Cell Culture Drug Resistance Testing (CCDRT) Cell Death Assays:
Misconceptions Versus Objective Data
What the Critics Say: C. The national Blue Shield TEC assessment
Completely ignoring all of the data presented in Part I of the present review, the national Blue Shield TEC assessment used a hypothetical analysis, based on differing scenarios. This analysis was ridiculous to the point of absurdity.
The authors went through the lengthy exercise of projecting possible "benefits" to the use of the assays for the purpose of deciding which patients should or should not be treated with chemotherapy. Thus, "balance sheets" for using the assay to make treat/no treat decisions in testicular cancer, breast cancer, and melanoma were presented. Based on the performance characteristics of the assays (statistically described according to Bayes' Theorem, see Part I of the present review), it was (correctly) concluded that patients could suffer harm from making treat/no treat decisions based solely on the basis of assay results.
But no one is using the assays in such a vacuum. No one has ever proposed using the assays for this purpose. The assay results are only a single piece of information, which have to be considered in the context of the entire clinical situation. Of course, there will be many "false negative" results in a disease of high responsiveness, such as testicular cancer. Just as there are a huge number of "false positives" in screening for prostate cancer with PSA testing (an
"unproven" laboratory test for which most Blue Shield organizations do provide payment). Were the assays to be used in previously-untreated testicular cancer, it would be no more appropriate to withhold treatment on the basis of across the board in vitro drug resistance than it would to withhold antibiotic treatment from a patient with gram negative bacteremia which was also in vitro drug resistant. However, antibiotic sensitivity tests could be used to aid in the selection of an aminoglycoside versus a third generation cephalosporin. What about untreated testicular cancer? Many clinicians would feel that all such patients must receive a given regimen. If they feel that way, they shouldn't order an assay. Other clinicians might correctly note that there are a variety of regimens used in the successful treatment of testicular cancer. All contain cisplatin, but some contain bleomycin/vinblastine, others contain etoposide, still others may contain drugs such as dactinomycin or ifosfamide. On the basis of the literature, one could make a reasonable case for selecting any of these regimens for the average patient. Yet their toxicity profiles are vastly different (e.g. bleomycin may cause pulmonary toxicity, while etoposide and ifosfamide may cause leukemia). What if a clinician with considerable experience in using the assays as a tool in cancer treatment is impressed that a cell culture assay shows high grade resistance to etoposide, but good sensitivity to bleomycin and vinblastine? Realizing that "proof beyond reasonable doubt" of assay efficacy in this setting could easily require an intention to treat study of a thousand patients (which might be immediately obsolete if, for example, cisplatin/gemcitabine is one day shown to be a better empiric regimen to the others before the assay-directed study was completed), would such a patient be harmed by treating him or her with PVB rather than cisplatin/etoposide, considering the poor in vitro activity of etoposide and the known leukemogenic risk?
And what about a patient with a disease like metastatic and drug-refractory ovarian or colon cancers? These are considered to be incurable diseases, yet many patients receive chemotherapy, which is their only or best prospect for prolonging their lives. What is "standard" therapy for these diseases? Wouldn't many patients wish to receive treatment with drugs showing good in vitro activity against their tumors, rather than with drugs showing poor activity, when all studies show that the former drugs are far more likely to work than the latter?
Yet the TEC assessment did not consider real world questions such as the above, and instead only considered extreme, fanciful applications of the assay that do not apply to the real world clinical situations for which the assays are currently (and appropriately) being used. As shown previously, 40 consecutive studies have shown that, when patients are treated with assay-"active" drugs, they have a superior treatment outcome compared to the study group as a whole, and when patients are treated with assay-"inactive" drugs, they have an inferior treatment outcome compared to the study group as a whole, and the advantage in being treated with assay-"active" drugs compared to being treated with assay-"inactive" drugs is a 7 to 9-fold greater likelihood of clinical benefit.
And, unlike the case with the comprehensive TEC review by California Blue Shield, the organizers of this and the other (erroneous and misleading) reviews did not seek input and rebuttal from the true experts in this field, which are the private sector physicians and laboratories who have been working in this field for more than 15 years and providing real-world services in this field for more than 10 years, as a full-time effort.