Blood Brain Barrier Disruption (BBBD) Chemotherapy

We are writing in support of osmotic blood brain barrier disruption (BBBD) as an important procedure for the treatment of patients with certain brain tumors. As members of the Cleveland Clinic Brain Tumor and Neuro-Oncology Center, a multidisciplinary group which includes neurosurgeons, radiation oncologists, neuro-oncologists, medical oncologists, nurses and a research infrastructure, we care for patients with CNS malignancies on a daily basis. This letter addresses the CMS proposed decision memo (CAG-00333N) that states, “The use of osmotic blood brain barrier disruption is not reasonable and necessary when it is used as part of a treatment regimen for brain tumors.”

The outcomes data which are well summarized in the memo, clearly suggest that for certain malignancies, BBBD is an efficacious treatment with manageable short-term complications and, more importantly, long-term preservation of cognitive function (McAllister). In one of the largest series of patients with primary CNS lymphoma (PCNSL) ever reported, 177 patients received BBBD, 25% of whom are still alive at 11 years of follow up (Angelov). In contrast, radiation-based regimens have essentially no survivors after 5 years (Miller). Thus BBBD offers excellent therapy for selected patients.

The memo cites the lack of randomized controlled trials that use BBBD in patients with brain tumors. With the exception of common cancers such as lung, breast and prostate cancer, most malignancies occur at numbers that are too small for phase III clinical trials to establish standards of care. Several reports have documented this problem in CNS malignancies. These reports include a recent publication by Abrey in the Journal of Clinical Oncology which discusses the impossibility of performing phase III clinical trials in patients with rare malignancies such as primary CNS lymphoma (Abrey, 2005). An analysis by Dale Kraemer, biostatistician at Oregon State University, has concluded that a phase III trial in primary CNS lymphoma would take 10 to 15 years to accrue a requisite number of patients for adequate statistical analysis. Clearly, such a trial is not feasible and is not reasonable scientifically.

Despite the absence of phase III data, the FDA has approved treatments for brain and other malignancies on the strength of phase II data. For example, temozolomide for the treatment of refractory anaplastic astrocytoma was originally approved on the basis of phase II data. Standard therapies for a number of other malignancies have emerged on the strength of case series and phase II trials. Current standards of care for primary CNS lymphoma, for example, include high dose IV methotrexate and chemotherapy with radiation therapy, both of which have been considered state-of-the-art management on the basis of phase II trials published in peer-reviewed journals. The same criteria have applied to the use of BBBD. While the technical aspects of this procedure are more complicated, the evidence in favor of this treatment modality is certainly of the same quality. Medicare has covered most procedures for less common malignancies without phase III data and should not deny coverage for patients who benefit from BBBD.

The memo states that the medical literature regarding BBBD has several additional limitations. The small numbers of cases reported is criticized. The recent report of 177 PCNSL patients treated with BBBD, however, is among the largest data set ever reported for this rare tumor (Angelov). The memo also states that the BBBD literature cannot be generalized to the Medicare population because ages are not reported or the populations are not of Medicare age. The report by Angelov, however, does separate patients older than 60 years: 30% survived at least 4 years, and 20% survived at least 6 years. While some BBBD data might not be specific for the Medicare population, it is well known that PCNSL patients in this population who receive radiation-based therapy have a rate of treatment related dementia in excess of 80% (Abrey, 2000).

Further advances in drug therapy have lent themselves uniquely to BBBD therapy for patients with CNS malignancies. For example, standard agents such as trastuzumab and rituximab for the treatment of her-2/neu positive breast cancer and lymphoma, respectively, have improved survival for patients with these malignancies. These molecules, however, do not cross the BBB and in general are not useful for treatment of CNS dissemination of these malignancies. Indeed, the incidence of brain metastases from breast cancer in the trastuzumab era has increased substantially (Bendell, 2003; Kirsch, 2005). Increasingly, women with controlled systemic disease face the threat of progressive brain metastases largely due to inadequate delivery of molecules such as trastuzumab. BBBD protocols are now addressing delivery issues in these patients with the hope of improving efficacy and quality of life. Furthermore, advances in other fields of medicine are exploring the use of enhanced delivery of agents such as proteins, genes, and nanoparticles for a wide variety of conditions such as Alzheimer’s disease. Reliable delivery to the brain is critical for development of these novel therapies.

