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Chemosensitivity and Resistance Assays: A Systematic Review?

Rational Therapeutics, and Malcolm C. Todd Cancer Institute, Long Beach Memorial Medical Center, Long Beach, CA

To the Editor:

Two related studies (Samson et al¹ and Schrag et al²) in the September 1, 2004, issue of the Journal of Clinical Oncology examine the use of chemotherapy sensitivity and resistance assays (CSRAs) in medical oncology.

In aggregate, these two studies find that eight of the 12 articles evaluated reveal positive results for assay-directed chemotherapy versus empiric selection, one reveals negative results, two reveal comparable results, and one lacked a comparator arm. We applaud the investigators for focusing attention on a technology that improves drug selection for patients. However, several issues warrant further consideration.

Schrag et al incorrectly define an assay as an "in vitro laboratory analysis that is performed specifically to evaluate whether tumor growth is inhibited... ." This definition obscures the fundamental difference between growth inhibition (clonogenic; thymidine incorporation, extreme drug resistance assay, etc) and cell-death (differential staining cytotoxicity, methylthiazolyldiphenyl-tetrazolium, adenosine triphosphate) end points. Cell death serves as an in vitro surrogate for drug-induced apoptosis, the most relevant of biologic measures, and must not be confused with older growth-based end points.

These articles have done a more profound disservice to investigators, physicians, and patients. A chemosensitivity test is a bioassay, defined in the dictionary as a "qualitative or quantitative analysis." Such tests are widespread in medicine and are used to measure chemical species (metabolic panel), the presence of metastases (positron emission tomography [PET] or computed tomography), antibiotic sensitivity (Kirby-Bauer) or estrogen receptors (ERs). Sensitivity, specificity, and positive and negative predictive accuracies are used to define any test’s utility, according to established standards. By these standards, many CSRAs, particularly the more robust cell-death end points, perform exceedingly well.

When the authors apply the standard of patient survival as it relates to assay results, they invent a new criterion that has never been applied previously to clinical tests. ER analyses, PET scans or the Kirby-Bauer method would be hard pressed to meet this parochial definition of utility. By standard criteria, the more than 1,600 published patient experiences with cell-death end points afford even the disinterested reviewer unequivocal evidence of their clinical utility.³

The authors’ assertions regarding low evaluability, slow turnaround, and failure to identify novel options, although applicable to older clonogenic tests, do not apply to the newer cell-death end points. In the thousands of specimens that we have analyzed, 90% are assessable for an average of 12 to 16 drugs or combinations, with reports provided to the physician by the seventh day following receipt in the laboratory. Furthermore, novel combinations identified by our group have gained widespread use^4,5 and have advanced to cooperative group studies.

Even with the application of these stringent criteria, Samson et al conclude, "Higher response rates were observed in most studies for assay-guided patients compared with those treated empirically, though differences were not always statistically significant." Always? After repeated unsuccessful efforts by investigators to formally evaluate these assays through the cooperative groups, the mantra "randomized trials are needed" has acquired a distinctly hollow ring.

It is ironic, that at a time when one CSRA applied to childhood leukemia is the subject of a highly touted international pharmacogenomics collaboration^6,7 the American Society of Clinical Oncology (ASCO) Task Force and the authors of the Blue Cross and Blue Shield Association Technology Evaluation should publish not one, but two analyses of the field that reveal largely negative results. There is extensive published literature validating these assays according to any and all customary standards. The dearth of evidence supporting benefit from clinical trial participation,⁸ and increasingly loud public outcry for improved outcomes in cancer⁹ strongly suggest that future ASCO Task Forces might use their resources more productively to develop avenues to incorporate these assays into clinical practice.

Author's Disclosures of Potential Conflicts of Interest

The author or his immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Robert Nagourney, Rational Therapeutics. Leadership Position: Robert Nagourney, Rational Therapeutics. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.

REFERENCES

1. Samson D, Seidenfeld J, Ziegler K, et al: Chemotherapy sensitivity and resistance assays: A systematic review. J Clin Oncol 22 : 3618 -3630, 2004[Abstract/Free Full Text]

2. Schrag D, Garewal H, Burstein H, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22 : 3631 -3638, 2004[Abstract/Free Full Text]

3. Transcripts of the Medicare Coverage Advisory Committee (MCAC) Meeting, Baltimore, MD, November 15-16, 1999

4. Nagourney RA, Link J, Blitzer J, et al: Gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed breast cancer patients. J Clin Oncol 18 : 2245 -2249, 2000[Abstract/Free Full Text]

5. Nagourney RA, Brewer C, Radecki R, et al: Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed ovarian cancer patients. Gynecol Oncol 88 : 35 -39, 2003[CrossRef][Medline]

6. Holleman AH, Cheok MH, et al: Gene expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med, 351 : 533 -542, 2004[Abstract/Free Full Text]

7. Winnick NJ, Carroll WL, Hunger SP: Childhood leukemia—New advances and challenges. N Engl J Med, 351 : 601 -603, 2004[Free Full Text]

8. Peppercorn JM, Weeks JC, Cook EF, Joffe S: Comparison of outcomes in cancer patients treated within and outside clinical trials: Conceptual framework and structured review. Lancet 363 : 263 -270, 2004[CrossRef][Medline]

9. Leaf C: Why we're losing the war on cancer—And how to win it. Fortune 149(6), March 22, 2004

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