RUMINATIONS ON LIVING WITH CANCER

These Ruminations were written by Thomas P. Vogl, over the course of the time that his mucosal melanoma was discovered to have metastasized until his death on May 31, 2010. They were written to keep family and friends scattered across the world informed. They are collected here in the hope that they will prove useful and supportive to others in my situation and their families. If they also help to change the way patients are treated by those members of the medical community that have M.D. degrees but that do not interact positively with patients, that is docs who I think are more appropriately called 'people mechanics' than physicians, that would be wonderful.

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I am rather amused that the message I started teaching to my bioengineering graduate students at Columbia in the early 1970's has come home to roost with me as the example. A little background for those of you not involved with biomedical research is in order.

Back then, and even to a large (but I hope smaller) extent today, there was (and is) palpable tension often leading to overt animosity and conflict between clinicians and bench scientists. It pained me every time I observed it even though I cannot recall a single incident where it was directed at me (beyond the required occasional jab). I pondered this problem at some length because it was getting in the way of my students acquiring the interpersonal skills they needed to succeed in their chosen field. I came to the conclusion, that it was a consequence of what might be described as evolutionary pressure during the training process. Put in one sentence, science is analytic and clinical medicine is synthetic. By that I mean that training as a scientist reinforces the mandate that conclusions are not drawn until all the data is in and even then accepted only tentatively until independently verified. Training as a clinician requires learning to make life and death decisions on (almost always) partial, incomplete data and inadequate models. The clinicians need help right now or in 24 hours at the most. Scientists are trained to look aghast at that attitude. Clinicians are frustrated by promises of help that hardly ever materialize in time for the patient they are currently treating. The exigencies of the situation mandate that the scientist/engineer learn to communicate in the clinicians language and not vice versa; an approach I managed to instill in some of my brighter students.

What has that got to do with me and my present situation? Twenty months ago, I was diagnosed with a mucous melanoma, a cancer so rare that the incidence is reported at around 1:10,000,000 and only 1% - 8% of all melanoma in Europe and the

. (It is genetically different from cutaneous melanoma in important respects.) About the same as your chance at winning the state lottery. (I was and continue to be teased about a rare person deserving a rare disease.) The tumor was detected very early so everyone agreed that the sensible course was to remove the tumor with that largest practical margins (in the upper jaw that is not easy). So I underwent my first surgery, a right maxillectomy. Dr. Norris of Dana Farber did a remarkable job that to a large extent saved my ability to speak even without the prosthesis in place. (The prosthesis is like a large, elaborate upper plate, produced by another genius, Dr. Jackson - but that is another story.) I doubt that there are half a dozen surgeons in the world who could replicate the technical success of the operation. According to the pathologists, the removed tissue was free of cancer at the margins.

Because the tumor is so rare, no one really can say or predict what can be expected to happen next. So we agreed that a course of radiation therapy to the site of the tumor was probably a good idea although I was told repeatedly that there is no way of predicting whether it would do any good. The conclusion of an article based on all 48 patients seen over 13 years (Arch Otolaryngol Head Neck Surg. 2003; 129: 864) is "The addition of radiotherapy tended to decrease the rate of local failure (P=.13) but did not significantly improve survival (P=.73) because of the high rate of distant metastasis disease." The radiation therapy itself consisted of six weeks of week daily travel to Hyannis by air; essentially an all day affair given the airline schedules. (I am most grateful to Cape Air for providing all this transportation gratis under their Angel Flight program.) What I did not expect was that it took me eight months after the end of the therapy itself to recover my former strength and activity level. I spent most of that time sitting exhausted in my recliner. The dire warning preceding the radiation was to expect massive pain, which never developed and some exhaustion. It was a completely pain free and totally exhausting experience.

About nine months thereafter, on a routine follow-up PET scan on which both Dr. Norris and I expected to see nothing, a hot spot was seen on a lymph node which, upon ultrasound guided needle biopsy (a totally benign, painless, minimally invasive procedure) a couple of weeks later turned out to everyone's surprise to be positive for metastatic melanoma. A very careful re-review of the scans by additional radiologists (all extremely competent) failed to turn up any signs of additional hot spots. The accepted wisdom, with which I concurred, is that if there is only a single node involved it should come out - if there is multiple node involvement then doubt is cast on the utility of surgery because if the greater likelihood of distant metastatic disease spread by the circulatory system. So, I had last week's surgery; when they opened me up they found about four other obviously malignant nodes that had not shown up on the scan (for reasons unknown and no theories). Of course they took them out and checked others further down stream to make sure they were clean. The surgery was, as I had expected given the surgeon, technically perfect. I have full range of motion of my arm and shoulder, never any pain, and I am healing nicely. A very recent article (N Engl J Med. 2007 356:285) states "Only about 20% of patients with positive sentinel nodes have metastatic disease in nonsentinel nodes if complete lymph-node dissection is performed..." I luck out again, but then I have a history of never winning raffles or door prizes.

I am, by one way of looking at it, 0 for 2. My retrospectroscope, which fails to have the 20/20 vision with which it is credited, is still not sure whether the radiation treatment was worth it. By a 60:40 odds, I suspect not, given that it robbed me of 8 out of 18 moths of productive time. Yet each decision, based on a synthesis of the information available at the time, was, in my opinion, flawless. (Calls from eager liability lawyers will most definitely not be welcome.)

The pathology reports from the current operation will become available early next week and will provide some hints as to how aggressive the melanoma is. We will be talking to Dr. Hodi, a melanoma oncologist at Dana Farber on the 26th. There are some experimental treatment protocols, known collectively as polyvalent melanoma vaccines which stimulate the patients immune system to fight the melanoma. What I do not know is whether any of these are suitable for mucosal melanoma or what the side effects may be (although rumor has it that they are mild). They are clearly less than the currently used high dose interferon therapy, which has horrible side effects and which I will not consider. Radiation is almost certainly also out, because it is too local.

I want to avoid any possible misunderstanding of what I have written. Nobody made any mistakes! Nobody gave me questionable advice! Everyone involved (surgeons and radiotherapists) did their jobs at astronomically high levels. That the outcome is not what anyone had hoped for is *nobody's* fault (except possibly that of my immune system). That clinical medicine is synthetic at its core is simply illustrated by my example. My father, who wrote the first text on cardiology had an aphorism that he coined and often repeated: "When it comes to medicine, the best is barely good enough." In my case, how barely is still to be determined.

What I will be adamantly insisting upon from here on out, is that quality, not quantity, of life be the overriding consideration. "The road to Hell is paved with good intentions" might as well have been written for clinical medicine.

Yesterday I had meetings with both the surgeon, Dr. Norris, and the oncologist, Dr. Hodi, about the upshot of which more later. In the month between my last surgery and these meetings, I have been giving myself a cram course in cancer immunology because all melanomas are the result of a failure of the immune system.

In my past life I have always avoided studying the immune system because it is, or appears to be, so messy. What I found most fascinating in my cram course was the déjà vu it inspired. In the first half of the 1950’s I was at Westinghouse Research where there was considerable interest in nuclear physics because of Westinghouse’s involvement in nuclear power. At that time new nuclear particles were being discovered and published every week and the zoo of particles was overwhelming. There was no theory relating these particles to each other or capable of making verifiable predictions. The relevant theory did not come along until a decade later – in the 50’s attempts at explanations were an exercise in numerology. I was not there then, but the same thing happened in the 1880’s and 1890’s with atomic spectroscopy – new lines reported every month with no idea what the numbers meant or how to relate them. The spectral lines were not understood until the advent of the Bohr atom and quantum theory more than a decade later.

My crash course persuaded me that immunology today is in the same position that atomic spectroscopy was in the 1890’s and nuclear spectroscopy was in the 1950’s. Lots of data, a confusion of nomenclature and no unifying theory with adequate predictive power, the sine qua non of a maturing science. On the basis of what I have read, I will make a prediction: If I were to show up with any melanoma 20 years from now, I would have a high probability (>80%) of being cured with a series of ‘vaccinations’ that stimulate the appropriate components of the immune system.

The current literature (remembering that the 2007 literature reflects, at best, the facts as known 12 – 18 months prior to the publication date) does not report any clinical trials of any drugs or combination of drugs that has a positive effect on more than 10 – 15% of the study population. There was nothing in the literature I could find that even hinted at or speculated about what distinguished the responding patients from the non-responders. Consequently, I decided on an algorithm for treatment selection: The percentage of the time that the side effects of the treatment are likely to prevent me from doing what I usually do cannot exceed the percentage of likelihood of successful treatment.

Let me at this point interject a plea to all of you, based on my experience in trying to put together my cram course. Please, please, support open source publication. It is an absurdity that I, living on the island and not near a medical school library, cannot access more than the abstracts of papers written describing research that my (and your) tax dollars paid for and that for profit journals want to charge me $20.00 - $50.00 per article to read. Write to your Congressperson and Senators, please! (End of diatribe.)

Unfortunately for me, that is then and this is now. None the less, in my conversations with Drs. Norris and Hodi, I learned a lot that is not obvious from the literature, and, in fact, contradicts some common wisdom. I entered the conversations with the firm intent to decline further radiation therapy on the grounds that violated the algorithm. The literature on melanoma (read cutaneous melanoma since mucousal melanoma is so rare) all agree that radiation therapy reduces the incidence of local recurrence but does not improve life expectancy because of metastases at distant sites. My experience with the first round of radiation therapy did not go as expected. The prediction was that at the end of the six weeks of daily radiation, I would be in considerable pain but that after four to six weeks I would be fully recovered. What actually happened was that I was never in any pain but had so little energy that it was all I could do to move from my bed to my recliner chair and this state lasted for three months and it was three or four more months before I was fully recovered. The idea that I spend the best eight or more months out of my remaining (relatively short) life that incapacitated is unacceptable to me.

Dr. Hodi persuasively explained to me that, for unknown reasons, head and neck cancers are significantly more responsive to radiation that cancers in other locations, with a response rate of 20 – 25% and significant success as measured by stable disease or remission. So, I am again, admittedly reluctantly, going to be talking to the radiation oncologist sometime before the end of the month. It appears from my conversation with Dr. Norris that there is a choice of both radiation modalities (photons or electrons) as well as advances on how the dosage is delivered so that it may not necessitate daily trips to Hyannis or Boston for six weeks. The advantage of electrons over photons is that they penetrate only a few centimeters (all that I need to irradiate the area where the lymph nodes were) and therefore is much easier on the deeper structures in the neck; the disadvantage is that it is much harder on the skin, and my skin is pretty flaky at best.

For both modalities there are now protocols that call for delivering more radiation per session with fewer sessions, which would certainly ease the significant transportation burden. Finding out what treatment, if any, will reduce the long term disability must await the discussions with Dr. McAnaw, the radiation oncologist in Hyannis.

Irrespective of the radiation treatment, Dr. Hodi is currently running two clinical trials of immune system stimulation therapy specifically directed at the pathways that are typical of mucosal melanoma; most, or all, of the other clinical trials underway are directed at another pathway more common to cutaneous melanoma. To be eligible for either trial I have to have ‘measurable disease’, that is a metastasis that shows up radiologically and therefore the effect of the treatment can be measured. While, of course, I would prefer to start such treatment immediately since if it works it will work better on metastases that are too small to be detected radiologically, I fully appreciate the need for this requirement, even as I selfishly wish it could be waved. In order to make sure that I can start the immunologic therapy as soon as practical, we will be doing a PET scan on me every four months. Since the last PET scan was in early December, the next one is only a few weeks away.

One of the things that has been puzzling me are the statistics relating to life expectancy. A five year survival probability of x% is all very well, but exactly when does the clock start? I asked. The clock starts on the cessation of the initial therapy for the condition. In my case, that is when the initial radiation therapy ended, in September of 2005. Consequently, I am already 18 month into the five year period. Since I am now officially ‘disease free’(at least until the next PET scan) I am clearly not in the lower range of 5-year survival predictions. Indeed, I was informed that I have a 20 – 25% chance of remaining disease free for the foreseeable future. We shall see, but there is reason for restrained optimism and no reason for ongoing concern.

As I mentioned in the first of these rumination, Reprise, medical decisions are intrinsically synthetic rather than analytic. My currently imminent decision on whether or not to undertake radiation therapy is, unfortunately for me, a case study in making decisions on inadequate information. First, a summary of the available information. I found seven papers relevant to radiation therapy:

Ballo, M.T. et al., “Combined-Modality Therapy for Patients with Regional Nodal Metastases from Melanoma” Int. J. Radiation Oncology Biol. Phys., 64:106-113 (2006)

Kienstra, M.A., & Padhya, T.A., “Head and Neck Melanoma”, Cancer Control 12: 242-247 (2005)

Grunhagen, D.J. et al., “Prognostic Factors After Cervical Lymph Node Dissection for Cutaneous Melanoma Metastases”, Melanoma Research 15: 179 – 184 (2005)

Owens, J.M. et al., “The Role of Postoperative Adjuvant Radiation Therapy in the Treatment of Mucosal melanomas of the Head and Neck Region”, Arch. Otolaryngol. Head Neck Surg. 119:864-868 (2003)

Ballo, M.T., et al., “Adjuvant Irradiation for Cervical Lymph Node Metastases from Melanoma”, Cancer 97: 1789 – 1796 (2003)

Lengyel, E., et al., “Malignant Mucosal melanoma of the Head and Neck – a Review”, Pathology Oncology Research, 9: 7-12 (2003) Also at: www.webio.hu/por/2003/9/1/0007

Lee, R.J., et al., Nodal Basin Recurrence Following Lymph Node Dissection for melanoma: Implications for Adjuvant Radiotherapy”, Int. J. Radiation Oncology Biol. Phys.,46: 467 – 474 (2000)

I will try to summarize what each of these papers presents from the perspective of its relevance to me, which as you will see, is fraught with uncertainty for several unavoidable reasons. The patient populations they study, although they all have melanoma, are very heterogeneous in terms of site of the primary lesion and the extent of disease at the time treatment was started. Despite this heterogeneity, the number of patients in each study, and particularly when broken down into cells, is small. The vast majority of the patients in these studies have cutaneous (skin) melanoma (CM) because the mucosal melanoma (MM, which I have) is so rare and carries distinctly different genetic alterations and biochemical pathway activity [Curtin et al., NEJM 353: 2135 (2005)].

Kienstra (2005) notes that MM “are rare lesions but have a poor prognosis. Because of their development in hidden, clinically silent areas, diagnosis often occurs late [not in my case] … contributing to the poorer outcome.”

