New Developments in ASCO versus COFIT Controversy:

ASCO Responds to Criticisms by the Clinincal Oncologists for Individualized Therapy ("COFIT")

Relevant URLs as of the morning of September 27, 2004

All appearing on the Medical News Today Website:  (Refutation by COFIT, of ASCO's recently stated position on  challenging the criticisms of COFIT, concerning ASCO's position on Chemosensitivity and Resistance Assays (CSRAs, otherwise known as cell culture drug resistance testing, CCDRT or "chemosensitivity testing")). Additional details concerning this controversy, which began around August 1, 2004 appear below on this website. (Statement by ASCO, challenging the criticisms of COFIT, concerning ASCO's position on CSRAs/CCDRT)  (Statement by Larry Weisenthal, rebutting the challenge by ASCO to COFIT's criticisms.  A better formatted version of Weisenthal's rebuttal appears below)   (Statement by Gregory D. Pawelski, regarding the self-serving nature of ASCO's position on CSRAs/CCDRT)

Text of my letter to ASCO, published also on the Medical News Today Website (3rd of above URLs)

To: Jenny Heumann Senior Public Affairs Manager, American Society of Clinical Oncology, for forwarding to members of ASCO panel on CSRAs.

Subject: The American Society for Clinical Oncology (ASCO) drafted comments defending ASCO against the criticisms of the Clinical Oncologists For Individualized Therapy (COFIT) concerning ASCO's recommendations on the use of Chemotherapy Sensitivity and Resistance Assays (CSRAs).

The following points address the assertions raised by ASCO and explain how ASCO continues to mislead the public concerning not only the utility of CSRAs, but more broadly, the practice of cancer medicine today.

ASCO's comment #1:

Study Selection Comments

-- The criteria for study selection were laid out a priori by the ASCO working group. Criteria were pre-specified, explicit, and transparent to all concerned. The criteria were reviewed, vetted, and approved by the ASCO working group. Both the Blue Cross and Blue Shield Association (BCBSA) group and the ASCO working group were open to including any assay, apotosis or otherwise, that had undergone rigorous enough evaluation to have informative data.

-- The BCBSA reviewers explicitly sought, but did not find, evidence comparing outcomes of assay-guided therapy that used cell death assays versus empiric therapy. Since evidence was lacking, conclusions were not possible.

My response to ASCO comment #1:

The problem is that ASCO is attempting to impose an entirely new standard for the evaluation of medical tests. The previous standard always used to evaluate any type of medical test (e.g. laboratory tests, radiographic tests, functional tests, etc.) has always been the correlative and predictive accuracy of the test. How well does an estrogen receptor assay predict for clinical benefit of tamoxifen? How well does a Her2/neu test predict for clinical benefit of Herceptin? How well does a bacterial culture and sensitivity test predict for clinical success or failure of penicillin therapy? How well does a CT scan or MRI scan or PET scan or CA-125 level or CEA level correlate with the presence and growth of a cancer? How well does a battery of immunohistochemical tests performed on tumor biopsies correlate with diagnosis and prognosis to treatment with different forms of therapy? Not only is test accuracy (not "efficacy") the established standard for evaluating every single test used in medicine, it is also the precise standard used by the FDA in approving a test kit for a proprietary CSRA. The FDA didn't require proof of "efficacy" (as it has never required proof of "efficacy" for any medical tests).

It is noteworthy that the ASCO group cited laboratory tests such as the estrogen receptor and prostate specific antigen in its rejoinder to COFIT. Neither of these tests would meet the entirely artificial criterion now advanced by ASCO. Neither of these tests has ever been shown to improve clinical outcomes.

Read again the precise language of the current ASCO rebuttal:

-- The BCBSA reviewers explicitly sought, but did not find, evidence comparing outcomes of assay-guided therapy that used cell death assays versus empiric therapy. --

Now, I challenge the BCBSA reviewers and the ASCO reviewers to apply this precise criterion to the estrogen receptor assay, the PSA, Her2/new, panels of immunohistochemical stains, PET scanning, or any other test used in cancer medicine. Apply this precise standard being demanded of CSRA testing and see how many other oncology tests meet the standard now being demanded of CSRAs. Do this honestly, and report your findings as prominently as you now report your technology assessment of CSRAs.