In summary, BBBD has a clear role for patients with primary CNS lymphoma, as well as for other CNS malignancies and should be regarded as reasonable and necessary. A decision by CMS not to cover BBBD would be counter to the overwhelming scientific evidence in its favor and inconsistent with CMS coverage policies regarding other treatments for PCNSL and other brain tumors. While BBBD requires specific training, expertise, and a dedicated team approach, selected patients clearly benefit from this method of chemotherapy delivery. Furthermore, patients with PCNSL and other brain tumors should have the opportunity to participate in BBBD clinical trials. Our nation has an ethical obligation to our patients to advance the state of the art of medicine. The development of new therapies for brain tumors and other CNS conditions using agents such as antibodies and genes will succeed only with adequate delivery to the brain. Medicare noncoverage of BBBD will severely limit this possibility.

David M. Peereboom, MD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center
Medical Oncology

Gene H. Barnett, MD
Chairman, Cleveland Clinic Brain Tumor and Neuro-Oncology Center
Neurosurgical Oncology

Lilyana Angelov, MD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center
Neurosurgical Oncology

Glen H.J. Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center
Neuro-oncology

Sandra Ference, CNP
Cleveland Clinic Brain Tumor and Neuro-Oncology Center
Nursing

Abrey LE et al. J Clin Oncol 18:3144, 2000Abrey LE et al. J Clin Oncol 23:5034, 2005Angelov L et al. Abstract submitted for Am Society of Clinical Oncology Meeting, 2007Bendell JC et al. Cancer 97:2972, 2003Kirsch DG et al. J Clin Oncol 23:2114, 2005McAllister L et al. Neurosurg 46:51, 2000Miller DC et al. Cancer 1994; 74:1383-97

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To Whom it May Concern:

We are responding to the proposed CMS decision for non-coverage of Blood-Brain Barrier Disruption (BBBD) chemotherapy for patients with malignant brain tumors. Thank you very much for the opportunity to comment. On behalf of our 7,000 members, the Oregon Medical Association wishes to strongly encourage CMS to reconsider the non-coverage proposal, and instead, consider coverage with evidence-based development. We understand that Edward Neuwelt, M.D., is submitting comment, and we fully support him.

The proposed decision states: “The use of osmotic blood brain barrier disruption is not reasonable and necessary when it is used as part of a treatment regimen for brain tumors. This NCD does not alter in any manner the coverage of anticancer chemotherapy.” Physicians around the country perform this procedure Dr. Neuwelt has been performing this procedure at Oregon Health & Science University (OHSU) for 25 years to treat rare malignant brain lesions that are often impervious to other therapies. It is essential to understand that since these patients suffer from rare conditions, it will be near impossible to produce statistically significant results. While we understand that evidence on BBBD may be considered lacking by some, we believe that the procedure warrants more review.

Further, we believe that a request for more research is consistent with the position stated in the draft decision:

“We propose that robust clinical studies that include Medicare beneficiaries are needed to identify which patients may benefit from BBBD used as part of a treatment regimen for brain tumors. Public comment has noted the historical barriers to conducting such studies. We believe that Medicare support for such studies may be accomplished through our Clinical Trials policy. The Clinical Trial Policy provides an opportunity for payment of some routine costs in a qualifying trial. See the Medicare NCD for Routine Costs in Clinical Trials (310.1), Medicare NCDs Manual, section 310.1, for a greater description of which costs would be covered.”

Given the number of years that the procedure has been performed successfully, and given that Dr. Neuwelt’s neurosurgical peers at other centers where BBBD is performed regard him as one of the leading and most innovative practitioners and scientists in this area of medicine, we hope that you will consider an alternative. We know that in the past, CMS has issued a decision of “coverage with evidence based development” as an option to non-coverage.