Lengyel (2003), which is the only paper focusing on MM, reviews 10 studies (some as early as the 1950’s) and concludes that “CM had a mean [5 year] survival rate that was higher (81 – 85%) than that (17.1% [range 0 – 48%]) for MM.” He points out that “The characteristics of the survival curves explained by the very different possible clinical courses of malignant melanomas, ranging from the highly-malignant, aggressive disease to a relatively low grade tumor.”

Grunhagen (2005) reports on 66 consecutive patients (over a 22 year period) an overall 50% survival of 27 months after cervical lymph node dissection. 15 received post operative radiation therapy; 4 of the 15 developed cervical recurrence. With more than one metastatic lymph node at dissection, the 50% survival rate was reached at 18 months.

Ballo (2006) reports considerably more optimistic numbers, with the 5-year survival of 49%. Since this is the most recent data and on a relatively large (245) group of patients, this study has to be given considerable weight taking into account the heterogeneity of the study population. His abstract concludes: “Although regional nodal disease can be satisfactorily controlled with lymphadenectomy and radiation, the risk of distant metastases and melanoma death remains high. A management approach to these patients that accounts for the competing risks of distant metastases, regional failure, and long-term toxicity is needed.” The long-term toxicity issue is not significant for cervical lymph nodes, but the probability of cervical recurrence is high.

Lee’s (2000) survival figures are similar (50% at 24 months) with the highest rate of recurrence in the cervical basin at 43% at 10 years, compared to 28% and 24% in the axillary and inguinal basins. The number of positive nodes also predicts nodal basin failure with the presence of 4 – 10 positive nodes predictive of a 46% failure rate. He concludes: “In summary, there are sufficient data to suggest that adjuvant radiation therapy to the nodal basin in high-risk patients with malignant melanoma decreases nodal basin failure rates. The impact on survival is uncertain, as many patients develop distant metastases and die of disease. However, the importance of local-regional control cannot be overlooked, and as more effective systemic therapy is developed and distant spread is decreased, the importance of local control may increase.”

Owens (2003) “The addition of radiotherapy tended to decrease the rate of local failure but did not significantly improve survival because of the high rate of distant metastatic disease.”

I will not bore you further before getting to the point: Should I, or should I not, agree to radiation therapy? The rationale for doing it is clear. It reduces local recurrence which may – it is really a pious theoretical hope without a shred of evidence – decrease the likelihood distant metastases.

The rationale for not doing it is not quite a clear but, I think, equally convincing. It may indeed be the case that my immune system may kick back in, or that the melanoma becomes indolent, or for some other reason I will end up surviving another ten or more years; this outcome has low probability. More likely is the generally accepted figure of 25-50% at five years with the odds for the lower end because of the six positive lymph nodes and that it is MM and not CM. I also know, from my experience with radiation therapy 18 months ago, that the therapy itself is quite tolerable, all the more so because the current recommendation is for a high dose of radiation twice a week rather than a lower dose daily, which means that I would travel far less frequently. However, it took me about eight months to get over the radiation therapy and return to full functionality. Most of that time I spent in my recliner, too exhausted to do much of anything.

Statistically, the most probable, but hardly inevitable, outcome for me is that distant metastases will develop sometime in the next 18 months and that I will live another 12 months after that. Does it make sense for me to spend 8 of those 18 good months exhausted from therapy that has only a marginal probability of extending my life or changing the outcome?

Time for a pop quiz: What would you decide and, more importantly, what is the rationale for your decision.

Today, Thursday March 22, I had a long and very useful conversation with Dr. McAnaw, the oncological radiation therapist at Cape Cod Hospital who did the radiation therapy following my first operation. We had an extensive, wide ranging conversation covering radiation modalities and dosages (electrons vs. photons -- hyper vs hypo-fractionation of radiation dosage, etc.) and the importance of shaping any radiation field to miss those areas that have previously been irradiated. We agreed that the growth characteristics of my melanoma were such that it would probably be 12 -18 month before a macroscopic tumor reappeared. We shall see. In the meantime, we decided to await the results of the PET scan scheduled for April 3 and call in the experts at Dana-Farber before making a decision on Radiation treatment at the end of April.

It has been an interesting few weeks, full of uncertainty, and while some decisions have been made, the uncertainty will continue for several more weeks. This is just an interim report.

Based on the considerations in the previous Rumination, we decided to postpone the decision on radiation therapy until the results of a PET scan on Tuesday, April 3^rd, were back. They did hand me a CD of the PET (but because of a miscommunication not the accompanying CT) while I was there. I looked at the scan, first by myself and on Friday together with Dr. McAnaw in Hyannis, and it appeared that there was a hot spot in the liver, but without the CT we could not be sure. On Monday, a complete CD arrived in the mail and there was no longer a question – there was an approximately 1 inch hot spot in the liver. I met with Dr. Hodi, the oncologist at Dana-Farber on Wednesday (11th) and we agreed that it was highly likely (that’s as far as one can go without a liver biopsy, which is not without its own considerable risks) since there was only a faint hint of the spot on the PET scan in December.

This finding, although not good news, does simplify the decision making. There is little point in irradiating the neck when the liver is a more immediate threat. Nor is there any point in doing anything drastic with the liver – while removing the malignancy surgically is a potential option, there is little point in doing so since the melanoma cells are circulating in my blood stream and will, in relatively short time settle elsewhere, with or without the surgery. Left to its own devices, the liver will fail in an average of a year, with a very large standard deviation, so anything from a couple of months to several years being reasonable.

Clearly, the only meaningful intervention is systemic, one that will address the metastases wherever they may occur. The only FDA approved systemic treatment for melanoma is Interleukin, which has so many toxic side effects that most people cannot tolerate the treatment and stop it before a year is out; it is also not very effective. There are, you will probably be surprised to learn, about 168 different experimental studies of melanoma drugs currently being conducted around the world. How to choose one for me? Well, first of all, almost all these studies address cutaneous melanoma (CM) which is genetically different from the mucosal melanoma (MM) which I have and which has an incidence of about 400 cases a year in the US. (number from Dr. Hodi, see also R.J. Patrick, et al., Primary Mucosal Melanoma, J. AM. Acad. Dermatol, 10.1016; published on line March 2, 2007 doi:10.1016/ j.jaad.2006.06.017). Since the genetic pattern and hence gene expression of CM and MM are different (Cutin et al., Distinct Sets of Genetic Alterations in Melanoma, NRJM 353:2135 (2005)) with CM usually expressing BRAF (a gene controlling another kinase) while MM are much more likely to express c-kit (a tyrosine kinase). Consequently, most of these trial drugs would probably not work on MM. (They only work 10% - 20% of the time on CM. This is not surprising since there are multiple pathways and these new drugs each suppress/inhibit only one. I was ‘pleased’ to see my thoughts along those lines confirmed this week by G.P. Gupta et al., Mediators of Vascular Remodeling Co-opted for Sequential Steps in Lung Metastisis, Nature 446:765-770 12 April 2007).

1) A mouse gp100 plasmid DNA vaccine developed by J. Wolchok at Sloane-Kettering on a canine model of what appears to be mucosal melanoma [P.J. Bergman et al., Development of a xenogenic DNA Vaccine Program for Canine malignant Melanoma at the Animal Medical Center, Vaccine 24:4582-4585 (2006) and J.D. Wolchok & Y.M. Singer, Current Topics in melanoma, Curr. Opin. Oncol. 19: 116-120 (2007)] (Dogs develop melanoma in their mouth or foot pads, which I would think are the animal model of MM and acral melanoma, respectively.)

2) A trial of Imatinib (also known as Glivec) which specifically targets c-kit, being run at Dana-Farber by Dr. Hodi. Dr. Hodi thinks that there is about a 30% chance of Glivec working, and while there is the potential for unpleasant side effects, they are reversible by discontinuing the drug.

There really is no good basis for choosing between these two, but since I am already a patient of Dr. Hodi and since the protocol at Sloan-Kettering would require a number of several day stays in NY, I have elected to go (first) with the local protocol. The first step is to determine whether my MM indeed does utilize the c-kit pathway, which will take about three weeks. (Discussion of alternatives can await the outcome of that test.) In the meantime, I will have an MRI of the brain on the 17th to check for brain metastases.

Meanwhile, back at the ranch, we are happy to report that our favorite restaurant in Boston has gotten even better. They have not only expanded to a second floor of seating but also expanded their menu. We ate there Wednesday evening and were surprised and delighted at the new dishes. We tried two, a sushi roll with king crab and eel, presented as a Godzilla-like snake and a tripe & menudo soup. Both were outstanding and the quality of their kim chee (which has always been superb and much better than anything in the stores) retains its prize winning position. Korean-Japanese fusion at Suishaya Restaurant, corner of Tyler and Beach in Boston’s Chinatown.

As soon as we can gauge that Tom’s reaction to the Glivec will be mild, we are planning to go to Italy for 10 days, mainly to Le Marches, hopefully in late May, early June. We hope it comes to pass – we are really looking forward to it.

You may have noticed discussions of clinical trials and patients circumventing them in both the popular (e.g., Wall Street journal, May 4, page A15) and in the scientific literature (news@nature.com, doi:10.1038/news061218-14; Nature Medicine 1/31/2007, doi:10.1038/nm0207-111b; Nature 446:474, 3/29/2007). To make a long story very short, these articles describe a conflict between the perceived needs of the patient population and the need for definitive clinical trials. The patients, who know they are dieing, want the right to take whatever drugs they feel might possibly help them; the FDA is concerned that some of these drugs might harm them further; and the supporters of clinical trials worry that the patient population they need might vanish.

Now that I find myself involved in a clinical trial, I am beginning to understand the frustration of the patients and some of the causes of that frustration. My sympathies, as a life-long scientist, were originally on the side of the clinicians running the clinical trials. While I still retain all my sympathy in support of their objectives, I also see how many unnecessary and easily avoided problems contribute to patient unrest. Problems that are irrelevant to the scientific objectives. I’ll use me as an example.

On April 3^rd I had a PET scan that showed a metastasis in my liver. On April 11^th, after the radiologist’s report was available, I met with the oncologist, Dr. Hodi at Dana-Farber (DFCI). I had already reviewed the literature and knew that of all the clinical trials of drugs for melanoma metastases only two were relevant for my mucosal melanoma (one at Sloan Kettering in NY and the other by Dr. Hodi). I readily agreed to sign up for his trial of Glivec (imatinib). He told me that it would take about three weeks for the samples of my tumor to be sent to Oregon to a lab that could determine whether my tumor was c-kit active, because the drug was specific for c-kit tumors. No other options were discussed.

After three weeks were up, during which I received no communication from DFCI, I sent e-mail to the research nurse at DFCI on Wednesday, May 2, and was told that the results from the lab were not back but were expected that Friday, or Monday the latest. I heard nothing from DFCI, so the following Wednesday (May 9th) I left voice mail for Dr. Hodi. We caught up with each other the next day.

It was an interesting conversation both because of what I learned and because of the facts I could connect thereafter. What I learned was that:

1. There was a considerable, but unspecified, delay in getting the samples from pathology and sending them off to the lab.

2. That the lab in Oregon was the only lab in the country qualified to do the complete gene expression profile with particular expertise/emphasis on c-kit.

3. That the lab has promised at least preliminary results by Friday or Monday (the 14th).

4. That a new PET scan will be done when I start the drug and again four weeks later to assess whether the drug had any effect.

I pointed out that a month has gone by during which my tumor was busy growing without any active intervention. When I asked Dr. Hodi why I had not been started on the drug a month ago, I was informed that the drug company will not provide the drug until after the c-kit sensitivity was confirmed. When I suggested to Dr. Hodi that he could have written a prescription for the drug at the time. He said that melanoma was not an approved use for the drug (it is approved for several other cancers) and that the insurance company might not have paid for it. I asked whether it would not have been appropriate for him to at least discuss the issue with me at the time, he said that without the c-kit information there would be no evidence that the drug would do any good. We left it at that.

It took me a day or two to realize how Kafkaesque this all is (in addition to being emotionally draining). Let’s go back to the time immediately after the PET scan when we elected to consider Glivec as the primary option. It is a clinical judgment to decide whether the drug may help. If it is unlikely to help, there is no point considering the clinical trial, particularly since I had made it clear that I did not intend to pursue any therapy with less than a 30% chance of success because of the side effects. Dr. Hodi thought that since it was a mucosal melanoma, there was a 30% chance that Glivec would be beneficial. Although I did not realize it at the time since no alternative was mentioned, there were, in fact, two options: Start the drug now or wait for the lab results. What is the rationale behind waiting for the test results? Thinking it over, I conclude that there are two contributing factors: The first is the clinical trial protocol end point: does the drug stops the tumor from growing. An unintended consequence of this prima facie reasonable end point is that the size of the tumor at the time of starting the trial is of no consequence to either the study or to the company supplying the drug. Consequently, no hurry. The second is that the requirement for prior testing saves the drug company money, since they do not have to supply the drug to patients without clear evidence that the drug is appropriately targeted. (I do not know, but will be interested to find out, whether the drug company would be willing to include patients in the study if they have purchased and used the drug while the lab work was being done.)

From the patients’ perspective this is all backwards. Nothing in the study protocol would be jeopardized by giving the patient the drug immediately. The correlation among gene expression, the drug, and tumor stasis/regression is just as valid whether the lab data is available at the end or the beginning of the four week drug-taking period. The cost argument is also rather spurious because it is not appropriate in the context of a phase II trial to value the drug at its market price; rather it should be valued at the incremental cost of producing it, which is a tiny fraction of the market price which has to include development costs. Last, but hardly least from the patient’s perspective, is the fact that a month out of a rather short life expectancy (in my case about a year with a large standard deviation) will be saved by starting the drug immediately, so that if it turns out that the drug does not help, or the side effects are too onerous, there is time to try an alternative before it is too late. If the drug does work, the residual tumor load is significantly smaller.

Given the mind set that such protocols display, is it any wonder that the patients are restive, dissatisfied, and seek alternatives? To add insult to injury, they are then vilified in the scientific press by the proponents of clinical trials. If, instead, those critics would support the tracking of those seeking to use unproved drugs and the monitoring of their experience by competent clinicians, the resulting data have the potential of providing valuable clues for the direction of future research. That such an effort would require some investment by FDA and NIH is obvious; their disinterest in doing so is equally obvious. Ensuring that the best interests of clinical trial participants take priority over everything except the validity of the results should be the task of the IRBs (Institutional Review Boards), but recent articles have suggested that they are often not up to the task.

