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Medical Policy: 02.04.29
Original Effective Date: August 2010
Reviewed: August 2011
Revised:
Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Description:
In vitro chemoresistance and chemosensitivity assays have been developed to provide information about the characteristics of an individual patient’s malignancy to predict potential responsiveness of their cancer to specific drugs. Thus, these assays are sometime used by oncologists to select treatment regimens for an individual patient. Several assays have been developed that differ with respect to processing of biological samples and detection methods. However, all involve similar principles and they share protocol components including: 1) isolation of cells and establishment of in vitro medium; 2) incubation of the cells with various drugs; 3) assessment of cell survival; and 4) interpretation of the result.
A variety of chemoresistance and chemosensitivity assays have been clinically evaluated in human trials. All assays use characteristics of cell physiology to distinguish between viable and non viable cells to quantify cell kill following exposure to a drug of interest. For the Oncotech Extreme Drug Resistance Assay (EDR®; Exiqon Diagnostics, Tustin, CA); and the ChemoFX® assay (Precision Therapeutics; Pittsburgh, PA) premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the tests are performed in a laboratory that is licensed by CLIA for high-complexity testing.
With few exceptions, drug doses used in the assays are highly variable depending on tumor type and drug class. But all assays require drug exposure ranging from several-fold below physiological relevance to several-fold above physiological relevance.
Chemoresistance assays are used to deselect potential chemotherapeutic regimens. The negative predictive value is a key statistical measure. Unless the negative predictive value is high, there is a chance the clinical decision-making based on a chemoresistance assay could inappropriately exclude an effective therapy. The negative predictive value will vary according to the prior probability of chemoresistance, as well as the assay’s sensitivity and specificity. Chemoresistance assays have the highest clinical relevance in tumors with low probability of response. However, it is still unclear who this information will affect clinical decision-making and whether health outcomes are improved as a result.
The EDR assay was specifically designed to produce a very high negative predictive value (>99%), such that the possibility of inappropriately excluding effective chemotherapy is remote in all clinical situations. However, clinical data are still inadequate to determine whether the use of EDR assays to deselect ineffective chemotherapies result in improved health outcomes. While the relevant clinical outcome in chemosensitivity assays focuses on improved survival, the relevant outcome associated with chemoresistance assays is more controversial. Advocates of the EDR assay point out that avoidance of the toxicity of ineffective drugs is the relevant outcome, while others point out that this represents an intermediate outcome and that improved patient survival is the relevant outcome for chemoresistance assays.
The bulk of the literature regarding extreme drug resistance assays have focused on correlational studies that correlate results from predictive in vitro assays with observed outcomes of chemotherapy. However, in these studies, the patients do not receive assay-guided chemotherapy regimens. Correlational studies are inadequate because they often aggregate patients with different tumor types, disease characteristics, chemotherapy options, and probabilities of response, therefore the accuracy of each assay used to predict response likely varies across different malignancies and patient characteristics. In addition, in correlational studies the method by which assay results are translated into treatment decision is not standardized. Without knowing the rules for converting assay findings into treatment choices, it is impossible to determine the effects of assay-guided treatment on health outcomes. The overall value of assay-guided therapy depends on the net balance of all health outcomes observed after treatment for all patients subjected to testing, regardless of the assay results or the accuracy of its prediction for response.
Results of 2 non comparative studies of ChemoFX® demonstrated statistically significant association of test results with patient outcomes in small populations of patients with breast and ovarian cancer. However, evidence thus far is insufficient to determine whether use of the test to select chemotherapy regimens for individual patients will improve outcomes.
The critical type of evidence needed to establish the effectiveness of chemosensitivity assays should come from comparative studies of assay-guided treatment versus physician-directed treatment. Relevant outcomes would include overall and disease-specific survival, as well as quality of life and adverse events.
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Prior Approval:
Not applicable
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Policy:
In vitro chemoresistance assays are considered investigational.
In vitro chemosensitivity assays are considered investigational.
