Originally published as JCO Early Release 10.1200/JCO.2004.05.065 on August 2 2004

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American Society of Clinical Oncology Technology Assessment: Chemotherapy Sensitivity and Resistance Assays

From the American Society of Clinical Oncology, Alexandria, VA

Address reprint requests to American Society of Clinical Oncology, Cancer Policy and Clinical Affairs, 1900 Duke St, Suite 200, Alexandria, VA 22314; e-mail: guidelines{at}asco.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION Disclosures of Potential... Appendix REFERENCES

 
PURPOSE: To develop a technology assessment of chemotherapy sensitivity and resistance assays in order to define the role of these tests in routine oncology practice.

METHODS: The American Society of Clinical Oncology (ASCO) established a Working Group to develop the technology assessment. The Working Group collaborated with the Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center. The Working Group developed independent criteria for selecting articles for inclusion in the ASCO assessment, and developed a structured data abstraction tool to facilitate review of selected manuscripts. One Working Group member and an ASCO staff member independently reviewed the 1,139 abstracts identified by the BCBSA comprehensive literature search, and by an updated literature search performed by ASCO using the BCBSA search strategy (1966 to January 2004). Of the 12 articles included in this technology assessment, eight were identified by the original BCBSA systematic review, one was provided by industry, and three were identified by the ASCO updated literature review.

RESULTS: Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice.

RECOMMENDATIONS: The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Disclosures of Potential... Appendix REFERENCES

 
Chemotherapy sensitivity and resistance assays (CSRAs) offer the potential of selecting cancer treatments based on responsiveness of individual tumors as measured using in vitro assays. Because of the possibility of tailoring treatment to individual patients—using effective agents while sparing unnecessary ones—there is an intrinsic appeal to this notion. A variety of CSRAs have been developed, and some have been studied in clinical trials. The American Society of Clinical Oncology (ASCO) embarked on a technology assessment of CSRAs in order to define the role of these tests in routine oncology practice.

Definition of CSRAs
A chemotherapy sensitivity assay refers to any in vitro laboratory analysis that is performed specifically to evaluate whether tumor growth is inhibited by a known chemotherapy drug or, more commonly, a panel of drugs. Sometimes these assays are referred to as chemoresistance assays because they identify agents that do not influence in vitro tumor cell growth. In this technology assessment, we refer to both types of analyses as CSRAs. They are contrasted with empiric therapy, which refers to choice of chemotherapy based on the clinical literature describing outcomes achieved when patients receive particular chemotherapy agents. This technology assessment summarizes the evidence on the use of CSRAs and offers recommendations for clinical practice regarding the utility of this technology. This review focuses exclusively on CSRAs performed on viable patient tumor tissue. These assays contrast with strategies such as immunohistochemistry, single gene expression, and transcript profiling, which are performed on nonviable patient tumor tissue and may also yield information predicting the likelihood of response to particular drugs. The best-known example in this latter category is HER-2 overexpression and trastuzumab response in patients with advanced breast cancer.

Technology Assessment Process
ASCO defines a technology assessment as a process for determining whether a procedure is appropriate for broad-based conventional use in clinical practice. The process used in this technology assessment followed defined ASCO policies and procedures. The topic of chemotherapy sensitivity and resistance assays was nominated and approved by the ASCO Health Services Committee (HSC), and subsequently approved by the ASCO Board of Directors.

Literature Review and Analysis
The HSC learned that the Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) had conducted a systematic review on this exact topic under contract to the Health Care Financing Administration. The HSC negotiated a collaborative relationship with BCBSA through which ASCO was granted access to the systematic review for use in the technology assessment development process. The Working Group convened in Chicago in June 2001, with representatives from the BCBSA TEC, to discuss the systematic review and to formulate a process for developing recommendations. The ASCO Working Group decided to use the BCBSA systematic review analysis as a template, but agreed to review the methods used, to identify additional relevant sources of information, and to review independently the articles selected for inclusion in the BCBSA systematic review. The BCBSA systematic review is published in this issue of the Journal of Clinical Oncology.¹