I must confess that I, even as knowledgeable researcher, feel abused by the system; I profoundly sympathize with those less knowledgeable and more terrified of the system than I am. They deserve the medical research community’s compassion and support and they are not getting it. No wonder there is such a burgeoning interest in alternative therapy and avoiding clinical trials.

It should not be necessary for me to add as I stated in a previous rumination (and it is a sad commentary on our society that it is indeed necessary), that calls from malpractice lawyers will most definitely not be welcome and will, in fact, be resented. What is needed is pressure on government agencies and drug companies to ensure prompt and appropriate care of patients in the time interval from their being considered for enrolment until the protocol actually starts. If there is a consumer organization or smart lawyer who can figure out how to require inclusion of appropriate wording into all clinical trial contracts/grants, I would be delighted to help them in any way I can.

The bottom line is that I have been deprived of a month that I can never get back. If the drug works, I am unnecessarily left with a tumor that has had the time to grow bigger (just how much bigger we won’t know until the next PET scan). If it does not work, or if the side effects are intolerable, that was a month in which a different therapy could have been explored. What is frustrating and infuriating is that there is not the slightest scientific justification for the delay – it is simply a consequence of “the system”.

As I am sure all of you who have traveled on business have observed, it is far easier on the one who travels, than on the spouse who remains behind. Therefore, it is not surprising that Katherine is far more upset, angry, and ready to clutch at any straw than I am. I predict that without changes in how the clinical trial system is run and how experimental drugs are made available to terminal patients and how the results are evaluated, the patient revolt we have seen to date is just the beginning. Without meaningful change, the pharmaceutical industry and the biomedical research community will deservedly bear the brunt of the frustration and anger of the public and the members of the research community will have no one but themselves to blame for the inevitable consequences. Unfortunately, it is the patients and their families that will needlessly suffer the most, both physically and mentally.

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 is 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.

We had a glorious time in Italy, spent entirely in the medieval part of whatever town we were in. While, alas, it is no longer true that one cannot get a bad meal in Italy, we had wonderful food and great wine, with the seafood on the Adriatic coast in Pesaro being particularly outstanding. I was also delighted to discover that the Wiener Schnitzel I make at home (with veal from Boston's North End) is better than the veal cutlet Milanese at an otherwise superb and highly rated restaurant in Milan. The osso bucco at the same restaurant is better than what we can make, possibly because they can get veal shanks and we have to make do with beef. The fish in the fish stores brought us close to tears because we did not have a kitchen and they had such an interesting variety of exquisite seafood so beautifully displayed.

We took lots of pictures and Katherine has begun posting stories and pictures on her blog, http://upislandeggs.blog-city.com/. Further episodes will be posted over the next few weeks. I felt great the whole time, and were it not for the radiological and pathological evidence to the contrary, I would remain convinced that I had at least another 20 good years left in me. I really cannot say that I feel any different now than I did at 60.

Only one thing kept the trip from being perfect, a sin of omission that also changed the path ahead. Several days before we left, I left voice mail for my medical oncologist, telling him that I would have a much more relaxed trip if I knew the results of the diagnostic radiology that had been performed a week earlier. The next day, his secretary called me to say that the doctor was out of town until the following Wednesday and that his nurse was also out of town until Monday. I asked her if she could e-mail me the reports but she did not have the authority to do that. She said that she would leave a note for his nurse who was expected back Monday morning, asking her to get the information to me before I left; she also suggested that I e-mail him and gave me his e-mail address. I sent an e-mail to both him and his nurse, explaining that giving me the report would greatly reduce my anxiety during the trip and giving them three routes (e-mail and two phone options) for reaching my while I was in

Italy

. No attempt was made to reach me, not even to tell me that they would not provide the information. What I got was silence. Unfortunately, in the few months that I have been his patient, this has happened twice before. In fact, at no time has he or anyone on his staff initiated any contact with me. I have always had to ask for information, even information such as the results of diagnostic studies, that I feel they should have provided without prompting from me. Add to that the fact that when both he and his nurse are out of the office, as happened when I called, his secretary did not or could not suggest that I speak with anyone with authority to act on his behalf, even for such a simple matter as pulling a report up on a screen and reading it to me.

Mulling over the lack of communication during several days of anxiety interrupted sleep produced by my concern over what the radiology reports might contain, I concluded that it would simply be a source of aggravation for me to participate in a phase I (initial human) trial of an experimental drug being carried out by an office with such a consistent reluctance to communicate.

The telephone communication we had on the day after we returned (June 20) would be very funny if it were not also a sad recap of the ongoing communication problem. At 8:00 am (all times approximate; quotes as close as I can recall them). I called the doctor and left voice mail:

"This is Tom Vogl. We are back and I have not received the radiology report from the scans done on May 23rd. I will appreciate receiving them at your earliest opportunity, preferably be e-mail or by phone. 508-... Thank you."

At 10:00 a.m. (after talking with Dr. Mc Anaw) I called his appointment secretary (AS):

Me: "This is Tom Vogl. I'd like to cancel the scans scheduled for the 26th and my appointment with the doctor on the 27th."

Me: [biting my tongue and focusing on what I care about]: "I still have not received the radiology report from May 23rd."

MD: "I got the message from you before you left. Let me pull up the report." (He then gave me a brief, accurate summary.)

Since my oncologist (whose medical and scientific knowledge and competence I continue to hold in the highest regard) is convinced that no viable therapeutic options exist for me, it seems a change of course in my care is called for. It makes no sense for me to commute to Boston for palliative care from a highly knowledgeable physician whose knowledge cannot help me and who has trouble communicating. My primary care physician on island in conjunction with the island's world-class hospice, and in consultation with medical and radiation oncologists in Hyannis who visit the island on a regular schedule can serve my limited needs at least as well, and with far less hassle.

So, yesterday morning I had a very positive conversation with Dr. Robert Mc Anaw, who was my radiation oncologist in Hyannis last year [both Katherine and I think he is great, for many different reasons] and we are on our way to set up a Hyannis based program of care for me.

As described to me by Dr. Mc Anaw, palliative care these days is defined as the other extreme from the 'let's go in with all guns blazing' approach of tertiary care facilities. (Excepting, of course as always, the truly great physicians, like Dr. Norris, who know better. Even in my wildest dreams I cannot discern how to thank Dr. Norris enough for not completing the neck dissection and thereby leaving me fully functional.) In palliative care, diagnostic tests are done only in response to symptoms and only symptoms are treated and controlled. My problem with this is that I am not an extremist and I do like to know what is happening. I can live with waiting for symptoms of liver failure or lung metastases, although I would be more comfortable with an occasional look while asymptomatic (say every six months), to get some idea of how slowly/rapidly the disease is progressing. What I doubt I can live with is not knowing whether there any brain metastases, and if there are, where they are. Behavior and mood changes resulting from brain metastases are far too subtle to be left to subjective diagnosis and far too hard on the family and caregivers when they occur. [Metastases in the brain stem are one thing; in the frontal cortex or hippocampus, quite another!] Consequently, I will make it a priority task to convince the new oncologist that a brain MRI is called for every three to four months. If Medicare won't pay for it, I guess I will have to. Likewise, I believe a whole body PET scan every six months, even when asymptomatic, is worthwhile. After all, melanomas have been known to regress and even go into remission in patients whose immune systems have suddenly kicked into high gear. The odds of this happening are small, probably as small as the odds of getting mucosal melanoma in the first place. But if it happens, it would be nice to know about it, rather than continually expecting the worst six months down the road.

I feel amazingly comfortable with this plan, provided I can get the occasional scan. No one can predict how long I will survive; there is a suggestion, based on the fact that I am still asymptomatic, that the tumor may be growing relatively slowly. If that is really the case, that would be very nice indeed. I would love to be able to make it another 18 months so that Katherine and I can celebrate our 30th anniversary. Who knows, it may happen and I may even go on to make it to 80.

I start with the good news: Much to everyone surprise I am still asymptomatic, feeling fine, and operating at 100%.

Before answering the question, how come? I need to write a coda to Rumination 7 in which I reported my final conversation with the medical oncologist in which I requested and received his summary of the radiology report. What I discovered several days later when I obtained the hard copy of that radiology report was the statement:

Simply put, this means that the hot spot in my liver, which is quite reasonably presumed to be a metastasis, has in just seven weeks halved its metabolic activity, a measure of its rate of growth.

Since every other physician who has seen this data has expressed their surprise and even opined that the spot might not be a metastasis, I find it both remarkable and extremely distressing that my then medical oncologist failed to mention this to me. In fact, I am still angry about it. So angry, in fact, that in thinking back over my life to see whether I had ever been so angry before, the only occasion which I found comparable, (not even during the at times unpleasantness surrounding my divorce in 1970), was back in 1957 when a coworker at Westinghouse Research Labs, Dr. Ernie Sternglass, out of curiosity opened the door to a furnace and, I thought at the time, ruined an experiment that had taken two weeks to set up. I have no idea what my former medical oncologist was thinking when he withheld that information from me. To me, as a patient, it certainly suggests the possibility of the appearance of a conflict of interest between his role of a personal physician and the director of an investigational drug study. What should be done by society at large to avoid such a perception in the future is a difficult question with scientific, psychological, and political components. I have my own opinions, but they would take us far a-field from the intent of these ruminations.

I am delighted to report that Dr. Norris, for whom I have the highest professional and personal regard, is back in the loop, as is Dr. McAnaw from Hyannis, whom Katherine and I both admire. Dr. Norris has ordered PET and MRI scans to be done on July 31st.

I received the radiology reports yesterday. Aside from a hysterically (word deliberately chosen for its derivation) funny computer generated typo, the results of the scans are unchanged in the ten weeks since the scans in late May.

{Here is the humor: The radiology report on the PET/CT scan, states in part "ABDOMEN/PELVIS: <clip> There has been a hysterectomy and a bilateral salpingo-oophorectomy. There has been a prostatectomy. <clip>" I conclude that I am a much operated upon true hermaphrodite.}

Unintentional humor aside (but it did cause much giggling and they do say laughter is the best medicine), this news is, literally, astounding. I have a very rare version of a relatively common cancer that, when metastasized as mine is, has no known treatment and is almost inevitably promptly fatal. Yet here I am, when I should be symptomatic and going down hill rapidly, feeling fine without any radiological evidence of disease progression. Let me hasten to say that this is not unheard of, just extremely rare. I am told of a surgeon at Mass General who had metastatic melanoma that went into remission for a decade. None the less, such stasis is as rare as my disease, and the driving force behind the stasis unknown. To say that the proximal cause of the stasis is that my immune system kicked in is undoubtedly true, but contains no more information than saying 'he went into remission'. To be a useful statement, an explanation of what caused the immune system to kick in is needed, but lacking; "not a clue" is the operative phrase.

Friends and relatives have stepped into the breach and offered a variety of causative explanations. In no particular order, they are:

In fact, nobody known what caused the remission and nobody knows how long it will last. However, both Katherine and I are inordinately pleased that it is happening and we will happily take whatever additional time this unexpected victory of immune system over cancer will give us. In this case I will even forgo my usual expectation that I will not disrupt other people plans by not doing what I say I will do, when I say I will do it, including dieing on schedule.

I certainly appreciate and enjoy the reprieve. None the less, it is most definitely disconcerting and unsettling (albeit in a far better way than the alternative) after six months on death row to be suddenly given, not a pardon, but a stay of execution of indeterminate length. While it is certainly true that all living things live with this uncertainty, I can assure you from personal experience that it feels very different after six months under a death sentence.

What happens next? The first step will be conversations with Drs. Norris and McAnaw, and it is far from clear to me what they will advise. A number of possible diagnostic tests suggests themselves ranging from the essentially non-invasive (chest and/or liver CT or MRI with contrast, an ultrasound of the liver with a new liver-specific technology), to the mildly invasive (a needle biopsy of some lymph nodes in the neck), to the more invasive needle biopsy of the lesion in my liver. Further down the line might be removal of some lymph nodes and radiation therapy. All this is very much up in the air at the moment. Lurking in the back of my mind is the realization that what turned my immune system back on is unknown, as is any knowledge of what might turn it back off. Consequently, it seems reasonable and prudent to consider any intervention in terms of what it might do to my immune system. I learned long ago that if one has an old piece of equipment or machinery that is running smoothly, one does not tinker with it.

My remission is holding up beautifully and I have no further formal medical workups planned until my next set of scans, PET and MRI, in early December.

That does not mean that there are not scientifically relevant and interesting things happening in which I cannot resist getting involved. In February I ran across an item (in the January 2007 issue of Optics & Photonics News, page 8), about a novel method for the detection of melanoma cells in blood plasma. Since there are not supposed to be melanoma cells circulating, any melanoma cells in the blood are malignant and potentially metastatic. I reproduce the article here since it is short and self-explanatory.

The paper whose results are described is Photoacoustic Detection of Metastatic Melanoma Cells in the Human Circulatory System, by R. M. Wright, J. A. Viator, et al., Optics Letters 31:2998 – 3000 (October 15, 2006).

This work intrigued me because I saw in it the opportunity for an early warning system for remission failure (PET scans cannot detect a metastasis smaller than 2 mm). I hoped that the opportunity to make serial determinations on a patient in remission from a rare melanoma would interest the study team. Dr. Norris kindly agreed to get in touch with the team in Missouri and make a referral. I subsequently called Dr. John Viator who invited me to come to Columbia, visit their lab, and run my blood sample through their equipment. So we arranged the visit for September 11.

Modern airlines being what they are, it takes as long to get from here to Columbia as from here to Europe, with more plane changes going to Columbia. In fact, to spend a few hours in Columbia I had to stay two nights, arriving the evening before and leaving before the crack of dawn the day after our meeting. Mercifully, the motels in Columbia are very reasonably priced.

The visit was an absolute delight. The evening I arrived I had dinner with my old friend from Westinghouse days, 'Rig' Rigler and his wife Bev. I had not seen him in 15 years and Bev in closer to 30. It was a nostalgic visit with wonderful people.

