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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 (sometimes in soft agar); (2) incubation of the cells with various drugs; (3) assessment of cell survival; and (4) interpretation of the result.
Tumor Chemoresistance Assay, also known as the nonclonogenic cytotoxic drug resistance (NCDRA) and extreme drug resistance (EDR), is intended to identify cancer patients who are not likely to respond to a specific chemotherapeutic agent. The NCDRA is intended to provide information that allows patients to avoid the adverse effects of chemotherapy from which they would not benefit medically. In the absence of assay results, patients would generally receive the first-line chemotherapy of choice for their disease.
The Tumor Chemoresistance assay is performed by first culturing a tumor sample in vitro. Once viable tumor colonies have been established, each culture is exposed to a selected chemotherapeutic agent. After standard period of time the test cultures are analyzed for the number of remaining viable tumor cells. The relative decrease in number of viable cells in the test cultures compared to control cultures is taken as an indicator of tumor cell resistance. If the in vitro tumor-cell sample is resistant to a particular agent, then the agent may not be recommended for treating the patient.
Tumor Chemosensitivity Assay, also known as the human tumor stem cell assay, is an in vitro technique designed to test the sensitivity of antineoplastic agents on cells from tumor specimens obtained from patients. The response of the tumor cell line in the laboratory is used to predict the effectiveness of the agent in the patient. More than one commercial method is available.
The assay is performed by first establishing in vitro colonies of stem cells isolated from a patient's tumor. Once viable tumor colonies have been established, they are exposed to selected single chemotherapeutic agents. After a predetermined period of time the number of colonies and number to colony forming cells in the culture are counted. The relative difference in cell number of colony forming cells in the culture are counted. The relative difference in cell proliferation in the test cultures compared to control cultures is taken as an indicator of tumor sensitivity. If an in vitro tumor-cell sample is sensitive to a particular chemotherapeutic agent, then the agent may be recommended for treating the patient.
A variety of chemosensitivity and chemoresistance 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. With few exceptions, drug doses used in the assays are highly variable depending on tumor type and drug class, but all assays require drug exposures ranging from several-fold below physiologic relevance to several-fold above physiologic relevance. Although a variety of assays exist to examine chemosensitivity or chemoresistance, only a few are commercially available. Available assays are outlined as follows:
Methods using differential staining/dye exclusion:
Methods using incorporation of radioactive precursors by macromolecues in viable cells:
Methods to quantify cell viability by colorimetric assay:
Methods using incorporation of chemoluminescent precursors by macromolecules in viable cells:
Methods using differential optical density:
The rationale for chemosensitivity assays is strongest where there are a variety of therapeutic options and there are no clear selection criteria for any particular regimen in an individual patient.
Commercially available chemosensitivity and chemoresistance assays are laboratory developed tests for which approval from the U.S. Food and Drug Administration (FDA) is not required when the tests are performed in a laboratory licensed by the CLIA for high-complexity testing. Such tests must meet the general regulatory standards of CLIA.
POLICYIn vitro chemosensitivity assays, including, but not limited to, the Histoculture Drug Response Assay, a fluorescent cytoprint assay, the ChemoFx assay, or the CorrectChemo assay, are considered investigational.
In vitro chemoresistance assays, including, but not limited to, Extreme Drug Resistance Assays, are considered investigational.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY8/1998: Approved by Medical Policy Advisory Committee (MPAC)
12/18/2000: "and extreme drug resistance (EDR)" added to third paragraph under "description" section.
2/8/2002: Investigational definition added
5/1/2002: Type of Service and Place of Service deleted
9/2/2004: Code Reference section completed, non-covered table added
8/5/2005: Code Reference section reviewed, no changes
10/17/2006: Policy reviewed, no changes
1/4/2007: Policy reviewed, policy statement rewritten for clarity
2/19/2008: Policy reviewed, no changes
4/24/2009: Policy reviewed, no changes
04/27/2010: Policy title changed from “In Vitro Chemotherapeutic Drug Assays” to “In Vitro Chemoresistance and Chemosensitivity Assays” to reflect the scope of the policy. Policy description extensively re-written to add information on available tests and how they are performed. Policy statement unchanged. Deleted outdated references from the Sources section.
06/21/2011: Policy reviewed; no changes.
04/26/2012: Policy reviewed; no changes.
08/07/2013: Policy reviewed; no changes.
06/09/2014: Policy description updated regarding the following: methods using differential staining/dye exclusion; methods using incorporation of radioactive precursors by macromolecules in viable cells; methods to quantify cell viability by colorimetric assay; methods using incorporation of chemoluminescent precursors by macromolecules in viable cells; and methods using differential optical density. Policy statement unchanged.
07/30/2015: Code Reference section updated for ICD-10.
09/11/2015: Policy description updated regarding commercially available assays. Policy statement for in vitro chemosensitivity assays updated to add the ChemoFx assay and the CorrectChemo assay as investigational. Investigative definition updated in the Policy Guidelines section.
SOURCE(S)Blue Cross Blue Shield Association policy #2.03.01
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.