Oregon physicians have had a quarter of a century to evaluate this treatment and have found it valuable. Clearly, Dr. Neuwelt is respected and trusted, receiving the bulk of referrals from physicians around the state. Non-coverage for this particular treatment does a great disservice to the Medicare patients who are unfortunate enough to have rare and often otherwise untreatable cancer. A ruling of non-coverage will leave a significant number of patients with cognitive damage even though they have won the battle against cancer. Please reconsider this decision and allow coverage with evidence-based development.

Thank you for the opportunity to provide comment.
Sincerely,
Andris Antoniskis, M.D.

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Thank you for your time and the opportunity to provide input into this decision making process.

This comment is in response to the proposed CMS decision, which is now in public comment as of 12/27/06, for non-coverage of Blood-Brain Barrier Disruption (BBBD) chemotherapy for patients with malignant brain tumors. We wish to recommend an alternative decision, preferably: “coverage with evidence-based development”. If this is not possible, then we request that no decision be made.

The proposed decision states: “The use of osmotic blood brain barrier disruption is not reasonable and necessary when it is used as part of a treatment regimen for brain tumors. This NCD does not alter in any manner the coverage of anticancer chemotherapy.”

The proposed draft decision also states: “We propose that robust clinical studies that include Medicare beneficiaries are needed to identify which patients may benefit from BBBD used as part of a treatment regimen for brain tumors. Public comment has noted the historical barriers to conducting such studies. We believe that Medicare support for such studies may be accomplished through our Clinical Trials policy. The Clinical Trial Policy provides an opportunity for payment of some routine costs in a qualifying trial. See the Medicare NCD for Routine Costs in Clinical Trials (310.1), Medicare NCDs Manual, section 310.1, for a greater description of which costs would be covered.”

The following clinical protocols are NCI approved via the Oregon Health & Science University Cancer Institute, and are currently accruing patients. The protocols are registered in the NCI Physician’s Data Query (PDQ) Clinical Trials Registry, and to our knowledge fulfill the CMS criteria for “deemed protocols”

We would like to thank the Centers for Medicare and Medicaid Services (CMS) for the opportunity to address the proposed decision memo for Blood Brain Barrier Disruption (BBBD) Chemotherapy (CAG- 00333N). We understand that the proposal is to recommend a national coverage determination that states “The use of osmotic blood brain barrier disruption is not reasonable and necessary when it is used as part of a treatment regimen for brain tumors.”

We would like to take this opportunity to provide comment on this proposed determination. In particular we would like to vigorously add our objections to the proposed determination and offer rationale, evidence and legal proceedings that it would seem have not been considered as a part of the analysis to date. We offer eight points of consideration that ought to be included or at least acknowledged in making a final determination on coverage for the Medicare population.

Points of Consideration: 1) Evidence Review: In the decision summary, a broad and substantial review of the available literature was undertaken. The clinical studies were all characterized. They all showed positive results. The analysis provided in making the decision however chooses to review each as an independent study and because the body of literature lacks a randomized controlled study, all is rejected as inadequate. Yet these patients suffer from rare conditions and in fact it would take years to accumulate enough patients to recognize statistically significant results. All of the available literature covers decades of work in this area, and all of it shows positive responses to barrier disruption and chemotherapy. Taken in toto, this is a substantial body of work supportive of the treatment for a wide variety of tumors but most specifically and most positively primary central nervous system lymphomas.

2) Public Input: The review cited initial public comments from July to August 2006. These comments were provided by a wide variety of people including patients, providers as well as the experts in the fields of brain tumor therapy. All but two were favorable, mostly extremely so. The analysis fails to give sufficient weight to the comments from individuals with the most experience with the diseases treated and who understand the current limitations to treatment, the difficulty for the patient and their families and the difficulties of obtaining Class III evidence in rare diseases.

3) Public Input for non-coverage: There were only two. These two objections essentially cited lack of Class III evidence as the reason to recommend non-coverage. No other objections were itemized in the analysis. This point is addressed next.