What has NEVER been shown, with ANY of the above tests is whether patients treated with the benefit of test information have higher response rates, longer durations of survival, less toxicity, or improved quality of life than patients managed without the benefit of test results. And these tests are used to select therapy in cancer patients no less than are the cell culture drug resistance tests currently being considered. Should a patient receive tamoxifen or chemotherapy? Should a patient currently on chemotherapy be maintained on the same chemotherapy, or should the patient be switched to a different form of chemotherapy? Are serial CT scans or MRI scans or PET scans better or worse at making this determination than are simply histories, physical examinations, and simple laboratory and "plain film" radiographic tests? We don't really know the answer to any of those questions; yet oncologists routinely order these tests and insurance companies routinely pay for them.

ASCO's comment #2:

-- Point of clarification: The COFIT group described that the ASCO group reviewed 1,139 published "clinical trials." There were nowhere near 1,139 published clinical trials of assay-guided therapy.

-- 1,139 was the number of "hits" using very wide literature search criteria, selected to make sure the ASCO and BCBSA groups didn't miss anything. The overwhelming majority of these articles dealt with technical aspects of assay development, not clinical outcomes of using assays to manage patients.

My response to ASCO comment #2:

COFIT did not intend to misrepresent the nature of the "1,139 abstracts identified by the BCBSA," which were described in the BCBSA as "limited to...studies using human subjects." It was not clear from either the BCBSA or ASCO papers exactly what these 1,139 abstracted publications represented, and I appreciate the ASCO clarification.

ASCO's comment #3:

Panel Composition Comments

-- It would be impossible to put together an ASCO working group that included members with expertise in each and every assay. The working group included individuals with broad expertise in CSRAs as a field. The working group participants are leaders in the cancer biology area; have knowledge of all types of assays; and understand the different mechanisms that exist for cell death, such as necrosis or apoptosis.

My response to ASCO comment #3

It was hardly "impossible" to have appointed a more representative panel. All CSRAs currently offered as a service to patients and oncologists are of two major types. Type I are assays based on cell proliferation or DNA synthesis. Type II are based on cell death. All three ASCO panel members worked largely with a single type of cell proliferation (Type I) assay, which was largely discredited in a critical editorial published in the New England Journal of Medicine in 1983. The key investigator in this group of three built his early career on a vigorous effort to promote this assay; in point of fact, he failed to complete a single prospective randomized clinical trial of the type he now demands of COFIT. Following the demise of his own favored technology, he has given many speeches in many venues over the past dozen years arguing against the utilization of CSRAs in clinical practice. Thus, he, along with the BCBSA authors, has an established prior bias against CSRAs based on cell death endpoints. The other two CSRA investigators also studied the same (Type I) methodology, and, in fact, were both at different times collaborators and co- workers with the lead ASCO panel member with CSRA expertise.

It would have been a very simple matter to exclude two of the three "Type I" CSRA investigators from the ASCO panel and to replace them with easily identifiable investigators with an equal (20 year) experience with the "Type II" (cell death) CSRAs.

ASCO's comment #4:

-- Members of the ASCO working group would have liked more than anyone for these assays to be shown to be ready for "prime time." Several of the investigators participating in the ASCO review spent years of their careers trying to develop truly clinically useful assays, and thus did not reach these conclusions lightly.

My response to ASCO comment #4:

Refer to my response to ASCO comment #3.

ASCO's comment #5:

Conflict of Interest Comments

-- The BCBSA is not "on record for its opposition to the use of CSRAs." The BCBSA does not make coverage decisions; the Plans identified by COFIT make those decisions independently of each other of the BCBSA.

My response to ASCO comment #5:

The first of the above is a demonstrably false statement. For just one of many citable proofs that the BCBSA has a long record of opposition to the use of CSRAs, please see:

Regarding the second of the above statements, it is true that the California Blue Shield Technology Assessment panel has twice approved (or, rather, approved and then re-affirmed) its coverage of CSRA services. What is unique about California Blue Shield, as opposed to the "national" BCBSA, is that California Blue Shield published and publicized its decision to evaluate CSRAs for coverage well in advance of the meeting at which the coverage decision was made. California Blue Shield then invited written comments and data submissions in advance of the meetings. California Blue Shield then invited and allowed for public comment and arguments at its meeting from all members of the medical community, including critics of the concept of providing coverage of CSRA, who were specifically invited by California Blue Shield to participate, along with known prominent proponents of CSRAs. After reading all the prior submissions and listening to the public commentary and debate, and after asking questions of the experts attending the meeting, California Blue Shield then held an open, public discussion and debate among its Technology Assessment Committee members, and, on both occasions, voted unanimously in favor of coverage.