Tuesday morning I met John on the UM Cancer center where they drew two vials of blood which Melvin, John's graduate student, immediately spun down. The immediate part is important, because that is the reason I had to go to Columbia myself instead of sending a blood sample. Even though I hope it will turn out that I will be able to send samples (see below), I am glad I went because of the opportunity to meet John and spend the day with him in his lab, walking around the campus, and attending a lecture on photoacoustics by Dr. Hao Zhang. Being back in a academic environment after nine years as a chicken farmer had me worried that I could no longer do science, but I found that it all (well, almost all) came back and I was able to make a few suggestions that John found helpful. Of these, if it works out, the one of most interest to me for purely selfish reasons and possibly of the greatest use to John (because of the greatly increased potential patient pool) has to do with the processing of the samples in such a way that the patient need not go to Columbia to have the blood samples drawn.

I won't go into the details of the protocol (if you want to see it let me know), but what needs to be done is to separate the erythrocytes (red blood cells), the leukocytes (white blood cells) and other mononeuclear cells and the plasma. Centrifuging after adding appropriate reagents to the blood produces four layers – the erythrocytes, one of the added reagents as a separator, the leukocytes and other mononeuclear peripheral blood cells including any melanocytes, and the supernatant plasma.

It turns out that unless the blood is spun down within a few minutes of being collected, the breakdown of the erythrocytes will contaminate the leukocyte layer, and since the erythrocytes absorb the same wavelength used to detect the melanocytes, even a minute contamination produces false positive results. However, once the leukocyte layer has been separated from the erythrocytes, it is stable. What I plan to explore in the next few weeks is whether a local clinical pathology lab can be persuaded to perform this straightforward separation. I should note, in passing, that a modification of the system using two laser beams at two different frequencies will be able to distinguish melanocytes from erythrocytes and solve that false positive problem, but that prototype system is still in the planning stage.

Yesterday, I received e-mail from John – no melanocytes in my blood samples. Despite the fact that the clinical implications and prognostic value of this test are unknown (I am contributing my blood samples as part of a very preliminary study) this clearly is better news than if melocytes were found. Sufficiently good news to be worthy of a glass of champagne to toast John in absentia.

John also sent me the protocol for processing the blood samples and I have already started the wheels turning to see whether the lab at the MV hospital, the Falmouth hospital, or in Boston can be persuaded to do it. If this works out, I will send monthly samples to John for processing.

The good news is that I feel just as hale and hearty as I did when I wrote Rumination 9 in late September and that there are a number of options now open to me that were not available a year ago. That is how fast melanoma research is moving.

The bad news is that in the repeat scans done November 28th, there is evidence of melanoma in two new places my liver. So the issue is what, if anything, to do now. In advance of meeting with Dr. Hodi (yes, Dr. Norris persuaded me to try again, hopefully with far better communication) I reviewed the literature and the available clinical trials.

Two immediately relevant new items in the literature caught my attention because they may provide clues as to how and why the immune system is, or is not, responding adequately. A recent review article, The Genome and Epigenome of Malignant Melanoma [C. Dahl and P. Guldberg, APMIS115: 1161 (2007)] and an item about Dacarbazine (below). Among interesting points in this review article is the fact that the tumor suppressor PTEN, a gene that is often mutated by cancers, is often inactivated in prostrate cancer (which I had) and in 30-40% of melanomas. They also report that aberrations in the Wnt signaling pathway, particularly APC, is related to colonic polyps (which I have and which run in my paternal family) and methylation of the APC promoter 1A is present in about 15% of melanomas. I will be most interested to find out from Dr. Hodi whether the science is far enough along to have these observations influence choice of therapeutic modalities. The paper quotes Miller et al., [N. Engl. J. Med., 355: 51 (2006)] in reporting a median survival of six months (no standard deviation given), which I have already beaten by a factor of two.

I have recently developed a possibly relevant hypothesis: For the past two years I have been annoyed by an unexplained skin rash that waxes and wanes. It last bothered me in Italy in June and was quiescent thereafter until November. In that interval an infection developed in the root of the molar holding my prosthesis, so the dentist and I are trying to save the tooth, rather than extract it. I have noticed that when the rash is at its worst, the tooth is at its best, and vice versa. The hypothesis is that the rash is a manifestation of a hyperactive immune system that is endeavoring to keep the melanoma in check (and fortuitously controls the tooth infection) and is the underlying cause of the remission this Spring. Unfortunately, I have no idea how to test my hypothesis. Any suggestions, anyone?

As those who have known me over the decades know, my track record for hypotheses that have been validated is pretty darn good (I'm really not trying to blow my own horn, it's just historical, and possibly relevant, fact). When I combine this hypothesis, hunch if you will, with the fact that I am adamant about maintaining as rectangular survival curve as can possibly be achieved, the possible therapeutic interventions are limited to relatively benign drugs that give my immune system a good kick. All the standard therapeutic modalities have serious side effects and do not increase life expectancy. Ditto for some of the newer modalities such as Dacarbazine [P. Lui et al, Cancer Treatment Reviews, doi:10.1016/j.ctrv.2007.06.004].

None the less, I am heartened by the number of, to me, acceptable clinical trials, not available a year ago, that are now on the books or imminent. (For those of you interested in reviewing all of them: http://clinicaltrials.gov/ct2/results?term=melanoma.)

In order of my preference, based on trials I knew about as of December 8, and what I knew about them, the three clinical trials in which I would consider participating are:

The Syntra trial of STA-4783 (Elescomol). Not yet FDA approved, but supposedly nearly there. I would be willing to wait a few weeks for it since it appears to be a very promising therapy.

NCT00094653 "MDX-010 Antibody, MDX-1379 Melanoma Vaccine, or MDX010/MDX-1379 Combination Treatment ..." I find this one very attractive because each arm is a promising approach; it requires me to be HLA-A*02901 positive, and I have no idea whether I am or not -- a lab test will answer that question. (The HLA histocompatibility complex acts as a ligand for some receptors (CD94/NKG2) on the surfaceof natural killer cells and for a subset of T cells that (hopefully) attack the melanoma cells. Its presence is needed to make the vaccine component of the trial effective.)

NCT00495066 "Compassionate Use Trial for Unresectable Melanoma with Ipilimumab (MXP-010).

Unfortunately, most clinical trials have become very weird beasts. I was planning to write a diatribe on the subject in this Rumination, but the 'Perspective' in the New England Journal of Medicine beat me to it (Hurray!) [NEJM 357:2219 (November 29, 2007) http://content.nejm.org/cgi/content/full/357/22/2219 ]. What fascinates me about this 'Perspective' is that all the benefits and pitfalls (see table from that paper, below) that were predicted when we discussed these issues in the 1970's when I was at the National Academy of Sciences have come to pass. What was not anticipated, and is the true horror story of the situation, is how many of these studies, funded by the drug companies, have turned into bad science driven by marketing considerations. From the Perspective (emphasis added):

" Although the traditional means of assessing drugs, therandomized, controlled trial, is the rightfully enshrined standardfor determining efficacy, such studies often have importantdrawbacks (see Table): limited size, making it difficult to detectuncommon adverse events; short duration, even for drugs designedto be taken for a lifetime; frequent reliance on placebos asthe comparator, limiting clinical relevance; termination aftera surrogate end point is achieved, without measurement of realclinical effects; and underrepresentation of patients with complexhealth problems, especially the elderly. Some of these limitationsresult from lax study protocols that are proposed by manufacturersand are too readily accepted by the FDA. But others are inherentin the randomized, controlled study design. No trial could everbe large enough to gather enough data to quantify the risksof all uncommon side effects, and studies lasting long enoughto document all clinical outcomes would be impractical if theyrequired many years of follow-up before approval could be granted.In addition, since the FDA generally doesn't require head-to-headcomparisons of similar drugs, preapproval trials are unlikelyto provide the comparative data that physicians, patients, andpayers need. Improvement in study designs could address someof these problems, but many are hardwired into the nature ofrandomized, controlled trials."

Strengths and Weaknesses of Randomized Controlled Trials and Observational Studies of Medications.

You do understand that the diatribe that I would have written would not be as gentle as NEJM's, because I feel that any experiment that does not allow for an equally useful amount of information to be extracted from all possible outcomes is a badly designed experiment. When two drug companies run trials on different drugs against the same disease and end up competing on the basis of "my drug ameliorated 9% of the cases" (whereas the other company's only ameliorated 7%) without any effort to determine whether the populations (7% and 9%) are the same or different, nor any effort to determine what differentiates the 7% (or 9%) from the rest of the tested population, are abominably bad science, but make sense from the marketeer's perspective. The Gleevec (Imatinib) study (for which my melanoma does not have the right genetic characteristics) appears to be a partial exception from this general attitude as apparently does the NCT00094653 Combination Treatment study that requires HLA-A*02901 to be present. At least they make an effort to prescreen the test population for features of known relevance to the action of the drug being tested. Note that in both these studies these restrictions are, as the mathematicians say, necessary but not sufficient. That is, the drugs are known not to work unless these conditions are met, but that does not mean that they will work if they are.

The foregoing was written on Saturday, December 8. What follows was written on December 14th.

"Medarex, Inc. (Nasdaq: MEDX) and Bristol-Myers Squibb Company (NYSE: BMY) today presented results from multiple clinical studies of ipilimumab (MDX-010), an investigational immunotherapy, for patients with advanced melanoma. The results demonstrated an anti-tumor response in some patients with advanced melanoma either as a monotherapy or in combination with other therapies. The results of the monotherapy study showed that 19% of patients (17/88) with advanced melanoma treated with ipilimumab experienced control of their disease, including tumor shrinkage and stabilization. The second presentation showed that complete or partial response was achieved in 13% of patients (46/356) with advanced melanoma when treated with ipilimumab alone or in combination with traditional chemotherapy (i.e., dacarbazine), interleukin-2, or a gp100 peptide vaccine. The results of this analysis also indicated that treatment with ipilimumab may take 12 weeks or longer to induce a response. These findings were presented at the American Society of Clinical Oncology's 2007 Annual Meeting in Chicago.

In the cohort of 23 patients who were treated at 10 mg/kg, disease control was achieved in 39% (9/23), which lasted six months or longer in nearly all patients (8/9)." [clip]

NEW YORK (Reuters) - Bristol-Myers Squibb Co and Medarex Inc on Monday reported mixed top-line results from three key studies of their experimental drug for advanced melanoma, but said the data were strong enough to seek approval from

U.S.

health regulators.

One of the three studies of the drug, ipilimumab, failed to meet its primary goal, which was to rule out a best objective response rate of less than 10 percent, the companies said.

Why the big flap? Because if it works in less than 10% of the people with metastatic melanoma, the market potential and therefore the profit is limited. The headlines:

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RTTNews) - Shares of Medarex Inc. (MEDX | charts | news | PowerRating) dropped almost 21% on Tuesday after the company revealed mixed results from three drug trials. The stock gapped open lower, drifting further throughout the morning. MEDX closed at $10.56, down $2.79.

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The real issue, it seems to me, is not on how many patients a drug works, but to devise methods of determining for which patients it will work. Yet in none of the clinical trial descriptions in the official database, nor in the consent forms I have seen for the two studies, is there any mention of any tests to try to discriminate between those trial participants for whom the regimen works from those for whom it does not. Clearly, nobody knows. Yet I find it hard to believe that no testable hypotheses exist. See Chin et. al. [Malignant melanoma: genetics and therapeutics in the genomic era, Genes & Development 20:2149 (2006) on line at www.genesdev.org/cgi/doi/10.1101/gad.1437206] and Fecher et, al. [Toward a Molecular Classification of Melanoma, J. Clinical Oncology 26:1606 (2007)].

Why does the FDA not insist on their inclusion in all clinical trials? How do they know whether the 20% of patients on which drug A works is the same or a different population that the 18% on which drug B works? If they do not know, nor attempt to find out, is that not inexcusably sloppy science?

On Wednesday, December 12 I met with Dr. Hodi. The meeting was productive, calm, and businesslike. I did not expect warmth and relevant conversation since I knew that was too much to hope for, but it was by far the least disturbing meeting with him so far. The conclusions from the visit are easy to summarize. There are three possible drug trials to consider:

The compassionate use trial of Ipilimumab that will be available locally by February and is currently available at other locations, including Yale.

The Elescomol (Syntra's STA-4783) trial for which no starting date estimates are available and which is a drug with a totally different mode of action from any of the others; everyone is optimistic about it, but it is definitely a shot in the dark with respect to any particular case.

Several companies are working on a new class of drugs, small molecule tyrosine kinase inhibitors, that inhibit c-Met. Of particular potential interest to me is the research being done at the University of Chicago by Puri et. al., [c-Met is a potentially new therapeutic target in the treatment of human melanoma. Clin. Cancer Res., 13:2246 (2007)]. Not having ever been involved in immunology, my understanding of the pathways involved is superficial and I am just beginning to learn about them; hence the following summary is subject to revision and I apologize in advance for my misunderstandings and mistakes. c-Met (Mesenchymal epithelial transition factor) is a proto-oncogene that is a tyrosine kinase membrane receptor for hepatocyte growth factor/scatter factor (HGF/SF) that is involved in melanocyte growth, and melanoma development and adhesion. So the inhibition of c-Met and HGF which is involved in both the proliferation and attachment of melanoma cells has been a target in melanoma research. Puri et. al., have been investigating two drugs, a synthetic small molecular weight tyrosine kinase inhibitor, SU11274, and a siRNA ('small Interfering RNA') that serve to interfere with the expression of specific genes. This approach has been very successful in laboratory experiments and is now ready for clinical trial in a Phase I study for which I may be eligible. Because my metastases are in the liver, this approach may make theoretical sense. I have no idea, at present, what the side effects might be, particularly potential long term side effects. That certainly will influence any decision.

I am still trying to investigate what interaction, if any, exists between the c-Met and the PTEN pathways. Stay tuned.

What I will actually do will be decided when I see Dr. Hodi again late in January.

The other news is that since I returned from Missouri, despite my efforts and efforts on my behalf, I was unable to locate a lab to run the plasma separation protocol for me, either on the Cape or in Boston. So, with the help of Bruce Kristal (thanks, Bruce) I bought a second hand centrifuge – costs no more than one trip to Missouri – and I'll go back to Missouri in January to observe/learn the protocol. More on that in January.

In the meantime, I look forward to our annual winter solstice party (December 23,noon to eight). You are all invited.

It has been an interesting start to 2008. On January 4th I met with Dr. Geoffrey Shapiro who went over with me in some detail the four phase 1 clinical trials he was currently conducting. We agreed that the trial of AZD1152, an aurora B kinase inhibitor, was the best match for me. My reasons for the choice are: the optimum dose had already been established; only the most minimal side effects have been observed in 30 patients; in the one melanoma patient on which the drug has been tried, extended remission has been observed. We agreed to start the study on January 14th.

