|Subject:||In Vitro Chemosensitivity Assays and In Vitro Chemoresistance Assays|
|Policy #:||LAB.00003||Current Effective Date:||06/28/2016|
|Status:||Reviewed||Last Review Date:||05/05/2016|
This document addresses in vitro chemosensitivity assays and in vitro chemoresistance assays. In vitro chemosensitivity assays and in vitro chemoresistance assays have been investigated as a means of predicting the in vivo tumor response to various chemotherapies. A variety of assays have been developed that differ in their processing and in the technique used to measure drug sensitivity. However, typically they involve the same four basic steps:
Results may be reported as drug sensitive, drug resistant or intermediate. Drugs identified as drug sensitive are thought to be a potentially effective in vivo chemotherapy. Therefore, clinical use of a chemosensitivity assay involves the positive selection of a type of chemotherapy. This contrasts with chemoresistance assays, which involve the deselection of potentially ineffective drugs.
Not Medically Necessary:
In vitro chemosensitivity assays, as a guide to selection of chemotherapeutic drugs for individuals with cancer, are considered not medically necessary in all cases.
In vitro chemoresistance assays including, but not limited to, extreme drug resistance assays are considered not medically necessary in all cases.
Evidence from available studies is insufficient to conclude that in vitro chemosensitivity testing leads to improved health management or outcomes. The majority of studies reported no survival benefit associated with chemotherapy based on chemosensitivity assays when compared to chemotherapy based on standard regimens or clinical indicators.
Few clinical studies have investigated the value of chemoresistance assays for the selection of chemotherapy. The literature contains only a limited number of randomized controlled trials evaluating the survival rate of individuals treated with assay-directed regimens compared with that of a control group treated with standard regimens.
Cree (2007), in a European multi-center prospective randomized controlled trial, studied tumor chemosensitivity assay directed chemotherapy versus physician's choice in recurrent platinum-resistant ovarian cancer. The primary aim of this trial was to determine response rate and progression-free survival following chemotherapy in individuals with platinum resistant recurrent ovarian cancer who had received treatment according to an adenosine triphosphate (ATP) based tumor chemosensitivity assay in comparison with physician's choice. A total of 180 subjects were randomized into two groups with median ages of 59 and 61 years. Ninety-four individuals received assay-directed chemotherapy and 86 received physician's choice therapy. The two primary end points studied were response rate and progression-free survival. Response could only be assessed in 147 subjects, and 40.5% achieved a partial or complete response in the assay-directed group versus a 31.5% response in the physician's choice group (P<0.3, not significant). In an intention-to-treat analysis, response rates were 31% in the assay-directed group vs. 26% in the physician choice group. Intention-to-treat analysis showed a median progression-free survival of 93 days in the physician's choice group and 104 days in the assay-directed group (HR 0.8, not significant). No difference was seen in overall survival between the two groups. The authors concluded the ATP based tumor chemosensitivity assay remains an investigational method in this condition.
Herzog and colleagues (2010) evaluated in vitro tumor responses to platinum therapy by performing chemosensitivity testing on tumors from 192 women with primary ovarian cancer. Tumors were categorized as responsive, intermediately responsive, and nonresponsive to chemotherapy. Median overall survival was 72.5 months for women with tumors classified as responsive, 48.6 months for intermediately responsive, and 28.2 months for nonresponsive (P=0.03; hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.50-0.97). The authors concluded that the prediction of response to platinum agents by the chemosensitivity testing was consistent with expected population response rates. Limitations of this series included restriction of the survival analysis to only platinum agents in the primary setting, lack of information on subsequent chemotherapy, death was used as the primary endpoint of the study, and no assessments of clinical tumor response or disease status at death were available.