This entirely open and transparent process stands in stark contrast to the closed and non-inclusive methods used by ASCO and the BCBSA.

ASCO's comment #6:

-- The COFIT group members fail to acknowledge explicitly their own overt conflicts of interest as providers and marketers of assay services.

My response to ASCO comment #6:

This is a false charge. The background of each of the COFIT members was explicitly stated, along with links to the web sites of each. It is completely clear that three of the named members are engaged in providing CSRA services. A fourth member, Dr. William R. Grace, has absolutely no conflicts of interest, as he does not provide these services and has no investments or holdings in entitites which provide these services. Dr. Grace is an esteemed clinical oncologist, who has held a number of high leadership positions in clinical oncology. Unlike ANY of the members of the ASCO or BCBSA panels, Dr. Grace has an extensive personal experience in utilizing information provided by cell death (Type II) CSRAs in the management of his patients. In Dr. Grace's words, he considers it "unethical" NOT to obtain CSRA information, when it is possible to obtain this information, in the management of his cancer patients.

ASCO's comment #7:

-- Regarding the alleged conflict of interest of ASCO working group members who have "built their careers on conducting trials of empiric therapy:" Since the earliest days of chemotherapy research, oncologists and patients have recommended prospective, randomized clinical trials to define standards of care around the world.

-- The National Cancer Institute, patient advocacy groups, and cancer specialists from all disciplines have endorsed this process. Such trials are extraordinarily powerful and reliable for determining how best to treat cancer. The oncology community has readily welcomed the use of predictive markers (such as estrogen receptor and HER2 for breast cancer, PSA for prostate cancer, and bcr/abl for leukemia, among others) into trials for cancer therapies. The use of such prospective treatment trials is an option available to any investigators who wish to demonstrate unequivocally the value of any cancer screening or treatment method.

My response to ASCO comment #7:

The degree to which "standard therapy" has been well documented in published clinical trials to be "effective" has been often overstated (or at least over assumed). Let's take ovarian cancer as only one of scores of obvious examples. "Standard" first line therapy for ovarian cancer is carboplatin plus Taxol. This therapy is very expensive (and, it must be noted, extremely remunerative to oncologists) and often toxic. What have 25 years worth of randomized clinical trials in ovarian cancer shown?

Firstly, there is no established difference (P = 0.24 on meta-analysis in published studies of the Advanced Ovarian Trialists Group) between platinum combinations and single agent alkylators (such as melphalan), which were used as far back as the 1960s.

Secondly, there is no clear advantage to platinum/Taxol over single agent platinums. So why do American oncologists use carboplatin/Taxol? First, because they just take it on faith that it is better. Second, because it pays very well. (It should be noted that, while the American Society of Clinical Oncology has consistently tried to extinguish the use of CSRAs in cancer chemotherapy, it has, at the same time, worked hard to preserve the system of reimbursement wherein medical oncologists had the impossible conflict of interest of choosing between different forms of chemotherapy with wildly differing profit margins.

In the absence of CCDRT, medical oncologists are free to choose from among many otherwise therapeutically equivalent regimens, with wildly differing profit margins, while the use of CSRA may severely constrain this choice. The American Society of Clinical Oncology has never supported nor suggested clinical trials to show that patients had equivalent outcomes in the presence and absence of differing profit incentives in choice of therapy.).

The current most active efforts in clinical trials in ovarian cancer are to "prove" that docetaxel (an on-patent drug) has a minuscule but statistically significant advantage over paclitaxel (a drug recently gone off patent). Few would presume to suggest that platinum/docetaxel is likely to produce a paradigm shift in treating ovarian cancer. So why are these trials being done? Because the ASCO-dominated cooperative oncology groups are receiving millions of dollars in investigator support from the large pharmaceutical company owning the docetaxel patent.