The Working Group developed independent criteria for selecting articles for inclusion in the ASCO assessment. To be included, a study had to compare outcomes for patients whose chemotherapy was chosen empirically (based on the clinical trial literature) versus patients for whom chemotherapy was chosen based on the results of CSRAs. Studies did not have to randomly assign patients to assay-guided or empiric therapy, but had to include a total of 20 or more patients per group. We excluded reports that only reported correlations between assay results and clinical outcomes. Numerous analyses were retrospective evaluations of whether assay results predicted clinical outcomes. Retrospective analyses were included, provided that assay results were used to assign treatment for a group of 20 or more patients.

One Working Group member (D.S.) and an ASCO staff member (M.R.S.) independently reviewed the 1,139 abstracts identified by the BCBSA comprehensive literature search, and by an updated literature search performed by ASCO using the BCBSA search strategy (1966 to January 2004). Seventeen abstracts met inclusion criteria. The full text of each of these articles was reviewed by a steering committee of the Working Group, and 11 articles were ultimately selected as meeting the inclusion criteria. These 11 include two reports not previously identified in the BCBSA review.

In order to identify additional articles regarding CSRAs, the Working Group contacted firms that market these products commercially and requested relevant literature. An additional 20 abstracts or articles were provided by these firms and reviewed by two members of the Working Group. One of these studies met inclusion criteria. Thus, in summary, of the 12 articles included in this technology assessment, eight were identified by the original BCBSA systematic review,^2-9 one was provided by industry,¹⁰ and three were identified by the ASCO updated literature review.^11-13 These same 12 studies are the subject of the BCBSA systematic review.

The Working Group developed a structured data abstraction tool to facilitate review of selected manuscripts. Three Working Group members (H.J.B., H.S.G., and D.S.) independently extracted data from each manuscript to create summary evidence tables. These were circulated to the Working Group for use in developing recommendations and consensus on the final manuscript.

Working Group Selection and Composition
The HSC convened a Working Group that included individuals with expertise in laboratory and clinical aspects of chemotherapy sensitivity and resistance assay development, clinical trial methodology, and guideline development. As per ASCO policies and procedures, the Working Group included core members from the HSC, ad hoc members with content expertise in the area of CSRAs, and a patient representative. One BCBSA representative (D.J.S.) served on the Working Group in an ex-officio capacity (see Appendix for a list of Working Group members and institutional affiliations).

CSRAs
Table 1 describes technical aspects of the CSRAs used in trials identified by the literature review. Table 2 summarizes the study design and findings from each study. These assays and the studies evaluating their performance are described in much greater detail in the BCBSA systematic review. The key features are summarized here in abridged format to provide practitioners with an overview of this challenging literature.

Limitations in the literature include small sample sizes, the lack of prospective studies, the generally low yield of assays, and the availability of newer chemotherapy and biologic agents since the advent of these trials. When interpreting the literature on this technology, clinicians should bear in mind the following considerations:

(1) How often does the assay yield clinically useful results? Is there a clear definition of what constitutes a successful assay? For technically challenging assays requiring colony formation, such as the human tumor cloning assay and surgical procedures including the subrenal capsule assay, the success rate of the procedure is modest, despite varying definitions of success. Moreover, preparation of the assay may involve complex laboratory work. This limits the ability to export this technology to nonresearch settings, and limits broad application of the technology to routine clinical practice. Assays that do not require cell culture have a theoretic advantage in that a larger fraction of specimens may yield interpretable results. Nevertheless, interpretation of these results may be compromised by the lack of a reference standard or clear cutoff to distinguish chemotherapy sensitivity from resistance, and difficulty related to standardization and reproducibility of laboratory technique. Assay results may take several weeks to analyze given the need for successful cell culture. This may pose a problem when there is a clinical basis for more rapid initiation of therapy.

