Medicare Advantage

Medical Policy

Title:

In Vitro Chemosensitivity and Chemoresistance Assays

Policy #:

MA06.021d

Policy

In vitro chemosensitivity and chemoresistance assays are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of these services cannot be established by review of the available published peer-reviewed literature.

Guidelines

This policy is consistent with Medicare's coverage determination. The Company’s payment methodology may differ from Medicare.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, in vitro chemosensitivity and chemoresistance assays are not eligible for payment under the medical benefits of the Company’s Medicare Advantage products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are excluded for the Company’s Medicare Advantage products. Therefore, they are not eligible for reimbursement consideration.

Description

IN VITRO CHEMORESPONSE ASSAYS INCLUDING IN VITRO CHEMOSENSITIVITY AND IN VITRO CHEMORESISTANCE ASSAYS

Assay-directed chemotherapy is a chemotherapeutic regimen based on characteristics that determine whether an individual is likely to benefit from treatment with a certain agent. It is a proposed alternative to empiric therapy, which is guided by practical experience rather than precepts or theory. An in vitro chemoresponse assay includes laboratory tests that determine the chemosensitivity or chemoresistance of carcinoma (tumor) cells to specific chemotherapeutic agents. An in vitro chemosensitivity assay determines the sensitivity of and resistance to carcinoma (tumor) cells to chemical agents. Tumor type, stage, aggressiveness, site, and treatment history are considered before an in vitro chemoresponse assay is performed. Each test involves the exposure of human tumor cell colonies (grown in tissue culture) to anticancer drugs, with subsequent observation for signs of cytotoxic effects. The purpose of an in vitro chemoresponse assay is to screen potential anticancer drugs for effectiveness against tumors.

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. These assays are sometimes used by oncologists to select treatment regimens for an individual patient. Several assays have been developed that differ with respect to processing of biologic samples and detection methods. However, all involve similar principles and share protocol components including: (1) isolation of cells and establishment in an in vitro medium; (2) incubation of the cells with various drugs; (3) assessment of cell survival; and (4) interpretation of the result. The tumor response to one of these assays is usually classified as drug-sensitive, drug-resistant, or intermediate. If an in vitro tumor cell sample is resistant to a particular chemotherapeutic agent, that agent is not recommended for treatment. Examples of assays include:

The Differential Staining Cytotoxicity assay
The EVA/PCD® assay
The fluorometric microculture cytotoxicity assay
Tritiated thymine incorporation
The Extreme Drug Resistance assay (EDR®)
The Histoculture Drug Resistance Assay
The Adenosine Triphosphate (ATP) Bioluminescence assay
ChemoFX®
CorrectChemo®

SUMMARY OF PEER-REVIEWED EVIDENCE

There are only a few comparative studies that evaluate use of a chemosensitivity assay to select chemotherapy versus standard care, and these studies do not report significant differences in outcomes between groups. A larger number of studies have used correlational designs that evaluate the association between assay results and already known patient outcomes. These studies report that results of chemosensitivity and chemoresistance assays are predictive of outcomes. However, these studies do not evaluate whether these assays lead changes in management and whether any changes in management lead to improved outcomes. In addition, interpretation of these studies is limited by heterogeneity in test methodology, tumor type, patient population, and chemotherapeutic agents. As a result, the clinical utility of chemoresistance and chemosensitivity assays has not been determined, and data are insufficient to determine whether use of the test to select chemotherapy regimens for individual patients will improve outcomes.

PRACTICE GUIDELINES AND POSITION STATEMENTS

NATIONAL COMPREHENSIVE CANCER NETWORK
The 2015 National Comprehensive Cancer Network (NCCN) guidelines for the treatment of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer (v.3.2014) states the following, “Chemosensitivity/resistance and/or other biomarker assays are being used in some NCCN Member Institutions. The current level of evidence is not sufficient to supplant standard-of-care chemotherapy (category 3).”

AMERICAN SOCIETY OF CLINICAL ONCOLOGY
The American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Chemotherapy Sensitivity and Resistance Assays, 2011 also does not recommend use of chemotherapy sensitivity and resistance assays, unless in a clinical trial setting.

References

Anticancer I. HISTOCULTURE DRUG RESPONSE ASSAY - HDRA. Available at: http://www.anticancer.com/HDRA_ref.html. Accessed August 2, 2023.

Bird MC, Godwin VA, Antrobus JH, et al. Comparison of in vitro drug sensitivity by the differential staining cytotoxicity (DiSC) and colony-forming assays. Br J Cancer. Apr 1987;55(4):429-431.

Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Chemotherapy Sensitivity and Resistance Assays. TEC Assessments. 2002; Volume 17, Tab 12.

Brown E, Markman M. Tumor chemosensitivity and chemoresistance assays. Cancer. Mar 15 1996;77(6):1020-1025.

