Positron Emission Tomography (NaF-18) to Identify Bone Metastasis of Cancer

NaF-18 PET for the detection of Bone metastasis should be covered. Sodium fluoride bone scans are highly sensitive for bone metastatic disease of both osteoblastic and osteolytic cancers. There is essentially no comparison with traditional Tc99m bone agents (MDP, HDP) versus NaF. Sodium Fluoride bone scans provide higher accuracy in differentiating benign from malignant lesions and provide a much more superior image quality. Also, with the "coctail" of FDG and NaF in one scan, patient care is drastically improved.

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1. CMS should approve broad coverage of NaF bone imaging because:
- it is a bone scan and should be covered
- the literature supports NaF PET bone scanning and in fact, shows that it is more accurate than traditional bone scans
- patients need access to an alternative to Tc-99m based bone scans because the supply of molybdenum has been problematic for the last two years and this could continue through 2010

2. If NaF is not broadly covered, then we recommend the creation of a national registry like the NOPR
- Our patients need access to NaF PET bone scans and the only way to ensure access for all Medicare beneficiaries nationwide under CED is a national registry

3. We have access to NaF for PET bone scanning Any radiopharmacy that can make FDG, which is most of them, can make NaF. Per the actual process, NaF has to be made first, and then combined with glucose to make FDG. Therefore, most of the country has immediate access to NaF right now. Why would we want to remain dependent on a foreign product such as Tc99m? All the Tc99m used in America has to be flown in from some other country. Unlike with oil, there is an immediate solution to this problem.

4. NaF PET bone scanning provides accurate scans, better than traditional Tc99m bone scans. I have a great deal of confidence in them. If I or anyone in my family needed a bone scan, I would definitely prefer a NaF PET bone scan, without any doubt.

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I would like to propose that the indications for NaF-18 PET studies is not limited to the investigation of bone metastasis. Why limit its use? This imaging procedure is also very effective for the assessment of non-oncologic disorders of bone. Since 2004 at Children''s Hospital Boston, we have performed in excess of 500 NaF-18 PET studies in children ranging from neonates to young adults. The vast majority of the indications have been for non-oncologic disorders (sports injuries, child abuse, etc.) with safe and effective results.

The images obtained are of very high spatial resolution. The studies can be completed in a short period of time and patients are able to go see their physicians quicker than with the classic MDP bone scan. SInce most of the PET scanners are PET/CT scanners, image fusion of bone PET and CT can be useful to improve anatomic localization of functional lesions.

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We are writing in response to the Centers for Medicare & Medicaid Services’ (CMS) request for comments on the proposed decision memorandum for the use of Positron Emission Tomography (PET) (¹⁸F-NaF) to identify bone metastasis of cancer. For the reasons stated in our earlier comment and reviewed below, we believe that the available evidence is sufficient to support Medicare coverage for ¹⁸F-NaF PET and PET/CT (referred to herein collectively as “PET”) imaging to identify bone metastasis of cancer either to inform the initial antitumor treatment strategy or to guide subsequent antitumor treatment strategy after the completion of initial treatment.

While we have been strong supporters of the Coverage with Evidence Development (CED) framework, and in particular the ¹⁸F-FDG National Oncologic PET Registry (NOPR), we do not believe that ¹⁸F-NaF coverage should be limited to a clinical study. We explain below why CMS would be fully justified in revising its proposed decision memorandum and providing coverage of ¹⁸F-NaF PET without requiring an additional process for study enrollment and CED. We strongly believe that the evidence indicates that ¹⁸F-NaF PET is equal or superior to the current covered technology in identifying bone metastasis of cancer, and encourage CMS to cover ¹⁸F-NaF PET for this purpose without restriction.

This letter is submitted jointly on behalf of the Academy of Molecular Imaging (AMI) - Institute for Molecular Technologies (IMT), the American College of Nuclear Medicine (ACNM), the American College of Radiology (ACR), and the Society of Nuclear Medicine (SNM). These organizations are composed of clinicians, academicians, researchers and nuclear medicine providers utilizing molecular imaging technologies, including integrated positron emission tomography/computed tomography (PET/CT). We represent tens of thousands of physicians, providers, and patients with regard to this technology, and have worked closely with CMS over the past several years to increase beneficiary access to PET and PET/CT through the development of the National Oncologic PET Registry (NOPR).

¹⁸F-NaF is an FDA-approved USP radiotracer that allows physicians to use PET to detect metastasis to the bone of many common cancers (including breast, lung, and prostate), thus facilitating the development of treatment programs for affected individuals. The Food and Drug Administration (FDA) conducted a formal review of PET drugs in 2000 that specifically deemed ¹⁸F-NaF to be safe and effective.[1]

Our original reconsideration request provided a detailed summary of the clinical evidence supporting the use of ¹⁸F-NaF PET. Most of this evidence is consolidated in the March 2009 Review of Published Literature on the Use of Sodium Fluoride F18 (¹⁸F-NaF) Positron Emission Tomography (PET) in the Evaluation of Altered Osteogenic Activity, prepared by the Cancer Imaging Program at the National Cancer Institute. [2] The Review summarizes results from 41 clinical trials published since 1992, including 10 well-controlled studies of ¹⁸F-NaF PET to identify bone metastases in adults. Several of these studies included subjects with multiple types of cancer; some study cohorts were specific to lung, breast and prostate cancer. These studies show that ¹⁸F-NaF PET is more sensitive and specific than ^99mTc-MDP bone scintigraphy for diagnosis and detection of bone metastases. In addition, at least one of these studies demonstrates that use of CT in conjunction with ¹⁸F-NaF PET further improves sensitivity and specificity, and enhances the ability to distinguish benign from malignant lesions.

In addition to the studies presented in the Review, our original reconsideration request identified two studies of ¹⁸F-NaF PET that had been published since the March 2009 review, as well as an additional 2006 ¹⁸F-NaF PET study that was not included in the Review. Our review of the literature referenced by CMS, including those studies we referenced in our original comment, supports the conclusion that sufficient evidence exists for CMS to establish unrestricted coverage for ¹⁸F-NaF PET.

The clinical evidence clearly demonstrates that ¹⁸F-NaF PET should be covered as medically reasonable and necessary. However, in addition, the increasing shortage of Technetium-^99m (^99mTc) should encourage CMS to expedite coverage for 18F- NaF PET as a validated and medically appropriate technology. As CMS is aware, ^99mTc is the daughter isotope of molybdenum-99 (⁹⁹Mo) and ^99mTc is the radionuclide used in approximately 80 percent of nuclear medicine scans worldwide. No bone imaging agents other than ^99mTc radiopharmaceuticals are currently covered by CMS for bone scintigraphy. The short (66-hour) half- life of ⁹⁹Mo and the even shorter (6-hour) half- life of ^99mTc preclude efforts to maintain an inventory of either radionuclide, and any interruption in production thus immediately compromises the clinical supply.

The U.S. supply of ⁹⁹Mo is entirely dependent upon the production capacity of a small handful of international reactors located primarily in Canada, South Africa, and the Netherlands. Since 2007, the domestic supply of ⁹⁹Mo and ^99mTc has fluctuated dramatically, as the aging foreign reactors have become increasingly prone to extended shutdowns for repair and maintenance. As CMS and U.S. clinicians are well aware, these shutdowns have increased in both duration and frequency in recent years, and very significantly compromise clinical care decisions that are dependent on bone scintigraphy.

For example, the unscheduled and continuing shutdown since May 2009 of the 52-year-old Chalk River facility in Ontario has forced thousands of hospitals throughout the United States to cancel or delay critical medical imaging procedures that depend upon ^99mTc. The Chalk River facility failed to meet its initial estimated repair completion date of late 2009, and it was recently announced that the facility will not return to production until April of 2010 at the earliest. Similarly, the Petten High Flux Reactor in the Netherlands experienced shutdowns in the past year, and is already scheduled to go offline for over half of 2010 (from February through at least August). Even Congress has recognized the urgency of this situation, as the House of Representatives recently passed legislation (H.R. 3276) that would promote the safe and reliable domestic production of ⁹⁹Mo/^99mTc. This legislation is currently awaiting action in the Senate. However, even the most expeditious passage of this legislation would not provide a remedy in the near term for the crisis currently facing patients.