On January 8th, I went out to Columbia, MO to spend a day with Dr. John Viator to learn how to prepare samples for his experimental test for melanocytes circulating in the blood (there are not supposed to be any). As I knew beforehand, the protocol is very straightforward and the necessary reagents are easy to obtain. I had already bought the centrifuge and the reagents, tubes, and pipettes all arrived last week. I will make the first dry run next week and send samples to John every six to eight weeks for him to run. I really enjoyed my visit because his experiments are so interesting and it is a rare pleasure these days to be able to give my gray matter a really good workout. To top it all off, he has a delightful family with two great kids. What more could one want?

The immediately past week has been an exhausting one. I spent the entire week, from early Monday (getting there through a snow storm) until Saturday morning in Boston, getting prepped for and receiving the first cycle of AZD1152 "chemotherapy". I put that in quotes, because AZD1252 is one of a new class of drugs that is quite different from the classic anti-cancer drugs, both in mechanism of action and in the image of side effects that the term chemotherapy evokes. AZD1152 works not by arresting cell division but by inhibiting the kinase responsible for arranging the chromosomes in proper alignment. Consequently, the daughter cells are either destroyed by normal p53 at subsequent checkpoints in mitosis or, in the absence (or inactivity) of p53 will be destroyed upon initiating the next cycle of division (because of their polyploidy). Experiments have demonstrated that the effect is much greater on cancer cells than on normal cells that also divide rapidly (mucosal, gut lining, and hair follicle cells) but the reason for this delightful effect are unclear. Details below.

On Monday lab tests (which were normal) and another PET scan that demonstrated some increase in the size of the liver tumors and the lymph node in my chest, as well as a new, small, lesion in my sacrum (the bone at the base of the spine). Clearly, it is time to try something to slow the progress of the disease.

Tuesday was devoted to installing a port. This was a minor surgical procedure, under sedation (not anesthesia), requiring three small incisions, two in my right shoulder and one in my neck, that runs a line (tube) from a small bulb resident under my skin below my clavicle up to my jugular vein and down into the right atrium of my heart. Now that it is in place, any drugs that I need infused, including the AZD1152, can be injected through my skin into the bulb. The procedure went very smoothly. The PA (physician assistant) who did it told me he usually does four a day. The sedation does leave one woozy and exhausted for the rest of the day so I spent the day in my room except for a sojourn to an excellent Vietnamese Pho restaurant for a very restoring bowl of noodle soup.

Wednesday and Thursday each were 13 hour days (7:00 am to 8:00 pm) in the CRC (Clinical Research Center) starting with EKGs and blood samples, a two hour infusion of the drug through the port, and blood samples every couple of hours for the rest of the day. The CRC nurses are knowledgeable, delightful, helpful, and busy. I got a lot of reading done in the comfortable recliner chair in which I spent my days. Katherine's iPod provided lovely classical background music for my reading. I also had a brief but informative chat with Dr. Shapiro who was on his way to Amsterdam for a meeting on AZD1152.

Friday was a short day in the CRC. One more EKG and a blood draw. The drug company requires that the EKGs be done on their machine which incorporates software that interprets the traces. Unfortunately, the interpreting software leaves something to be desired and kept reporting that I have a right bundle branch block, sometime first and sometimes second degree. Of course, I have no such thing, which had to be confirmed by a hospital EKG machine which requires different pads glued to me. I am reasonably sure that the problem is my normal bradycardia (slow heart rate) which confused the software's interpretation algorithm. Unfortunately for me – I wanted to go home – I had to stay over until Saturday for one last blood sample. Then I could dash to the airport and arrived back on island at 11:40.

Yesterday (Wednesday) I went back to Boston for a blood draw and a 'how are you feeling'. The chemistry came back disgustingly normal, including the white cell count which is the real issue (leukopenia is a known possible side effect which I happy to avoid).

Since this is a rumination, I feel free to discourse at random. I have been looking for an opportunity to bring some stray thoughts in, but it has not presented itself. Since I think it is important, I'll stick it in here. As most of you know, I am, and always have been, the opposite of a hypochondriac (hyperchondriac does not sound right and the spell checker doesn't recognize it). None the less, I find myself considering (worrying is too strong a word, at least so far) whether every twinge or ache, which I most certainly have cheerfully ignored in the past, may not be symptomatic of a new or enlarged lesion. So far, it has never been, but I cannot prevent the thought from crossing my mind. I would not be surprised that to a greater or lesser degree it happens to everyone in my situation. It is probably just egotism (or a better understanding of pathophysiology), but I feel that I panic far less than most people in my situation. I can notice the reaction in me, but (so far) I can brush it off within a couple of minutes with the help of a few deep breaths and a little objective analysis.

While on the subject of stray ruminations, although the realization did not hit me until several days later, having the port in place is amazingly reassuring and calming,. As I told one of the nurses in the CRC, having the port in was nearly as good as moving to Oregon. With a port, the problems with potassium induced pain that brought on the execution by lethal injection cases now before the Supreme Court go away, because it is potassium in the peripheral veins that cause the excruciating pain; directly to the heart avoids the issue. An air embolism would do as well as potassium. Even though I knew of the Oregon studies that demonstrated that the suicide rate in Oregon among terminal patients decreased after the passage of the Death with Dignity law (http://egov.oregon.gov/DHS/ph/pas/docs/year8.pdf), it was amazing to me how reassuring and anxiety relieving it is to know that, de facto, I retain control of my life. I am confident that I will actually live longer knowing that I have control. It avoids (as they have found in Oregon) seeking to terminate life sooner for fear of not having the control when it is ultimately needed. You have to be there to appreciate it. So, please, I ask you, dear reader, for your own sake when you get to that point in your life, make every effort to pass a Death with Dignity law in your own state now, before it is too late for you. (End of sermon.)

What follows deals with the details of AZD1152. Readers uninterested in scientific esoterica, can stop reading here.

AZD1152 is a small molecule (relative to the size of proteins and other biologic molecules) that suppresses the activity of aurora B kinase. A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). Phosphorylation usually results in a functional change of the target protein.Two aurora kinases, A and B, control two critical stages of cell division (mitosis): Aurora A is essential for the assembly of the spindles and centromere maturation and separation; aurora B is active for chromosome alignment, segregation, and movement as they separate. [See V. M. Bolanos-Garcia. Aurora kinases, Int. J. Biochem & Cell Biol. 37: 1572 (2005) and M. Carmena & W. Earnshaw. The Cellular Geography of Aurora Kinases, Nature Rev., Molec. Cell. Biol. 4: 842 (2003).]

Because errors in mitosis provide a source of genetic instability that is typically associated with tumorigenesis, and aurora A has been identified as a bona vide oncogene, and aurora kinases are over expressed in a number of tumors, aurora kinase inhibition make an interesting target for anticancer therapy. [See N. Keen & S. Taylor. Aurora-kinase Inhibitors as Anticancer Agents, Nature Rev. Cancer 4: 927 (2004) and R. Carvajal et al. Aurora Kinases: New Targets for Cancer Therapy, Clin. Cancer Res. 12:6869 (2006).] The paper by Keen is exceptionally lucid and well written.

The specifics of AZD1152 pharmacodynamics is described by Wilinson et al. AZD1152, A Selective Inhibitor of Aurora B Kinase, Inhibits Human Tumor Xenografts Groeth By Inducing Apoptosis, Clin. Cancer res. 13:3682 (2007); by Evans et al. The Selective Aurora B Kinase Inhibitor AZD1152 Is A Potential new Treatment for Multiple Myeloma, Brit. J. of Haematology doi:10.1111/j. 1365-2141 2007.06913.x (11 Sept. 2007); and by Yang et al. AZD1152, A Novel And Selective Aurora B Inhibitor, Induces Growth Arrest, Apoptosis, and Sensitization For Tubulin Depolymerizing Agent Or Topoisomerase II Inhibitor In Human Acute Leukemia Cells in vivo And in vitro, Blood 110: 2034 (2007)].

A reference that Dr. Artemis Simopoulos sent to me [Xia et al. Melanoma Growth is Reduced in Fat-1 Transgenic Mice: Impact of Omega-6/Omega-3 essential Fatty Acids, PNAS 103:12499 (15 Aug 2006).] made me decide that increasing my omega-3 intake may help and cannot hurt. From the abstract:

"The results showed a dramatic reduction of melanoma formation and growth in fat-1 transgenic mice. The level of n-3 fatty acids and their metabolite prostaglandin E3 (PGE3) were much higher (but the n-6_n-3 ratio is much lower) in the tumor and surrounding tissues of fat-1 mice than that of WT animals. The phosphatase and tensin homologue deleted on the chromosome 10 (PTEN) gene was significantly up-regulated in the fat-1 mice. In vitro experiments showed that addition of the n-3 fatty acid eicosapentaenoic acid or PGE3 inhibited the growth of B16 cell line and increased the expression of PTEN, which could be partially attenuated by inhibition of PGE3 production, suggesting that PGE3 may act as an antitumor mediator. These data demonstrate an anticancer (antimelanoma) effect of n-3 fatty acids through, at least in part, activation of PTEN pathway mediated by PGE3."

Schatton et al. Identification of Cells Initiating Human Melanomas, Nature 451: 345 (17 Jan 2008) describes the greater specific tumorigenic capacity of ABCB5 positive cells compared to ABCB5 negative cells. While they do not classify these cells as stem-cells, the theory that there is a subpopulation of malignant cells that solely have the ability to metastasize has received a significant boost.

Bundscherer et al. Antiproliferative and Proapototic Effects of Rapamycin and Celecoxib in Malignant Melanoma Cell Lines. Oncology Reports 19: 547 (2008). According to this paper, celecoxib's action is independent of COX2 expression by the tumor and nor does it induce cell cycle arrest. Consequently, it would appear that it does not interfere with the action of AZD1152. This makes me give serious consideration to increasing my celecoxib (Celebrex) intake.

I had my scheduled re-scans on Tuesday. I had predicted that I was stable or possibly slightly regressed. To the bemusement of my docs I was right on the button. By the standard we are using, the PET scan, my “prevascular and hepatic tumor burden had decreased. There has been an increase in the size and avidity of the right cervical lymph node and upper abdominal lymph node. The right sacral lesion is unchanged.” None the less, according to the CT with contrast “There is a mild increase in upper abdominal and periportal lymphadenopathy. There are innumerable hepatic metastases … Increased conspicuity to subcentimeter pulmonary nodules and stable hylar adenopathy.”

Translation: Although there are a lot of tiny metastases in my liver, they are less actively growing that at the last scan. My blood tests of liver status are within the normal range. The tumors in the lymph nodes are growing very slowly. To this I can add that I am feeling fit as a fiddle, my body strength continues to be normal (I can toss 50 lb feed bags around much as I could 20 years ago); none the less and even without disease, age takes its toll: I tire a little more easily and getting up off the floor is not as easy as it was a decade or two ago.

I had a long chat with Dr. Shapiro (who is in charge of the phase I clinical trials for solid tumors and who I think is terrific) and we agreed that it makes no sense to switch from what we are currently doing and which is keeping me stable to some other protocol which may, or may not, be better. New drugs and new results on melanoma patients are appearing weekly if not daily. The longer I stay stable the more likely it is that a effective novel therapy will be available when my melanoma starts to progress.

It may be my optimism rather than biomedical reality, but the large number of stable lesions in my liver suggest to me that when I do start to progress my liver will fail rapidly. When that happens, faster is better (I hate itching).

AstraZenica, the drug company that produces the AZD-1152 which I am taking, has discontinued its clinical trial of the drug on solid tumors (and is focusing on the drug for leukemia because they are having success at the much higher doses that are safe only for leukemia patients who have deranged white blood cells anyhow). A total of 91 patients with a variety of solid tumors have participated in the trial – I was number 91. Of these 91, two patients have achieved stability – a woman with lung cancer and I. We are both getting the same dose although she weighs only 55% as much as I do. {The wonders of questionable clinical trial designs!} What no one knows is whether it is the drug that is the cause of the stability or something else, e.g., we have more active immune systems, we are taking some other drug that is having a beneficial effect, something in our life styles or environment, or …

Both are violated in many, if not most, clinical trials. The primary purpose of any study should not be compromised; however, the associated opportunity to collect ancillary data – not necessarily in all patients, probably not statistically significant data, but, none the less, data potentially capable of providing useful clues that may improve efficacy, save time and future trial costs, and provide hints on patient selection – should never be ignored, but usually are.

When I see Dr. Shapiro next week, I am going to propose a simple n-of-1 experiment, that is an experiment in which I become my own control. Assuming I remain stable at my next scan early in September, that during the next two month cycle we do the infusion every week instead of every two weeks and see whether this produces any change in the results, e.g., more regression than the slight avidity decrease we just saw and, possibly no progression elsewhere. I would agree to not change any of the other drugs I am taking for the course of the experiment. This would at least give a clue as to the contribution that AZD-1152 is making to the stability and provide some data to better inform the decision of whether to continue on this drug or try something else.

The only likely side effect, if any, of this change may be leucopenia (a decrease in white blood cells). Biweekly blood tests will catch this and we can discontinue the weekly infusion if need be. Since I have not had any problem with leucopenia on the current regime, and since when used for leukemia patients who are administered over six times my dose no serious side effects are observed (leucopenia is irrelevant in leukemia since it is malignancy of the white blood cells) it is more than reasonable to expect no other potential problems. [Why did they anglicize leucopenia by using a c rather than a k, but left leukemia alone?]

Does this mean that it will happen? Given the nature and attitudes of IRBs (Institutional Review Boards) as currently constituted (and complaints and discussion of their shortcomings populate the literature) and drug company lawyers, I estimate the probability of this simple experiment actually going forward at less than 20%.

The experiment that I proposed in Rumination 14, to get infused weekly instead of bi-weekly, (back issues are archived at http://upislandeggs.com/Ruminations.htm) was, as I predicted, turned down. The primary and overriding reason is that any deviation from an approved protocol must be reviewed and approved by the IRB (Institutional Review Board) of the hospital performing the study, the IRB of the drug company whose drug is being used, and the FDA. The excuse for this bureaucratic excess is that it is in place to protect the patients on the studies. I do not dispute that patients on studies (and otherwise) require and deserve protection. They also deserve to have the maximum possible information/data extracted from the experimental treatment in which they have volunteered to participate. Even more do they deserve, as long as the primary objective of the study is met, to have the option of modifying the treatment to explore the possibility of enhancing the benefit to the patient. Ascertaining whether the experimental treatment is of benefit to the patient and, if it is not, discontinuing the treatment not because it is doing harm but simply because the patient has better things to do with his/her time (including exploring other potentially beneficial therapeutic options) is also a significant benefit, as is the scientific goal of ascertaining why the patient is doing well for reasons other than the experimental treatment.

