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Electronic Letters to:
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Electronic letters published:
![[Read eLetter]](/icons/misc/sectionDOWN.gif){kind=icon}
Predictive Accuracy of Chemosensitivity Testing
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Gregory D. Pawelski, Retired none, none
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gdpawel{at}comcast.net Gregory D. Pawelski, et al.
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In 1983, medical publications introduced assays based on "cell-death" (not cell-growth). This was a good five years before understanding the concept of apoptosis (apoptosis is a genetically programmed cell death pathway which exists in all cells, which is supposed to cause them to commit suicide if they become functionally deranged, but doesn't function properly in cancer cells, allowing them to grow abnormally without committing suicide, which can be triggered to occur by effective anti- cancer drugs). Because clinical oncologists did not understand apoptosis then, these pioneering publications with "cell-death" (instead of cell growth) endpoints were ignored, and neither clinical trials nor the application of cell death drug resistance assays were supported by academic and private practice clinical oncologists. The clinical utility and clinical accuracy of cell culture drug resistance testing with cell-death endpoints has now been proven. 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. How about 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 NCI'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 in 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 Assay Testing (a test to pre-identify which chemo drugs would benefit the patient). While being faced with a large number of choices of otherwise equally acceptable therapies, oncologists select the treatments which generate the most income for private practices or generate the least inconvenience for the clinical research institutions. In the absence of Cell Culture Assay Testing, oncologists will continue to base their drug selections on reimbursement more than on any other single factor. Absent assay testing, they are free to choose the most remunerative therapy (5). By utilizing Cell Culture Assay Tests, they do so either because they want to choose the treatment which is most likely to work or that is what their patients want. Afterall, even ASCO endorses "patient's treatment preferences." Either way, they are forced to consider information going beyond reimbursement. The traditional criteria ever used to evaluate laboratory tests has been the predictive 'accuracy' of the test. The American Society of Clinical Oncology (ASCO) reviews of cell culture assay tests specifically excluded all studies reporting the predictive 'accuracy' of the tests. In other words, they excluded reports that only reported correlations between assay results and clinical outcomes. Instead, ASCO reviews included old, previously-reviewed studies comparing outcomes of patients who had treatment based on assay results versus patients with empirically chosen therapy. The criteria of laboratory assay 'efficacy', as opposed to laboratory assay 'accuracy' sound reasonable, but it is unprecendented with regard to any other laboratory test ever evaluated. None of the available laboratory tests used in the selection of treatments for cancer patients have ever been tested for 'efficacy'. This includes estrogen receptor, progesterone receptor, Her2/neu, immunohistochemical staining for tumor classification, bacterial culture and sensitivity testing, CT, MRI and Pet Scans to measure tumor response to treatment. The only data supporting any of them relate to test 'accuracy', and there is a total lack of information regarding test 'efficacy'. (randomized trials with outcome measurements for diagnostic tests) Also, no one is seriously proposing that any of the molecular tests now available (Oncotype DX, EGFR amplification/mutation) should have to be proven 'efficacious', as opposed to merely 'accurate', before they are used in clinical decisions regarding treatment selection. ASCO says that there is no literature establishing clinical 'efficacy' of assay tests, because the costs of such clinical trials are prohibitive, granting agency support is non-existent, and no other analogous tests have been or will likely ever be subjected to such an unreasonably high bar criterion for clinical use. Cell culture assay tests have been well proven to have predictive 'accuracy' with that of estrogen receptor, progesterone receptor, Her2/neu and the newer molecular tests. In light of the precious little in the way of guidance from clinical trials with respect to best empiric therapy (where the only thing that has been proven to correlate with treatment decisions is reimbursement to the prescribing oncologist) and the importance of basing cancer treatment at least in part on patient preferences, it is entirely reasonable to support judicious application of laboratory tests which have been well characterized with respect to test 'accuracy'. This is a diagnostic test and should be held to that criteria, and not to that of therapy. This laboratory test is a tool for the oncologist. The oncologist should take advantage of all the tools available to him/her to treat a patient. And since studies show that only 25-30% of patients do respond to chemotherapy that is available to them, there should be due consideration to looking at the advantage of human tissue assay tests to the resistance that has been found to chemotherapy drugs. Cell culture drug resistance testing is for preventing use of known anti-cancer drugs that are not likely effective in the specific tumor. Cell culture drug sensitivity testing tries to determine specific drug and dose effectiveness. The distinction between sensitivity and resistance is more semantic than substantive. In virtually all forms of cancer, clinical trials have failed to identify best drug regimens for use in all individuals with a given form of cancer. Oncologists have been documented to use reimbursement (payment to the oncologist) as the most important criterion for selecting between the large array of otherwise equally acceptable regimens. The established criterion on which to judge all laboratory tests used to help in the selection of cancer treatment is test 'accuracy' and not test 'efficacy'. Cell culture assay tests with cell-death endpoints have been exceedingly and reproducibly well established to be usefully 'accurate' in correlation with and predicting for clinical outcomes, including tumor response and patient survival. Molecular assays have established absolutely no data relating to assay 'efficacy', and with much less data relating to assay 'accuracy' than exist to support the application of cell culture assays. ASCO is an organization which has been zealous in its support of an inherently corrupt system which won't allow drugs to be chosen on the basis of tumor biology but instead protects the ability of oncologists to choose drugs largely on the basis of profit margin or least inconvenience to research clinics. There should an expansion of reimbursement to promote even greater utilization and development of laboratory-based mechanisms for improving the match between tumors and an ever-increasing number of partially effective and very expensive drug therapies. Sources: (1) http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page8#Section_297 (2) http://content.healthaffairs.org/cgi/content/abstract/25/2/437 (3) http://www.nytimes.com/2006/03/08/health/08docs.html?ex=1145160000&en=584b5c2aa35995a3&ei=5070 (4) http://patternsofcare.com/2005/1/editor.htm (figure 37, volume 2, issue 1, 2005) (5) http://www.positivehealth.com/test/articles.asp?i=1832 |
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