This shortage has led to a significant reduction in the availability of bone scintigraphy. As a result, many Medicare beneficiaries with cancer who need bone imaging now face the prospect of lengthy delays or alternative diagnostic procedures that may involve greater radiation dosage, less accuracy, or higher cost. Fortunately, the radiotracer ¹⁸F-NaF is unaffected by this severe shortage, as ¹⁸F-NaF is also widely available across the United States through a network of cyclotrons. Indeed, our best estimate is that ¹⁸F-NaF is currently available to 99 percent of all hospitals nationwide. Thus, the availability of ¹⁸F-NaF PET bone imaging as a CMS-approved alternative to conventional bone scintigraphy performed with ^99mTc agents (e.g., ^99mTc-MDP) will ensure that beneficiaries suffering from cancer will have access to these essential imaging procedures.

On the basis of the evidence presented above and in our original comment letter, we strongly encourage CMS to amend NCD CAG-00065R and adopt a policy providing coverage for ¹⁸F-NaF PET in identifying bone metastasis of cancer that is not restricted to study enrollment. This will afford Medicare cancer beneficiaries clinically necessary access to accurate bone imaging, even if they are distant from a trial center.

Should CMS nevertheless determine that ongoing evidence collection is necessary on the clinical value of oncologic ¹⁸F-NaF, we would work with CMS to support a ¹⁸F-NaF PET clinical data registry developed and operated by the professional societies and imaging community stakeholders. While the literature supports coverage of NaF bone imaging outside of CED, we believe that coverage of ¹⁸F-NaF PET via CED could be conducted efficiently, so as to offer Medicare beneficiaries broad access to a much- needed imaging technology while simultaneously allowing CMS to collect even more information than already exists on the clinical value of oncologic ¹⁸F-NaF PET.

Based on our considerable experience with the National Oncologic PET Registry (NOPR) we would be willing to meet with CMS and the Agency for Healthcare Research and Quality (AHRQ) to discuss appropriate study design for a ¹⁸F-NaF PET registry. We estimate that the number of oncologic ¹⁸F-NaF PET bone scans that would be performed under CED would be relatively limited, perhaps totaling half the number of oncology scans that were registered through the original NOPR process.

Regardless of the precise parameters of CMS’s final coverage decision, the PET imaging community notes that while many providers have significant experience with FDG-PET imaging techniques, fewer providers have routinely offered bone imaging with ¹⁸F-NaF PET. We have assured CMS that we recognize the importance of ensuring that PET imaging centers and physicians quickly gain the imaging, interpreting and reporting skills necessary to maximize the benefit for these cancer patients. To this end, we have already begun to develop training materials to educate providers on the relevant technical and clinical challenges, and will diligently disseminate such information widely through webcasts, self-guided training programs, FAQs, sample protocols, and other means. (For example, AMI will broadcast the first of several educational webcasts on January 19, 2010, at no charge to the imaging community.) These resources will be both publicly accessible on imaging organizations’ websites and made available via other means of communication.

Finally, in light of the aforementioned severity and expected long-term duration of the ^99mTc shortage, we urge CMS to act quickly and expeditiously to reach a determination on ¹⁸F-NaF PET to mitigate further disruption in the availability of bone imaging to beneficiaries.

We appreciate the opportunity to provide comments regarding ¹⁸F-NaF PET, and look forward to working with CMS to provide any additional information that you would find valuable in your decision making process.

Sincerely,

/s/
Timothy J. McCarthy, PhD
President, AMI

/s/
Harvey L. Neiman, MD, FACR
Executive Director, ACR

/s/
Jay A. Harolds, MD, FACNP
President, ACNM

/s/
Thom Tulip, PhD
Chairman, IMT Steering Committee

/s/
Michael M. Graham, PhD, MD
President, SNM

/s/
Douglas Blayney, MD
President, ASCO

* * *

[1] See Food and Drug Administration, Positron Emission Tomography Drug Products; Safety and Effectiveness of Certain PET Drugs for Specific Indications, 65 Fed. Reg. 12,999 (2000), available at http://www.fda.gov/ ohrms/dockets/98fr/031000a.txt. (“FDA reviewed its records and, under Sec. 314.161, determined that sodium fluoride F 18 injection was not withdrawn from sale for reasons of safety or effectiveness. Accordingly, the agency will list sodium fluoride F 18 injection in the Orange Book’s ‘Discontinued Drug Product List’ section, which delineates, among other items, drug products that have been discontinued from marketing for reasons other than safety or effectiveness. Because sodium fluoride F 18 injection was not withdrawn from sale for reasons of safety or effectiveness, it is still a listed drug, and FDA can approve ANDAs that refer to it.”)
[2] Cancer Imaging Program, Division of Cancer Treatment and Diagnosis, National Institutes of Health, Review of Published Literature on the Use of Sodium Fluoride F 18 (¹⁸F-NaF) Positron Emission Tomography (PET) in the Evaluation of Altered Osteogenic Activity (Mar. 2009).

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Houston, December 29, 2009

Centers for Medicare & Medicaid Services Technology Assessment Committee

Dear Members,

This letter is to strongly support CMS to provide coverage for F-18 fluoride PET (and PET/CT) scanning for staging and monitoring of bone metastases in patients with breast cancer. Bone metastases are the commonest type of metastases from breast cancer, which is, in turn, the commonest form of malignancy in adult women in the US. Bone metastases cause significant morbidity, including pain, fractures, functional disability secondary to fractures, spinal cord compression, and inconvenience related to the need for specific forms of treatment, such as external radiotherapy, orthopedic surgery, in addition to cancer chemotherapy, endocrine therapy and molecularly targeted treatments. Radionuclide bone scanning is one of the most sensitive imaging modalities to detect bone metastases and determine the extent of disease in a single, whole-body image. This very commonly used and critically useful form of imaging is now threatened by the world-wide shortage of Molybdenum/Tc-99, the Radioisotope used for bone scanning. A perfectly appropriate substitute for Tc-99 bone scan would be an F-18 fluoride PET (and PET/CT) scan, which would also provide metabolic information in metastatic deposits. Therefore, approval of F-18 fluoride PET (and PET/CT) scan coverage would not only solve the issue of Tc-99 availability, but it would, in fact, provide coverage for a better test in the form of F-18 fluoride PET (and PET/CT) scans. This test would provide a proven tool for detection of bone metastases, determination of extent of bone metastases throughout the skeleton and metabolic information that would allow monitoring of the effectiveness of treatments for metastatic breast cancer.

I strongly encourage CMS to rapidly institute coverage for F-18 fluoride PET (and PET/CT) scanning, without the need for CED, to avert the approaching crisis secondary to the Molybdenum /Tc-99 shortage, but perhaps more importantly, to open access for Medicare/Medicaid recipients to an improved imaging modality.

Please do not hesitate to contact me should you require additional information or clarification about this important issue.

Sincerely,

Gabriel N. Hortobagyi, MD, FACP
Professor and Chairman
Department of Breast Medical Oncology
The University of Texas M. D. Anderson Cancer Center
1515 Holcombe Blvd., Unit 1354
Houston, TX 77030-4009

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December 30, 2009

Jeffrey Roche, MD, MPH
Medical Officer, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244-1850

Dear Dr. Roche:

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services' (CMS's) proposed national coverage decision (NCD) for Positron Emission Tomography (NaF-18) to Identify Bone Metastasis of Cancer (CAG 00065R1) (CAG-00065R). America's Health Insurance Plans (AHIP) is the national association representing nearly 1,300 health insurance plans providing coverage to more than 200 million Americans. We are pleased to submit these comments on behalf of our members.

