Medical Policy: 02.04.47 

Original Effective Date: August 2014 

Reviewed: June 2017 

Revised: June 2017 

 

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:

The goals of chemotherapy treatment are to utilize the most effective agents for killing tumors or cancer-cells, while avoiding patient toxicity. Various factors are taken into consideration when choosing a chemotherapy regimen including the type of cancer, stage of cancer, other medical conditions of the individual, concomitant drug therapies, and previous chemotherapy. Clinical assessment, imaging techniques, and surgical staging are considered the standards of care for identifying response to therapy.

 

In vitro chemotherapy sensitivity and resistance assays (CSRAs) have been proposed as methods for determining response and for customizing cancer therapies for individuals.  CSRAs are in vitro laboratory analyses of sample cells taken from a primary or metastatic tumor (before or after treatment with chemotherapy) to provide predictive information regarding a tumor’s particular chemotherapy sensitivity or resistance.

  • Chemosensitivity Assays:  The goal of in vitro chemosensitivity assays is to assist with the selection of chemotherapy drugs for the treatment of cancer in individuals based on the response of each patient’s tumor cells to a specific chemotherapeutic agent(s). Tumor cells are obtained from the individual with cancer, cultured in the laboratory, and exposed to a specific drug or battery of drugs over a period of time. This assay is intended to predict the sensitivity of various tumors to chemotherapeutic agents to assist with the selection of chemotherapy drugs with the intent of identifying more effective protocols which would then translate into improved clinical survival/outcomes.
  • Chemoresistance Assays:  In vitro chemoresistance assays are intended to identify or deselect chemotherapy drugs that are non-responsive (resistant) to a specific tumor and not recommended as part of the treatment protocol.  During the assay, tumor cells are cultured and exposed to concentrations of selected chemotherapeutic agents over a prolonged period of time. Tumors are reported as having high, intermediate or low drug resistance, with the assumption being that drugs with low resistance may be effective in vivo (i.e. within the body), while high-resistance drugs may be less effective.

The use of in vitro assays to detect chemosensitivity or resistance has not yet been translated into routine clinical practice. The ability of these tests to identify active and inactive chemotherapy agents in the laboratory setting does not necessarily translate into an accurate and clinically useful prediction of patient response to therapy and patient survival. The precise pathway of apoptosis (i.e., cell death) is difficult to determine and is dependent on several factors, including tumor cell type and volume, the drug combinations being used and the doses that are being prescribed. Some tumor cell components provide protection of the cancer cell against chemolytic agents and act as transporters moving the drugs away from the tumor cells.

 

A major limitation of chemosensitivity and chemoresistance assays (CSRAs) stems from the need to use in vitro cell culture. In vitro sensitivity or resistance to an agent does not ensure in vivo (i.e., testing on a living organism) response because of a variety of host factors, including drug concentration within the body, vascularity to the tumor or the presence of pharmacologic sanctuaries, such as the blood-brain barrier, and detoxification of the drug within the body. Additionally, tumor growth in vitro may not mirror tumor growth in vivo, nor can it be established that the biopsy tissue used in the assays is truly representative of the entire tumor. The genetic variations suited to survival in culture may yield an altered phenotype. Additionally, the immune system is known to interact with, and in some instances alter, the growth of tumor. Other limitations of in vitro assays include the need for complex labor intensive laboratory work, the generally low yield of assays and the prolonged time required for results which limits the ability to allow for early prediction of therapy response.

