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In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins

University of California, Irvine, Chao Family Comprehensive Cancer Center, Orange, CA

David S. Alberts

University of Arizona Cancer Center, Tuscon, AZ

To the Editor:

The recent article by Schrag et al¹ criticized the field of chemosensitivity and drug resistance, concluding that these types of in vitro assays are not yet ready for prime time. The panel of authors attempted to present evidence that in vitro drug response assays should not be used clinically. An informed reader might find this article an anachronism. This issue was addressed by an exhaustive Medicare Coverage Advisory Committee (MCAC) in 1999.² A panel of physicians selected by the Department of Health and Human Services reviewed hundreds of articles from the literature and heard two days of testimony by experts in the field in an open hearing. The panel voted unanimously that although chemosensitivity assays should not be covered, drug resistance assays should be paid for.

Current Medicare guidelines reimburse for drug resistance assays. Why the distinction? Drug resistance and drug sensitivity are not equivalent.^3-5 It has been clear for more than 20 years that the original clonogenic stem-cell assay was best suited to the identification of drug resistance.⁶ It is therefore somewhat puzzling that Schrag et al focused on chemosensitivity studies, four of which were carried out in the 1980s. Schrag et al offered a review that closely paralleled Brown and Markman’s previous article sponsored by Aetna Life and Casualty Company.⁷ In this case, the articles reviewed by Schrag et al were selected by the Blue Cross and Blue Shield Association. An informed reader wonders how an industry-sponsored selection of 12 papers could be considered an adequate representation of a literature composed of some 790 peer-reviewed articles (according to PubMed search on "chemosensitivity assays"). It should be noted that some members of the American Society of Clinical Oncology (ASCO) panel withdrew from authorship on the basis of their view that the panel’s conclusions were not balanced. The majority of citations offered are significantly flawed and of only historical interest. Clonogenic assays, which comprised three of the 12 papers, have long been known to be fraught with various technical problems, and are no longer offered on a commercial basis.⁴ The reader was reminded of Von Hoff’s article, "He’s not going to talk about in vitro predictive assays again, is he?"⁸ Citing discarded technologies as a rationale for dismissing more recent accomplishments of the field lacks the scientific rigor one expects from peer-reviewed literature. Perhaps this article’s classification as a "special article" precluded peer review. Similarly, methyulthiazol diphenyl tetrazolium bromide dye conversion and ATP assays are not offered nationally on a commercial basis. Fortunately, technology has moved on. Cortazar and Johnson’s 1999 peer-reviewed discussion⁹ of chemosensitivity testing concluded that "the data accumulated thus far show that in vitro-selected chemotherapy seems to be at least as effective as empiric therapy. The technologies for selecting chemotherapeutic regimens are well established."

The current indication for in vitro drug response assays is to detect drug resistance rather than chemosensitivity. Medicare based its coverage policy on the ability of in vitro assays to identify drug resistance with more than 90% accuracy, compared with 70% accuracy for detecting chemosensitivity.^3-6 Currently, in vitro drug resistance assays are performed in laboratories that follow careful quality controlled methods that adhere to College of American Pathologists and Clinical Laboratory Improvement Amendments (CLIA) guidelines. Modern laboratory practices have been implemented to address the lack of standards that were of concern at the time these technologies were initially developed.¹⁰ Differential Staining Cytotoxicity and Extreme Drug Resistance (EDR) assays are widely utilized for the purpose of eliminating agents determined to be ineffective.^9-13 The extent of physician use is exemplified by the more than 9,000 tumor specimens submitted for EDR assays in 2004 (personal communication March 2005). In that these drug resistance assays are Medicare covered technologies, they may have been a more reasonable topic for an extensive review and objective criticism.

Management of cancer patients on an empirical basis using a trial and error approach for second and third line therapy is the current standard, but it leads to toxicity without benefit, a result both patients and clinicians would choose to avoid if possible. In vitro drug resistance assays can provide some guidance in this regard. One cogent concern raised by the ASCO panel was how in vitro assays address tumor heterogeneity, an important consideration for clinicians. We often see patients with favorable response at one site develop new lesions at other sites, necessitating a change in therapy. The key point is that resistance and progression at one site is cause for declaring tumor progression. Thus, a drug resistance result obtained from a single tumor sample for a specific drug is evidence of the presence of a nonresponsive population in at least one site, alerting the physician to avoid such an agent. Validation of the clinical relevance of EDR testing results has been demonstrated by Mehta et al¹³ for breast cancer and Holloway et al¹⁴ for ovarian cancer. These authors reported that women who were treated with agents falling into the extreme drug-resistance category on the basis of in vitro testing against the single-site specimens submitted to the laboratory had significantly inferior survival compared with women who received agents that showed low drug resistance in vitro. Further, a recent study of 119 paired synchronous samples of epithelial ovarian cancer found congruent results for extreme drug resistance in 89% of cases.¹⁵

Despite the dramatic increase in the number and diversity of therapeutic agents, less than 10% of cancer patients with disseminated disease are cured by chemotherapy, and prolongation of survival for the majority of cancer patients is measured in months rather than years. How can this situation be addressed as we continue to wage war on cancer? Targeted therapeutics holds out the promise of tailoring treatment to each patient on the basis of their cancer’s own unique bioprofile. The paradigm shift arises from the view that targeted therapeutics should be directed by an assay that can detect cancer-specific pathways in a given patient’s tumor for which targeted agents are available, such as basing trastuzumab administration on fluorescence in situ hybridization (FISH) assays for HER2 gene amplification. While this is an enlightened approach, the reservoir of currently available agents is limited. The big question is to determine if this "new approach" of using bioassays to direct therapy can be applied to the current set of conventional cytotoxic agents? In other words, can in vitro drug response assays form a bridge from the previous empirical era to the new era of assay-directed targeted therapy?