General Comments
We support CMS's intent to ensure that all patients receive the most effective and appropriate treatments and procedures as indicated by sufficient levels of clinical evidence. AHIP and our member plans have supported CMS's effort to review evidence on the use of the NaF-18 radioisotope for positron emission tomography (PET) to identify bone metastasis of cancer. We are aware that the radioisotope NaF-18 was first used in radiological tests as early as the 1960s before it was replaced with technetium-99m (Tc-99m); which is currently the most widely used radioactive isotope for medical diagnostic studies. Therefore, our members support CMS's proposed decision that the current evidence does not sufficiently demonstrate that the results of NaF-18 PET imaging to identify bone metastases improve health outcomes of beneficiaries with cancer and that open and full coverage of PET NaF-18 should not be provided at this time. Our members do, however, support coverage of PET NaF-18 through CMS's Coverage with Evidence Development (CED) mechanism.

Currently, 2-[F18] fluoro-2-deoxy-D-glucose (FDG) is the only nationally covered radioisotope for use in PET for cancer imaging, and coverage is provided for many cancers and stages of treatment through the CED mechanism. Data is collected and analyzed for these CED efforts by the National Oncologic PET Registry (NOPR) Working Group and we support NOPR's efforts in working with CMS to collect and analyze PET FDG use data. However, as we stated in our previously submitted comments on this issue in June 2009, were CMS to provide coverage of PET NaF-18 for bone metastases through CED similar to the current requirements for PET FDG for solid tumors, our members, while supportive, stress the need to improve the data collection criteria:

• Data collected through CED for PET NaF-18 for bone metastases should focus on determining safety and effectiveness of this diagnostic test for specific patient populations and sub-populations, as well as cancer type and stage, and clinical settings, and CMS should request that CED data collection efforts provide data separately for each cancer type as PET NaF-18 may impact the management of one type of cancer differently than another.
• All CED data collected should validate, beyond physician self-reported data, a change in treatment or patient management due to the use of PET NaF-18 and whether or not any treatment change resulted in actual benefit or improved outcomes to the patient. Unfortunately, evidence on perceived change in clinical management is open to many biases, including the potential to help guide future coverage decision-making.

  CED efforts should provide Medicare with the best possible data to assess which treatment options align with the evidence, and also help achieve improved patient outcomes. This information will help clinicians to assess whether the addition of new diagnostic tests provides a net health benefit for patients.

At this time, the available evidence suggests that PET NaF-18 has the ability to detect bone metastases. It is not clear, however, that PET NaF-18 has the diagnostic accuracy across all patients, or that the results from this imaging test change prescribed treatment or result in improved patient outcomes. However, AHIP and our member plans are aware of the current worldwide shortage of Tc-99m, due to an unplanned shutdown of a North American nuclear reactor that supplies the material used to generate this radioisotope, and encourages CMS to carefully review available evidence on NAF-18 and its effectiveness to help provide coverage through CED for this alternative test while the shortage is being addressed.

AHIP strongly encourages CMS to continue to review emerging evidence for each cancer type and patient population in regards to the use of PET NaF-18, with concern for the myriad pathophysiological differences between types and stages of cancers and patient outcomes.

Thank you for the opportunity to provide comments on this issue.

Sincerely,

US Environmental Protection Agency. Technetium-99 Fact Sheet. Last updated on Monday, February 9th, 2009: http://www.epa.gov/rpdweb00/radionuclides/technetium.html. Accessed June 18, 2009.

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Thank you for the opportunity to comment upon the use of 18F Sodium Fluoride (NaF) bone scans for the detection of bone disease (CAG 00065R1). I am the director of PET/CT and Nuclear Medicine at Scottsdale Medical Imaging Ltd (SMIL), a community based private practice radiology practice in Scottsdale, Arizona. I have been performing and interpreting gamma camera based 99m Tc MDP-bone scans for the last 15 years. Over the last two years, our practice has begun utilized 18F-NaF bone scans for the evaluation and early detection of bone metastasis and other orthopedic and spinal conditions.

It has been my experience and that of the other four nuclear medicine physicians in my practice that the information obtained from 18F-NaF bone scans is far more superior to that of conventional gamma camera acquired bone scans with 99mTc MDP. I see from the additinal responses to the CMS comment period on 18F-NaF bone scans and in talking to my colleagues around the country that others have had similar positive experiences using 18F-NaF. Also, there are over 40 well documented publications that have provided convincing scientific data showing the increased sensitivity and accuracy of 18F-NaF compared to conventional 99mTc MDP imaging, confirming my impression as well.

Not only do we find 18F -NaF bone scans to be of important benefit to our patients for the early detection of osseous metastasis, leading to a significant impact on patient care, but with consistently fewer equivocal results than with 99m Tc- MDP we have noted fewer ancillary tests being ordered to confirm the diagnosis of bone metastasis. Consequently, the 18F-NaF bone scans can reduce the cost of medical care in the oncology population.

As compelling as the information obtained from 18F-NaF bone scans is in providing appropriate clinical care to our patients, having the capability to use an alternate form of bone imaging agent is critical to the delivery of timely care in times of national shortages. The ubiquitous supply of 18F-NaF will prevent the disruptive cycle of supply interruption of Technetium from occurring in this country and make us independent of foreign suppliers of Technetium product.

Finally, we have found that the use of 18F-NaF bone scans in patients with spine pain who are being considered for minimally invasive treatment options, such as facet injections, to be far superior to conventional bone scans in helping to select both the appropriate level of intervention and the appropriate candidacy selection for the procedure.

In conclusion, I would strongly urge CMS to allow reimbursement of 18F- NaF bone scans. Such a decision will have a positive impact on the care and management of patients with osseous disease.

Thank you for your consideration,

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Personal Care Molecular Imaging

We have performed over 15 F-18 sodium fluoride PET bone scans on the clinical level.

Quite simply, they are vastly superior to conventional planar bone scan imaging, and also vastly superior to SPECT imaging. Why?, because the PET bone scan requires a low dose CT for attenuation correction of the data, and this low dose CT data is available from the vertex to the toes. The combination of metabolic information extracted from the PET portion as well as the anatomic detail of low dose CT make for a combination that is unparalleled and unequaled in both lesion detection sensitivity, as well as etiology specificity.

Not only does the F-18 sodium fluoride PET bone scan demonstrate the ability to elucidate very fine bony abnormalities, the addition of low dose CT vastly increases the accuracy with which such lesions can be categorized as to represent arthritic/degenerative changes, trauma, or true lesions that could represent infection or malignancy.Approximately half of the PET bone scans we have performed were performed because the conventional planar bone scan was markedly suboptimal in both technique and interpretation, most of the time the interpretation of the PET bone scan were completely different than the initial interpretations of conventional bone scan imaging, markedly changed patient management for the better.

It is a fact, that many of the bone scans performed in the United States, are read by radiologist with little or insufficient training in nuclear medicine, generating interpretations that are quite simply pathetic; this coupled with the inherent limitations of purely metabolic imaging without concomitant low dose CT anatomic co-registration, make for a very suboptimal situation regarding patient care.

F-18 sodium fluoride PET bone scans interpreted by nuclear medicine experts have no parallel.

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As the Chair and Co-chairs of the National Oncologic PET Registry (NOPR) Working Group, we are writing in response to the Centers for Medicare & Medicaid Services’ (CMS) request for public comment on the proposed decision memorandum for the use of Positron Emission Tomography (PET and PET/CT) with the radiopharmaceutical fluorine-18 sodium fluoride (¹⁸F-NaF) to identify bone metastasis of cancer, and the proposal to provide coverage for ¹⁸F-NaF PET through the use of Coverage with Evidence Development (CED).

