Rumination 14

Rumination 14: Still Crazy Stable After All These Years.

By

Thomas P. Vogl

July 4, 2008

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 …

There are two fundamental precepts of experimental design:

1. Experiments must be designed so that no matter what the outcome, useful information results.
2. Experiments must be designed so that the amount of information obtained is maximized.

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%.

Stay tuned.