One must recall the extraordinary difficulty in proving the efficacy of chemotherapy in general and of specific drug regimens in particular in studies of non-assay-directed chemotherapy. Only with extremely large studies (and sometimes only with meta-analyses of extremely large studies and sometimes, e.g. platinum-based chemotherapy of ovarian cancer, not even then) has it been possible to document that chemotherapy of any type produces survival advantages compared to no chemotherapy at all, in many clinical situations. The quite impossible challenge of documenting the clinical standard of "efficacy" (as opposed to the heretofore traditional laboratory standard of "accuracy") with these non-proprietary, public domain technologies was, in fact, pointed out by Dr. Maurie Markman (a noted critic of Human Tumor Assays) who correctly wrote that "even if it were possible to establish the efficacy of [the assays] in a particular situation, this would do nothing at all to establish the efficacy of [the] assays in any other situation".

The challenge of "validating" a single test for a single treatment in a single disease is challenging enough (e.g. estrogen receptor in breast cancer, which has still, after 30 years, only been shown to correlate with clinical outcome and has yet to be shown to improve clinical outcome, despite the fact that Dr. Daniel F. Hayes, at the time the Director of the Georgetown U Breast Cancer Program and a member of ASCO's "Tumor Expert Guidelines Panel" has referred to Estrogen Receptor as being "the best predictive factor in oncology"). Now consider the challenge of "validating" a test for 40 different drugs which can be used in tens of thousands of combinations in hundreds of diseases. If documented clinical "efficacy" is the standard to be demanded of non- proprietary laboratory tests, then clinicians should abandon all tests currently used in their practices. It will be interesting to see which standard is applied in the future to other laboratory tests associated with the prediction of drug resistance, such as tests based gene expression patterns.

It is very easy to say "prospective clinical trials should remain a priority;" it is quite another to support such trials. In point of fact, the cooperative oncology groups (the only organizations capable of carrying out clinical trials of the scope necessary to address the questions of interest) have consistently refused to cooperate with the proponents of cell culture drug resistance testing (CCDRT) to carry out the needed trials. For example, the Gynecologic Oncology Group has refused to consider clinical trials of cell culture drug resistance testing with cell death endpoints (which are the assays with the greatest body of clinical validation), while supporting "Big Pharma" trials, supported by millions of dollars from "Big Pharma" which go to support both the trials and the individual investigators. All that the proponents of CCDRT can offer the cooperative groups is donated assays and the prospects of improving the clinical results of cancer chemotherapy, but this is not enough to motivate the cooperative groups to do the clinical trials.

ASCO's comment #8:

Analytic Method Comments

-- It is misleading to assert a measure such as predictive accuracy is sufficient to demonstrate test utility.

-- Tests are useful to clinicians only if the information they provide guides or changes patient management and thus improves patient outcomes. Improved outcomes may include: longer duration or greater quality of life, or decreased adverse effects of treatment. Many experts have published on these established principles for assessing diagnostic and other clinical tests. When test developers (and marketers) or other advocates request a National Coverage Decision from CMS' Medicare Coverage Advisory Committee, they are expected to provide evidence that clinical decisions based on results of their test improve patient outcomes (e.g., PET for various indications).

My response to ASCO comment #8:

There is not a single laboratory test which has been shown to improve patient outcomes. The standard always used to evaluate laboratory tests is predictive accuracy (sensitivity and specificity) and perceived clinical utility in the judgement of the clinician ordering or performing the test. The ASCO and BCBSA panels made no attempt to justify their decision to apply a completely unprecedented criterion ("efficacy"), while totally ignoring any consideration whatsover of the well established criterion always used before in evaluating tests of this type ("accuracy").

ASCO's comment #9:

-- The goal of these assays should not be to determine sensitivity/specificity, but to demonstrate through prospective trials that such assays can be employed to change treatment for the better. To date, there are insufficient data for such a demonstration.

My response to ASCO comment #9:

ASCO's and the BCBSA's clearly biased panels are attempting to unilaterally impose an entirely unprecedented criterion for evaluating laboratory tests, while ignoring the established criterion (used by the FDA and all other relevant regulatory agencies).

ASCO's comment #10:

-- The COFIT group fails to acknowledge the possibility of real harm to some patients from misguidedly directing them away from a potentially effective
chemotherapy regimen based on an inadequately evaluated clinical test.

