Rumination 17. Dear Diary

Rumination 17. Dear Diary

By

Thomas P. Vogl

October 5, 2008

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."