The NOPR was originally developed in response to a CMS proposal to expand coverage for ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) to include cancers and indications not otherwise eligible for Medicare reimbursement. Under the CED framework, Medicare coverage for these cancers can now be obtained if certain data are provided to a clinical registry. For the past three years, the NOPR has implemented this registry and shared the resultant data with CMS under contract, in addition to publishing this practice-based evidence in the peer-reviewed scientific literature. Given the NOPR’s extensive experience in implementing registry-based CED for FDG-PET, we wish to provide CMS with our observations concerning certain logistical and methodological issues that we believe CMS should consider if it elects to cover ¹⁸F-NaF PET only through CED.

Based on our review of the Proposed Decision Memorandum and our experience with the NOPR, we are cautiously optimistic that a CED registry for ¹⁸F-NaF PET could be developed within the parameters outlined in the Proposed Decision Memorandum. In particular, we are prepared to work with CMS and the Agency for Healthcare Research and Quality (AHRQ) to explore ways in which the existing NOPR infrastructure could be used to collect such additional data, so as to provide Medicare beneficiaries with access to ¹⁸F-NaF PET at a time when shortages of ⁹⁹Mo and ⁹⁹m-Tc are creating significant restrictions on the availability of many diagnostic imaging procedures.

At the same time, however, we would nevertheless caution that it will be difficult for such a registry, even if well-designed, to generate the types of outcomes data that CMS and AHRQ outlined in the Proposed Decision Memorandum. As CMS is aware, the NOPR CED registry was designed to determine whether the availability of FDG-PET for oncologic indications led to changes in clinical management of patients with suspected or proven cancer. However, these evidentiary standards for studies associated with CED registries have since been heightened by AHRQ. As the Proposed Decision Memorandum articulates, coverage under CED requires that the associated clinical study answer one or more of the following questions: 1) Whether a the procedure provides a change in the likelihood of appropriate referrals for palliative care; 2) Whether the procedure is associated with improved quality of life; or 3) Whether the procedure is associated with improved survival.

As a clinical community, we are working to develop a testable set of hypotheses to demonstrate an improvement in outcome based on these requirements. Yet despite the fact that obtaining such data is clearly desirable, the practical challenges inherent in this effort are manifest. For instance, one key challenge will be how to timely link registry data to the claims data, thus enabling CMS to draw a reasonable inference that a bone scan conducted today led to a change in outcome at some later time. A second clinical challenge is that certain tumor types, like breast and prostate cancer, often require long observation periods before there can be confidence in the outcomes data collected. Perhaps the greatest challenge will be defining appropriate control populations, to meet the requisite standard that the use of the diagnostic test results in a beneficial change in comparison to either its non-use or the use of a similar test (e.g., conventional bone scintigraphy). Although several different control population scenarios have been considered, each is associated with important biases that could limit the reliability of the resultant evidence.

If the evidentiary standards for a ¹⁸F-NaF PET CED registry are indeed as strict in practice as they appear in the abstract, it is our clinical opinion that it will be exceptionally difficult for many medically reasonable and necessary diagnostic procedures to meet these requirements. Certainly, the new CED standards may generate valuable data in the initial diagnostic scan context, where the availability or the absence of a scan could be shown to have been the deciding factor in the choice of treatment for metastatic cancer. However, these new evidentiary standards are significantly less applicable in situations where the procedure in question constitutes only one element in a battery of intermediate clinical management decisions that a physician and patient make over the course of treatment. Obtaining such a conclusive determination even in the context of a randomized controlled clinical trial would be exceptionally challenging. Requiring that an intermediate imaging technique demonstrate a direct and quantifiable impact on either quality of life or survival in the absence of a randomized controlled clinical trial is, in most instances, neither reasonable nor feasible.

In conclusion, should CMS determine that it is necessary to limit coverage of ¹⁸F-NaF PET to a clinical study under CED, we would welcome the opportunity to share our experience in developing and administering the NOPR, and to bring that experience to bear on the development of a similar ¹⁸F-NaF PET registry. However, would also appreciate the opportunity to meet with CMS and AHRQ to discuss the application of the clinical study questions to diagnostic imaging, and to discuss the appropriate study design for a ¹⁸F-NaF PET registry.

Thank you for the opportunity to provide these comments. We look forward to working with CMS to provide any additional information that would be valuable to the decision making process.

Sincerely,

/s/
Bruce E. Hillner, M.D., Chair

/s/
R. Edward Coleman, M.D., Co-chair

/s/
Anthony F. Shields, M.D., Co-chair

/s/
Barry A. Siegel, M.D., Co-chair

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December 29, 2009

BY ELECTRONIC DELIVERY

Louis B. Jacques, MD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Mail Stop C1-09-06
Baltimore, Maryland 21244

Re: Proposed Coverage Decision Memorandum for Positron Emission Tomography (NaF-18) to Identify Bone Metastasis of Cancer (CAG-00065R and CAG-00065R1)

Dear Dr. Jacques:

The Association of Community Cancer Centers (ACCC) appreciates this opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS) proposed national coverage decision (NCD) on positron emission tomography (PET) (NaF-18) to identify bone metastasis of cancer.¹ ACCC is a membership organization whose members include hospitals, physicians, nurses, social workers, and oncology team members who care for millions of patients and families fighting cancer. ACCC’s more than 900 member institutions and organizations treat 60 percent of all U.S. cancer patients when combined with our physician membership. We are often at the front line in fighting cancer and therefore have a unique perspective on the importance of advanced imaging technologies, such as Na-F18 PET, to decisions about patient care and improving health outcomes.

In the Proposed Decision Memorandum, CMS describes its intent to cover NaF-18 PET imaging when "the beneficiary’s treating physician determines that the NaF-18 PET study is needed to inform the initial antitumor treatment strategy or to guide subsequent antitumor treatment strategy after the completion of initial treatment, and when the beneficiary is enrolled in, and the NaF-18 PET provider is participating in," a prospective clinical study "that is designed to collect additional information at the time of the scan to assist in initial treatment planning and in identification of symptomatic bone metastases."² CMS makes this proposal after concluding that NaF-18 PET is "promising," but "the evidence of clinical benefit is not yet conclusive and is not generalizable to the Medicare patient population."³ In particular, CMS states, "there is inconsistent evidence that the results of NaF-18 PET scans are used to alter recommended treatment strategy."⁴ CMS also reports that it found "no conclusive evidence of improved patient oriented health outcomes related to NaF-18 PET studies for routine follow-up or monitoring of suspected bone metastases, except for the diagnosis of bone metastases in patients with symptomatic evidence of bone pain and with no other imaging findings of bone metastasis."⁵

We agree that NaF-18 PET is promising, and we appreciate CMS’s recognition that beneficiaries should have access to this service. We believe that the evidence is sufficient to cover the test as prescribed by physicians, however, without coverage with evidence development (CED). As described in the National Institutes of Health literature review cited in the Proposed Decision Memorandum, there is evidence that NaF-18 PET is "more sensitive and selective than conventional bone scans for diagnosis and treatment of bone metastases."⁶ This conclusion is supported by the Evan-Sapir (2006) study CMS cites in the Proposed Decision Memorandum that found that, "compared with bone scans, NaF-18 PET/CT is highly sensitive and specific for detecting bone metastases in patients with high-risk prostate cancer, and has the potential to change patient management."⁷ NaF-18 PET also offers advantages to patients, such as a shorter wait between injection and imaging, compared to other bone scan methods. In addition, unlike bone scans using 99mTC, there have been no shortages of the resources needed to perform NaF-18 PET. ACCC believes that Medicare should allow patients and physicians to select the most appropriate imaging methods for each patient, and we encourage CMS to cover NaF-18 PET to ensure that patients have a choice of effective imaging modalities.