Kim and colleagues (2010), in a prospective clinical trial, attempted to determine the most accurate analytic method to define in vitro chemosensitivity and to assess the accuracy of ATP-based chemotherapy response assay (ATP-CRA). Forty-eight individuals with chemo-naïve, histologically confirmed, locally advanced or metastatic gastric cancer were enrolled in this study and treated with combination chemotherapy of paclitaxel 175 mg/m2 and cisplatin 75 mg/m2 for a maximum of six cycles after obtaining specimen for ATP-CRA. Investigators performed the receiver operator characteristic curve analysis using individual responses by WHO criteria and obtained ATP-CRA results to define the method with the highest accuracy. Median progression-free survival was 4.2 months (95% CI: 3.4-5.0) and median overall survival was 11.8 months (95% CI: 9.7-13.8) for all those enrolled. The chemosensitivity index method demonstrated highest accuracy of 77.8% by ROC curve analysis, and the specificity, sensitivity, positive and negative predictive values were 95.7%, 46.2%, 85.7%, and 75.9%. The in vitro chemosensitive group showed higher response rate (85.7% vs. 24.1%) (P=0.005) compared to the chemoresistant group. The authors concluded that ATP-CRA could predict clinical response to paclitaxel and cisplatin chemotherapy with high accuracy in individuals with advanced gastric cancer and results support the use of ATP-CRA in further validation studies and assay-guided clinical trials. However, there were numerous study limitations noted including: the study took almost 3 years to enroll 36 subjects acceptable for evaluation; many samples were not enrolled due to bacterial contamination and an inadequate amount of tissue; the study was terminated early due to a very poor accrual of subjects, which resulted in an inadequate power to test the accuracy as originally planned; study results needed validation by an independent cohort; the study may have been subject to bias because the clinical response was evaluated in participating centers by investigators who were blind to the in vitro chemosensitivity results but there was no independent review of response evaluation.
Multiple non randomized studies have been published involving a microculture kinetic (MiCK) assay and leukemia or lymphoma (Kravtsov, 1994; Kravtsov, 1996; Kravtsov, 1998; Kravtsov, 1999; Liminga, 2000; Strickland, 2013). The MiCK assay has been purported to indicate which type of chemotherapy may be most effective against the tumor cells of a particular individual; however, current published evidence is insufficient to demonstrate its clinical utility.
In 2010, Ballard and colleagues studied the MiCK assay in endometrial cancer specimens. Endometrial cancer specimens from total abdominal hysterectomies were processed at a central laboratory. Single and combination regimens were tested: combinations of doxorubicin, cisplatin, and paclitaxel and carboplatin and paclitaxel (Gynecologic Oncology Group [GOG] 209 endometrial cancer phase III trial arms) as well as single agent testing with paclitaxel, carboplatin, doxorubicin, cisplatin, ifosfamide, and vincristine (active agents in GOG trials). Apoptosis was measured continuously over 48 hours. Fifteen of 19 individuals were reported to have had successful assays. The highest mean chemo sensitivity was noted in the combination of cisplatin, doxorubicin, and paclitaxel with lower mean chemosensitivity for carboplatin and paclitaxel. Combination chemotherapy had higher chemosensitivity than single drug chemotherapy. However, in 25% of subjects a single drug had higher chemosensitivity than combination chemotherapy. As single agents, ifosfamide, cisplatin, and paclitaxel had the highest kinetic unit values. The authors concluded that MiCK may be useful in future new drug testing and individualizing the chemotherapy management of endometrial cancer. Limitations of this study included a small sample size.
Salom and colleagues (2012) performed a prospective, non-randomized multi-institutional trial to determine if the MiCK assay could predict the best therapy for ovarian cancer. Specimens were submitted from 210 subjects between May, 2006 and September, 2010. A total of 60 specimens could not be used due to an insufficient number of viable cancer cells (40% of the 60), spontaneous necrosis in transit (17%), or transit delays. The remaining 150 subjects had tumors analyzed for patterns of in vitro assay of drug effects on ovarian cancer cells. The assay was performed prior to initiation of chemotherapy; however, results were not provided to the treating physicians and treatment was selected based on clinical criteria. Individual outcomes were compared to the drug-induced apoptosis observed in the assay. Overall survival in primary therapy, chemotherapy naïve patients with Stage III or IV disease was longer if an individual received a chemotherapy which was best in the MiCK assay, compared to shorter survival in those who received a chemotherapy that was not the best. Standard therapy with carboplatin plus paclitaxel (C + P) was not the best chemotherapy in the MiCK assay in 44% of subjects studied. If an individual received C + P and it was the best chemotherapy in the MiCK assay, their survival was longer than those receiving C + P when it was not the best chemotherapy in the assay. Relapse-free interval for those receiving primary therapy was longer if the best chemotherapy from the MiCK assay was received. Response rates (CR + PR) were higher if physicians used an active chemotherapy based on the MiCK assay. The authors stated that this study justifies a randomized trial, and quantifies the benefits in outcomes on which a randomized study can be developed (for power determinations and study size requirements). Limitations of this study included lack of randomization.
