin in the treatment of myelodysplastic syndromes. Blood. 1991;78:1658-63.

Stohlawetz P, Dzirio L, Hergovich N. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood. 2000;95:2983–9.

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.

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.

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.

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.

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.

Ten Bokkel H, 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.

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 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):1175-79.

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.

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.

USA Today. 3/11/07. Accessed 3/12/07.

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, 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.

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, 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.

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.

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.

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.

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.

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.

A-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 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.

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.

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.

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.

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. Blood. 1990;76:24–30.

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.

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.

Zhang W, Gordon M, Lenz H. Novel approaches to treatment of advanced co

Abel 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.

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.

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 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.

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.

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, 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, 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.

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.

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.

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.

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. 2006;70:34-48.

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.

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.

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 V, Disalvo W, Meyer L, Gragnev K, Gibson J, Hoopes P, Strawbridge R, Hammond S, Van Dyk E, Rigas J. Fatigue and plasma cytokines in a randomized double-blind placebo-controlled trial of epoetin alfa in patients undergoing combined modality therapy for unresectable non-small cell lung cancer (NSCLC). Proceedings of the American Society of Clincal Oncologists (ASCO). 2003;22:733.

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.

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.

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.

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.

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.

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.

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, 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, 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

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.

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.

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.

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.

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.

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, 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.

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.

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.

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.

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, 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.

Coiffier B, Boogaerts M, Kainz C. Impact of epoetin beta versus standard of care on quality of life in patients with malignant disease. 6^th 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.

College of American Pathologists. Special announcement. Notifiction to all users of proactice 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.

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, 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.

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.

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 Maematolgy. 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 transfectant. Semin Hematol. 1991;28:152-7.

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.

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).

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.

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.

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.

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

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.

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

Dunphy P, Petersen A, Cox R, Bagshaw M. 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;16:1173-8.

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.

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.

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.

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

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.

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

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

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

Faults 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.

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.

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. J Clin Oncol. 1995;13:2077-83.

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.

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.

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.

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.

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.

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

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. ACSO. 1999.

Glaser C, Millesi W, Kornek G, Lang S, Schull B, Watzinger, Christoph F, Lang S, Selzer E, Lavey R. Impact 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.

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.

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

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 Ocol. 2005;23:9377-86.

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

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.

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.

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.

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.

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. 1995;92(11):68-75.

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.

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.

Henze G, Michon J, Morland B, Perek D, Rizzari C, Zoubek A, EPO INT51 Study Group. Phase III randomized study: efficacy of epoietin alfa in reducing blood transfusions in newly diagnosed pediatric cancer patients receiving chemotherapy. American Society for Clinical Oncolgy (ASCO) Annual Meeting. 2002.

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 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.

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.

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.

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.

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 A, Hurria A, Williams D. 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;Vol.102:11.

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.

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.

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.

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.

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.

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.

Kotsori A, Alexopoulos C. Abstract No: 18554 from ASCO Annual Meeting Proceedings Part I. Journal of Clinical Oncology. 2006:24(20 June Suppl):18S.

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.

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

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.

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

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 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.

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.

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.

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.

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.

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

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, 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, 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, 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.

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

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.

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.

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.

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.

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.

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.

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

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.

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.

Mercadante S, Gebbia V, Marrazzo A, Filosto S. Anaemia in cancer: pathophysiology and treatment. Cancer Treat Rev. 2000;26:303-11.

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 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.

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.

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.

Mohyeldin A, Lu H, Dalgard C. Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma. Neoplasia 2005;7:536-43.

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.

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.

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.

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.

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.

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.

New York Times – Business Section. Sec asks Amgen about anemia drugs. 3/1/07. Accessed 3/2/07.

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.

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.

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.

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.

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.

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;129:206-09.

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.

Panares R, Garcia A. Bevacizumab in the management of solid tumors. Expert Rev Anticancer Ther. 2007;7:433-45.

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.

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.

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.

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.

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.

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;14:2731-7.81.

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.

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.

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.

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.

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.

Ribatti D. A potential role of erythropoietin in angiogenesis associated with myelodysplastic syndromes. 2002;16:1890-1.

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.

Rickles F, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res. 2001;102:V215-24.

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.

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;89:831-37.

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 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.

Rossert J, Eckardt K. Erythropoietin receptors: their role beyond erythropoiesis. Nephrol Dial Transplan. 2005;20:1025-28.

Rytting M, Worth L, Jaffe N. Hemolytic disorders associated with cancer. Hematol Oncol Clin North Am. 1996;10:365-76.

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.

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, 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.

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, 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.

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.

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.

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, 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, Williams D. Weekly epoetin alfa treatment of anemia in patients with cancer not undergoing therapy. Journal of Supportive Oncology. 2006;4:129-35.

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.

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 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.

Spivak J. Iron and the anemia of chronic disease. Oncology (Williston Park). 2002;16(9 Suppl 10):25-33.

Stein R, Abels R, Krantz S. Pharmacologic doses of recombinant human erythropoietin in the treatment of myelodysplastic syndromes. Blood. 1991;78:1658-63.

Stohlawetz P, Dzirio L, Hergovich N. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood. 2000;95:2983–9.

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.

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.

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.

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.

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.

Ten Bokkel H, 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.

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 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):1175-79.

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.

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.

USA Today. 3/11/07. Accessed 3/12/07.

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, 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.

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, 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.

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.

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.

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.

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.

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.

A-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 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.

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.

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.

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.

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. Blood. 1990;76:24–30.

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.

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.

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.

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.

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.

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.

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.