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. Aug 20 2011;29(24):3328-3330.

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. May 1997;3(5):741-747.

Cree IA, Kurbacher CM, Lamont A, et al. A prospective randomized controlled trial of tumour chemosensitivity assay directed chemotherapy versus physician's choice in patients with recurrent platinum-resistant ovarian cancer. Anticancer Drugs. Oct 2007;18(9):1093-1101.

Ellis RJ, Fabian CJ, Kimler BF, et al. Factors associated with success of the extreme drug resistance assay in primary breast cancer specimens. Breast Cancer Res Treat. Jan 2002;71(2):95-102.

Eltabbakh GH, Piver MS, Hempling RE, et al. Correlation between extreme drug resistance assay and response to primary paclitaxel and cisplatin in patients with epithelial ovarian cancer. Gynecol Oncol. Sep 1998;70(3):392-397.

Eltabbakh GH. Extreme drug resistance assay and response to chemotherapy in patients with primary peritoneal carcinoma. J Surg Oncol. Mar 2000;73(3):148-152.

Gallion H, Christopherson WA, Coleman RL, et al. Progression-free interval in ovarian cancer and predictive value of an ex vivo chemoresponse assay. Int J Gynecol Cancer. Jan-Feb 2006;16(1):194-201.

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. Jan 17 1990;82(2):117-124.

Grigsby PW, Zighelboim I, Powell MA, et al. In vitro chemoresponse to cisplatin and outcomes in cervical cancer. Gynecol Oncol. Jul 2013;130(1):188-191.

Herzog TJ, Krivak TC, Fader AN, et al. Chemosensitivity testing with ChemoFx and overall survival in primary ovarian cancer. Am J Obstet Gynecol. Jul 2010;203(1):68 e61-66.

Hetland TE, Kaern J, Skrede M, et al. Predicting platinum resistance in primary advanced ovarian cancer patients with an in vitro resistance index. Cancer Chemother Pharmacol. May 2012;69(5):1307-1314.

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. Oct 2002;87(1):8-16.

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. Sep-Oct 2005;25(5):3453-3459.

Jung PS, Kim DY, Kim MB, et al. Progression-free survival is accurately predicted in patients treated with chemotherapy for epithelial ovarian cancer by the histoculture drug response assay in a prospective correlative clinical trial at a single institution. Anticancer Res. Mar 2013;33(3):1029-1034.

Lee JH, Um JW, Lee JH, et al. Can immunohistochemistry of multidrug-resistant proteins replace the histoculture drug response assay in colorectal adenocarcinomas? Hepatogastroenterology. Jun 2012;59(116):1075-1078.

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. Aug 2009;114(2):246-252.

Kern DH, Weisenthal LM. Highly specific prediction of antineoplastic drug resistance with an in vitro assay using suprapharmacologic drug exposures. J Natl Cancer Inst. Apr 4 1990;82(7):582-588.

Kim JH, Lee KW, Kim YH, et al. Individualized tumor response testing for prediction of response to Paclitaxel and Cisplatin chemotherapy in patients with advanced gastric cancer. J Korean Med Sci. May 2010;25(5):684-690.

Krivak TC, Lele S, Richard S, et al. A chemoresponse assay for prediction of platinum resistance in primary ovarian cancer. Am J Obstet Gynecol. Jul 2014;211(1):68 e61-68.

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. Jan 1998;9(1):51-57.

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. Nov 2003;189(5):1301-1307.

Matsuo K, Bond VK, Eno ML, et al. Low drug resistance to both platinum and taxane chemotherapy on an in vitro drug resistance assay predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer. Int J Cancer. Dec 1 2009;125(11):2721-2727.

Matsuo K, Eno ML, Im DD, et al. Clinical relevance of extent of extreme drug resistance in epithelial ovarian carcinoma. Gynecol Oncol. Jan 2010;116(1):61-65.

Matsuo K, Eno ML, Im DD, et al. Chemotherapy time interval and development of platinum and taxane resistance in ovarian, fallopian, and peritoneal carcinomas. Arch Gynecol Obstet. Feb 2010;281(2):325-328.

Matsuo K, Bond VK, Im DD, et al. Prediction of Chemotherapy Response With Platinum and Taxane in the Advanced Stage of Ovarian and Uterine Carcinosarcoma: A Clinical Implication of In vitro Drug Resistance Assay. Am J Clin Oncol. Aug 2010;33(4):358-363.

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. Apr 2001;66(3):225-237.

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. Oct 2009;29(10):4243-4249.

Nagourney RA. Ex vivo programmed cell death and the prediction of response to chemotherapy. Curr Treat Options Oncol. Mar 2006;7(2):103-110.

Nagourney RA, Blitzer JB, Shuman RL, et al. Functional profiling to select chemotherapy in untreated, advanced or metastatic non-small cell lung cancer. Anticancer Res. Oct 2012;32(10):4453-4460.