A successful CSRA should have a high yield and provide interpretable results for the majority of patients whose tumor tissue undergoes analysis. Results should also be available within a time frame that permits choice of the "in vitro best regimen" versus standard empiric therapy. The cutoffs used to distinguish resistance from sensitivity should be consistent and easily determinable.

(2) Do assay results depend on the particular lesion biopsied? In most analyses, variability of assay results across different biopsy sites is not evaluated. A particular assay may be performed more than once, but generally the same tumor cell suspension is used each time. Sampling tumor from multiple sites, for example, should yield a similar chemotherapy sensitivity and resistance profile. This is an important, but seldom addressed, control for reliability of the assay results. Development of successful chemotherapy sensitivity and resistance assays will require determination of how assay results vary across different disease sites (eg, primary tumor versus visceral metastasis) obtained from a single patient. It is also not clear if CSRAs built on tissue obtained early in the tumor's history correspond to results that might be obtained downstream with relapse and sequential treatments. Finally, it should be stated that, for patients to have a CSRA performed, they must have tumors that can be obtained via biopsy, paracentesis, or other methods. This could lead to selection biases in the studies reviewed here. For example, patients in the studies would be more likely to have a greater tumor burden and thus a poorer prognosis.

(3) Does assay-guided therapy affect the choice of chemotherapy agent? An important clinical parameter that clinicians seek in published reports is an assessment of how often performance of the assay makes a difference for the patient. Difference might be manifest in terms of selection of a particular chemotherapeutic agent or combination, rejection of the treatment which might otherwise have been used if assay results were unavailable, a decision not to treat if the tumor comes back resistant to a number of agents, a decision to pursue treatment if the tumor comes back surprisingly sensitive compared to what might have been expected from the clinical setting, and so on. This type of information, however, is unavailable in the published literature on CSRAs and is not easily obtained.

Often, the chemotherapy combination that looks most promising on the basis of the CSRA is the very same one that would have been chosen in the absence of assay results. This is particularly evident in the analyses of small-cell lung cancer, where both assay-guided and empiric treatment strategies have typically recommended etoposide and cisplatin. If the assay rarely alters the recommended treatment strategy, the impact of assay results on clinical decision-making can only be minor. CSRAs can only add value if they distinguish between one of several treatment options. If their results consistently serve to validate the use of the same set of drugs that would be selected on the basis of the clinical trial literature, their utility is limited.

Summary of Literature and Recommendations for Practice
The Working Group's review of the literature found that little has changed since the review published by Cortazar and Johnson in 1999.¹⁶ The concept underlying CSRAs remains a compelling one. Unfortunately, there does not appear to be a single assay that is ready for routine integration into the clinical setting. The absence of a suitable CSRA for routine clinical use reflects problems in the technical success and yield of the assays, the lack of adequate prospective evaluation of CSRAs in clinical trials, and the tendency of CSRAs to recommend treatments that would be given empirically.

The single study of a resistance assay that met the Working Group's inclusion criteria deserves special mention. The Loizzi et al¹³ study was designed to compare response rates to chemotherapy for recurrent ovarian cancer among patients receiving either assay-guided therapy or empiric treatment. This was a prospective, but not randomized, clinical trial including 100 consecutive patients (50 treated by assay-guided regimen; 50 empirically). A subset analysis looking at secondary end points among the platinum-sensitive group revealed a survival difference; no survival difference was seen in the platinum-resistant group. Because standard treatment for recurrent ovarian cancer includes platinum therapy, and owing to the lack of a randomized design and the small number of patients, this study has not made an impact on current treatment recommendations. In addition, the chemotherapy regimens selected under assay-guidance are nearly identical to those selected by empiric treatment. This makes it hard to understand the dramatic difference in survival. It is a provocative finding, which may justify large, randomized, prospective clinical trials with similar treatment elements.