4) Randomized Clinical Trial: The analysis provided suggested that in the end it was the distinct lack of randomized controlled clinical trials that lead to the decisions for non- coverage. Unfortunately, for conditions such as primary central nervous system lymphoma, there may never be enough patients to complete a randomized controlled study of competing treatment options. This is a rare condition. In the 1994 review by Miller, et al, Massachusetts General Hospital identified 104 patients over 31 years(1). During the time it would take to accumulate enough patients for an RCT, new therapeutic developments would and in fact have come along to significantly alter the options for treatment and a huge treatment bias is introduced through differences in care over such a length of time. This decision effectively sets a standard for rare diseases that cannot be met and sets a precedent by which all treatments for rare conditions will therefore eventually be non- covered.

5) Randomized Clinical Trial for Procedures: The Analysis states that ‘although our analysis must for clarity include discussion of the anticancer chemotherapy drugs that are administered after disruption of the blood brain barrier, we are not making a determination here about the reasonableness and necessity of anticancer drugs and biologicals for the treatment of brain tumors’. In the analysis, the decision for non-coverage lies solely with the lack of a randomized clinical trial for the procedure of blood brain barrier disruption itself. This raises another question of precedent. This decision now implies the intention that for the CMS, any procedure, past or future will necessarily be subjected to the same level of Class III evidence in order to avoid non-coverage. Many surgical procedures currently covered and thought appropriate have never and will never (and ethically should never) be subjected to the rigors of a randomized clinical trial. It has proven extremely difficult to perform an RCT for surgical procedures because of the very problems cited in the analysis, namely selection bias and study design.

6) We read with interest that the analysis was completed without the benefit of a Medicare Coverage Advisory Committee (MCAC) review. In this situation it would appear that a review by the MCAC would be warranted and in fact ideal because the analysis involves to a significant degree the successful treatment of a rare disease, primary central nervous system lymphoma, a limited number of people with a general understanding of the disease process, a very few experts in the field with significant understanding, and a procedure whose available literature shows uniformly positive results. An MCAC review would provide an opportunity for the CMS to fully explore the issues generated here such as while the limitations unique to the disease process generate controversy in the analysis of the literature, the procedure in question has the backing of those most knowledgeable in the field.

7) Decision for Non-coverage would put current patients in treatment in a precarious position and their providers in a legal catch- 22. The current protocols for the treatment of primary central nervous system (CNS) tumors with blood brain barrier disruption and intra-arterial chemotherapy, particularly for those with primary central nervous system lymphoma, call for a 12 month course of treatment. In the event of a non- coverage determination, it is suggested by the analysis that reimbursement for the procedure would cease immediately, leaving patients currently in treatment in limbo. Having reviewed the available literature and analyzed the risks and benefits of BBBD therapy verses other chemotherapy options that include whole brain radiation therapy these patients have elected to avoid radiation therapy because of the well published late side effects. They will be faced with limited viable options that do not include radiation. In addition, care providers and payers put themselves in a legal liability quandary if a successful intra-arterial chemotherapy protocol is stopped mid-treatment solely because of the decision for non-coverage. In 2002 in Dardinger, exr., v. Anthem Blue Cross & Blue Shield et al., the State Supreme Court of Ohio upheld a judgment in favor of the plaintiff’s surviving family when the third party payer in question decided to discontinue coverage in the midst of a monthly intra-arterial chemotherapy treatment regimen for CNS tumors. Judgment: $30 million.(2) Finally can any new patient make an informed choice about his or her therapeutic options knowing that a regimen with a greater than 10 year history of safety and with known efficacy and which avoids the use whole brain radiation therapy, exists but will not be covered? What legal exposure does that leave for the providers?

