There is scarcely an oncologist who would not acknowledge the need for laboratory tests to guide selection from among an ever expanding armamentarium of increasingly expensive though not universally effective chemotherapy agents. Indeed, it is hardly possible these days to receive FDA drug approval for a new drug absent the parallel introduction of a companion pharmacodiagnostic test to guide patient selection. The need was felt no less keenly in the early 1980’s when all hope in the oncology community was affixed to a single cell culture technology – the clonogenic, or human stem cell, assay. And when that one particular technology was found to be lacking in some ways and misunderstood in others all hope was abandoned.
A quarter of a century farther along oncology has changed dramatically but the need for tests to guide therapy selection has only increased. And in that quarter of a century new cell culture methods have been developed which circumvent the shortcomings of the early cell colony forming methods. The newer methods are based upon induction of cell death in the entire tumor cell population, a far more appropriate endpoint considering what is now understood about apoptosis and its critical role both in tumorigenesis and in cytotoxic drug therapy. Many other equally dramatic changes have occurred over the past 25 years in the development of these tests – and the tests themselves have been subjected to rigorous scrutiny in more than 100 peer-reviewed and uniformly positive studies. And yet some reviewers pointedly ignore both the new technologies and the studies which support them and instead base conclusions on technologies and methods that were abandoned by nearly everyone 20 years ago. Clearly, the topic impels thoughtful re-examination. We will strive here on this site and in all other ways to provide clinicians and patients with supportable facts which, we believe, speak for themselves. Having done so, we are comfortable in allowing any reviewer acting in good faith to reach his or her own conclusion.
WHY IS THERE CONTROVERSY?
The standard for judging laboratory tests has always been accuracy, reproducibility, and utility. Historically, laboratory tests have never been judged by their effect upon treatment outcomes. For example, estrogen and progesterone receptor testing (ER and PR) to guide the use of hormonal therapy drugs such as tamoxifen has never been shown in a prospective randomized trial to improve response or survival in breast cancer. It is not that the studies were performed and the tests failed to show treatment benefit – rather, it is only that prospective, randomized trials are never carried out for the purpose of demonstrating improved outcomes on the basis of having performed certain laboratory tests . On the other hand, no physician would be surprised to learn that ER expression has been shown in retrospective studies to correlate positively with response to hormonal treatments.
Despite the fact that, until recently, no laboratory test ever had been shown in a prospective, randomized clinical trial to improve patient outcomes, many such tests are viewed as invaluable. This is because the tests are accurate and reproducible and – based upon retrospective correlation studies - the tests are known to correlate reliably with the clinical or biological phenomena which they are intended to detect, measure, or predict.
RANDOMIZED TRIAL SHOWS IMPROVED SURVIVAL WITH CYTOMETRIC PROFILING
In a landmark study involving the use of cytometric profiling in the setting of relapsed chronic lymphocytic leukemia there was a 2.5-fold greater mortality at one year in the group receiving standard, empiric therapy (Protocol arm) compared to the group receiving cytometric profiling-directed therapy (DiSC/TRAC Assay arm). (20% mortality in the Protocol arm versus 8% mortality in the DiSC/TRAC assay arm, p=0.04).1
This is the first-ever trial in which a laboratory test was held to the unprecedented standard of improving overall survival in cancer. The results of this study are consistent with those of hundreds of other studies, in which treatment with drugs found active in cytometric profiling assays correlated positively with higher rates of response, progression-free survival, and overall survival.
CONSISTENTLY POSITIVE CORRELATION IN HUNDREDS OF VALIDATION STUDIES
Personalized Cancer Cytometrics (PCC) has been subjected to greater scrutiny in clinical trials than most other tests used routinely in oncology – not only in terms of the number of studies of PCC accuracy and reproducibility but also with respect to correlation with clinical outcomes. Data from more than 100 studies uniformly demonstrate close correlation between prospective predictions of drug activity and patient chemotherapy response - and also, where such follow-up data are available, with overall survival. In meta-analysis of cell death-based PCC studies, an assay “positive” drug was 7.5 times more likely to produce objectively-measured patient response than an assay “negative” drug.
PCC, therefore, can identify for each patient drugs which have higher than average likelihood of producing clinical benefit and also drugs which have lower than average likelihood of producing clinical benefit. The claim is modest and unambiguous. Study after study has borne out the claim and no person who is familiar with the large body of published literature which supports PCC has ever disputed it. Many physicians today order the tests routinely for their patients because they continually see real clinical benefit.
