Medical Policy: 02.04.47
Original Effective Date: August 2014
Reviewed: June 2017
Revised: June 2017
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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.
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.
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:
Examples of commercially available chemosensitivity and chemoresistance assays include, but may not be limited to:
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.
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.
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.
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."
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.
Chemosensitivity and chemoresistance assays, including but not limited to the following are considered investigational for all indications:
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.
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