by Gdpawel on Mon Jun 28, 2010 04:53 PM
by Gdpawel on Sun Sep 26, 2010 01:10 AM
The cell-based assay utilized by the recently defunct Oncotech was the EDR (extreme drug resistance) assay, a soft agarose tritiated thymidine assay, which is a direct descendent of the old original Salmon/Von Hoff Human Tumor Stem Cell or clonogenic assay of the late '70s/early '80s. This is the assay ASCO talks about in their infamous 2004 tech assessment of CSRAs (chemo senstivity and resistance assays). Over twenty year old material that had been discredited twenty years ago.The so-called ASCO expert panel who did this tech assessment included only three investigators who had ever worked in the field of cell culture assay technology: Dan Von Hoff, Anne Hamburger and a German named Hanauske who worked with Von Hoff in San Antonio. All three were old-line "Human Tumor Stem Cell" (clonogenic) assay workers, who (along with Salmon) convinced the oncologic community that clonogenic assays were the only valid approach to chemosensitivity testing (no one had ever heard of apoptosis back then).The newer studies of apoptosis occurred during the heyday of the oncogene discovery period in cancer research, where oncogene products were frequently found to be associated with cell growth and where cancer was most prominently considered to be a disease of disordered cell growth. In contrast, the concept of apoptosis (programmed cell death) had yet to become widely recognized. Also unrecognized were the concepts that cancer may be a disease of disordered apoptosis/cell death and that the mechanisms of action of most if not all available anticancer drugs may be mediated through apoptosis.When problems with proliferation-based assays emerged, there was little enthusiasm for studying cell death as an alternative endpoint. These factors explain the abandonment of research into cell culture assays by American universities and cancer centers by the mid-80s. However, clinical laboratories began to offer cell culture assay with cell-death endpoints as a service to patients in the USA by the late 1980s, and studies of cell culture assays continued in Europe and Asia.The clonogenic assay failed and it dragged down the whole field of inquiry along with it. So basically, the panel consisted of various oncologists who knew nothing about the technology and data, along with three proponents of a long-ago discredited approach which had nothing to do with the technologies (assays with cell-death endpoints), and with no one at all who understands anything at all about the newer technologies and published data pertaining to them.In the tech assessments, the authors invented a brand new criterion for validating a laboratory test. The existing standard had always been the "accuracy" of the test. This is true for every single test used in cancer medicine, from estrogen receptors to bacterial culture and sensitivity testing to panels of immunohistochemical stains to diagnose and classify tumor to Her2/neu and CA-125 to MRI scans, CT scans, PET scans and on and on. Yet they never even attempted to review the voluminous literature which defined the "accuracy" of cell death assays, and instead restricted their analysis to a consideration of papers which tried to address the issue of whether the use of the assays actually improved patient outcomes. They lumped together the old and long abandoned technologies (clonogenic assay, subrenal capsule assay, etc.) with the cell death assays. And yet, even in their own review, there were five studies with cell death assays and patient outcomes that were improved in four of the five studies and one negative study wasn't even relevant, because the authors did their tests on subcultured cells (as opposed to "fresh" tumor cultures) and tested the cells in monolayers (as opposed to three dimensional cell clusters). They ignored all studies having to do with "accuracy," the criteria used in tech assessments of all previous laboratory and radiographic tests, and only included studies dealing with "efficacy," a standard never met by any laboratory or radiographic test. Were they to have reviewed studies showing that the use of estrogen receptor improved treatment outcomes, they would have found no publications at all. Were they to have reviewed papers showing that the use of panels of immunohistochemical stains to subclassify tumors improved treatment outcomes, they would have found no publications at all. Were they to have reviewed studies showing that treatment outcomes were improved through the use of MRI scans or PET scans or CT scans to monitor growth and shrinkage of tumors (for the purpose of influencing the decision to continue the same chemotherapy or to change chemotherapy), as opposed to simply following patients with history, physical, simple plain radiographs, and simple lab tests, they would have found no publications at all. A "valid" tech review would have started with the published "accuracy" of the tests, and would have included in excess of 2,000 published correlations, in all types of neoplasms from acute leukemia to breast cancer to ovarian cancer to colon cancer and so forth, every single one of which showed that patients treated with drugs "active" in the assays had significantly higher response rates than patients treated with drugs which were "inactive" in the assays. They would have noted a half dozen papers which also showed that patients treated with drugs "active" in the assays also enjoyed significantly longer survivals. They would have made note of the preliminary studies which supported the concept that the use of the assays influenced treatment decisions which resulted in superior outcomes. A "valid" technology assessment would have concluded that the weight of the available evidence supports the decisions of individual oncologists to make at least selective use of these assays in their clinical practices. What is it that ASCO was saying? Cell culture assays should not be used outside the confines of a clinical trial setting. The same people who maintain that assay-directed therapy should not be used until proven in prospective randomized clinical trials, are the same people whose entire careers are utterly dependent upon mega-trials funded by pharmaceutical companies (that, plus fees from speeches they give for these companies), are the same people who control the clinical trials system, the grant review study sections, and the journal editorial boards. Why else would they want this technology tested under the clinical trial setting? Opponents of cell culture assay testing can blow all the smoke screens they want, but the fact is that every single time advocates for cell culture assays have been given fair consideration by an impartial, non-ASCO adjudication, the decision has been made that this testing is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. It is only when ASCO or the insurance industry has been appointed itself as the judge/jury/prosecutor/defense rolled into one and not invited input from all "relevant" parties that the decisions have been unfavorable.Opponents of cell culture assays are insesently confused with the old "clonogenic" chemosensitivity assays, the one that Dan Von Hoff had been discredited long ago. When most academic oncologists refer to "chemosensitivity testing," they are virtually always referring to and thinking about the "human tumor stem cell" assay or "clonogenic" assay. Yet this technology hasn't been used by any private sector laboratory for more than twenty years. Nor has it ever been advocated the clonogenic assay as the best cell culture assay. But Von Hoff had tried to sell it, not within the confines of a clinical trial, but as a service to patients.
by Gdpawel on Mon Oct 25, 2010 09:51 PM
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