Rutherford and colleagues (2013) reported results of a prospective, noninterventional, multicenter cohort study designed to assess whether the ChemoFX® assay was predictive of outcomes among women with histologically confirmed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Physicians were blinded to the assay results and treatment was selected based on the oncologist's medical judgment from 1 of 15 prospectively specified protocols. A total of 262 (78.2% of total) had both available clinical follow-up data and a ChemoFX result. Cancer cells were classified based on the ChemoFX result as sensitive, intermediate, or resistant to each of several chemotherapeutic agents. Those treated with an assay-sensitive regimen had a PFS median of 8.8 months, compared with 5.9 months for those with assay-intermediate or -resistant regimens (HR=0.67, p=0.009). Mean overall survival was 37.5 months for women treated with an assay-sensitive regimen, compared with 23.9 months for those with assay-intermediate or -resistant regimens (HR=0.67, p=0.010). Although study results may show potential promise, the selection of a chemotherapeutic agent was not based on assay results but on physician judgment and the impact on health outcomes cannot be determined.
In an observational multicenter study, Krivak and colleagues (2014) examined whether a chemoresponse assay could identify platinum-resistance prior to treatment. A total of 276 women with International Federation of Gynecology and Obstetrics stage III-IV ovarian, fallopian, and peritoneal cancer were enrolled. Tumor responsiveness was evaluated using a chemoresponse assay and treatment consisted of a platinum/taxane regimen following surgical cytoreduction. The majority of women had 4-8 cycles of chemotherapy. The primary endpoint of the study was progression-free survival (PFS). The median follow-up period was 23 months and 193 (70%) had disease progression during this time. Assay results for carboplatin were available for 231 women, with 44 (19.1%) reported as resistant to this therapy in the chemoresponse assay. Assay results for paclitaxel were available for 226 women, with 49 (21.7%) classified as resistant. The median PFS was 16.6 months and 11.8 months for assay nonresistant and resistant tumors, respectively.
The American Society of Clinical Oncology (ASCO) (2011) does not recommend the use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individuals outside of the clinical trial setting. ASCO cited an insufficient evidence base to support the use in oncology practice. ASCO indicates that a review of the literature did not identify any chemotherapy sensitivity and resistance assays for which the evidence was sufficient to support the use in oncology practice.
The National Comprehensive Cancer Network® (NCCN) clinical practice guidelines include recommendations for ovarian cancer including fallopian tube cancer and primary peritoneal cancer (V2.2015). These guidelines indicate that current level of evidence for chemosensitivity/resistance assays is not sufficient to supplant standard of care chemotherapy (category 3). A category 3 recommendation is based on any level of evidence but reflects major disagreement.
At the present time, the clinical utility of in vitro chemosensitivity and chemoresistance assays are unproven. A survival outcome benefit in randomized controlled clinical trials has not been demonstrated.
Chemotherapy sensitivity and resistance assays may also be called human tumor stem cell drug sensitivity assays, nonclonogenic or clonogenic cytotoxic drug resistance assays, tumor stem cell assays, or differential staining cytotoxic assays. These assays are intended to provide oncologists with information which assists in the selection of chemotherapy drugs, to select potentially more effective chemotherapy regimens and to avoid the toxicity of potentially ineffective chemotherapy drugs for an individual.
In vitro chemosensitivity assays are proposed to screen potential anticancer drugs, predict the effect of these drugs on tumors and determine the most appropriate chemotherapeutic regimen. The process assumes that the drugs most effective for treating a particular cancer can be identified. Therefore, in vitro chemosensitivity assays involve tumor cells obtained from an individual which are cultured and exposed to specific drugs in the laboratory setting. This process is done over a set period to evaluate survival and resistance of tumor cells to selected drugs. The ineffective drugs, where extreme resistance is exhibited, are eliminated. Examples of in vitro chemosensitivity assays include but are not limited to:
In vitro chemoresistance assays are reported to provide similar information as in vitro chemosensitivity assays. In addition, they also are said to deselect those drugs that are of no benefit. One of the most widely used techniques is the Extreme Drug Resistance assay (EDR®). In this assay, cultured cells are exposed to high concentrations of selected chemotherapeutic agents for prolonged periods, far exceeding the exposure anticipated in vivo. Cell lines that survive this exposure are characterized as showing extreme drug resistance. These drugs are then considered potentially ineffective and a physician may be prompted to select another chemotherapeutic agent.