I am a concrete example that may illustrate the problem. Of the 91 patients with solid tumors in the AZD-1152 trial, only two (me and a woman with lung cancer) exhibited no progression of disease – our diseases are stable. Patients with cancer occasionally exhibit stable disease without treatment. The standard explanation is that their immune systems are responding appropriately to the disease. Consequently, there is a very real question whether AZD-1152 is actually effective in a few percent of the population because of the specifics of the genetics of our tumor or whether the drug is ineffective in solid tumors given the dose limitations imposed by side effects. This is not an academic question. If a trial drug is working, the patients should certainly stay on it. If their stability is unrelated to the drug, then it would be far better for them to try a different regimen, sooner rather than later when their natural defenses which are keeping the disease stable start to crumble. The patients, of course, have no basis for making such a decision and their oncologists are prevented by the bureaucratic red tape from ever finding out. In my case, the experiment I proposed was both simple and safe: Give the infusion every week instead of every other week and check the white cell count twice as often. If it starts to drop significantly, discontinue the experiment. Since my count dropped only once, after the first infusion, and then only slightly, the risk in my case is minimal, not zero, but minimal. Other patient’s white counts have/will react differently but individual differences are not taken into account in the early trials, which, in my opinion, is one of the principal reasons so many expensive Stage III trials fail.

It is only since I have become personally involved that I have realized how absurd the IRB system has become since its initiation for patient protection. A large part of the problem is the amazing reliance that has developed on the legal fiction of ‘informed consent’; the paper work for which consume the IRBs (and whose primary function is to protect the pharmaceutical industry, hospitals, and doctors from lawsuits). The reality is that the typical patient, even the very well educated and informed one, does not have either the background or the technical knowledge to perform the scientific evaluation that is required to give *informed* consent, that is, knowledgably concur that the experiment to be performed on him/her can reasonably be expected to bestow a perceived benefit that overrides the risks. Only the lawyers who wrote the rules for the IRBs can persuade themselves that giving informed consent and signing an informed consent form are in any way a comparable activities or indicative of the same mind set. The correspondence is pure fiction. The reality is that the patient is told about possible benefits and adverse effects orally and then told to take the form home and read it or, if you prefer and want to get started - a delay may jeopardize your slot in the study - just sign here.

In the July 18, 2008, issue of Science, page 324, is an amazing example of the absurd damage to science and scientific progress that the current IRB implementation has brought on. It is reported that a respected team of scientists at the University of Tokyo have been forced to retract a paper because “it apparently failed to obtain informed consent from tissue donors or from their IRB. Observers believe the problem stems in part from guidelines that do not sufficiently explain how to handle samples collected before

Japan

established informed consent procedures.” Now I am not suggesting that IRB rules and regulations should not have teeth. However, retraction is a totally inappropriate remedy for any cause other than scientific error or fraud. As it stands, readers of the journal will know only that the paper has been retracted and will assume that it contains erroneous data or misleading conclusions, when that is not the case. This cuts the heart out of what the archival record means in science and illustrates the potential for, and the reality of, abuse of power inherent in IRBs. It punishes the scientific community, not the ‘perpetrators’.

On a different note, I was reliably informed that the experiment of treating weekly instead of bi-weekly had been performed in Holland (the home country of the developer of the drug) and that they found that some fraction (I have no idea what fraction) of the patients developed leucopenia on the weekly treatment, which is why they opted for the bi-weekly protocol. That may well be true, but is that a good reason not to try it on a patient (me) who had only the mildest leucopenia in response to the first treatment and never thereafter? Particularly, since the weekly trial could be stopped at any time? Further, the weekly infusion was not on patients with stable disease. Yet further, in that the same dose was given to all patients irrespective of their weight. Still further, since the trial has officially been terminated and only the few patients who are stable are, by courtesy, continuing to receive the drug – but of course only under the conditions imposed by the original protocol, now discontinued because it did not work. And beyond all that, that rarity, the proposed experiment is on a patient, me, who can give meaningful informed consent. The lawyers win, patients and science loses, and all asses are covered. Sic transit gloria mundi.

I want to state quite clearly that I do not blame any individual physicians or teaching hospitals for this state of affairs. None of them wanted this absurd system foisted upon them. However, some blame does accrue to them collectively. If they, collectively, announced that unless the system was appropriately modified they will conduct no further clinical trials, the system would be changed within months. But who will volunteer to take the responsibility for herding cats?

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I was recently asked on what evidence I based my decision to take celecoxib (Celebrex, a COX-2 inhibitor) and the omega-3 fatty acids (fish and flax oil). Since this is a very reasonable question, I thought it appropriate to replicate my answer in these Ruminations. The COX-2 / omega-3 story is complicated since they interact in their biochemistry via the prostaglandin pathways. My choice was also based on my genetics.

Let me begin with the science by providing a bibliography of some of the more relevant papers. I have copies of most of them if anyone is interested enough to read them. Otherwise, the titles will suffice to suggest the basis of my decision:

A. Bundschere et al., Antiproliferative and proapoptotic effects of rapamycin and celecoxib in malignant melanoma lines. Oncology Reports 19: 547 - 553 (2008)

C. Lee et al., Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor gamma during malignant melanoma progression. J. Cutaneous Path. (2008) doi:10.1111/j.1600-0560.2007.00939.x

S. K. Lee. et al., Vitamic C suppresses proliferation of the human melanoma cell SK-MEL-2 through inhibition of COX-2 expression and the modulation of insulin-like growth factor II (IGF-II) production. Cell. Physiol. 216: 180 - 188 (2008)

Kast, R.E., Melanoma inhibition by cyclooxygenase inhibitors: role of interleukin-6 suppression, a putative mechanism of action, and clinical implications. Med. Oncol. 24: 1-6 (2007)

K. Muller-Decker et al., The cyclooxygenase-2 mediated prostaglandin signaling is causally related to epithelial carcinogenesis. Mol. Carcinog. 46: 705-710 (2007)

J-C Marshall et al., The effects of a cyclooxygenase-2 (COX-2) expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production. J. Carcinog. 6: 17 doi:10.1186/1477-3163-6-17 (2007)

J. C. Marshall et al., The use of a cyclooxygenase inhibitor (Nepafenac) in an ocular and metastatic animal model of uveal melanoma. Carcinogenesis 28: 2053 - 2058 (2007)

F.J. Lejeune et al., Complete and long-lasting regression of disseminated multiple skin melanoma metastases under treatment with cyclooxygenase inhibitor. Melanoma Res. 16: 263-265 (2006)

K. S. Wilson, Cyclooxygenase-2 inhibition and regression of metastatic melanoma. Melanoma Res. 18(?): 465-466 (2006)

K. S. Wilson, et al., Clinical activity of Celecoxib in metastatic melanoma. Cancer Invest. 24: 740 -746 (2006)

S. Xia et al., Melanoma growth is reduced in fat-1 transgenic mice: Impact of omega-6/omega-3 essential fatty acids. PNAS 103: 12499-12504 (2006)

Y. Denkins et al., Role of w-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma. J. Lipid Res. 46: 1278 - 1284 (2005)

C. Denkert et al., Expression of cyclooxygenase-2 in human malignant melanoma. Cancer Res. 61: 303 - 308 (2001)

The COX-2/ Omega-3 story is particularly relevant in my particular case for two reasons that, until I thought about it, I had previously always thought were unrelated.

I have had a life-long affliction from hereditary polymorphic light eruptions (PMLE). My mother had a mild case, I have a severe case, and one of my daughters has an intermediate case. In the past, if I spent 15 minutes in the sun, three days later I would break out in typical PMLEs. Several very competent dermatologists have tried to help over the years, including a course of PUVA (psoralen & UV light), but nothing helped. Until I started taking omega-3 supplements. With the usual dose, the PMLEs decreased significantly in severity and on the double dose I am now taking they have disappeared completely.

I also have hereditary colonic polyps (not polyposis). Both my parents died of colon cancer. I had my first polyp removed at age 40 and few harvested every couple of years since, until I started taking 200 mg/day of Celebrex about 7 years ago. Since then, not a single polyp in three scopings. If 200 mg/day will completely suppress the colonic precancerous lesions, might my melanoma also have similar pathways, given my genotype? 400 mg/day is the clinically accepted maximum dose so why not see if that will help, given that I have no cardiovascular risk factors. (The Celebrex also does a great job keeping my lumbago/sciatica under control.)

That is why I concluded that it would be prudent to increase my intake of both omega-3 fatty acids and COX-2 inhibitor. Neither can do me significant harm. Given my genetics, I think that they are likely to do me some good by reducing tumerogenesis. That is why I proposed the experiment to Dr. Shapiro to increase the frequency of AZD-1152 for one cycle to see if it makes a difference. It may well be, given that AZD-1152 at the accepted tolerable dose has not been a success in over 90% of solid tumor patients, that my stability derives from the omega-3 / Celebrex in collaboration with my immune system and not the AZD-1152. It would be nice to find out, but given the rules under which the IRBs and FDA have chosen/been forced to operate, it will not happen. So, I really have no meaningful choice but to stay on the current regimen and travel to Boston every other week for two days for infusion, even though that effort may have no bearing on my well being and it would be so easy to find out whether or not it does. Alas, we will probably never know.

There is a glimmer of light at the end of the tunnel. Current commentary by scientists and clinicians express the growing realization that anti-cancer monotherapy block-buster drugs are illusive if not illusions. Whether this will cause the pharmaceutical companies to explore and collaborate on novel multi-drug therapies or abandon the development of anti-cancer drugs remains to be seen.

Since so much has happened so fast, and despite the fact that I dislike reading (and writing) diaries, it seems that the best way to describe it is chronologically. At the end of this piece is a discussion of significant changes in cancer research that are just over the horizon and that offer hope to the next generation of cancer patients.

Sunday, September 28. This is the first time in two weeks that, with the help of a few Tylenol, I feel collected enough to write. There is no way around it; it has been a rough time during which I aged at least ten years and was fighting to get the decade back one year at a time. (Which I did in 10 days.)

It started innocently enough on Monday, September 15, with a late afternoon meeting with Dr. Geoff Shapiro and Dr. Bruno Bastos (Geoff’s charming new associate) to go over the protocol for the SCH 717965 study, sign the consent forms, and review the expected side effects, which, it was clear, are significant and unpleasant but, because of the short half-life (1.5 – 2 hours) of the drug were expected to last at most a day or two. I went into this with my eyes open and expecting nothing too awful, and it turned out worse than any of us expected.

Tuesday morning I had a biopsy of the malignant lymph node in my neck to provide a 'before treatment'' specimen. The rest of Tuesday and Wednesday passed uneventfully with PET and CT scans (except for being knocked down by a panel van backing into a parking space while crossing the street to spend some free time at the MFA – minimal damage done and a great show of Art Nouveau jewelry).

Thursday the serious part began. I arrived at the CRC (Clinical Research Center) at 7:00 am, and after some preliminary labs the eight hour infusion began around 8:00 using both lumens of my port, one for the drug and the other for a large assortment of meds including anti-diarrhea, anti-nausea, and antibiotic (the drug is known to drop white counts precipitously albeit briefly). A scopolamine patch behind my ear (the experimental drug crosses the blood-brain barrier and is known to produce vertigo) and an IV in my arm for blood samples completed the getup.

Things went very well indeed most of the day with no discomfort or nausea. I had a egg salad sandwich and a fruit cup for lunch and was feeling quite chipper, although I knew that the problems would show up near or after the end of the infusion (even though the pharmacokinetics suggest that by then half of the infused drug had already cleared the system). The changes it instigated in a large number of pathways obviously are much longer lasting.

Near the end of the infusion (at least that’s when I think it was because I don’t remember an IV pole in the bathroom with me although I am so used to them that I may be misremembering) the diarrhea hit and with it, much to my surprise, the classic symptoms of shock – a cold sweat and light headedness. When I came out of the bathroom my blood pressure was down to 70/40 that the prompt administration of two liters of saline (one through each lumen, running wide open) soon fixed. I am still puzzled by the hypovolemic shock. The diarrhea was not that large a volume and I was neither bloated nor was there any obvious swelling of the extremities. Even after the two liters of saline, my urine output was still negligible. Into what compartment did all that water vanish?

This may be the right point say how impressed I have been over the past year with the astounding competence, caring, dedication, and compassion of everyone connected with the CRC – Cheryl the receptionist, the women who take your vital signs and escort you into the CRC, the entire nursing staff of whom I single out Susan Aikey only because she is my nurse and I have spent the most time with her – every last one of them are amazingly wonderful and competent people as is obvious from having watched them deal with their patients. If every ICU in the country were staffed and run like the DFCI CRC, medical care would be of much higher quality.

I stayed in the CRC, in my very comfortable recliner, for another hour or so, to recuperate and get my blood pressure to stabilize. In anticipation of this kind of reaction to the drug, I had elected to stay at the Best Western motel that is immediately adjacent to DFCI and is accessible with only a few steps across a courtyard from the hospital complex. I’m glad I did because it took me more than half an hour, with rests in chairs thoughtfully provided by DFCI, for the trip of usually five minutes, picking up a container of wonton soup for my dinner on the way through the food court. I slept like a log.

The next morning, Friday, I went back to the CRC for blood work and vital signs and to make sure my blood pressure had returned to normal. It had. None the less, I felt tired, weak, and unsteady, rather like the morning after major surgery (except for the absence of pain). I had aged 10 years in 24 hours and was very glad to be home after five days in Boston.

I really expected to bounce back by Monday, but it did not happen. To add injury to insult, I noticed that my sense of taste and smell had disappeared. I could not tell whether a patty was beef or lamb! Everything else I could live with, but not that! No cliffhangers – taste did come back two weeks later.

