RUMINATIONS
ON LIVING WITH CANCER
by
Thomas P.
Vogl, Ph.D.
Introduction
and Copyright Statement
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. 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.
These Ruminations are copyrighted, but permission is granted to
reproduce them by individuals and organizations who do so without financial
gain of any sort, provided proper credit is given to the author and either:
(1) They are reproduced in their entirety, without deletions or
changes, including this introduction, or
(2) They are excerpted in sections no smaller than an entire unedited paragraph,
in which case a reference to a site or location where the entire document may
be obtained as easily as the material in which the excerpt appears must be
provided.
Ruminations
1: Reprise
By Tom Vogl
I am rather amused that the message I started teaching to my
bioengineering graduate students at
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
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
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.
Ruminations 2: Reprieve
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
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
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.
More when I know more, in a few weeks.
Cheers,
Tom.
Ruminations 3: Radiation Therapy Decisions
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
Ruminations 4: PET Results, Decisions, & Uncertainties
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 3rd, 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
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
That leaves only two possible relevant trials:
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.
So, the uncertainty continues for at least a few more weeks.
Meanwhile, back at the ranch, we are happy to report that
our favorite restaurant in
As soon as we can gauge that Tom’s reaction to the Glivec
will be mild, we are planning to go to
Cheers,
Tom.
Rumination 5 – The Lost Month
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
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 3rd I had a PET scan that showed a
metastasis in my liver. On April 11th,
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
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
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.
Rumination 6: Intermission
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
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
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
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.
Rumination 7: The Path Ahead
We had a glorious time in
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
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
"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
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."
AS:"OK. Can I tell the doctor the reason?"
Me: "If he is
interested, he may call me."
"Goodbye."
At
MD: "My AS
tells me you want to talk to me."
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.)
Me: Thank you.
MD: Goodbye.
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
So, yesterday
morning I had a very positive conversation with Dr. Robert Mc Anaw, who was my
radiation oncologist in
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.
Rumination 8: Whodathunkit!
Written
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:
ABDOMEN/PELVIS: There has
been interval decrease in FDG-avidity of
the right hepatic lesion
without a clear CT correlate with an
uptake ratio of about 1/2
that of the brain (6.5 SUV vs. 13 SUV)
previously with an uptake
ratio near 1.0 (7.2 SUV vs. 7.8 SUV).
No other abnormal FDG
activity is noted in the liver.
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
Written
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:
A Jesus freak in
Katherine's support
Someone turned the
right prayer wheel in
Ingesting large
quantities of flax and fish oil
Miracles happen
The relaxed Vineyard
lifestyle
Tom's positive
outlook and attitude
The good karma that
chickens create
Taking COX-2 inhibitors
(Celebrex)
Proximity to
Chilmark (see X-Files)
You are invited to
add your own favorite explanation.
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.
Life is interesting
– stay tuned.
Rumination 9. An Experiment in
Diagnostics
By Tom Vogl
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
Modern airlines being what they are, it takes as long to get
from here to
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
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
All in all, a great summer.
Rumination 10: Not So Glad Tidings.
by Thomas Vogl
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
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 surface of 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 (
" Although the traditional means of assessing drugs, the randomized, controlled trial, is the rightfully enshrined standard for determining efficacy, such studies often have important drawbacks (see Table): limited size, making it difficult to detect uncommon adverse events; short duration, even for drugs designed to be taken for a lifetime; frequent reliance on placebos as the comparator, limiting clinical relevance; termination after a surrogate end point is achieved, without measurement of real clinical effects; and underrepresentation of patients with complex health problems, especially the elderly. Some of these limitations result from lax study protocols that are proposed by manufacturers and are too readily accepted by the FDA. But others are inherent in the randomized, controlled study design. No trial could ever be large enough to gather enough data to quantify the risks of all uncommon side effects, and studies lasting long enough to document all clinical outcomes would be impractical if they required many years of follow-up before approval could be granted. In addition, since the FDA generally doesn't require head-to-head comparisons of similar drugs, preapproval trials are unlikely to provide the comparative data that physicians, patients, and payers need. Improvement in study designs could address some of these problems, but many are hardwired into the nature of randomized, 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.
I based my choices in part on an announcement that appeared
on
"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
[clip]
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]
On Monday, there was a big flap with many stories in the press:
Mon Dec 10,
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:
********************************************************************************************
*MEDX hits 52-week
low at 10.16
Wednesday,
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.
Wednesday's slide moved the stock below support to a new 52-week low.
**********************************************************************************************
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?
Sufficient onto each day is the diatribe thereof. Enough.
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
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
In the meantime, I look forward to our annual winter
solstice party (December 23,
Rumination 11. Nothing Ventured, Nothing Gained by
Thomas P. Vogl
January 24, 2008
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 unt