My response to ASCO comment #10:

In almost every situation in clinical oncology, there is not one established "best" standard therapy which has been proven in clinical trials to represent the clear-cut, "best" treatment. In virtually every situation, rather, there is a choice between drugs and drug regimens, which could often be made literally by flip of a coin, and, on average, patients would fare just as poorly or just as well. To again continue with the ovarian cancer example, one could use the assays in the first line situation to help guide a choice between single agent platinum, platinum/paclitaxel, or cyclophosphamide/doxorubicin/platinum. In the second line treatment situation, there are easily a half dozen drugs and drug regimens which any expert clinical oncologists would accept as being of equal efficacy when administered to populations of patients. No one could seriously argue that a patient would be harmed by using a well-validated CSRA, performed by an experienced and trusted CSRA laboratory, to aid in deciding between these half dozen choices.

As a specific example, one of our patients was an ovarian cancer patient with primary resistance to paclitaxel/carboplatin who then underwent tandem stem cell transplant/high dose chemotherapy regimens (at a cost of more than $250,000) at a major university, NCI-designated cancer center without ever achieving a response. At a time when she had bulky, non-cytoreducible abdominal and pleural disease, CSRA testing confirmed resistance to single agent cisplatin, carboplatin, and gemcitabine, but good activity for the gemcitabine/carboplatin combination. She subsequently received gemcitabine/carboplatin as an outpatient, achieved a durable complete response, and returned to work full time as an oncology nurse, where she remained well, for more than four years. Indeed, early anecdotal results of this type occurring in diseases in which there was no existing clinical trials literature accelerated clinical trials of this regimen in diseases in which assay-directed responses had been observed.

Any laboratory or radiographic test is capable of being misused. Empiric chemotherapy treatment is certainly capable of being misused, and I am certain that the members of the ASCO panel would concede that literally hundreds of thousands of patients have been harmed (and not infrequently killed) by empirically administered chemotherapy, much of it given inappropriately in a reimbursement system strongly supported by ASCO which provides great financial incentive for infusion chemotherapy over oral chemotherapy and for chemotherapy over supportive care. The fact that a laboratory test might theoretically be misused is an argument for physician education, and not an argument for banning a potentially useful test.

ASCO's comment #11:

-- If the COFIT group believes that its data are compelling, then it should be easy to develop and execute a prospective trial that demonstrates the superiority of their assay over empiric therapy.

-- When such data exist, the ASCO working group will be in a position to revisit the question.

My response to ASCO comment #11:

Many such trials have been designed and presented to ASCO-dominated cooperative oncology groups. ASCO has paid lip service to the "high priority" that such trials should receive, while doing absolutely nothing to facilitate these trials. The great failings of the entire clinical oncology clinical trials system were recently exposed in a well-researched and well-written article published in the March 22, 2004 issue of Fortune Magazine:

Such an article, critical of the entire clinical investigation culture epitomized by ASCO, could only have come from outside of the academic oncology community, as it is an indictment of the entire clinical trials system so mindlessly used by the ASCO panel in its continuing attempts to disparage, denigrate, and bury a long-needed improvement in the management of cancer patients.

My final remarks:

Think of all the objections to this testing. Now try to design all of the clinical trials which would be needed to meet all of these objections and think of how much money these would require and who is going to provide this money for public domain, non-proprietary tests and how many years the studies would take and how many patients will continue to receive ineffective or suboptimum treatment in the interim. The body of information will never be sufficiently large and complete and definitive to encompass even a reasonable fraction of the situations where the information provided by the tests would be helpful.

Now ask the questions: What is the potential risk? What are the potential benefits? What is the probability that these tests really do provide information which can improve the drug selection process in individual clinical situations? What is the potential cost? How does the benefit/risk ratio balance out? What is the (financial) cost as a percentage of total costs relating to management of patients on chemotherapy (including the costs of radiographic and laboratory studies performed only to determine if a given form of treatment is working or not)? What are the long term costs if drug selection always remains an empiric, one-size-fits-all, trial and error process? What would be the impact on improving existing technologies (through the attraction of more laboratory and clinical investigators into the field) and developing new technologies should these assays become more widely used?

If one wishes to see an example of an entirely rational technology advance, in a human disease crying out for precisely such a technology advance, supported by an entirely consistent (if understandably incomplete) body of data, where the advance continues to be held hostage to a high bar of extraordinarily difficult clinical trials which the critics have been entirely unwilling to support, in an area (laboratory testing) for which such trials would be entirely unprecedented, one need look no further.

Larry M. Weisenthal, M.D., Ph.D.
Medical Director, Weisenthal Cancer Group
15140 Transistor Lane
Huntington Beach, CA 92649