In February 2007, National Heritage Insurance, the Medicare administrator for the state of California, concluded a year-long, comprehensive review of data relating to PCC and ruled in favor of complete coverage of the service for Medicare patients, even after taking into consideration an earlier and much-publicized ASCO review. One of the reasons that National Heritage rejected the ASCO position is because the ASCO reviewers admitted that they selectively had ignored precisely those data which are most relevant: the data which demonstrate the accuracy, reliability, and perceived utility of cell death-based PCC profiling.
In omitting data pertaining to PCC test accuracy, the ASCO review panel sought to impose criteria which never before had been applied to any laboratory test.
However, there is even more to consider when weighing the position of ASCO’s review.
ASCO TECHNOLOGY REVIEW
ASCO’s recommendations were based upon a review of 12 previously-published clinical studies which focused only on outmoded cell-growth assay methods. Drug induced cell-death as a surrogate for apoptosis is the most relevant biological measure and must not be confused with growth-based (Cell Proliferation) testing. The panel made no attempt to distinguish cell death from cell growth techniques and yet there have been dozens of studies of Cell Death assays, producing the overwhelming majority of PCC data published in the past decade.
Not only did the ASCO panel fail to discriminate studies of Cell Death assays from studies of Cell Proliferation assays, the ASCO panel pointedly cast aside all evidence of assay accuracy, stating, “We excluded reports that only reported correlations between assay results and clinical outcomes.” In other words, the ASCO panel deliberately ignored the only standard which ever has applied to medical laboratory tests.
Another troubling aspect of the ASCO review relates to the composition of the ASCO panel and specifically to the qualifications and potential conflicts of interest of the reviewers. No investigator actively working with PCC profiling technologies incorporating the new-generation, cell-death endpoint was included on the panel - all had links to the older and largely abandoned methods. Even more glaring in its bias is the fact that no such cell-death assay expert was even consulted. This would have been very easily accomplished because the cell death endpoint is now used by nearly every reputable investigator in the field who has published within the last ten years. In fact, no notice of any sort was accorded to the many dedicated researchers in this field that such a review even was contemplated. Instead, the panel acted in virtual secrecy. Not only was no outside PCC research expert consulted, not a single physician was consulted from among the many who are ASCO’s own members who use Personalized Cytometric Profiling routinely to assist in choosing chemotherapy drugs for their patients.
One such experienced PCC user is a well-respected medical oncologist, an ASCO member, and former President of his state's medical oncology society. His statement appears in the written record of a CMS/Medicare hearing: “My experience with cell death CSRAs [this is the term used in the ASCO review to describe personalized cytometric profiling] is that they have accuracy in predicting clinical outcomes and defining novel chemotherapeutic synergies. They also have frequent curative value in treating many adult malignancies which the current medical literature has deemed incurable…I believe that it would be unethical for me not to use such CSRAs in my practice.”
We believe that the composition of the panel, along with ASCO’s failure to seek comment from respected experts in the field - or even from oncologists who use the tests - coupled with the deliberate exclusion of the entire body of the most highly relevant data created a bias which is not consistent with a balanced and credible technology assessment.
COMPARING TWO TECHNOLOGY ASSESSMENTS
Contrast the ACSO approach with that of Medicare Administrator, National Heritage Insurance Company (NHIC) which conducted its own technology assessment. NHIC held several open and well-publicized hearings - reaching-out to gather testimony and scientific evidence from physicians, PCC researchers and experts, drug companies, and also from PCC critics. All interested parties were invited to attend and participate. NHIC spent an entire year reviewing the full body of published PCC data and especially seeking the advice of independent physicians who actually use PCC in their medical practices. The technology assessment was personally headed by the Medical Director of National Heritage. The result was a Local Coverage Determination in which PCC became fully-approved for Medicare beneficiaries.
Note that this coverage determination was recently reversed by Palmetto Blue Cross of South Carolina when it was appointed Medicare Administrator for the state of California. Palmetto never undertook its own technology review, as did National Heritage, but instead relied only upon the flawed - and even biased - ASCO review. Thus, as of this writing, Medicare beneficiaries and, in many cases, patients with private insurance, are once again deprived of payment for - and thereby access to - these potentially life-extending PCC technologies. To contrast the findings of National Heritage’s openly-conducted and unbiased review versus the closed and highly-skewed (we hold that it was skewed by ASCO’s admitted censorship of highly-pertinent data and also by its failure to seek independent testimony) but much more highly-publicized ASCO review, please click here.