More than three decades ago, Salmon and Hamburger¹⁶ attempted to follow the lead of specialists in infectious disease by applying their "culture and sensitivity testing" concept to human malignancy. As with many paradigm-shifting ideas, this one was ahead of its time. Two major impediments blocked successful implementation of "chemosensitivity testing" at the time this approach first received broad attention. First, the assay methodologies themselves were not rigorously validated for broad use, and second, only a handful of modestly active chemotherapeutics were available. It is no surprise, then, to find that although early randomized trials that tested the hypothesis that assay selected therapy would be better than "physician’s choice" resulted in higher response rates, no significant improvements in overall survival were found. Enabling advances over the past 30 years in both the technology of in vitro tumor culture methods and in the diversity and safety of agents used to treat cancer led to Medicare coverage for in vitro drug resistance assays. Is it appropriate to conclude that these assays don’t work, or should we consider that flaws in their early implementation obscured their appropriate application to detect drug resistance? In other words, should we throw the baby out with the bathwater? While it is clear that in vitro drug resistance assays can assist physicians in the elimination of ineffective drugs, it may be time to revisit the question "can assay directed therapy prolong patient survival?" Partially on the basis of the recent article by Loizzi et al¹⁷ demonstrating a significant survival advantage for ovarian cancer patients who were treated with assay assisted therapy, the Gynecological Oncology Group has approved the concept of performing a trial to assess assay directed therapy for patients with platinum resistant epithelial ovarian carcinoma. We await the results of this and other "assay directed" trials with the hope that the time for successful tailored therapeutics has finally come.

Authors' Disclosures of Potential Conflicts of Interest

The following authors or their 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. Consultant: John P. Fruehauf, Oncotech, Inc. Stock Ownership: John P. Fruehauf and David S. Alberts, Oncotech, Inc. 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. Schrag D, Garewal HS, Burstein HJ, 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]

2. Medicare Coverage: MCAC Laboratory and Diagnostic Services Panel Human Tumor Assay Systems. Minutes of November 15-16,1999, Meeting. http://www.cms.hhs.gov/mcd/viewmcac.asp?where=index&id=36

3. Fruehauf JP, Bosanquet AG: In vitro determination of drug response: A discussion of clinical applications. PPO Updates, Principles and Practices of Oncology 7 : 1 -17, 1993

4. Fruehauf JP: Assay Assisted Treatment Selection for Women with Breast or Ovarian Cancer. Endocrine-Related Cancer 9 : 171 -182, 2002[Abstract]

5. Chu E, DeVita VT. Principles of cancer management chemotherapy, in DeVita VT, Hellman S, Rosenberg S (eds): Cancer: Principles & Practice of Oncology (ed 6). Philadelphia, PA, Lipincott, Williams and Wilkins, 2001 , pp 289 -306

6. Alberts DS, Samon SE, Chen HS, et al: In-vitro clonogenic assay for predicting response of ovarian cancer to chemotherapy. Lancet 2 : 340 -342, 1980[CrossRef][Medline]

7. Brown E, Markman M: Tumor chemosensitivity and chemoresistance assays. Cancer 77 : 1020 -1025, 1996[CrossRef][Medline]

8. Von Hoff DD: He's not going to talk about in vitro predictive assays again, is he? J Natl Cancer Inst 82 : 96 -101, 1990[Abstract/Free Full Text]

9. Cortazar P, Johnson BE: Review of the efficacy of individualized chemotherapy selected by in vitro sensitivity testing for patients with cancer. J Clin Oncol 17 : 1625 -1631, 1999[Abstract/Free Full Text]

10. Clark GM, Von Hoff DD: Quality control of a multicenter human tumor cloning system: The Southwest Oncology Group experience, in Salmon SE, Trent JM (ed): Human Tumor Cloning. New York, NY, Grune & Startton, 1984 . pp 255 -265

11. Bosanquet AG, Johnson SA, Richards SM: Prognosis for fludarabine therapy of chronic lymphocytic leukemia based on ex vivo cytotoxic drug response by DiSC assay. Br J Haematol 106 : 71 -77, 1999[CrossRef][Medline]

12. Weisenthal LM: Clinical correlations for cell culture assays based on the concept of total tumor cell kill. Contrib Gynecol Obstet 19 : 82 -90, 1994[Medline]

13. Mehta RS, Bornstein R, Yu IR, et al: Breast cancer survival and in vitro tumor response in the Extreme Drug Resistance Assay. Breast Cancer Res Treat 66 : 225 -237, 2001[CrossRef][Medline]

14. Holloway RW, Mehta RS, Finkler NJ, et al: Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients. Gynecol Oncol 87 : 8 -16, 2002[CrossRef][Medline]

15. Tewari K, Mehta RS, Burger RA, et al: Conservation of in vitro drug resistance profiles in epithelial ovarian cancer. Gynecol Oncol 98: in press, 2005

16. Salmon SE, Hamburger AW, Soehnlen B, et al: Quantitation of differential sensitivity of human tumor stem cells to anti-cancer drugs. New Engl J Med 298 : 1312 -1325, 1978[Medline]

17. Loizzi V, Chan JK, Osann K, et al: Survival outcomes in patients with recurrent ovarian cancer who were treated with chemoresistance assay-guided chemotherapy. Am J Obstet Gynecol 189 : 1301 -1307, 2003[CrossRef][Medline]

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