Having gone through all this, I did hope that it had done me some good and the following Thursday (September 25), still very tired and shaky, I went back to Boston for a repeat PET scan. After the scan I met with Andrew who had already reviewed the scan with the radiologist. Andrew was surprised that I was not recovering faster since all my labs, except for white count, had returned to near normal, to which all I could say was “so am I”. (The temporary abnormalities in the labs, from white count to liver function were pretty amazing – quite a drug.)The results of the PET scan were not encouraging. What we had expected to find was that the ‘avidity’ (the metabolic activity) of the metastatic hot spots had decreased significantly. But, no decrease could be found. I arrived home at 8:30 in the evening, having gotten up at 4:15 am, so tired that I just fell into bed.

Friday morning I awoke feeling tired and shaky as usual but mid-morning, like flipping a switch, I suddenly got back at least eight of the ten years, with only a slight headache, easily treated with Tylenol, as a reminder of what I had been through. Today, Sunday, the headache is less but still there and the other residual symptoms are fading fast. On Thursday I will go back to Boston to meet with Dr. Shapiro and decide where we go from here.

Tuesday, September 30. Andrew called in the morning to give me surprising news. The drug company (Bristol-Meyers-Squib) that makes the anti-CLA4 antibody, Ipilimumab (my son-in-law, Bill Colbert, tells me that ipilimumab is a Swahili word meaning "my stomach hurts") last Thursday informed all the clinical trail centers that any patient not on the drug by the next day (last Friday) will not be allowed in a trial because of "manufacturing problems". This was the drug I was planning to go on if the Cdk-inhibitor did not work. I am reliably informed that drug companies have pulled this stunt before. My disgust knows no bounds and there is no recourse. Free enterprise, Republican version, in action. Is it not time for NIH and FDA to define, run, and publish the drug trials, combining drugs from different companies as suggested by research and patient needs (at drug company expense)?

Friday, October 3. Yesterday, I went up to Boston on the 6:00 am boat, as usual, to meet with Dr. Shapiro to decide what to do next. That morning's lab results showed that I was as back to normal, as I felt. We had an extended and very fruitful conversation reviewing the options now that Ipi is no longer available. There are basically two options. One is to start on one of three currently available Hsp90 inhibitors, one of which, by Schering, had demonstrated efficacy against canine mucosal melanoma. We agreed that if, note the big if, we knew that my melanoma had one of the aberrant pathways that Hsp90 modulates then it would certainly be worth trying. The reason that study is not permitted is as pathetic as it is insulting: For a biopsy tissue sample to be analyzed/sequenced, the patient must sign an IRB approved release. One of the main reasons to do the analysis is not just for the patient but for the generation of a database of cancer cell characteristics (see below). At this point which characteristics will turn out to be important are unknown. If they were known, there would be no need to do the research. But the IRB insists that a patient cannot sign a blanket release, for example, "I allow the pencil tip size piece of tissue taken from me to be used for any legitimate research purpose that does not identify me without my explicit permission" is deemed unacceptably broad by IRBs that require the specific end purpose(s) to be explicitly stated. Talk about a catch 22! Joseph Heller would be proud.

It also turns out that the PET scan last week that showed no decrease in avidity is a very poor predictor of the drug's efficacy. It was expected to be, but it turned out not to be; that's the nature of research. But the patient must still go through the two hour procedure anyhow, because it was written into the protocol approved by the FDA and that remains cast in concrete. The straightjackets imposed by the FDA and the IRBs are clearly counterproductive to patient safety and comfort, optimal care, and cost containment.

So, what we decided, since the drug certainly was having effect on me (the disappearance of my dermatitis and my hair loss both demonstrate effects on rapidly dividing cells) was to continue as we had planned for the current cycle but at half the drug dose. The next infusion will be next Thursday. Then, as originally planned, three weeks later another infusion and a repeat biopsy and definitive PET and CT scans that will give a realistic reading on whether the drug works on me or not. I am very comfortable with this plan. At half the dose, I expect to recover from the side effects far more rapidly.

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It should not come as a surprise that I have been contemplating the state of cancer research and cancer drug research, different but interrelated subjects. I was therefore utterly delighted with the editorial in Nature (Nature 455: 138, 11 September 2008) which starts:

"Beneath cancer's daunting complexity lies a simplicity that gives grounds for hope.

"For several years now, large-scale cancer-genome studies have made it increasingly clear that a tumour cell is a genetic disaster area littered with mutations that differ not only from one type of cancer to the next, but from one patient to the next. Pharmaceutical companies have had to accept that Gleevec, a drug that treats a form of leukaemia by targeting a specific gene product, is almost certainly going to be a rare exception in the therapeutic arsenal; most cancers are far too complex to yield to such a magic bullet.

"That message was hammered home with new statistical power in three studies released last week."

The three studies focused on three different solid tumors. To make a long story short, the results are that

"The studies took a more comprehensive approach than previous large cancer-genomics studies, by simultaneously analysing genetic sequences, copy-number variations, expression arrays and other forms of data. The Johns Hopkins team looked at all the active genes in tumours from a few dozen patients; the Genome Atlas team looked at selected genes in tumours from 206 patients. Taken together, their results show that no single mutated gene lies at the heart of any of these tumours. The pancreatic tumour samples, for example, showed an average of 63 genetic mutations each — with considerable variation from one sample to the next."

Shortly thereafter, the New England Journal of Medicine (NEJM 359: 1367-1380, 25 September 2008) published a review article on the molecular origins of cancer, focusing on non-small-cell lung cancers, about 85% of all lung cancers. By comparing the rate of genetic abnormalities among the two types of non-small cell cancer (Squamous cell and Adenocarcenoma) and small cell cancer, they found that except for abnormalities in p53 which appeared in 50 – 75% of all the tumors, almost all of the other mutations occurred less than 20% of the time. These low percentages strongly suggest to me that we are not aggregating the data in the right way.

Taken together, these results lead to some obvious and far more interesting less obvious conclusions. The obvious ones, mentioned in my previous Rumination, is the demise (the sooner the better) of the block buster model of pharmaceutical research and with it, the demise of the one-drug-company-sponsored, one-drug-at-a-time clinical trial.

The less obvious ones deal with how the data are being analyzed, a problem that has its roots in the organization of medical education and practice, which is organized almost entirely along organ system lines. Consequently, I propose asking the question (which I have not yet seen in print but expect to momentarily): Given the poor data aggregation displayed above, does it make really sense to sort cancers primarily by organ and secondarily by cell type (as all four of these studies have done), or does it make more sense to cluster by molecular profiles? I submit, as a testable hypothesis, that the initiating processes responsible all cancers, only secondarily modulated by organ system or cell type, will be a well defined subset of mutations and epigenetic events or precursors out of the broad spectrum of genetic and epigenetic changes that have been recorded to date.

Put another way, cells throughout the body are more alike than they are different, particularly when it comes to the cell's internal reproductive mechanisms and controls, which are what goes awry in cancer. I therefore suggest that the research effort focus on obtaining a sufficiently large number of genetic, epigenetic, copy number, and proteonomic profiles of individual cancers of all types and from all organs so that the statistical power of cluster analysis and other statistical techniques (see the 4 September 2008 issue of Nature for a focus on "Science in the petabyte age") can be brought to bear on the question of which cancers are similar by virtue of their molecular profiles, not by virtue of the organs or cells involved. My prediction is that the number of these clusters will be far fewer than current pessimistic estimates.

This, in turn, leads to the currently unpalatable conclusion that clinical oncology as well as cancer research needs to be reorganized by molecular profiles rather than organ systems and that drug companies must develop mechanisms for cooperation on drug development and trials that focus on multi-drug treatment of the (soon to be identified) common constellations of molecular profiles.

One organization that agrees with this analysis was recently founded by my friends Dr. Jennifer Carter and June Kinoshita. They call it N-of-One. If you are interested in what they are doing and planning, their website is N-of-One.com. Because the website is still under development you will need to go to the 'REGISTER' tab in the upper right hand corner and enter a password: newvisitor – no further registration or identification is needed. [Publication of the password in this blog has been authorized by Dr. Carter.]

Note added in proof: I urge you to read the Commentary by Heng in the current issue of J. of the American Medical Assoc. [H. H. Q. Heng, The Conflict Between Complex Systems and Reductionism, JAMA 300:156-1581 (October 1, 2008)]. He concludes (but do read the whole article):

"The unpredictable nature of the [genetic and epigenetic] heterogeneity will force the consideration of the significance of clinical exceptions, because complex disease results in highly diverse responses that include many exceptions to the general rules. Furthermore, heterogeneity is not simply "noise" but a key component of evolution directly related to the human disease conditions and must also be considered when designing interventions such as cancer therapies. Clinical therapies must be individualized, balancing the parts of the system and the response of the patient as a whole. Clinical research on pharmaceutical agents needs to focus more on the differential responses within diverse patient populations."

The paper is two pages long and I would have included it here, but it is copyrighted, so I can only provide copies upon request to individuals, under the fair use exception. (Of course, you, the tax payer, probably paid for its writing, and undoubtedly its thinking, under an NIH grant, However, the law, in its wisdom, requires you to pay to read what you have already paid for.)

The news is all good. Three weeks ago I had another infusion of the Cdk-inhibitor at half the original dose and with additional fluid support. No serious side effects and it took me just four days to fully recover, for my white count to return to normal, and the tiredness to go away, nor was there any loss of smell or taste. This week we did repeat PET and CT scans that showed not only solid stability (no new spots in my liver) but an observable response to the drug in that the avidity of some of the old lesions had decreased (less dense, i.e., less metabolic activity). Things are definitely looking up!

With these radiology results (which Andrew, ever thoughtful and considerate, gave me over the phone the same day!), I had the third infusion on Wednesday, again half dose and fluid support. This time the side effects were even less than before. While still a little shaky the evening of the infusion, by the next morning (Thursday) I felt fine – no nausea, no diarrhea, and only the slightest of headaches. By Friday morning I felt so well that both Katherine and I were amazed. I was so surprised I went over to the hospital and had them run my chemistry. My white count was back to normal and while the anemia is still there it clearly is bothering me much less. I can only surmise that my body is getting acclimated to the drug and handling it much better. This suggests that we could increase the dosage without any major consequences in terms of side effects.

Rumination 21. Experimental design 101
                                                         By
                                           Thomas P. Vogl
                                             March 5, 2009

I have just spent a week in Boston, arriving late Tuesday 2/25 and finally getting home on Tuesday, 3/3 because the Nor'easter on Monday canceled both buses and planes (I spent six hours at the airport after which Cape Air canceled the delayed flight.) Wednesday and Thursday were devoted to scans - ECHO cardiogram, CT scan, and two PET scans, one with FDG and the other with FLT. The FDG is the usual pet scan using glucose with a radioactive tagged fluorine atom attached; the FLT is a fluorothymidine with a tagged fluorine atom that identifies high thymidine kinase-1 activity. FDG allows visualization of glucose metabolism which indicates how active the cell is; FLT allows visualization of DNA turnover, a measure of cell division (proliferation). If you think of cells as rabbits, FDG PET tells you how much they are running around and FLT PET tells you how fast they are breeding. FDG PET is a recognized and approved procedure; FLT is still experimental and it looks like it is more useful for blood cancers, such as the lymphomas, than for solid tumors like carcinomas, melanomas, etc. On Friday I had the first infusion of the new drug, AUY922, an Hsp90 inhibitor and endless hourly EKGs, (I suspect the plethora of EKGs are the contribution of the lawyers who may have had more input into the experimental design than the scientists.) The only side effect was a tolerable level of diarrhea.

The scans showed that in the five weeks since my previous scan the size of my metastases had increased only slightly despite the fact that there had been no treatment during that time and that the treatment in the previous three to six weeks had been ineffective. Looking back over my shoulder at the whole sequence of events since my initial surgery in July of 2005, it is clear that my mucosal melanoma is exceptionally indolent considering that mucosal melanoma is known to be especially aggressive and fast growing, even compared to dermal melanoma. Now, whether this is due to particular strengths in my immune system, or a genetic peculiarity of my melanoma, or the effect of some combination of the Celebrex and fish and flax oils, all of which actively reduce inflammation, is not known and cannot be determined. However, I'll take what I can get. The reason it cannot be determined is relevant to the primary topic of this rumination.

An obvious experiment would be for me to stop taking the Celebrex and fish/flax oils for four to six weeks and see if the disease progress has increased; then, as a check, resume the three 'drugs' (technically the oils are not drugs) and see if the progression again slows down. What is wrong with this scenario? There are three possible outcomes: (1) progression increases when the drugs are withdrawn and decreases when they are resumed; (2) progression increases when the drugs are withdrawn and continues to increase when they are resumed; (3) progression does not change throughout. In case 1, the conclusion that the drugs are of benefit is reasonable; in case 3, the conclusion that the drug is of no benefit is reasonable; but in case 2 the conclusion that the drug is of no benefit is not reasonable because the increase while the drugs were withdrawn may have overwhelmed the immune system and that the drugs, while effective before, are no longer up to the task. So, in that case, we have learned nothing. Consequently, it is a poorly designed experiment because it is a fundamental principle of experimental design that a well designed experiment yields useful information irrespective of the outcome of the experiment. It is a dictum as fundamental to experimental design as 'Above all do no harm' is to medicine.

So, in that spirit, let us examine the design of clinical trials. To make the discussion concrete, consider an (imaginary) drug, TPV001, that in animal experiments has been shown to produce an effective treatment (of some disease) at a dose of 60 U(nits).

The first step is to clearly state the objectives of the experiment. I submit that the appropriate objective is 'Is this drug effective in humans without producing unacceptable side effects'. Put more formally, can we disprove the statement (null hypothesis) that TPV001 is ineffective or that it causes unacceptable side effects. Let us further suppose that we can afford to test the drug on 40 individuals and that this is a sufficient number to satisfy the statistical requirements.

What the drug companies have elected to do is to divorce the primary objective (does it work) from the secondary objective (and can it do so without unacceptable side effects) and give primacy to the secondary objective. In fact, they ignore the primary objective until they have established whether the secondary objective can be met. This is called a phase I dose escalation trial. So, they take their 40 patients and give the drug to the first 10 patients at a dose of 15U. These patients exhibit no side effects and no therapeutic benefit. What has been learned from this experiment? Essentially nothing -- no side effects (that's nice), no therapeutic benefit (not a surprise at this dose). If the drug companies were honest with these patients they would have told them from the beginning that the chance of this dose doing them any good at all was minimal.

The next group of 10 patients get 30 U. Of the 10, two have mild side effects, say one has fatigue lasting less than 48 hours and the other mild diarrhea lasting less than a day. One of these patients showed a slight therapeutic benefit. What does this experiment show? Not much. It suggests that the drug may work on people and that at this dosage the side effects are mild and the therapeutic effect, milder.