Paradoxically, although there is not yet any compelling evidence that CSRAs should be integrated into routine oncology care, the rationale for their development has increased. When few chemotherapeutic options are available and the array of choices is limited, the potential impact of CSRAs is also circumscribed. Over the past decade, a large number of new therapeutic agents (eg, oxaliplatin, irinotecan, multiple monoclonal antibodies) have been US Food and Drug Administration approved and the array of choices facing oncologists has grown ever more complex. The increasing number of choices makes the rational basis for developing CSRAs even more compelling. This is particularly true for those advanced malignancies with short median survival. A review of several large clinical trials demonstrates that, in the absence of CSRAs, the clinical efficacy of different chemotherapy regimens is very similar.¹⁷ For diseases with short median survival, patients often do not maintain the functional status necessary to receive more than one chemotherapeutic regimen and thus selecting the regimen with the greatest chance of inducing a response is indeed an important goal.

Although the Working Group finds no circumstance in which chemotherapy sensitivity and resistance assays should be obtained to make treatment recommendations in routine clinical practice, this view should not be misconstrued to suggest that this strategy lacks opportunity for further research, particularly with newer therapies. As laboratory techniques become more automated and high throughput analyses become easier to obtain and interpret, better assays will be developed. The in vitro approach to determining drug sensitivity and resistance continues to have great potential to spare patients the morbidity of ineffective chemotherapy regimens. Evaluation of these technologies within the context of appropriate research studies should be strongly encouraged within the oncology community.

Thus, based on the evidence from studies that compared outcomes for patients treated with empiric chemotherapy to those treated using assay-guided chemotherapy, the use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Selection of chemotherapeutic agents on the basis of results of CSRAs is not warranted based on the current body of evidence. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

Recommendations for Future Research
In order to traverse the gulf between the laboratory and the clinic, pilot studies of CSRAs need to establish that the laboratory techniques are technically feasible, yield interpretable results in a high proportion of patients within a time frame adequate for influencing clinical decision-making, and result in treatment recommendations that differ from standard clinical algorithms. Once a CSRA meets these criteria, prospective clinical trials to evaluate clinical efficacy are necessary. These studies should randomly assign patients to the regimens identified on the basis of in vitro testing (the "in vitro best regimen"), or to empiric therapy with the standard regimen based on clinical trial data. The end points in these clinical trials should include survival as the clinical measure of outcome. Trials analyzing response rate and/or time to progression might also be informative, but less definitive. In addition, it would be important to discuss any planned clinical study design(s) with regulatory agencies before beginning the studies. This would assure that if the studies demonstrated positive results, they could be used for regulatory approval for wide scale use of a particular CSRA. Unfortunately, the Working Group is not aware of any ongoing or planned studies that include the design elements outlined here.

Finally, it must be acknowledged that the available technology for predicting tumor response to chemotherapy and targeted biologic agents has developed dramatically in the decades since the first efforts to use CSRAs. Trials that take advantage of bioinformatic technologies (eg, gene microarrays) now stand as a viable competing strategy for selecting treatments based on features of tumor biology, and should ideally be conducted alongside traditional in vitro sensitivity assays.

	Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION Disclosures of Potential... Appendix REFERENCES

 
The following contributors 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. Acted as a consultant within the last 2 years: Axel Hanauske, Eli Lilly & Co, Hoffman-La Roche, iOnGen; Rowan T. Chlebowski, AstraZeneca, Novartis, Aventis, Eli Lilly & Co. Performed contract work within the last 2 years: Axel Hanauske, Eli Lilly & Co, Hoffman-La Roche. Served as an officer or member of the Board of a company: Anne Hamburger, Biocell, Analytical Biosystems Corp. Received more than $2,000 a year from a company for either of the last 2 years: Axel Hanauske, Eli Lilly & Co; Jaffer Ajani, Novartis, Aventis, Sanofi, Taiho; Rowan T. Chlebowski, AstraZeneca, Novartis, Aventis, Eli Lilly & Co.