National Comprehensive Cancer Network (NCCN). Guidelines v1.2014 Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. June 2, 2023. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed Auguat 2, 2023.

Rutherford T, Orr J, Jr., Grendys E, Jr., et al. A prospective study evaluating the clinical relevance of a chemoresponse assay for treatment of patients with persistent or recurrent ovarian cancer. Gynecol Oncol. Nov 2013;131(2):362-367.

Salom E, Penalver M, Homesley H, et al. Correlation of pretreatment drug induced apoptosis in ovarian cancer cells with patient survival and clinical response. J Transl Med. 2012;10:162.

Samson DJ, Seidenfeld J, Ziegler K, et al. Chemotherapy sensitivity and resistance assays: a systematic review. J Clin Oncol. Sep 1 2004;22(17):3618-3630.

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. Nov 1 1993;53(21):5181-5187.

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. 1996;24:173-185.

Strickland SA, Raptis A, Hallquist A, et al. Correlation of the microculture-kinetic drug-induced apoptosis assay with patient outcomes in initial treatment of adult acute myelocytic leukemia. Leuk Lymphoma. Mar 2013;54(3):528-534.

Tian C, Sargent DJ, Krivak TC, et al. Evaluation of a chemoresponse assay as a predictive marker in the treatment of recurrent ovarian cancer: further analysis of a prospective study. Br J Cancer. Aug 26 2014;111(5):843-850.

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):395-399.

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. Sep 15 2006;12(18):5454-5463.

von Heideman A, Tholander B, Grundmark B, et al. Chemotherapeutic drug sensitivity of primary cultures of epithelial ovarian cancer cells from patients in relation to tumour characteristics and therapeutic outcome. Acta Oncol. Feb 2014;53(2):242-250.

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. Jan 17 1990;82(2):110-116.

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. Jan 1 1991;67(1):20-27.

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. Jan 1992;65(1):27-32.

Xu JM, Song ST, Tang ZM, et al. Predictive chemotherapy of advanced breast cancer directed by MTT assay in vitro. Breast Cancer Res Treat. Jan 1999;53(1):77-85.

Yung WK. In vitro chemosensitivity testing and its clinical application in human gliomas. Neurosurg Rev.1989;12(3):197-203.

Coding

CPT Procedure Code Number(s)

THE FOLLOWING CODES ARE USED TO REPRESENT ChemoFX® TEST/ASSAY:

81535, 81536

THE FOLLOWING CODE IS USED TO REPRESENT IN VITRO CHEMORESISTANCE AND CHEMOSENSITIVITY ASSAYS:

89240

THE FOLLOWING CODE IS USED TO REPRESENT THE ChemoFX® TEST/ASSAY:

0564T

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

This service is experimental/investigational for all diagnoses.

HCPCS Level II Code Number(s)

N/A

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From MA06.021d:

06/24/2026	This policy has been reissued in accordance with the Company's annual review process.
10/01/2025	This policy has been reissued in accordance with the Company's annual review process.
07/10/2024	This policy has been reissued in accordance with the Company's annual review process.
01/01/2024	Effective 01/01/2024 this policy applies to New Jersey Medicare Advantage (MA) lines of business.
08/23/2023	The policy has been reviewed and reissued to Communicate the Company's contiunued position on In Vitro Chemosensitivity and Chemoresistance Assays.
02/23/2022	This policy has been reissued in accordance with the Company's annual review process.
12/16/2020	This policy has been reissued in accordance with the Company's annual review process.
01/01/2020	This version of the policy will become effective on 01/01/2020 due to a coding update and another change. The following code is being added to this policy: 0564T Additionally, procedure code 81536 is being added to this policy

Revisions From MA06.021c:

09/12/2018	The policy has been reviewed and reissued to communicate the Company’s continuing position on In Vitro Chemosensitivity and Chemoresistance Assays.
06/21/2017	This policy has been reissued in accordance with the Company's annual review process.
05/06/2016	This policy has been identified for an ad hoc CPT code update, effective 05/06/2016. ChemoFX® TEST/ASSAY has a specific CPT code as of 01/01/2016; therefore, the following CPT code does not represent ChemoFX® TEST/ASSAY as of 01/01/2016: 8924

Revisions From MA06.021b:

01/01/2016

This policy has been identified for the CPT code update, effective 01/01/2016.
The following CPT code has been added to this policy:81535

Revisions From MA06.021a:

11/06/2015

Revised policy number 06.02.14f was issued as a result of the department's annual review process. The references were updated accordingly. The policy was updated to be consistent with current template wording and format. The policy statements and adoptable sources remain the same.

Revisions From MA06.021:

01/01/2015

This is a new policy.

Version Effective Date:

1/1/2024

Version Issued Date: