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Healthy Skepticism International News

June 2006

Influences on Oncologists’ prescribing of chemotherapy

I was a spouse/caregiver to an ovarian cancer patient. I became intensely interested in cancer medicine by virtue of working through, enduring and surviving my wife’s illness. I’ve gotten a street education by virtue of voluminous reading and hundreds of hours of past and ongoing personal communication with noted authorities in the field. To paraphrase Martin Luther King Jr.: “A scientific communication should be judged on the quality of its content and only secondarily, or not at all, on the qualifications of its author.”

The American Society of Clinical Oncologists (ASCO) says oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient’s health status and treatment preferences.

So what about those published reports of clinical trials?

More chemotherapy is given for breast cancer than for any other form of cancer and there have been more published reports of clinical trials for breast cancer than for any other form of cancer.

According to the National Cancer Institute’s March 31, 2006 official cancer information website on “state of the art” chemotherapy for recurrent or metastatic breast cancer, it is unclear whether single-agent chemotherapy or combination chemotherapy is preferable for first-line treatment. At this time, no data support the superiority of any particular regimen. So, it would appear that published reports of clinical trials provide precious little in the way of guidance [1].

In the total absence of guidance from published reports of clinical trials then, what basis are treatment regimens selected instead? ASCO says that this should be further based on a patient’s health status and patient treatment preferences.

So what is being done?

Recently published in the journal Health Affairs is a joint Harvard/Michigan study entitled, “Does reimbursement influence chemotherapy treatment for cancer patients?” The authors documented a clear association between reimbursement to the oncologists for the chemotherapy of breast, lung, and colorectal cancer and the regimens which the oncologists selected for the patients. In other words, oncologists tended to base their treatment decisions on which regimen provided the greatest financial remuneration to the oncologist [2].

A March 8, 2006 New York Times article described the study. One of the more interesting aspects of the story was a comment from an executive with ASCO, Dr. Joseph S. Bailes, who disputed the study’s findings, saying that cancer doctors select treatments only on the basis of clinical evidence [3].

So ASCO’s Dr. Bailes maintains that drugs are chosen only on the basis of “clinical evidence.”

Yet Dr. Neil Love reported a survey of breast cancer oncologists based in academic medical centers and community based, private practice medical oncologists. The former oncologists do not derive personal profit from the administration of infusion chemotherapy, the latter oncologists do derive personal profit from infusion chemotherapy, while deriving no profit from prescribing oral-dosed chemotherapy.

The results of the survey could not have been more clear-cut. For first line chemotherapy of metastatic breast cancer, 84-88% of the academic center-based oncologists (who are motivated to keep off-protocol patients out of their chemotherapy infusion rooms to reserve these rooms for on-protocol patients) prescribed an oral-dose drug (capecitabine), while only 13% prescribed infusion drugs, and none of them prescribed the expensive, highly remunerative drug docetaxel.

In contrast, among the commuity-based oncologists, only 18% prescribed the non-remunerative oral-dose drug (capecitabine), while 75% prescribed remunerative infusion drugs, and about 40% prescribed the expensive, highly remunerative drug docetaxel [4].

There are patients who have progressive disease after first-line therapy, only to enjoy a dramatic benefit from second or even third line therapy, and these patients would have been much better served by receiving the most probable active treatment “the first time around.”

The existence of this profit motive in drug selection has been one of the major factors working against the individualization of cancer chemotherapy based on cell culture analysis (a pre-test to identify which chemo drugs would most benefit the patient) [5].

In the absence of a cell culture assay (Whole Cell Profiling), oncologists will continue to base their drug selections on reimbursement more than on any other single factor [6]. Absent assay testing, they are free to choose the most remunerative therapy.

By utilizing Whole Cell Profiling, they do so either because they want to choose the treatment which is most likely to work or that is what their patients want. After all, even ASCO endorses “patient’s treatment preferences.” Either way, they are forced to consider information going beyond reimbursement.

The whole cell profiling method differs from existing DNA and RNA tests (molecular profiling) in that it assesses the activity of a drug upon combined effect of all cellular processes, using several metabolic and morphologic endpoints. Other tests, such as those which identify DNA or RNA sequences or gene expression of individual proteins often examine only one component of a much larger, interactive process.

Researchers have put their efforts into molecular profiling as a way of predicting patient response to anti-cancer drug therapies. However, no gene-based test can discriminate differing levels of anti-tumor activity occurring among different therapy drugs. Nor can available gene-based tests identify situations in which it is advantageous to combine the new “targeted” drugs with other types of cancer drugs. So far, only cellular profiling has demonstrated this critical ability.

Not only is this an important predictive test, it is also a unique tool that can help to identify newer and better drugs, evaluate promising drug combinations, and serve as a “gold standard” correlative model with which to develop new DNA, RNA, and protein-based tests that better predict for drug activity.

The new cancer drugs are expensive, costing patients and insurance carriers $5,000 to $7,000 or more per month of treatment. Patients, physicians, insurance carriers, and the FDA are calling for predictive tests that allow for rational and cost-effective use of these drugs.

Cellular profiling holds the key to solving some of the problems confronting a healthcare system that is seeking ways to best allocate available resources while accomplishing the critical task of matching individual patients with the treatments most likely to benefit them.

NCI made an attempt years ago to study assay-directed therapy of lung cancer on its own.

1. Their expertise was in establishing permanent cell lines and they only tested tumors after first culturing them to amplify their cell number (these were all passaged, grown up, multiplied, replated). The result was that their assay evaluability rate for primary lung cancers was only 11% (a very dismal result).

2. The second problem they had is that they were selecting subpopulations. Subsequent work showed that you get different results when you test passaged cells compared to primary, fresh tumors.

3. The third problem is that the ability to get lung cancer to actually grow is an independent marker for virulent disease. It was actually the single greatest negative predictor for survival in one study.
So the NCI concluded that it was too much trouble and not all that useful. That was the attitude thereafter.

There have now been 5 different studies of the relationship between the results of cell culture drug resistance testing (CCDRT) and patient survival in ovarian cancer, and all 5 studies show significant correlations between CCDRT and patient survival [7-10, see ]http://weisenthal.org/ov_surv.htm].

And a very new test, called EGFRx (TM), predicted accurately for the survival of patients treated with “targeted” drugs like Iressa or Tarceva (both are small molecule targeted therapies) [11].

Gregory D. Pawelski

Wernersville, Pennsylvania 19565, USA

 

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