LACK OF FULL DISCLOSURE IN THE ASCO ASSESSMENT
Finally, there is the issue of conflict of interest. The American Society of Clinical Oncology (ASCO) performs admirably in advancing medical knowledge, upholding standards of care, and also in many other ways. However, at its heart, ASCO is a trade organization which promotes the professional interests of its members. Such interests include, among many others, those which are financial. In an era in which physicians’ profits are threatened on all fronts, ASCO functions as a political action organization, working closely with Medicare and routinely lobbying legislators to protect the incomes of medical oncologists. We find this to be reasonable and entirely honorable. However, an area of concern for oncologists and therefore for ASCO has been the issue of what is called the “drug concession,” a phrase which describes oncologist revenues which derive from the sale of chemotherapy drugs to cancer patients.
Traditionally, physicians have been able to purchase chemotherapy drugs at wholesale prices and then mark-up the drugs to patients when they administer them at their offices or in free-standing chemotherapy infusion centers. Separate stories have appeared in The New York Times1, on the NBC Nightly News2, and elsewhere examining the practice of oncology drug mark-up. Further, at least one academic study3, involving 9,357 cancer patients and conducted jointly by the University of Michigan and Harvard University, concluded that physicians take into account the amount of “margin” afforded by one drug over another when choosing from otherwise equally-acceptable drug regimens. (An ASCO spokesperson later disputed but could not disprove these findings.) In theory, a test which helps to guide therapy selection could erode to some degree the wide latitude currently enjoyed by oncologists in prescribing drugs on the basis of “physician’s best judgment.” This potential for bias does not, by itself, nullify the opinions expressed in the ASCO review but, in fairness, the issue probably should have been disclosed by the reviewers as a potential conflict of interest.
Matutes E, Bosanquet AG, Wade R, et al, The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry. Leukemia (2013) 27, 507–510; doi:10.1038/leu.2012.209. Link to full text.
Abelson R. Pay Method Said to Sway Drug Choices of Oncologists, New York Times, March 8, 2006.
Ellis, R. Cancer Docs Profit from Chemotherapy Drugs. NBC Nightly News, September 21, 2006.
Jacobson, M., O'Malley, A.J., Earle, C.C., et al. Does Reimbursement Influence Chemotherapy Treatment For Cancer Patients?, Health Affairs 25(2):437-443, 2006.
DRUG PANELS, FEES, AND INSURANCE
Dr. Weisenthal individually designs a panel of drugs to be tested for each patient based upon what is appropriate to the patient's clinical situation and also what is possible with respect to the size and condition of the biopsy specimen that is sent to us.
Physician requests for specific drugs, including new drugs, are always honored.
As you might expect, fees for Functional Tumor Cell Profiling certainly are influenced by the number of drugs tested. However considerable expense and effort accrues in our obtaining and processing (disaggregation, cell concentration, etc.) the specimen. Processing usually takes several hours of technician and technologist time, along with reagents, disposable labware, etc.. Dr. Weisenthal's slide and data interpretation generally requires at least 8 hours of his time. Therefore, a base testing fee applies, to which an incremental per-drug fee is added. The fee per drug is relatively much smaller than the base fee and so there never is any question that drugs are added to panels inappropriately, although each additional drug tested does add expense and effort to the testing process and these expenses must be recovered.
Insurance coverage for Functional Tumor Cell Profiling varies depending upon the reimbursement policies of the patient's insurance carrier and the provisions of his or her specific insurance policy.
Some insurance carriers cover most or all of the testing fees, excluding normal co-payments and deductible amounts. However, other insurance carriers pay for only a portion of the costs and other carriers may deny claims completely.
As a courtesy to your patient, we gladly will submit insurance claims to the carrier.
Medicare does not cover cytometric profiling studies in the state of California.
Once we receive a specimen for testing, we notify each patient by priority mail of the probable cost of his or testing and offer the patient the opportunity to decline our testing services and thereby avoid testing costs. If a patient elects to receive our services he or she receives a bill from us after we have completed testing and have reported test results to the ordering physician.