Moreover, although ACCC generally supports efforts to expand the body of evidence supporting clinical decision-making, we are concerned that limiting access to NaF-18 PET to beneficiaries who are enrolled in clinical trials would be overly restrictive. CMS notes that three clinical trials currently are recruiting participants to study oncologic uses of NaF-18 PET for detecting metastases,⁸ but it is not clear how many beneficiaries could participate in those trials or whether other studies would meet the requirements outlined in the Proposed Decision Memorandum. Because Medicare beneficiaries often are excluded from clinical trials due to co-morbidities or do not have access to providers who participate in trials because of where they live, the proposed decision could deny access to NaF-18 PET for a large number of beneficiaries. Rather than limiting coverage to beneficiaries who participate in a study, we recommend that CMS encourage beneficiaries and providers to participate in studies but not require participation for coverage of NaF-18 PET.

ACCC is grateful for CMS for its continuing efforts to expand coverage of diagnostic imaging for beneficiaries fighting cancer. Our members constantly search for tools to appropriately diagnose, treat, and manage cancer, and ACCC looks forward to continuing to work with CMS to establish coverage decisions that allow beneficiaries to access important technologies.

We would be pleased to answer any questions regarding these comments. Please contact Matt Farber at 301-984-9496 ext. 221 if ACCC can be of any assistance as CMS continues to evaluate NaF-18 PET.

Sincerely,

cc: Tamara Syrek Jensen, JD
Stuart Caplan, RN, MAS
Jeffrey Roche, MD, MPH

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Having utilized f18-pet bone scan imaging for the past year it can be stated without reservation that it is dramatically more accurate in identifying whether certain areas of uptake are related to malignancy or benign processes. This is because the addition of CT makes such an accurate localization of the uptake. Also, the dramatic sharpness of the images certifies the region of interest is real rather than vague. A real patient protector.If approval is not forthcoming a NOPR like trial would be in order. Routine bone scans are not only less sensitive, but much less specific. This is the best advance in bone scan lesion detection in decades. It takes also less patient time to perform, to uptake, and finally it takes the uncertainty out of the reading process.

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PET NaF-18 bone imaging is a more accurate modality than simple bone scanning for detection and characterization of bone lesions, especially metatases. It has and will provide more accurate staging for most cancers, and will be more likely to upstage cancers and save money in the long run. It provides an alternative for staging patients when technetium is unavailable (as has commonly occurred recently). It has been used extensively in my state (Washington) and I would like to provide that added diagnostic accuracy for my patients. At a minimum, please allow NaF-18 PET to fall under NOPR rules.

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NaF PET bone imaging is to be used in place of and is superior to routine bone scintigraphy and SPECT bone imaging, as demonstrated in the published literature referenced by CMS.

PET bone imaging with NaF-18 provides multiple benefits over routine scintigraphy with Tc-99 MDP:

1) Imaging with NaF can start 90 minutes after injection in contrast to Tc-99 MDP bone scintigraphy that requires a 3-hour delay. This results in faster turn around time for patients who are often in pain and cannot wait long.

2) PET bone imaging provides a whole body tomographic study whereas standard bone scintigraphy with SPECT imaging is limited to tomography over 1-2 fields of view with SPECT so as to not overlengthen the SPECT imaging time. Because it is a whole body tomographic study, the improved resolution of NaF PET/CT (over SPECT) will apply to any lesion anywhere within the skeleton. On the contrary, because of its length of acquisition, MDP SPECT imaging is usually only performed over an area of pre-existing pain/findings and may not be performed over other areas where more subtle lesions could not suspected on the basis of a simple planar scintigraphy.

3) Contrary to traditional bone scintigraphy which is qualitative, PET bone imaging is quantitative and provides an accurate measure of bone turnover in every area or lesion of the skeleton. This permits the objective assessment and follow-up of bone disease, bone healing and bone lesions during a course of treatment.

More specifically for cancer patients, this PET bone imaging will provide:

1) An increased ability to detect subtle metastatic lesions that were not detectable by routine scintigraphy. In time, this will alter patient care and management. More specifically for patients found to have early bone metastases, it will permit early detection of stage IV disease and will enable early initiation of appropriate chemotherapy or hormonal therapy and will avoid costly and futile surgical resection of the primary tumor. This is expected to have the most impact in prostate and breast cancers.

2) An improved ability to determine response of bone metastases to chemotherapy or hormonal therapy. Because the uptake of NaF in bone metastases will be measurable objectively, it will permit to follow response of these lesions.

More specifically for non-cancerous bone imaging, NaF PET/CT will enable imagers to better evaluate response of bone grafts for healing, and healing versus loosening for joint replacements.

In both cancer patients and orthopedic patients the availability of a synchronous bone CT scan performed by the PET/CT will allow more accurate assessment of the areas of increased NaF uptake wherever they occur in the skeleton.

In conclusion, for the above reasons CMS should approve broad coverage of NaF bone imaging and because it is more accurate than traditional bone scans.Furthermore, in area of Tc99m/Mo99 shortage patients need access to an alternative to Tc-99m based bone scans because the supply of molybdenum has been and will remain problematic for the foreseeable future. Approving NaF PET/CT would not only permit better bone imaging for our patients and less delay in care during times of Tc99m shortage, it would also enable suppliers of Tc99m to dedicate limited amounts of Tc99m available to the manufacturing of radiotracers having no PET equivalent.

If NaF is not broadly covered, we would recommend the creation of a national registry like the NOPR - Our patients need access to NaF PET bone scans and the only way to ensure access for all Medicare beneficiaries nationwide under CED is a national registry.

Finally, NaF for PET bone scanning is broadly available commercially making NaF PET/CT a valid option for our patients, many of them having suffered from the shortage of Tc99m.

In our personal experience with NaF PET bone scanning at the University of Washington, the NaF PET/CT has been found to be an invaluable tool in the evaluation of cancer patients. The scan has been highly sensitive and more than MDP bone scintigraphy, and the availability of a fused CT scan has permitted confident detection of early bone metastases.

For all the above reasons, I recommend that CMS should approve broad coverage of NaF bone imaging.

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There is a significant body of literature (most of the published by groups around Einat Even-Sapir, Israel and Holger Schirrmeister, Germany) indicating the higher sensitivity and specificity of NaF bone scan compared to conventional bisphosphonate bone scan. It should be noted, however, that NaF bone scan is more expensive to acquire (higher cost of a PET scanner compared to a SPECT camera) and more time consuming to read than bisphosphonate bone scan. Therefore, the indications for NaF bone scan should be very selective, and reimbursement similar to FDG PET is needed. At the same time, bone scan is being replaced in many cancers by FDG PET.

In my view NaF and FDG are two of many PET radiotracers that we will hopefully have in a few years for “personalized PET scan.” Furthermore, prostate cancer patients would benefit most from NaF bone scan. In particular, the higher resolution of PET would probably help in an early detection of bone metastasis in prostate cancer patient with increasing PSA after radiation therapy with curative intent.

Based on the above, and considering the national shortage of Technetium, I believe that approval of NaF bone scan for staging and restaging of prostate cancer with or without NOPR-type data collection would benefit our patients.

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I am an oncologic imaging subspecialist with broad expertise in PET-CT imaging. I was trained in PET-CT at MD Anderson Cancer Center where I spent 12 years on faculty, and subsequently moved to Seattle, WA to join a radiology practice that was opening a PET-CT service. I have used F-18 NaF PET-CT, and have ready access to the radiopharmaceutical though out supplier, PETNet.

In my opinion, CMS should approve broad coverage of NaF bone imaging because it is a bone scan, and is different from PET-CT for cancer imaging. The lack of procedure codes for this exam and limitations on the number of covered PET-CT scans that a given patient can have has made it exceedingly difficult to get one of these scans when they are needed. The literature supports NaF PET bone scanning and in fact, shows that it is more accurate than traditional bone scans. Lastly, in an era when molybdenum-based technetium generators are in exceedingly limited supply, we have encountered numerous instances in which Technetium-based bone scan agents have not been available for weeks at a time, and we need this alternative bone scanning technique for the inevitable future instances of this shortage.

If broad coverage for NaF PET-CT is not provided, then I strongly recommend a national registry like the NOPR for this technique. The NOPR has proven to be an excellent, controlled method of initially covering an imaging modality and subsequently analyzing the data to decide CMS coverage in the future.

