Rumination 6: Intermission

Rumination 6: Intermission

May 24, 2007

Several unexpected events have occurred since I wrote Rumination 5 on Sunday, May 13th. The first occurred on Monday, when Dr. Hodi called me in the evening to tell me that the lab results have finally come back and showed that my melanoma did not have the c-kit mutation but rather c-kit replication and therefore Glivec would be an ineffective treatment. (This news, while very disappointing, does not change my mind about anything I wrote in Rumination 5; the patient should have the right to make the decision whether the risks involved in what may turn out to be futile treatment are worthwhile for him or her.)

On Tuesday morning I began a serious exploration of my second choice therapy, the much publicized vaccine developed by Dr. Wolchock at Sloan-Kettering that has been so successful in treating melanoma in dogs that it has been approved for veterinary use by USDA.  Through the good offices of a caring friend (with good connections) we took the first steps in finding out how I might be able to get access to the vaccine.  The route, not simple (more on that below), involves getting FDA approval for “Compassionate Investigational New Drug” (C-IND) use of the drug. This lead to an extended conversation between Dr. Hodi and Dr. Wolchok from which it emerged, as Dr. Hodi explained to me, that the vaccine, as produced, will not work on humans.  The reason for is somewhat involved, so bear with me. The vaccine is derived from human melanoma DNA and is effective in producing an appropriate immune response in dogs because it is DNA from a different species, i.e., it is xenobiotic.  For a vaccine based on this principle to work in humans, it would need to be derived from melanoma in a different species, that is, to be xenobiotic to Homo sap. I’m sure this is being worked on, but is not here yet. So, alas, that route, in which I had invested much expectation, is out as well.

There is one last, not very promising, clinical trial to consider, but first a return to the issue of patients rejecting trials and going for unapproved drugs,  I had been vaguely aware for many years that a process for getting terminal patients unapproved drugs existed, and if someone had said Compassionate IND to me, I would have known what they were talking about. What I learned from my recent experience was how difficult it was to find out about C-INDs, let alone actually obtain one. Anyone not well connected into the system either through friends or an activist physician is unlikely to find out about, let alone obtain a C-IND. Why this should be, I can only speculate but I suspect two major reasons: The time demand on the physician both from the amount paperwork required by the FDA in the initial application and the inevitable ongoing reporting requirements; and the concern about potential liability. I note that a Google search for C-IND information yields only a single hit, and that is from an organization in the UK http://www.proventus.org.uk/page52.html.

Yet the C-IND process could, and should, be the avenue for bringing these terminal patients back into the purview of the system.  If C-INDs were easy to obtain, requiring simply an e-mail from a physician to the FDA to initiate the process, and the FDA maintained the database of all patients on C-INDs, including diagnosis, drug dosages, and outcome, an enormously useful database would be compiled that could provide many clues for future avenues of clinical research at a relatively low cost compared to formal clinical trials.  Even more important in the long run, the easy availability of C-INDs would remove a major cause of the alienation of patients from the medical community. Equally important will be the requirement for a waver from the patient to disable the malpractice suit machine in the not unlikely event that the treatment does not work or causes harm.

{Let me take this opportunity to get on my soapbox.  Malpractice suits, except in the case of obvious negligence (e.g., amputating the wrong leg or removing the wrong kidney) are counterproductive because they penalize the practitioner instead of the system.  In fact, their net effect is to strengthen a malfunctioning system by increasing, rather than decreasing rigidity, when the latitude to explore alternative systems is essential for the future of medical care in the U.S. }

On Wednesday, 5/23, I had another brain MRI and whole body PET scan, and then met with Dr. Hodi.  My reading of the scan is that the liver tumor is growing (from 27mm to 37mm in about seven weeks), not quite as fast as I had feared. The radiologists report (who may find other  tumors that have formed) is pending.

The bottom line is that there are no accepted treatment options for me to consider (as far as I am concerned, I do not consider Interluken a viable option because it has so many horrible side effects, and is not that efficacious). There are not even any relevant Phase II clinical trials. There is one Phase I trial of BMS-663513, a monoclonal antibody (anti-CD137) that has relatively few and minor side effects and is designed as a general stimulant to the immune system – it is not melanoma specific.  Dr. Hodi is in charge of the study at Dana-Farber. An interesting review article on CD137 (also known as 4-1BB) is: Dual Immunoregulatory Pathways of 4-1BB Signaling, D.S. Vinay et al;, J. Molecular Medicine, 84: 726-736 (2006).

 I am going to go out on a limb and predict that there will never be a single magic bullet, or block-buster drug – that will treat cancer.  The evidence I see accumulating [Mediators of Vascular Remodelling Co-opted for Sequential Steps in Lung Metastasis, G. P. Gupta et al., Nature 446: 765-770 (12 April 2007) and Combinatorial Cancer Immunotherapy, F. S Hodi & G. Dranoff, Advances in Immunology 90: 341-368 (2006)] to me strongly suggests that effective treatment of cancer will require the simultaneous control of several pathways, that is a spectrum of drugs. That is why I do not expect any pleasant surprises for myself from the anti-CD137 trial. To employ such a spectrum of drugs, drug delivery systems that can efficiently target the malignancy while avoiding (to the largest possible extent) normal tissues will be needed to prevent overwhelming side effects.  Unfortunately, as I said to someone recently, such drug delivery systems are still in the delivery room, and their Apgar scores don’t look very good.

As suggested by Dr. Jacobs, our GP, Katherine has started to talk to the MV Hospice. We all agreed that it is better for us to get to know one another before there is a crisis. The island hospice services are superb, as we have observed several times as friends of ours have had occasion to use them. Katherine says that the people she met are all very kind, practical, and professional.  They will be easy to work with. I will meet with them in July, both separately and together.

So, with Dr. Hodi’s concurrence, Katherine and I have decided to take a break from five stressful months and go to Italy for two weeks leaving June 4. Milan , Perugia , Assisi , Pesaro , and back to Milan , returning the 19th. (Getting flight reservations on such short notice, particularly using frequent flyer miles was a 3.5 hour ordeal. It  also used up just about all the miles in my account, but they would have vanished with me anyhow.)

After I return, on June 26, I’ll have another set of scans and in all likelihood then participate in the anti-CD137 trial, much more as a willing guinea pig hoping to help future patients than in the hope of it doing me much good. So the next Rumination is scheduled after I begin the clinical trial, sometime after the 4th of July. We expect to have only very sporadic e-mail access while we are gone.