	Appendix

TOP ABSTRACT INTRODUCTION Disclosures of Potential... Appendix REFERENCES

 
Appendix

	Acknowledgment

 
The Working Group wishes to express its gratitude to Drs Jose Baselga, Patricia Cortazar, David S. Mendelson, Charles W. Penley, John M. Rainey, Robert L. Ruxer, and Antonio C. Wolff for their thoughtful reviews of earlier versions of this technology assessment. Special thanks to Dr David G. Pfister who established the Working Group to address this topic during his tenure as Chair of the ASCO Health Services Committee. Finally, thanks to Jerome Seidenfeld and the Blue Cross and Blue Shield Association Technology Evaluation Center for their collaboration.

	NOTES

 
Disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION Disclosures of Potential... Appendix REFERENCES

 
1. Samson DJ, Seidenfeld J, Ziegler K, et al: Chemotherapy sensitivity and resistance assays: A systematic review. J Clin Oncol 22:10.1200/JCO.2004.04.077

2. Cortazar P, Gazdar AF, Woods E, et al: Survival of patients with limited-stage small cell lung cancer treated with individualized chemotherapy selected by in vitro drug sensitivity testing. Clin Cancer Res 3:741-747, 1997[Abstract]

3. Gazdar AF, Steinberg SM, Russell EK, et al: Correlation of in vitro drug-sensitivity testing results with response to chemotherapy and survival in extensive-stage small cell lung cancer: A prospective clinical trial. J Natl Cancer Inst 82:117-124, 1990[Abstract/Free Full Text]

4. Shaw GL, Gazdar AF, Phelps R, et al: Individualized chemotherapy for patients with non-small cell lung cancer determined by prospective identification of neuroendocrine markers and in vitro drug sensitivity testing. Cancer Res 53:5181-5187, 1993[Abstract/Free Full Text]

5. Shaw GL, Gazdar AF, Phelps R, et al: Correlation of in vitro drug sensitivity testing results with response to chemotherapy and survival: Comparison of non-small cell lung cancer and small cell lung cancer. J Cell Biochem Suppl 24:173-185, 1996[Medline]

6. Von Hoff DD, Clark GM, Stogdill BJ, et al: Prospective clinical trial of a human tumor cloning system. Cancer Res 43:1926-1931, 1983[Abstract/Free Full Text]

7. Von Hoff DD, Sandbach JF, Clark GM, et al: Selection of cancer chemotherapy for a patient by an in vitro assay versus a clinician. J Natl Cancer Inst 82:110-116, 1990[Abstract/Free Full Text]

8. Von Hoff DD, Kronmal R, Salmon SE, et al: A Southwest Oncology Group study on the use of a human tumor cloning assay for predicting response in patients with ovarian cancer. Cancer 67:20-27, 1991[CrossRef][Medline]

9. Wilbur DW, Camacho ES, Hilliard DA, et al: Chemotherapy of non-small cell lung carcinoma guided by an in vitro drug resistance assay measuring total tumour cell kill. Br J Cancer 65:27-32, 1992[Medline]

10. Xu JM, Song ST, Tang ZM, et al: Predictive chemotherapy of advanced breast cancer directed by MTT assay in vitro. Breast Cancer Res Treat 53:77-85, 1999[CrossRef][Medline]

11. Kurbacher CM, Cree IA, Bruckner HW, et al: Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer. Anticancer Drugs 9:51-57, 1998[Medline]

12. Maenpaa JU, Heinonen E, Hinkka SM, et al: The subrenal capsule assay in selecting chemotherapy for ovarian cancer: A prospective randomized trial. Gynecol Oncol 57:294-298, 1995[CrossRef][Medline]

13. 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]

14. Kern DH, Drogemuller CR, Kennedy MC, et al: Development of a miniaturized, improved nucleic acid precursor incorporation assay for chemosensitivity testing of human solid tumors. Cancer Res 45:5436-5441, 1985

15. Kern DH, Weisenthal LM: Highly specific prediction of antineoplastic drug resistance with an in vitro assay using suprapharmacologic drug exposures. J Natl Cancer Inst 82:582-588, 1990[Abstract/Free Full Text]

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

17. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002[Abstract/Free Full Text]

Submitted May 12, 2004; accepted June 3, 2004.

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