8) Other New Evidence: The authors of the analysis ask for any other or new evidence not considered in the preparation of the decision memo. The Blood Brain Barrier Disruption Consortium recently submitted to the American Society for Clinical Oncology their most recent long term survival data in patients with primary central nervous system lymphoma and primitive neuroectodermal tumors. These data underwent peer review and have been accepted by the American Society for Clinical Oncology for presentation at the 43rd annual meeting June 1-5, 2007. In a retrospective review of 177 patients treated by the consortium over 23 years with primary CNS lymphoma treated with osmotic blood brain barrier disruption and intra-arterial methotrexate based chemotherapy, 80% achieved either a complete or partial response. 40% attained progression free survival at 5 years, and a 40% survival plateau at 8 years was seen in the < 60 age="age" group.(3) Massachusetts General Hospital Experience over a 31 year period in which 104 patients were identified with primary central nervous system lymphoma and who were treated primarily with radiation. There were essentially no survivors beyond 5 years(1). It is noteworthy not only how successful the therapy in question is shown to be, but it is also important to note the length of time over which these patients in both studies were accrued. In a second similarly submitted and accepted review by the consortium, 29 patients with primitive neuroectodermal tumors were treated with blood brain barrier disruption and intra-arterial chemotherapy. Of that group, 59% had either a partial or a complete response, 40% survived at 4 years, and 30% at 8.7 years. 20% are alive >11 years. This data should be considered in any review of the merits of the procedure Blood Brain Barrier Disruption.

Recommendations

We respectfully request that the CMS reconsider its proposed decision and recommend instead that the use of Blood Brain Barrier Disruption in the treatment of CNS tumors is reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act. This form of treatment has been shown to be one of the best methods available in the treatment of primary CNS lymphoma, comparing favorably to all other available treatments all without exposing patients to the untoward significant long term risks of whole brain radiation therapy, and includes a significant number of long term survivors. The data reviewed is sufficient to allow a favorable review. The alternative, a sustaining of the non-coverage recommendation, would leave the Medicare population with a significant lack of access to quality care. It would leave them only alternative therapies where the risks of neurotoxicities are particularly significant in the Medicare population. It risks leaving a significant number of people with irreversible long term cognitive damage despite having won the battle against their cancer.

In the event that the CMS is unable to conclude that the use of Blood Brain Barrier Disruption is reasonable and necessary, we request that any decision be withheld at this time pending further review. There are ample data contained herein that warrants further study by the CMS. Consideration for a review by the MCAC should be seriously undertaken.

Finally, in the event that limitations to coverage are to be applied, strong consideration should be given to the recommendation that the CMS establish coverage for Blood Brain Barrier Disruption with evidence based development. This concept has been developed by the CMS and has precedent in cancer therapy. Specifically it would allow for the continued treatment with Blood Brain Barrier Disruption for Medicare patients under the support of Medicare and the CMS at those centers committed to trying to collect the data necessary to complete the kind of analysis that was outlined and requested in the memo.

Once again thank you for your consideration of the above discussion regarding the proposed decision memo for Blood Brain Barrier Disruption chemotherapy. If you have questions or require additional information, please do not hesitate to contact us at (614) 293-5440. We submit this, respectfully yours,

John McGregor, M.D., FACS
Assistant Professor Clinical
Department of Neurological Surgery
Director, Blood Brain Barrier Disruption Program

Herbert Newton, M.D., FAAN
Professor of Neurology, Pediatrics & Oncology
Director, Division of Neuro-Oncology
Esther Dardinger Chair in Neuro-Oncology
Co-Director, Dardinger Neuro-Oncology Center

E. A. Chiocca, M.D., Ph.D
Chairman and Dardinger Family Professor
Department of Neurological Surgery

The Ohio State University Medical Center
410 West 10th Avenue
Columbus, Ohio 43210
(614) 293-5440

(1) Douglas C. Miller, M.D., Ph.D., Fred H. Hochberg, M.D., Nancy L. Harris, M.D., Michael L. Gruber, M.D., David N. Louis, M.D., and Henry Cohen, M.P.H, Pathology with Clinical Correlations of Primary Central Nervous System Non-Hodgkin’s Lymphoma, CANCER, August 15,2994, Volume 74, No. 4

(2) Dardinger v. Anthem Blue Cross & Blue Shield, 98 Ohio St. 3d 77, 2002-Ohio- 7113. http://www.sconet.state.oh.us/rod/newpdf/0/2002/20 02-ohio-7113.pdf