 

Though the assays may differ in their technologies and processes in measuring sensitivity or resistance, they share 4 basic steps:

  • Isolation of cells
  • Incubation of cells with drugs
  • Assessment of cell survival
  • Interpretation of the result 

Examples of commercially available chemosensitivity and chemoresistance assays include, but may not be limited to:

  • ChemoFx Assay
  • Differential Staining Cytotoxicity (DiSC) Assay
  • Duke University Chemotherapy Assessment Test
  • Extreme Drug Resistance (EDR) Assay (no longer commercially available)
  • Fluorescence (Cytoprint) Assay
  • Histoculture Drug Response Assay (HDRA)
  • Methyl Thiazolyl-Diphenyl-Tetrazolium Bromide (MTT) Assay
  • Microculture Kinetic (MiCK) Apoptosis Assay (Also known as CorrectChemo)

ChemoFx ® Assay (Helomics Inc., formerly Precision Therapeutics Inc., Pittsburg, PA): ChemoFx is a drug response marker. It quantifies an individual cancer patients probable tumor response up to 12 various chemotherapeutic and biologic agents providing both sensitivity and resistance information. Small tissue samples from surgery, two core needle biopsies or ascites or pleural fluid of ovarian, endometrial, cervical, breast, lung and colorectal tumor types may be tested. Cells are cultured in a growth medium in the laboratory over a period of time and subjected to chemotherapy drugs or drug combinations. It is proposed that ChemoFx assay can provide predictions of responses to specific agents alone or in combination. The level of cell kill is recorded for each drug across multiple doses. This assay is utilized to help guide physician’s treatment decisions to assist in determining which chemotherapies are least likely to work and which are most likely to work for an individual patient.  

 

Duke University Chemotherapy Assessment Test
In using this test, “messenger RNA” from a cancer patient’s tumor cells are extracted and the messenger RNA is labeled with fluorescent tags and placed on a tiny glass slide called a gene clip. When scanned with a special light, the fluorescent RNA emits a telltale luminescence that demonstrates how much RNA is present on the chip, and this reading indicates which genes are most active in a given tumor. This is then used to predict which chemotherapeutic agent(s) will be most powerful in treatment the specific tumor. Current studies are assessing the ability of this test to predict how patients with breast, ovarian and leukemia respond to various anti-cancer drugs.

  

Differential Staining Cytotoxicity assay: This assay relies on dye exclusion of live cells after mechanical disaggregation of cells from surgical or biopsy specimens by centrifugation. Cells are then established in culture and treated with the drugs of interest at 3 dose levels; the middle dose is that which could be achieved in therapy; 10-fold lower than the physiologically relevant dose; and, 10-fold higher. Exposure time ranges from 4 to 6 days; then, cells are restained with fast green dye and counterstained with hematoxylin and eosin (H&E). The fast green dye is taken up by dead cells, and H&E can then differentiate tumors cells from normal cells. The intact cell membrane of a live cell precludes staining with the green dye. Drug sensitivity is measured by the ratio of live cells in the treated samples to the number of live cells in the untreated controls.

 

The Extreme Drug Resistance Assay (EDR Assays ®) (Exiqon Diagnostics, Tustin, CA – no longer commercially available)
In this assay human tumor cells are cultured and exposed to high concentration of drugs for a prolonged period. Tumor cells that survive this overwhelming exposure are considered to demonstrate “extreme drug resistance.” 

 

Fluorescence Cytoprint Assay (FCA)
The fluorescence cytoprint assay (FCA) can assess multiple chemotherapeutic agents using small (approximately 500 cells) tumor aggregates very quickly (approximately 1 week). FCA tumor chemosensitivity has been studied in patients with malignant gliomas.

 

The Histoculture Drug Response Assay (HDRA) (AntiCancer Inc., San Diego, CA). The HDRA determines both drug sensitivity and resistance. This assay evaluates cell growth after chemotherapy treatment based on colorimetric assay that relies on mitochondrial dehydrogenases in living cells. Drug sensitivity is evaluated by quantification of cell growth in a three dimensional culture (collagen matrix). There is an inverse relationship between the drug sensitivity of the tumor and cell growth. Concentrations of drug and incubation times are not standardized and vary depending on drug combination and tumor types.

 

Methyl Thiazolyl-Diphenyl-Tetrazolium Bromide (MTT) Assay
The MTT assay involves single tumor cell suspensions which are exposed to chemical MTT. If the cell is metabolically active, blue crystals are produced. There is an inverse relationship between the drug sensitivity of the tumor and cell growth. Concentrations of drug and incubation times are not standardized and very depending on drug combination and tumor type. 