Apoptosis: The innate ability of a cell to undergo programmed death due to detrimental or incompatible derangements in its DNA.
Assay: A test to determine the make-up or potency of a drug.
Cytotoxic drug: Drugs that possess a destructive action on specific cells; often refers to drugs used to fight cancer, such as chemotherapy.
In vitro: Within a glass, petri dish or test tube; in an artificial environment; outside of the body.
In vivo: Within the living body.
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When Services are Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as not medically necessary.
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
ChemoFX, Helomics Corp.
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
ChemoFX, Helomics Corp.
|86849||Unlisted immunology procedure [when specified as in vitro chemosensitivity or in vitro chemoresistance assay, ex vivo analysis of programmed cell death]|
|87999||Unlisted microbiology procedure [when specified as in vitro chemosensitivity or in vitro chemoresistance assay]|
|89240||Unlisted miscellaneous pathology test [when specified as in vitro chemosensitivity or in vitro chemoresistance assay]|
Peer Reviewed Publications:
Government Agency, Medical Society, and other Authoritative Publications:
Chemotherapy Sensitivity and Resistance Assays
Clonogenic Cytotoxic Drug Resistance Assays
Differential Staining Cytotoxic Assays
Extreme Drug Resistance Assay (EDR or EDRA)
Ex-vivoanalysis of programmed cell death (EVA/PCD™) assay
Human Tumor Stem Cell Drug Sensitivity Assays
Microculture Kinetics (MiCK) assay (Correct Chemo™)
Nonclonogenic Clonogenic Cytotoxic Drug Resistance Assays
Tumor Stem Cell Assays
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Reviewed||05/05/2016||Medical Policy & Technology Assessment Committee (MPTAC) review.|
|Reviewed||05/04/2016||Hematology/Oncology Subcommittee review. Rationale, Background, Reference and Index sections updated.|
|01/01/2016||Updated Coding section with 01/01/2016 CPT changes; removed ICD-9 codes.|
|Reviewed||05/06/2015||Hematology/Oncology Subcommittee review. Description, Rationale and Reference sections updated.|
|Reviewed||05/14/2014||Hematology/Oncology Subcommittee review. Rationale, Reference and Index sections updated.|
|Reviewed||05/08/2013||Hematology/Oncology Subcommittee review. Rationale, Reference and Index sections updated.|
|Reviewed||05/09/2012||Hematology/Oncology Subcommittee review. Rationale, Reference, and Index sections updated.|
|Reviewed||05/18/2011||Hematology/Oncology Subcommittee review. Rationale, Background, Definition, and Reference sections updated.|
|Reviewed||05/12/2010||Hematology/Oncology Subcommittee review. Description, rationale, references, and index updated.|
|Reviewed||05/20/2009||Hematology/Oncology Subcommittee review. Title, description, rationale and references updated.|
|Reviewed||05/14/2008||Hematology/Oncology Subcommittee review. Rationale, references and index updated.|
|Reviewed||05/16/2007||Hematology/Oncology Subcommittee review. References and rationale updated.|
|Reviewed||06/08/2006||MPTAC review. Rationale and references updated.|
|Reviewed||06/07/2006||Hematology/Oncology Subcommittee review.|
|11/18/2005||Added reference for Centers for Medicare and Medicaid Services (CMS) – National Coverage Determination (NCD).|
|Revised||07/14/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
|Pre-Merger Organizations||Last Review Date||Document Number|
|04/28/2005||LAB.00003||In Vitro Chemotherapy Sensitivity and In Vitro Resistance Assays|
|WellPoint Health Networks, Inc.||12/02/2004||2.11.04||Human Tumor Cell In Vitro Chemosensitivity Assay|
|12/02/2004||2.11.15||Human Tumor Cell In Vitro Chemoresistance Assay|