(3) L. Angelov, N. D. Doolittle, T. Siegal, D. F. Kraemer, D. Peereboom, K. Jahnke, S. Ference, G. Barnett, J. McGregor, E. A. Neuwelt, on behalf of The Blood Brain Barrier Disruption (BBBD) Consortium; Blood Brain Barrier Disruption (BBBD) and Intra-arterial Methotrexate based therapy for Newly Diagnosed Primary CNS Lymphoma: The BBBD Consortium Experience, Control/Tracking Number: 07-AB-31829-ASCO

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Dear Drs.Phurrough,Jacques,Turner, and Rollins,

Thank you for the opportunity to respond to the NCD proposal for blood brain barrier disruption and subsequent administration of chemotherapeutic agents. As an interventional neuroradiologist at the Cleveland Clinic working with the members of the Brain Tumor Institute, I have personal experience both with the treatment as well as the patients. (My colleague Dr. Angelov has promised to correspond also in an effort to share some data.)

I found your review of the literature to be quite comprehensive. Nevertheless I was somewhat mystified by the similarly broad stroke of the conclusion/ coverage proposal. Specifically, there is clearly some acknowledgment that the PCNSL regimen detailed by Neuwelt et al is efficacious and with better results than those described by the NCI for conventional high dose chemotherapy. Kraemer et al documented that the response of the disease was proportional to the intensity of chemotherapy (no doubt highest if the blood brain barrier is open). And McAllister et al demonstrated that there is no significant impairment of cognitive function (unlike salvage radiation treatment.) My personal experience has been extra-ordinarily positive relative to this subset of brain tumor patients: the responses I have witnessed are frequently dramatic and durable. Why then, is this lumped with all other CNS primary and secondary neoplasms for denial of coverage? The politics of this sweeping proposal also make little sense if one considers the consituency of Americans who back Senator Brownback's proposed "Kianna's Law," the Abigail Alliance, and in the case of HIV related PCNSL, ACT UP.

Beyond PCNSL, I would agree that there needs to be much more rigorous data, which in the context of rare diseases is often difficult to collect in a randomized process among widely dispersed medical centers with limited patient flow to justify site monitors, data entry personnel etc. This is the perfect scenario for an RFP piloting secure electronic data collection, perhaps even as part of the clinicaltrial.gov web site.

In conclusion, my personal experience leads me to strongly believe that BBBD chemotherapy for PCNSL is highly efficacious (in a way in which no other brain tumor treatment has demonstrated in my 20 years of practice.) I hope that you would give some consideration to ammending your proposal.

Sincerely,

TJM

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It is possible that the proposed NCD would have relatively little effect on Medicare's coverage. For example, if the patient were hospitalized and the chemotherapy was introduced to targeted areas by catheter to increase local exposure, with radiographic guidance, vascular visualization, etc, the fact that mannitol was also injected at one point - but the cost of mannitol itself was not covered by CMS per NCD - would have little impact on the overall procedure. Is CMS's intention not to cover the entire procedure - the proposed NCD appears might be interpreted to non-cover the cost of the mannitol. [This would be similar to the outcome of CMS's NCD on prolotherapy, where the treatment proscribed is not well defined. All the services of a lidocaine and/or steroid injection for pain relief, fluoroscopy, etc are covered. So whether the provider adds phenol to a lidocaine injection (because he believes in prolotherapy) or equivalently, simply adds a bit of lidocaine to a prolotherapy service, the phenol is the only component of the overall service which is not covered under the NCD on prolotherapy.]

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Commentary:

The CMS is proposing to issue a National Coverage determination that states; “the use of osmotic blood brain barrier (BBB) disruption is not reasonable and necessary when it is used as part of a treatment regimen to brain tumors”.