There have been no studies published with a randomized, prospective, design to evaluate these tests. Therefore to date, the clinical utility of chemoresistance and chemosensitivity assays has not been determined, and the data are insufficient to determine whether use of these tests to select chemotherapy regimens for individual patients will improve outcomes. Most studies have been relatively small correlational designs that evaluated the association between assay results and already known patient outcomes; and, most acknowledge that larger studies are needed. Furthermore, unexpected limitations have arisen including sampling bias due to heterogeneity of tumors and insufficient biospecimen processing resulting in data which cannot be evaluated.
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Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Modifers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
The extreme drug resistance assay is a multistep laboratory procedure that might be identified by the following CPT codes:
- 88358 Morphometric analysis; tumor (eg, DNA ploidy)
- 88305 Level IV - Surgical pathology, gross and microscopic examination
- 88104 Cytopathology, fluids, washings or brushings, except cervical or vaginal; smears with interpretation
- 87230 Toxin or antitoxin assay, tissue culture (eg, Clostridium difficile toxin)
- 88313 Special stains; Group II, all other (eg, iron, trichrome), except immunocytochemistry and immunoperoxidase stains, including interpretation and report, each
- 89050 Cell count, miscellaneous body fluids (eg, cerebrospinal fluid, joint fluid), except blood;
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Selected References:
- Samson DJ, Seidenfeld J, Ziegler K et al. Chemotherapy sensitivity and resistance assays: a systematic review. J Clin Oncol 2004; 22(17):3618-30.
- 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 2003; 189(5):1301-07.
- Eltabbakh GH. Extreme drug resistance assay and response to chemotherapy in patients with primary peritoneal carcinoma. J Surg Oncol 2000; 73(3):148-52.
- Mehta RS, Bornstein R, Yu IR. Breast cancer survival and in vitro tumor response in the extreme drug resistance assay. Breast Cancer Res Treat 2001; 66(3):225-37.
- 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 2002; 87(1):8-16.
- Matsuo K, Eno ML, Im DD et al. Clinical relevance of extent of extreme drug resistance in epithelial ovarian carcinoma. Gynecol Oncol 2010; 116(1):61-5.
- Matsuo K, Bond VK, Eno ML et al. Low drug resistance to both platinum and taxane chemotherapy on an in vitro drug resistance assays predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer. Int J Cancer 2009; 125(11):272-7.
- Tiersten AD, Moon J, Smith HO et al. Chemotherapy resistance as a predictor of progression-free survival in ovarian cancer patients treated with neoadjuvant chemotherapy and surgical cytoreduction followed by intraperitoneal chemotherapy: a Southwest Oncology Group Study. Oncology 2009; 77(6):395-9.
- 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 1990; 82(2): 110-6.
- Iwahashi M, Nakamori M, Nakamura M et al. Individualized adjuvant chemotherapy guided by chemosensitivity test sequential to extended surgery for advanced gastric cancer. Anticancer Res 2005; 25(5):3453-9.
- Ugurel S, Schadendorf D, Pfohler C et al. In vitro drug sensitivity predicts response and survival after individualized sensitivity-directed chemotherapy in metastatic melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology group. Clin Cancer Res 2006; 12(18):5454-63.
- Karam AK, Chiang JW, Fung E et al. Extreme drug resistance assay results do not influence survival in women with epithelial ovarian cancer. Gynecol Oncol. 2009 Aug;114(2):246-52. Epub 2009 Jun 4.
- Moon YW, Sohn JH, Kim YT et al. Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided versus empirical chemotherapy in unresectable non-small cell lung cancer. Anticancer Res. 2009 Oct;29(10):4243-9.
- Herzog TJ, Krivak RC, Fader AN et al. Chemosensitivity testing with ChemoFx and overall survival in primary ovarian cancer. Am J Obstet Gynecol. 2010 Jul;203(1):68.e1-6. Epub 2010 Mar 12.
- Burstein HJ, Mangu PB, Somerfield MR et al. American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Chemotherapy Sensitivity and Resistance Assays. J Clin Oncol 2011. Epub ahead of print 2011 Jul 25. doi: 10.1200/JCO.2011.36.0354.
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Policy History:
Date Reason Action
August 2011 Annual review Policy renewed
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*Current Procedural Terminology © 2010 American Medical Association. All Rights Reserved.
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