 

Microculture Kinetic (MiCK) Assay (Also known as CorrectChemo) – (DiaTech Oncology, Franklin, TN). Diatech Oncology utilizes a proprietary and patented technology called CorrectChemo, also known as the Microculture Kinetic (MiCK) assay, licensed from Vanderbilt University. This assay relies on measures of programed cell death or apoptosis, after patients tumor cells are exposed to a broad range of chemotherapy agents. The optical density of the cells is measured over time, to create a density-by-time curve. A sudden increase in optical density is associated with cell apoptosis; the extent of the drug induced apoptosis is a measures of the cell’s sensitivity to that agent.

  • Measures apoptotic cancer cell death to predict chemotherapy treatment outcomes within 72 hours.
  • The assay has been used in more than 50 different tumor types.
  • Based on the result, DiaTech Oncology provides the treating oncologist with a clinically relevant drug-induced apoptosis profile of tumor cells of an individual cancer patient.

Summary

Although a number of uncontrolled clinical trials have been conducted, standards have not been established for the use of tumor in vitro chemosensitivity or chemoresistance assays in clinical practice. To date the majority of studies have been small in participant numbers, correlational in design, and do not evaluate outcomes of individuals receiving assay-directed therapy compared with those who receive physician/empiric-driven therapy. Well-designed prospective controlled clinical trials are needed to determine the potential clinical role of assay-directed therapies and their impact on tumor response and patient survival. At this time there is insufficient evidence to demonstrate the clinical correlation between the use of these tests and improved patient health outcomes. Further, professional society/organizational consensus support in the form of published guidelines is lacking. Although an active focus of research, the clinical utility of in vitro chemoresistance and chemosensitivity assays has not yet been established.

 

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

NCCN Guidelines Version 1.2017 Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer

Chemotherapy/resistance assays and/or other biomarker assays are being used in some NCCN Member Institutions to aid in selecting chemotherapy in situations where there are multiple equivalent chemotherapy options available; however, the current level of evidence (category 3) is not sufficient to supplant standard of care chemotherapy. Thus, the NCCN Panel felt that in vitro chemosensitivity testing to choose a chemotherapy regimen for recurrent disease situations should not be recommended (category 3), owing to the lack of demonstrable efficacy for such an approach. The ASCO also does not recommend use of chemotherapy sensitivity and resistance assays, unless in a clinical trial setting.  Note that a category 3 recommendation reflects strong disagreement about the intervention.

 

American Society of Clinical Oncology (ASCO)

In 2011, the American Society of Clinical Oncology (ASCO) Clinical Practice Guideline Update on the Use of Chemotherapy Sensitivity and Resistance Assays states: "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 in in-vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority." 

  

Regulatory Status

Commercially available chemosensitivity and chemoresistance assays are laboratory developed tests for which approval from the U.S. Food and Drug Administration is not required when the tests are performed in a laboratory licensed by the Clinical Laboratory Improvement Act (CLIA) for high-complexity testing. Such tests must meet the general regulatory standards of CLIA. 

 

Prior Approval:

 

Not applicable.

 

Policy:

Chemosensitivity and chemoresistance assays, including but not limited to the following are considered investigational for all indications:

  • ChemoFx Assay
  • Differential Staining Cytotoxicity (DiSC) Assay 
  • Duke University Chemotherapy Assessment Test
  • Fluorescent (Cytoprint) Assay
  • Histoculture Drug Response Assay (HDRA)
  • Methyl Thiazolyl-Diphenyl-Tetrazolium Bromide (MTT) Assay
  • Microculture Kinetic (MiCK) Apoptosis Assay (Also known as CorrectChemo)

Results of the available studies fail to provide sufficient evidence that testing with chemoresistance and chemosensitivity assays leads to improved health outcomes in patients with cancer. To date, the majority of the available studies failed to demonstrate a survival benefit with chemotherapy regimens selected based on chemosensitivity and chemoresistance assays, compared with chemotherapy regimens selected based on traditional clinical factors. Well-designed randomized controlled trials (RCTs) are needed to determine the clinical utility of chemosensitivity and chemoresistance assays compared with traditional clinical factors to guide treatment selection and improve clinical outcomes including tumor response, time to progression and overall survival.