Marc Jacobson, M.D. Via Radiology Seattle, WA

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December 23, 2009

Re: Proposed Decision Memorandum for Positron Emission Tomography (NaF-18) to Identify Bone Metastasis of Cancer (CAG 00065R1) (CAG-00065R)

From: Clinicians, Radiologists, Nuclear Medicine Physicians at Swedish Cancer Institute, Seattle, WA.

F18-NaF Bone PET imaging is available from our PET provider and is used daily. The availabilty of F18-NaF at our institution has improved the diagnostic accuracy of bone scintigraphy over the past 7 years. We believe this is a more accurate test than conventional scintigraphy and have relied on F18-NaF Bone PET scans to treat and stage our patients since 2002. We have a high level of confidence in the performance of F18-NaF Bone PET imaging.

CMS should approve broad coverage of F18-NaF PET bone imaging because: it is simply a better bone scan and bone scanning is broadly approved by CMS; the literature supports F18-NaF PET bone imaging and consistently demonstrates that it is more sensitive and accurate than traditional bone scans; patients need access to an alternative bone scan due to the prolonged issues associated with Mo99m shortage that has placed limits on access to Tc99m based tracers.

Alternatively, if CMS believes that additional evidence is required, we support the creation of a national registry (NOPR) to gather evidential data on the performance of F18-NaF Bone PET.

Our Medicare patients need access to F18-NaF PET Bone Scans and the only way to ensure accesss for all Medicare beneficiaris nationwide is through broad coverage or a national CED registry.

Thank you for your consideration of these comments.

Erin Ellis, MD,Oncologist, Swedish Cancer Ins
Saul E. Rivkin, MD, Oncologist, Swedish CA Ins
Henry Kaplan, MD, Oncologist, Swedish Cancer Inst
John Fitzharris, MD Oncologist, Swedish Cancer Ins
Mehmet Fer, MD, Oncologist, Swedish Cancer Inst
Timothy Mate, MD, Radiation Oncology, SCI
Vivek Mehta, MD, Radiation Oncology, SCI
James V. Rogers, MD, Diagnostic Radiology, Swedish
Carolyn Wang, MD, Diagnostic Radiology, Swedish
Sarah Sheikh, DO, Diagnostic Radiology, Swedish

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I believe that CMS should approve broad coverage of NaF-18 bone imaging because:

1. It is a bone scan and should be covered
2. The literature supports NaF PET bone scanning and in fact, shows that it is more accurate than traditional bone scans
3. Patients need access to an alternative to Tc-99m based bone scans because the supply of molybdenum has been problematic for the last two years and this could continue through 2010. It has been difficult to get standard bone scans done in needed situations.

If NaF is not broadly covered, then I recommend the creation of a national registry like the NOPR.Our patients need access to NaF-18 PET bone scans and the only way to ensure access for all Medicare beneficiaries nationwide under CED is a national registry.

We do have access to NaF-18 radioisotope for PET bone scanning in our community Thank you for thorough consideration.

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Men’s Health Network (MHN) appreciates CMS’s proposed coverage with evidence development for 18F-NaF. However, we considerately request that CMS extend full coverage to 18F-NaF for PET. We also request that CMS issue a final national coverage decision as soon as possible, to facilitate patient access to critical PET scans. PET scans are a critical component in the development of treatment programs for cancer patients with suspected bone metastases.

MHN is concerned about the negative impact on prostate cancer and other cancer patients. Men with advanced prostate cancer are at high risk for development of bone metastases, resulting in clinically significant skeletal morbidity and severe bone pain. Although advances in the treatment of prostate cancer have extended life expectancy, 65% to 75% of patients with advanced disease will develop bone metastases, resulting in accelerated bone resorption and a loss of skeletal integrity that is associated with significant skeletal morbidity, including pathologic fractures, spinal cord compression, and debilitating bone pain.

As far as we are aware, no safety issues have been reported with 18F-NaF, and the FDA conducted a formal review of PET drugs in 2000 that specifically deemed 18F-NaF to be safe and effective. Moreover, the National Cancer Institute has conducted an extensive literature review that evaluates the clinical value of 18F-NaF for bone imaging.

As CMS knows, there is a growing shortage of the Technetium-99m (Tc-99m), the radionuclide used in approximately 80 percent of nuclear medicine scans worldwide, including PET scans. Molybdenum-99 (Mo-99) decays into the medical isotope Tc-99m. Unfortunately, the domestic supply is entirely dependent upon the production capacity of a small handful of international reactors located primarily in Canada, South Africa, and the Netherlands. Since 2007, the domestic supply of the isotopes has fluctuated dramatically, as the aging international reactors have become progressively more prone to extended shutdowns for repair and maintenance. This isotope shortage has led to a significant reduction in the availability of bone scintigraphy. As a result, many Medicare beneficiaries with cancer who need bone imaging immediately face the prospect of lengthy delays or alternative diagnostic procedures that may involve greater radiation dosage, less accuracy, or higher cost.

Coverage of 18F-NaF for PET would help alleviate the impact of the Mo-99/Tc-99m shortage, by providing an alternative, but equally safe and effective, isotope for certain nuclear imaging scans. Moreover, it will free up the limited supply of Tc-99m for other nuclear medicine procedures and other patients.

Congress has recognized the urgency of this situation. The House of Representatives has recently passed legislation (H.R. 3276) that would promote the safe and reliable domestic production of Mo-99. This bill is now in the Senate.

We ask that in the final decision CMS consider full coverage of 18F-NaF PET to facilitate immediate patient access to 18F-NaF PET.

MHN appreciates the opportunity to provide comments regarding 18F-NaF for PET.

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1. CMS should approve broad coverage of NaF bone imaging because:

2. If NaF is not broadly covered, then we recommend the creation of a national registry like the NOPR - Our patients need access to NaF PET bone scans and the only way to ensure access for all Medicare beneficiaries nationwide under CED is a national registry

3. We have access to NaF for PET bone scanning

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As an expert in treatment of bone sarcomas and bone metastases, NaF PET would be a welcome and extremely useful study. It would for the first time provide quantitative instead of qualative data concerning osteosarcoma and Ewing''s sarcoma primary and metastatic disease - and also permit much better decisions to be made concerning both chemotherapy options and local control strategies. I would Strongly Encourage the adoption of very Broad coverage for both work-up, treatmetn evaluation and re-staging of all cancers involving bone and/or bone metastases. This better information should make quality adn quantity of life better for citizens with cancer involving bones.

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1. CMS should approve broad coverage of NaF bone imaging because it is a bone scan that should be covered, the literature supports NaF PET bone scanning and shows that it is more sensitive and accurate than traditional Tc-99m bone scans and patients need access to an alternative to Tc-99m based bone scans because the supply of molybdenum has been problematic for the last two years and this could continue through 2010 and beyond.

2. If NaF is not broadly covered, then CMS should consider creation of a national Coverage with Evidence Development registry like the NOPR. Patients need access to NaF PET bone scans and the only way to ensure access for all Medicare beneficiaries nationwide under CED is a national registry.

3. We have access to NaF for PET bone scanning, so access to the radiopharmaceutical and PET scanner in our area is readily available and could be implemented immediately.

4. The scans are quite exquisite in their image, especially compared to Tc-99m bone scans. They provide quite a high level of resolution which improves the sensitivity and accuracy which would likely improve patient care while reducing radiation dose because of the much shorter half-life of NaF compared to Tc-99m.

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On behalf of Alliance HealthCare Services and its Alliance Imaging division, the largest provider of PET/CT services in the nation, we appreciate the opportunity to comment on CMS’s reconsideration of its coverage for NaF-18 PET/CT in connection with the identification of bone metastasis of cancer. As stated in our previous comments on the subject of expansion of Medicare coverage for PET/CT, we strongly encourage CMS to establish a coverage framework which ultimately relies on the professional judgment of treating physicians to determine the appropriate use of PET/CT without imposing unnecessary burdens or preconditions on such physicians’ ability to obtain Medicare coverage for their patients.