The next group of 10 get 45 U. Four have mild side effects, one had more severe but still acceptable side effects, and one has severe enough side effects to cause concern. Three patients demonstrate some therapeutic benefit, say lack of progression. While some information can be gleaned from knowing whether it is the patients who had the side effects were the ones who benefited from the treatment, the most likely (and usual) result is that some of the patients who benefited had no side effects.

Undaunted, because the FDA has approved the protocol and it is, therefore, set in concrete, they forge ahead to a dose of 60U for the last group of 10 patients. Now there are 4 severe and 4 moderate side effects and some therapeutic response in 6 patients. They conclude that four severe reactions is too much and go on to the phase II trial (therapeutic efficacy) at 45 U.

At 45 U, the phase II trial fails to show adequate efficacy in a sufficient number of patients and the drug is abandoned. This is the fate of about 80% or more of the drugs entering phase I trials. What an incredible waste of time and money. All that has really been shown is the well known fact that people differ greatly in response to drugs and that the average response of a group of ten patients totally fails to capture the extent of the variation.

With the same number of subject, there is a much better way, i.e., a way that yields far more information without any added danger to the patients. In fact, when compared to the current system, it diminishes the danger to the most at risk group (the last ten subjects) and an enhances the likelihood of benefits to the group least likely to benefit under the current system (the first ten subjects).

As before, start the first ten patients at 15U. If they show no adverse reaction, escalate the dose to 30U for each of those patients, Continue the dose escalation on each patient until the criteria used before to establish the unacceptability of side effects is reached, but on each patient individually. Note that this does not subject any patient to more risk that they would be exposed to if they had been part of the 40 patient group described above (much less risk for the last 10). But it has huge advantages: It immediately relates the dose, side effects,and therapeutic efficacy for each individual patient; it assures each patient that if there is therapeutic potential for him/her, then it will be reached; and it allows an immediate initial quantitative determination of not only the average maximum tolerable dose (MTD) but also of its variance.

Assume that from this first group of 10, it is determined that the MTD is 42 +/- 16 U. Then the next group of 10 patients can be started at, say, 41-16 (1 SD below the mean) at 26 U and the dose escalation might be in 10U steps instead of 15U steps as it was in the first group.

By the time all four groups of 10 have been through this study, so much more will be known: the MTD for all 40 subjects individually and its variance; the therapeutic response of each of the 40 to their individualized MTD; the side effects of each individual at their MTD and whether it is correlated with therapeutic efficacy, and even dose-response curves. Last, but not least, each of the 40 patients will have had the same optimal opportunity to benefit from the trial. Little, if any, of such data are available from Phase I studies as currently carried out.

The pharmaceutical companies are not incompetent and they have highly skilled scientists and statisticians in their employ. The same can be said about the FDA, possibly not quite as enthusiastically. Consequently, I find it difficult to believe that the current system is the result of negligence or stupidity. That leaves the question of how the current state of affairs came about and why it continues. It is a mystery. As the detectives would have it, cui bono? I cannot figure it out. Maybe a reader can enlighten me. I will appreciate it.

The collected Ruminations may be found at http://upislandeggs.com/Ruminations.htm
and my e-mail address at the bottom of the page at http://upislandeggs.com/

Rumination 24. Building Destructive Empires
By
Thomas P. Vogl
September 27, 2009

Sutent was a roaring success for me initially. The scans two months after starting Sutent showed stable disease and the side effects were minimal. So, of course, we continued the Sutent with scans scheduled two months later (September 2). Unfortunately, a funny thing happened on the way to the forum. In mid-August, two days before the Agricultural Fair that we were scheduled to work for four days, my bi-weekly labs showed that my LDH (a non-specific liver function measure) jumped almost 50% from two weeks before. Curious, but not alarming. The next day (after spending the day setting up for the fair), I spiked a fever and thought, probably correctly, that I had a virus at a most inopportune time. By the next day I had what was most likely my first ever attack of acute hepatitis with all the classic symptoms except jaundice accompanied by just a little pain, mainly discomfort. Ten days later we did the scheduled scans and there were significant changes in the liver. So, in preparation to switching to a new experimental regimen, a PD-1 inhibitor (more below), we discontinued the Sutent. Within 24 hours the symptoms had markedly decreased and within three days they were gone. I also discovered that the fatigue, for which Sutent is famous, had been sneaking up on me so slowly that I did not notice, after having been absent (as far as I could tell) the first few weeks of treatment. What a pleasant surprise to have the hepatitis gone and my energy back!

Last week I met with Dr. Hodi and Laurie Chiambalero, the research nurse on the Phase 1b PD-1 study. It was a delightful, positive meeting in which we covered all the bases. The drug, MDX-1106, will be infused every two weeks at 10mg/Kg, the dose considered optimal (see http://www.asco.org/ASCOv2/Meetings/Abstracts&vmview=abst_detail_view&confID=55&abstractID=34904) and, aside from occasional scans, there will be no reason for additional trips to Boston. After the first infusion, for which I elect to stay in Boston overnight just in case of untoward side effects, infusions will all be one day trips. So far, only twenty patients have been recruited into the study so relatively little is known about side effects other than that there is no discernible pattern to date. Since I worked with Laurie on another study with Dr. Shapiro, I feel very comfortable working with her and Dr. Hodi. I have decided, however, that if this study does not help me, I will not participate in any further studies unless there is biological evidence that the drug is relevant to my tumor's deranged pathway(s).

The reason I feel relatively optimistic about this very new drug, is that (briefly) it binds a receptor (PD-1) on the surface of the melanoma cells. This binding blocks the activation of a protein that would otherwise be activated and inhibit the function of T-cells, a component of the immune system that could destroy the abnormal tumor cells. The English language is inimical to double negatives, so it has a great deal of difficulty in dealing with immunology, which is full of them. So another way of explaining what the PD-1 inhibitor does is that by inhibiting production of a protein that inhibits T-cell attacks on the cancer cells, it disinhibits the functioning of the immune system.

Since my immune system has clearly been doing a pretty good job of keeping the tumor progressing far slower than expected, suppressing this obstacle to allowing the full force of my immune system to act against the tumor suggests that the results will be encouraging. This assumes, of course, that my tumor produces this protein, and that we do not know. We shall see.

Added in proof: The astounding positive results of PLX4302 (a BRAFV600E inhibitor) on metastatic melanoma (http://www.medicalnewstoday.com/articles/152309.php ) were announced a few days ago. Slides from my tumor are being tested for this mutation. Results in a few weeks.

However, the PD-1 study will not start for another few weeks. The reason for that brings me to the the title of this Rumination.

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I asked when the study would begin, and I was told that the IRB (Institutional Review Board) paperwork still needed some i's dotted and t's crossed. Probably an unnecessary delay, but OK. I then asked where (which of three infusion facilities at DFCI) the infusion will take place and was told that this was also an IRB decision. To me, that was the last straw, so I will vent my frustration and anger at IRB misfeasance here. For my many readers who may not be aware of the history of IRBs, IRBs were created by Congressional mandate (see, e.g., http://en.wikipedia.org/wiki/Institutional_review_boardhttp://en.wikipedia.org/wiki/Institutional_review_board

for the laudable purpose “to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in a research study “ Each facility (hospital, research institution, university) establishes its own independent IRB that must follow the guidelines/rules mandated by FDA and NIH.

Unfortunately, but essentially inevitably, this laudable purpose has been perverted to generate a bureaucracy that, de facto, functions to protect its local institution using patient protection as a club to expand its empire and exert ever increasing control over the research enterprise by non-scientist/non-physician administrators, and, equally important to protect the organization from adverse publicity and law suits. (I won't mention the for profit rent-an-IRB scams further.) Only rarely do administrators value the goal of their institution over their own aggrandizement and CYA (Cover Your Ass)– those select few are worth their weight in platinum. The literature is rife with examples. The example I encountered is probably typical. Consider the three infusion facilities at DFCI. Either they are of equal quality and competence, in which case the choice among them is completely irrelevant to protecting “the rights and welfare of patients”, or they are unequal in some way relevant to patient protection in which case the IRB, to fulfill its mandate, should tell doctors to only assign patients to the best one and be raising hell with the hospital administration to correct shortcomings in the others. In neither case is it appropriate for the IRB to assign patients to a particular infusion facility. It is a failure of top management to curb the mission creep and power enhancement that is the personal goal of every administrator and manager in every institution, public or private.

The problem is widespread. The most famous CYA case was a study of the effect of maintaining the prescribed sterility actions in emergency situations (in this case placing central lines) on subsequent complications. A study at one hospital in the mid-West, when they assigned a staff member (I believe a nurse) to accompany a team and remind them of sterile procedures showed a marked decline in complications. When they asked NIH for grant support to try this at other hospitals before a general recommendation was made (after all an additional staff member costs money and their presence must be cost effective) the NIH Office of Human Subjects Research (OHSR, the NIH IRB that covers grant applications) said that they could not do this without obtaining the informed consent of the patients. Picture this: a seriously ill patient in the Emergency Department or the ICU must be asked to sign a waver to allow a nurse to remind the doctor to wash his/her hands! National publicity and ridicule eventually reversed this bizarre decision. Unfortunately, the incident did nothing to change the behavior of IRBs or of the OHSR. Delays of significant research projects by IRB hairsplitting and nit-picking continue unabated. As my example from DFCI illustrates, such intrusive incursions are ubiquitous. It may not be killing research by the death of one thousand cuts, but it certainly slows research, and wastes enormous amounts of time and money. What has happened to staying within the stated mandate, let alone using a modicum of common sense?

Have any of you ever seen, let alone read, a consent form that can pass IRB muster? I have in front of me copies of the two consent forms I signed for the PD-1 study. The main one, which is consent to the study, runs 26 single spaced pages. (Think about the median reading competence of the U.S. population!) Reasonably enough, the first three pages outline the purpose of the study and alternative treatments for the patient's condition. The next six pages are devoted to explaining the screening and the protocol including explanations of what EKGs, urine tests, blood tests, etc. involve. The last 16 pages are devoted to a laundry list of what can conceivably go wrong without any attempt to put these events into perspective or to inform the reader what is known about the incidence of these events to prior patients. Does this not serve far more to protect the institution, no matter what may happen, rather than meaningfully inform the patient? Now, particularly in Phase I trials, the number of prior patients may be small and the data scanty. None the less, is this not the kind of information needed to allow an informed consent?

The other consent form I signed runs only ten pages to allow for for the collection of a few additional tubes of blood for immunological studies. What is particularly fascinating and worrying is that this immunologic study is the primary basic research component of the study -- can the efficacy of this drug be predicted from the patient's immunologic status and can the effect of the drug on patients be monitored by changes in their immunologic status? Some obvious questions: Why is this not a part of the original consent and should any patients not agreeing to this be allowed in the study? Having already agreed to blood draws in the primary consent form, does it really need ten more pages of boiler plate to allow the draw of a few more tubes? What a fantasy world of philosophical theory the IRBs live in at what cost to society with consent forms written to protect the institution and providers rather than inform of the patient.

A similar fate for similar reasons has befallen HIPAA. HIPAA started as a drive to force standardization on medical insurance claim forms (which never happened). Added were attempts to increase electronic transactions and, in the process protect patient's medical records from inadvertent or malicious disclosure to others. See http://www.hipaaps.com/main/background.html for an overview. In a nutshell, HIPAA ended up saying that the patient has control (in a sense, ownership) over his/her medical record and may dictate to whom they may or may not be disclosed. Enter the bureaucracy and the empire building CYA administrator. When I asked Dr. Hodi to give me copies of all the reports (Labs, radiology, etc.) as soon as they were received, either in person, by FAX, or e-mail, I was informed that the local HIPAA administrator has decreed that all patient requests for such information must come through the Medical Records Department (which, of course, is his bailiwick). To ensure that this will happen, he has decreed that all printing and e-mailing from the DFCI computer system will be monitored and that any printing or e-mail of any medical record is essentially prohibited and exceptions will be investigated and have to be justified. For empire building, what a great ploy using the fear of large fines as club; for CYA it is an ideal excuse for the most arcane restrictions that require lots of staff to oversee – see my budget and my empire grow; for doctor-patient communication, what a disaster.

Equally horrifying is the unintended but pernicious influence of HIPAA on research. If patient data can be shared only under an immense bureaucratic paperwork burden, it most often will not be shared, vital data/information becomes unavailable, and the whole point of the enterprise, improving patient care, is slowed if not stopped cold. All this because in our society, personal medical information is considered in the same light as information on personal sexual activity was viewed in Victorian England. My personal view on the matter is that if anyone in the world can benefit by reading my medical record, they are welcome to do so. If this requires publication of my record in the New York Times, sure, go ahead. Given the national obsession with medical privacy, I am not suggesting that HIPAA be scrapped. Rather, I suggest that individuals have the right to waive or opt-out of HIPAA. People are allowed to waive trial by jury even in capital cases, and to waive many other rights conferred by law if they choose to do so and if in so doing no one else is harmed. Why not HIPAA?

I am also very curious as to why the senior clinical investigators, who bring their institutions both prestige and a copious flow of direct and overhead funds, have chosen to roll over and play dead in response to this assault upon their time, energy, and patients. As a group within their own institution, and nationally through their organizations such as ASCO (American Society for Clinical Oncology), they have considerable power and clout, if only they would choose to exercise it. A lobbyist to Congress would be useful. A more immediate need is a publicist to inform the general public of what the interference of these hair-splitting, nitpicking bureaucrats are doing to delay their care, intrude upon the doctor-patient relationship, slow down finding desperately needed treatments, and use up money that could be used for research. A very important role for the publicist should be to regularly publicize IRB and HIPAA absurdities. A little ridicule would go far to rationalize the behavior of both IRBs and HIPAA administrators.

I end with a plea to those of my readers who are lawyers or who have friends who are lawyers: Could one of you please come up with a blanket waiver for patients who wish to exempt their medical records from HIPAA safeguards. Of course, the institution and providers releasing those records must be held harmless in perpetuity for that release. It would also be necessary that the document requires the immediate release of the information as it is generated, lest the institution generates further paperwork obstacles to the prompt release of information.

The collected Ruminations may be found at http://upislandeggs.com/Ruminations.htm

and my e-mail address at the bottom of the page at http://upislandeggs.com/

(I use this circumlocution to suppress spam).