 

Procedure Codes and Billing Guidelines:

  • To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 81535 Oncology (gynecologic), live tumor cell culture and chemotherapeutic response by DAPI stain and morphology, predictive algorithm reported as a drug response score; first single drug or drug combination
  • 81536 Oncology (gynecologic), live tumor cell culture and chemotherapeutic response by DAPI stain and morphology, predictive algorithm reported as a drug response score; each additional single drug or drug combination (List separately in addition to code for primary procedure)
  • 89240 Unlisted miscellaneous pathology test
  • 86849 Unlisted immunology procedure

 

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.
  • Precision Therapeutics, ChemoFx.
  • Diatech Oncology, Microculture Kinetic (MiCK) assay.
  • Hans Neubauer, et. al. Predicting Resistance to Platinum-Containing Chemotherapy with the ATP Tumor Chemosensitivity Assay in Primary Ovarian Cancer. AntiCancer Research 28:949-956 (2008)  
  • Histoculture Drug Resistance Assay (HDRA) Anticancer Inc., San Diego, CA.
  • The EVA-PCD® functional profile (Ex Vivo Analysis of Programmed Cell Death), Rationale Therapeutics.
  • The Extreme Drug Resistance assay (EDR Assays ®), Exiqon Diagnostics, Tustin, CA
  • National Comprehensive Cancer Network (NCCN) Version 1.2017 Ovarian Cancer, Fallopian Tube Cancer and Primary Peritoneal Cancer.
  • ECRI Institute. Hotline Response. In Vitro Chemosensitivity Assays for Predicting Ovarian Cancer Response to Chemotherapy, July 2014.
  • Centers for Medicare and Medicaid Services National Coverage Determination (NCD) for Human Tumor Stem Cell drug Sensitivity Assay (190.7).
  • UpToDate. First Line Chemotherapy for advanced (stage II or IV) Epithelial Ovarian, Fallopian Tubal, and Peritoneal Cancer, Thomas J. Herzog, M.D., Deborah K. Armstrong, M.D., Topic last updated August 9, 2016.
  • Linda Bosserman, et al. The Microculture-Kinectic (MiCK) Assay: The Role of a Drug-Induced Apoptosis Assay in Drug Development and Clinical Care, American Association of Cancer Research (AACR), published online first August 3, 2012, DOI:10.1158/0008-5472. CAN-12-0681.
  • National Comprehensive Cancer Network (NCCN) Version 2.2015 Ovarian Cancer.
  • UpToDate. Medical Treatment for Relapsed Epithelial Ovarian, Fallopian Tubal or Peritoneal Cancer: Platinum-Sensitive Disease, Robert L. Coleman, M.D., Paul Sabbatini, M.D., Topic last updated April 24, 2017.
  • 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. PMID 22302409
  • 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. PMID 23954900
  • 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. PMID 25003664
  • 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. PMID 24530815
  • 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. PMID 22873358
  • 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. PMID 23482777
  • 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. PMID 16445633
  • 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. PMID 20227055
  • 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. PMID 23583416
  • 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. PMID 22580657
  • 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. PMID 22924433
  • 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. PMID 23713890
  • Tanigawa N, Yamaue H, Ohyama S, et. al. Exploratory phase II trial in a multicenter setting to evaluate the clinical value of a chemosensitivity test in patients with gastric cancer (JACCRO-GC 04, Kubota Memorial Trial), Gastric Cancer 2016 Apr 19(2):350-60. PMID 26385385

 

Policy History:

  • June, 2017 - Annual review, Policy revised
  • June 2016 - Annual review, Policy renewed
  • July 2015 - Annual review, Policy revised
  • August 2014 - Annual review, Policy revised
  • September 2013 - New policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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