Chemotherapy experts refute ASCO recommendations on use of drug sensitivity and resistance assays

A group of leading chemotherapy experts assembled as the Clinical Oncologists for Individualized Therapy (COFIT) refute the findings of the American Society of Clinical Oncology (ASCO) technology assessment panel regarding the use of chemotherapy sensitivity and resistance assays (CSRAs).

The investigators, led by Robert Nagourney, M.D., Larry Weisenthal, M.D., Ph.D., Robert Hoffman, Ph.D. and William Grace, M.D., promote research and application of a specific class of CSRAs that measure drug-induced cell death. These assays have been clinically validated for the selection of optimal chemotherapy regimens for individual patients.

The ASCO panel reported that the use of in-vitro CSRAs to select chemotherapy should be limited to clinical trials and not made available for use in oncologic practice. After reviewing 1,139 published clinical trials, the panel members selected 12 studies that met their criteria and based their recommendations on this limited series. Results of the panel’s findings are reported in this week’s issue of the Journal of Clinical Oncology -- ASCO’s official publication.

CSRAs are in-vitro laboratory analyses that use fresh human tumor biopsies to determine which drugs or combinations of chemotherapeutic agents have the highest likelihood of response for individual cancer patients. Conducted and applied correctly, these analyses enable doctors to individualize and optimize treatments while minimizing the risk of toxicity from chemotherapy.

Assay-directed therapy is based on the premise that each patient’s cancer cells are unique and therefore will respond differently to a given treatment. This is in stark contrast to standard or empiric therapy, in which chemotherapy for a specific patient is based on results from prior clinical studies.

“While we agree with ASCO’s conclusion that CSRA research should be a priority, we take issue with the composition of the panel, the methods for trial selection, the analytic process and, most fundamentally, with the suggestion that the data does not support the utility of these tests,” said Dr. Nagourney, who serves as medical/laboratory director of Rational Therapeutics (Long Beach, Calif.), and has published extensively in the field. “ASCO’s findings could potentially limit patient access to a technology that has proven capable of identifying active treatments.”

Dr. Weisenthal added, ”Both BlueCross/Blue Shield and ASCO demonstrated systemic bias and a lack of expertise in arriving at their conclusions.” Dr. Weisenthal is a 25-year investigator and author in the field. He serves as medical/laboratory director of the Weisenthal Cancer Group (Huntington Beach, CA).

Drs. Nagourney, Weisenthal, Hoffman, and Grace are among a growing number of oncology specialists who support the use of CSRAs that measure drug induced cell death. They assert that the ASCO panel’s analysis is flawed in the following four key areas:

1. Study Selection

ASCO’s recommendations were based on a review of 12 previously published clinical studies, many of which focused on older 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 testing. The panel made no attempt to distinguish cell death from cell growth techniques. While the panel’s criticisms regarding slow turnaround and low evaluability rates may be applicable to the older cell-growth tests, the negative conclusions reached by the panel simply do not apply to newer cell-death assays. In fact, cell death assay results have consistently correlated with response, time to progression and survival.

2. Composition of the panel

Investigators actively working with CSRAs based on cell death were not represented or even consulted by the ASCO panel.

3. Conflicts of Interest

While ASCO states that no limiting conflicts were identified among its panel members, their assessment was performed under a collaborative relationship with the Blue Cross and Blue Shield Association (BCBSA). Both insurance groups are on record for their opposition to the use of CSRAs. Dr. Weisenthal noted that many of the ASCO panel members have built their careers on conducting trials based on empiric therapy, and have a vested interest in maintaining the status quo with respect to how chemotherapy is administered. Cooperative oncology groups, which have focused their attention exclusively on empiric therapy trials, have consistently refused to conduct the same clinical trials that the ASCO panel claims should be “a priority.” This conflict of interest among the panel members is indicative of a systemic problem in the oncologic community regarding how doctors are reimbursed for chemotherapy drugs by Medicare and insurance companies. This issue has been the subject of recent investigative reports in the media.

4. Analytic Method

The ASCO panel analyzed CSRAs based on patient outcome -- a criterion that holds such assays to a standard not met by any other clinical test in cancer medicine, and which has seldom been met by the empiric chemotherapy treatments supported by ASCO. Were the panel to have applied a more standard measure of performance such as predictive accuracy, the results of its analysis would have been markedly different and in favor of the use of CSRAs in clinical practice.

“CSRAs offer an objective alternative to the off-the-shelf, ‘best guess,’ trial and error therapy typically used to treat cancer patients,” added Dr. Nagourney. “Assays based on cell death have proven very effective in identifying novel treatment combinations for a variety of cancers. It is unfortunate that organizations such as ASCO have consistently declined to carry out studies to assess the value of cell death CSRAs.”

Ironically, as the ASCO panel released its findings, an international study published in the August 5, 2004 issue of the New England Journal of Medicine reported that cell death CSRAs are effective in identifying gene expression patterns that correlate with clinical drug resistance. The study, titled “Gene Expression Patterns in Drug Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment” employed a cell death assay to examine drug resistance at the molecular level.

“My experience with cell death CSRAs is that they accurately predict clinical outcomes and define novel chemotherapeutic synergies. They also have frequent curative value in treating many adult malignancies which the current medical literature has deemed incurable,” said Dr. Grace. “I believe that it would be unethical for me not to use such CSRAs in my practice.”

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