While we support CMS’ proposal to cover NaF PET/CT through Coverage with Evidence Development (CED), we believe the literature and clinical need justify the use of NaF PET/CT based solely on the professional judgment of the treating physician.

In support of the clinical efficacy of NaF-18 PET/CT, we offer the following background and supporting data. NaF-18 was developed as a skeletal imaging agent by Medi+Physics (now GE HealthCare) in the early 1970s and was approved for use as NDA # 17-042 on February 24, 1972. The product was discontinued in 1975 due to production and distribution limitations given NaF-18’s short half-life (less than 2 hours) and the small number of positron imaging devices in service at the time. Due to the growth in availability of, and the number of indications for PET/CT, neither of these obstacles exists today.

Sodium fluoride F-18 injection has been in routine clinical use in a number of clinical sites with the radiotracer being prepared in-house at those facilities with a cyclotron or by ordering the agent on prescription from a central PET/CT center. Considerable clinical experience has now been accumulated with NaF-18 skeletal imaging performed with advanced imaging and CT co-registration systems.

Of note, NaF-18 PET/CT has been shown to have higher sensitivity, specificity, positive predictive value, and negative predictive value than (99mTc-MDP) planar bone scintigraphy (BS), SPECT, and FDG PET/CT alone in the assessment of the presence of bone metastasis in patients with high risk prostate cancer (1). In fact, NaF-18 PET/CT may have sensitivity, specificity, positive predictive value, and negative predictive value that is nearly twice that of the standard technetium bone scan (1, 2). This is especially the case in the spine and pelvis, where the sensitivity of BS may drop to 40% or below (3). The finding in prostate cancer has been duplicated in patients with breast cancer, where more than twice as many lesions were found with NaF-18 PET/CT than with BS, resulting in changes in clinical management in greater than 15% of the patients enrolled in two separate studies (2, 4). NaF-18 PET/CT was also shown to have twice the sensitivity and negative predictive value as FDG PET/CT, while the later had a greater specificity and positive predictive value. By combining the two PET/CT studies, near 100% sensitivity, specificity, negative and positive predictive value could be achieved, a result that is not dependent on anatomic location (unlike with BS as mentioned above). Investigation into the use of NaF-18 PET/CT in evaluation of newly diagnosed lung cancer also showed altered clinical management in greater than 10% of patients as compared to BS (5).

In total, more than 41 clinical trials investigating the use of NaF-18 PET/CT as a bone imaging agent have been published since 1992. These studies indicate that NaF-18 PET/CT is superior to 99mTc-MDP planar scintigraphy or SPECT in detecting primary bone cancer and skeleton metastases from a wide range of cancers, including cancer of the breast, lung, and prostate. NaF-18 PET/CT has proven to be more sensitive and specific than other techniques, resulting in altered clinical management in a significant number of patients. The use of low-dose CT in conjunction with NaF-18 PET/CT improves sensitivity and specificity, and improves the ability to distinguish benign from malignant lesions. There is an approved NDA for sodium fluoride F-18 injection, indicated for PET/CT as a bone imaging agent to defined areas of altered osteogenic activity (NDA 17-42). The FDA''s prior approval of this agent for this indication demonstrates the existence of adequate safety and effectiveness information for this product. Furthermore, a widespread shortage of Technetium-99m (Tc-99m) — the only radioisotope approved for bone scans — has significantly reduced cancer patients’ access to bone cancer imaging. Providing coverage for NaF-18 PET/CT would allow Medicare beneficiaries who require imaging for bone metastases to reduce the lengthy delays they may now experience when prescribed a BS, or eliminate the need to consider alternative diagnostic procedures that may involve greater radiation dosage and provide a less accurate diagnosis.

In conclusion, we believe the effectiveness and safety data indicate that NaF-18 PET/CT has an important role to play in the management of a range of cancers that are likely to metastasize to the bone. We believe that, given the shortage of Tc99m that the Nuclear Medicine community is experiencing, and most likely will continue to experience, NaF-18 PET/CT may in fact be required in order to provide patients with the level of care that they should expect to receive. Therefore, on the basis of the existing clinical and safety evidence, and the clinical need for a study to supplement Tc99m Nuclear Medicine scan, we ask that CMS cover NaF-18 for use in oncology without restriction.

Sincerely yours,

Mark P. Carol, M.D.
Chief Medical Officer
Alliance HealthCare Services

(1) Einat Even-Sapir, MD, PhD; Ur Metser, MD; Eyal Mishani, PhD; Gennady Lievshitz, MD; Hedva Lerman, MD; and Ilan Leibovitch, MD , The Detection of Bone Metastases in Patients with High-Risk Prostate Cancer: 99mTc-MDP Planar Bone Scintigraphy, Single- and Multi-Field-of-View SPECT, 18F-Fluoride PET, and 18F-Fluoride PET/CT, J Nucl Med 2006; 47:287–297.

(2) Holger Schirrmeister, Albrecht Guhlmann, Jo¨rg Kotzerke, Claudia Santjohanser, Thorsten Ku¨hn, Rolf Kreienberg, Peter Messer, Karin Nu¨ssle, Klaus Elsner, Gerhard Glatting, Harald Tra¨ger, Bernd Neumaier, Christoph Diederichs, and Sven N. Reske, Early Detection and Accurate Description of Extent of Metastatic Bone Disease in Breast Cancer With Fluoride Ion and Positron Emission Tomography, J Clin Oncol 17:2381-2389. 1999

(3) Holger Schirrmeister, Albrecht Guhlmann, Klaus Elsner, Jorg Kotzerke, Gerhard Glatting, Marion Rentschler, Bernd Neumaier, Harald Trager, Karin Nussle and Sven N. Reske Sensitivity in Detecting Osseous Lesions Depends on Anatomic Localization: Planar Bone Scintigraphy Versus 18F PET, J Nucl Med 1999; 40:1623-1629

(4) Nishikant Damle1, Chandrasekhar Bal1, Gurupad Bandopadhyaya1, Lalit Kumar2 and Praveen Kumar, Role of 18F Fluoride PET/CT in the detection of bone metastases in breast cancer patients, J Nucl Med. 2007; 48 (Supplement 2):142P

(5) Holger Schirrmeister, Gerhard Glatting, Jurgen Hetzel, Karin Nu¨ssle, Coskun Arslandemir, Andreas K. Buck, Kerstin Dziuk, Andreas Gabelmann, Sven N. Reske, and Martin Hetzel Prospective Evaluation of the Clinical Value of Planar Bone Scans, SPECT, and 18F-Labeled NaF PET in Newly Diagnosed Lung Cancer J Nucl Med 2001; 42:1800–1804.

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IN my experience with the NaF-18 bones, the NaF-18scans are better for the patents. The resolutionon the pictures are better then Tc bone scans. The NaF-18 scans can be put into several differentviews like axial,sagittal, coronal planes. It canalso put into a 3-D or MIP were the image can berotate 360 degrees. The Tc bone scan can only beviewed in two planes. The NaF-18 scan seems topick up more tumors then the Tc bone scan. Withthe better resolution, different planes to viewthe images and the greater detectable, the NaF-18is better over all exam for the patient. Thanks
Matt Murphy RRT.

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I have been fortunate enough to run a Nuclear Medicine clinic at a VA hospital equipped with a state of the art PET-CT machine that I started to use for oncologic bone scans with F-18 about 2 years ago when a Tc-99m shortage started melooking for alternatives. Curiously enough the literature''''s justification for using F-18(Na)as a much superior agent (compared to the usual Tc-99m MDP bone scan)was there all along. I had read it. It just didn''''t register. When I did my first F-18(Na) scan I was shocked at my own stupidity. The scans were superb and remarkably more useful with the built in PET-CT fusion than everything I had done for 30 years. I should have been using PET-CT for oncology bone scans to fulfil my committment as a physician to provide the best in care for my patients. Once I started doing these scans I could not go back to inferior planar and SPECT Tc-99m bone scans. Thank God I''''m a veteran if I ever need a bone scan. I''ll get it in my own shop with the best diagnostic information I can get, not the best diagnostic information I can get paid for!