How you can reach that determination is astonishing. Every physiology text, every neurosurgeon, every medical oncologist and even those of us in radiation oncology acknowledge that the blood brain barrier prevents cytotoxic agents from penetrating the brain in full dose. All acknowledge that the BBB is the limitation in treatment of brain tumors with chemotherapy. Various people have shown that, even in humans, blood brain barrier can be disrupted using an osmotic diuretic such as manitol and it can be done relatively safely in the hands of people who know what they are doing. This is not a game for amateurs; it is complicated and it should not be undertaken by those who are not qualified. Dr. Neuwelt and his colleagues have shown how to do it and people who train with them do know how to do it. Given the absolute desperation in which these patients find themselves, it is absolutely astonishing to me that you would conclude that BBB disruption “is not reasonable or necessary”.

It is true that randomized clinical trials are lacking. Penicillin never went through a randomized clinical trial nor have cardiac transplants. The fact that conventional chemotherapy and radiation are considered the standard of treatment for primary CNS lymphomas does not mean that they are the best treatment. They have achieved their status by default, not by trial.

I am a radiation oncologist who is considered to be very experienced in the field of treating lymphoma. For non-hodgkin’s lymphoma I have treated between five and six thousand patients. I stress that I have treated them, I have done more than just reviewed their charts. Out of that number I have approximately thirty patients with primary CNS lymphomas. I have two long term survivors, and they are the only two out of those thirty. They are patients whom I was able to convince that the best thing best thing for them was to go out to Portland, Oregon and be treated by Ed Neuwelt. Not only are they long time survivors but they have no other sequelae such as cognitive dysfunction associated with whole brain radiation. I think it is fair to say that the value of blood brain barrier disruption has not been established by clinical trials. Such trials for these patients are very difficult to pull off and require multi institutional participation. There are only a few places in the country that actually do this kind of work, and I wish that my institution here at the University of Pennsylvania were one of them. It isn’t because we don’t have people here who are willing to put in the effort to master this kind of treatment. But for those who do master it, it is wrong to say that this is not reasonable or necessary. The use of those adjectives is what is not reasonable or necessary.

Let me tell you that if I had a primary CNS lymphoma, I would fly out to Portland, Oregon and undergo blood brain barrier disruption and intra arterial chemotherapy. I know something about this field and that for me would be my treatment of choice. I don’t think it is essential that there be randomized clinical trials, although I think that they are desirable and helpful. They are helpful to convince people who need convincing. I have seen enough of this particular disease and enough of Dr. Neuwelt’s treatment to know that there is nothing better for this problem than his technique of treatment. How can it be “unreasonable” to try to overcome the very limitation that exists on the efficacy of chemotherapy in treating brain tumors? How can that be unreasonable? “Un-established” perhaps, possibly even dubious, but “unreasonable?” I really think that it is an erroneous choice of adjective. In the treatment of primary CNS lymphoma, in my opinion, it is the most reasonable thing that can be done. God knows the rest of our treatments have accomplished very little, and that includes radiation on which I am supposed to be something of an expert.

Neuwelt has an abstract for this year’s ASCO that reports on 177 primary CNS lymphoma (non AID’s related) patients treated with BBB disruption. Forty % are progression free at 5 years. Do you know how remarkable that figure is? A survival plateau after 8 years! In most series 5 year progression free patients are anecdotal! and no cognitive injuries, which are significantly by common with radiation treatment. It astounds me that you would look at all the evidence and the alternatives of treatment and conclude that this modality should not be supported by Medicare. I am disgusted at the statement you intend to release. Your proposed determination is an intellectual disgrace.

Eli Glatstein, MD
Morton M. Kligerman Professor
Vice ChairmanRadiation Oncology

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I beleive that BBBD should be covered by Medicare.Any potential opportunity to reduce the need for irradiation of the brain should be allowed. The mortality rates as you described are higher and when irradiation is used it can affect the cognitive function, which if you were to meet many of those patients you would understand why we should not limit the possible treatment options. I beleive that if you set standards such as those you identified; being treated by an expereinced Physican in a regional facility should make this treatment option safer. I beleive that we need to provide all options to patients who suffer from brain tumors whihc may allow them to maintain their cognitive abilities, which will lead to a better quality of life.

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