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The decision to approve F18 bone scintigraphy should be rather elementary. With the anticipated shortage of Tc on the horizon, and the superior count statistics achieved with F18 and consequent increased resolution and anatomic localization, the utilization of F18 bone scans on current generation PET scanners will provide for enhanced patient care and management. Having interpreted more than 1000 F18 bone studies, I have found that F18 bone scintigraphy is clearly superior to the results obtained with conventional bone scintigraphy studies.

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Dear CMS,

I would like to comment on the review of NaF-18 for bone metastases. I have had the opportunity to utilize Na-F in a select number of patients. As have others who have published, I found the images to be of superior quality to standard MDP studies, and was most impressed with the combination of PET and CT (for improved specificity). I support the approval of Na-F as an alternative to MDP for a number of reasons. First, the sensitivity and specificity with Na-F is much higher than with MDP, approaching 100%. Patient radiation dosimetry is similar (actually lower at the bone surface for Na-F). The addition of low mA CT is extremely beneficial, and should save additional x-rays, CTs, and MRIs. This will ultimately be cost effective as well as shorten the patient''s evaluation period (and lessen anxiety due to the oft-requested additional testing). Waiting time between injection and imaging is much shorter with Na-F (i.e., 45-60 minutes vs. 3 hours for MDP), and every patient who undergoes Na-F imaging received a tomographic study which dramatically improves quality and lesion detectability. There are two other areas for consideration. Most studies of new therapeutic agents require monitoring examinations, often bone scans in patients with cancer. The superiority of Na-F would seem to be very important for an accurate assessment of patient response to investigative agents. Finally, there are a number of tumors which are traditionally negative on MDP studies while bony metastases are truly present (false negative). These tend to be tumors whose bone metastases are "lytic", such as thyroid, renal, myeloma, etc. It would be of great value to assess the accuracy of Na-F in these cases, again, to improve staging, monitoring response to therapy, and perhaps prolonging survival. Summarily, I feel Na-F would be a useful addition to MDP for the evaluation of bone lesions (benign and malignant) and should be approved.

Respectfully,
Michael S. Kipper, M.D.
Clinical Professor of Radiology, UCSD

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We used NaF-18 PET/CT for research purposes in the past 3 years at our institution and were impressed with the high quality of the images and the diagnostic accuracy of this imaging test. The published results of our studies confirm this. More importantly, our colleagues in Oncology used the information from these bone scans to change the management of their patients. At a time when the supply of Tc-99m MDP is unreliable, having the ability to better image the skeleton is a wonderful addition to the diagnostic armamentarium of the clinicians and should definitely be considered for reimbursement.

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As the Clinical PET Specialist for several Florida based imaging providers I would like to express my support of PET bone imaging with NaF-18.

Frankly, it is long overdue. The technological benefits of PET over general Nuclear Medicine bone imaging (including SPECT) are clearly superior as documented in almost every clinical study. Unlike many other advances in imaging technology, PET bone imaging has few if any negatives:

Generally NaF PET Bone imaging is a NO-Brainer and I speak for many when I say "Thank you for, not only recognizing its benefits, but for making it accessible to the public"!

Respectfully,
Darren R. Miller

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As an owner and operator of three PET/CT centers (as well as a Nuclear Medicine Technologist), I can categorically state that the availability of F-18 in major metropolitan areas is more than adequate to accomodate the increase in utilization for F-18 PET Bone Scans. This in turn will greatly reduce the strained demands on nuclear medicine departments for Tc99m based scans including standard nuclear bone scans. In addition, numerous clinical journal articles have more than demonstrated an increase in sensitivity and specificity of F-18 PET Bone Scans over Tc99m based gamma bone scans as well as dramatic improvements in spacial and contrast resolutions thus leading to improved interpretive results. This is absolutely a case where public policy can effect a dramatic improvement over the quality and availability of this vital diagnostic tool in fighting cancer. Not only for Medicare recipients but in effect for all patient populations as the availability of F-18 Pet Bone Scans will help alleviate the demands on all Tc99m based scans. There is no real reason not to approve F-18 Bone Scans for general use without any further evidenced based trials. If that is the only way to advance this study, however, then it should be approved in such a way as to make this scan readily available for all Medicare recipients in as easy a format as possible. The shortage in Mo-99 and thus Tc99m will only become much worse over time before we see any improvement many years in the future.

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The study of NaF-18 in its efficacy of lesion detection is an appropriate study to perform as decided by CMS. However, additional issues must be considered in the unique uses of this type of study; namely, that aside from its broad use as a diagnostic tool, this tool should also be strongly considered for certain ''niche'' applications for which this may be the ONLY or BEST tool to use. Some applications to consider are as follows, but by no means are the only ones:

1) Dual tracer scanning - CMS is not considering using the Hoegerle 1998 and other similar articles in its diagnotic evaluation. However, this particular application of imaging may be a diagnostic advantage in these situations. Performing multitracer evaluations not only improved diagnostic accuracy, but also saves the patient from getting serial scans (ie. FDG and NaF scans, instead of just a single FDG+NaF scan; etc.). This alone would be a huge cost and time saving to both the patient and the clinic.

2) With a growing obese population, the diagnostic capabilities of traditional Tc-99m based bone scanning is becoming extremely limited. This is where NaF-18 PET scan would certainly add value, much as is analogous to Cardiac PET perfusion imaging with NH3 or Rb-82 tracers, vs. the perfusion SPECT tracers.

3) Analogously to Cardiac PET vs. SPECT imaging, NaF also has better tracer kinetics, and allows shorter times for imaging, and yet yielding far greater diagnostic quality images than would be possible by SPECT in the same time span. The superiority of the diagnostic quality of NaF-18 in even the regular population (let along the obese) is clear, as pointed out by the Evan-Sapir 2006 and other similar articles. Time saving also leads to cost savings.

4) Bone scans have a wide variety of uses. One of them is the confirmation of disease presence of osseous metastatic disease in patients being evaluated for bone palliation radionuclide therapies such as Quadramet (Sm-153 EDTMP), Metastron (Sr-89 Cl), etc. Whereas Quadramet and other similar agents are pharmaceutically similar to the Tc-99m agents (and thus better evaluated by them for therapy), agents such as Metastron, and newer ones in development such as Ra-223 are pharmacologically more similar to NaF-18 kinetics, and better evaluated by PET than SPECT tracers. Additionally, Ra-223 may have potential applications beyond palliation (once approved), and accurate knowlege of isotope distribution using pre-therapy NaF-18 scanning will be vital.

5) Of note, current Tc-99m bone scanning goes far beyond malignancy evaluation, and is important for detection of benign etiologies such as infections/osteomyelitis, fractures, etc. NaF-18 is probably more accurate for these evaluations than current traditional methods.

6) There are some inherent advantages in PET, in particular, its quantitative nature, which are very useful in the evaluation of benign diseases.

7) Of practical importance already mentioned by many others is the worldwide shortage of Tc-99m tracers for the foreseeable future, which limits the availability of bone scans in general, one of the most basic Nuclear Medicine procedure which continues to be used by Oncology and other fields. Of note, countries like Israel and others have allowed the use of NaF-18 scanning on this basis, which is vital to the workup of many patients.

In summary, CMS should consider not only the broad uses of NaF PET, but also specific ''niche'' uses as briefly outlined above for which NaF imaging provides unique information not available by other means. It would also provide a time and likely also cost effective strategy in many situations, and should be available as an alternate, if not also amongst the first line imaging procedures, to the traditional bone scanning.

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