Coverage Policy Manual
Policy #: 1997146
Category: Laboratory
Initiated: January 1996
Last Review: April 2018
  Chemosensitivity and Chemoresistance Assays, In-Vitro (ChemoFX, Oncotech Extreme Drug Resistance Assay)

Description:
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. Thus, 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.
 
Background
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 physiological relevance to several-fold above physiological 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:
  • The Differential Staining Cytotoxicity assay (Bird, 1987). 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 tumor 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 EVA/PCD™ assay (available from Rational Therapeutics). This assay relies on ex vivo analysis of programmed cell death, as measured by differential staining of cells after apoptotic and nonapoptotic cell death markers in tumor samples exposed to chemotherapeutic agents. Tumor specimens obtained through biopsy or surgical resection are disaggregated using DNAse and collagenase IV to yield tumor clusters of the desired size (50-100 cell spheroids). Because these cells are not proliferated, these microaggregates are believed to more closely approximate the human tumor microenvironment. These cellular aggregates are treated with the dilutions of the chemotherapeutic drugs of interest and incubated for 3 days. After drug exposure is completed, a mixture of Nigrosin B & Fast green dye with glutaraldehyde-fixed avian erythrocytes is added to the cellular suspensions (Nagourney, 2012). The samples are then agitated and cytospin-centrifuged and, after air drying, are counterstained with H&E. The end point of interest for this assay is cell death, as assessed by observing the number of cells differentially stained due to changes in cellular membrane integrity (Nagourney, 2006).
 
Methods using incorporation of radioactive precursors by macromolecules in viable cells:
  • Tritiated thymine incorporation measures uptake of tritiated thymidine by DNA of viable cells. Using proteases and DNAse to disaggregate the tissue, samples are seeded into single-cell suspension cultures on soft agar. They are then treated with the drug(s) of interest for 4 days. After 3 days, tritiated thymidine is added. After 24 hours of additional incubation, cells are lysed, and radioactivity is quantified and compared with a blank control consisting of cells that were treated with sodium azide. Only cells that are viable and proliferating will take up the radioactive thymidine. Therefore, there is an inverse relationship between update of radioactivity and sensitivity of the cells to the agent(s) of interest (Yung, 1989).
  • The Extreme Drug Resistance assay (EDR®)(5) (commercially available at Exiqon Diagnostics, Tustin, CA) is methodologically similar to the thymidine incorporation assay, using metabolic incorporation of tritiated thymidine to measure cell viability; however, single cell suspensions are not required, so the assay is simpler to perform. Small tissue samples are incubated with the drug(s) of interest for 5 days at doses ranging from 5-fold below to 80-fold above concentrations that would reflect physiologic relevance. Subsequently, tritiated thymidine is added to the culture, and uptake is quantified after various incubation times. Only live (resistant) cells will incorporate the compound. Therefore, the level of tritiated thymidine incorporation is directly related to chemoresistance. The interpretation of the results is unique in that resistance to the drugs is evaluated, as opposed to evaluation of responsiveness. Tumors are considered to be highly resistant when thymidine incorporation is at least 1 standard deviation above reference samples.
 
Methods to quantify cell viability by colorimetric assay:
  • The Histoculture Drug Resistance Assay (HDRA; AntiCancer Inc., San Diego, CA) (Anticancer, 2014). This assay evaluates cell growth after chemotherapy treatment based on a colorimetric assay that relies on mitochondrial dehydrogenases in living cells. Drug sensitivity is evaluated by quantification of cell growth in the 3-dimensional 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 type.
 
Methods using incorporation of chemoluminescent precursors by macromolecules in viable cells:
  • The Adenosine Triphosphate (ATP) Bioluminescence assay. This assay relies on measurement of ATP to quantify the number of viable cells in a culture. Single cells or small aggregates are cultured, and then exposed to drugs. Following incubation with drug, the cells are lysed and the cytoplasmic components are solubilized under conditions that will not allow enzymatic metabolism of ATP. Luciferin and firefly luciferase are added to the cell lysis product. This catalyzes the conversion of ATP to adenosine di- and monophosphate, and light is emitted proportionally to metabolic activity. This is quantified with a luminometer. From the measurement of light, the number of cells can be calculated. A decrease in ATP indicates drug sensitivity, whereas no loss of ATP suggests that the tumor is resistant to the agent of interest.
  • ChemoFX® (Precision Therapeutics, Pittsburgh, PA) (Therapeutics, 2014). This assay also relies on quantifying ATP based on chemoluminescence. Cells must be grown in a monolayer rather than in a 3-dimensional matrix.
 
Methods using differential optical density:
  • Microculture Kinetic (MiCK) assay (Diatech Oncology, Franklin, TN) (Oncology, 2014). Similar to the EVA/PCD assay, this assay relies on measures of programmed cell death. In the assay, tumor cells are exposed to multiple concentrations of drugs and cultured. 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 drug-induced apoptosis is a measure of the cell’s sensitivity to that agent.
 
The rationale for chemosensitivity assays is strongest when there are a variety of therapeutic options and there are no clear selection criteria for any particular regimen in an individual patient.
 
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.
 
Coding
Effective 3/2015, CPT published a specific CPT code for this service:
 
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: each additional single drug or drug combination (List separately in addition to code for primary procedure)
 
(81536 can be used in conjunction with 81535)
 
Prior to March 2015
There are no specific CPT codes for these tests. The Extreme Drug Resistance assay is a multistep laboratory procedure that might be identified by the following CPT codes:
 
88358: Morphometric analysis; tumor
 
88305: Level IV surgical pathology, gross and microscopic examination
 
88104: Cytopathology, fluids, washings or brushings; except cervical or vaginal; smears with interpretation
 
87230: Toxin or antitoxin assay, tissue culture
 
88313: Special stains; Group II
 
89050: Cell count, miscellaneous body fluids
 

Policy/
Coverage:
In vitro chemosensitivity assays, including but not limited to the histoculture drug response assay, fluorescent cytoprint assay and extreme drug resistance assays do not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, in vitro chemosensitivity assays, including but not limited to the histoculture drug response assay, fluorescent cytoprint assay and extreme drug resistance assays, are considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
This policy was originally developed in 1996 because of developing interest in use of in vitro chemosensitivity and chemoresistance testing as a way to predict the clinical responsiveness of cancers to specific drugs.
 
Chemoresistance Assays
This policy references a 1995 Blue Cross Blue Shield Association Technology Evaluation Center Assessment of chemoresistance assays that pointed out that the clinical utility of chemoresistance assays will depend on the prior probability of response to a given chemotherapy.  Since chemoresistance assays are used to deselect potential chemotherapies, the negative predictive value is the key statistical measure. In other words, what is the likelihood that chemoresistance as measured in vitro will correspond to a lack of clinical effect? Unless the negative predictive value is high, there is a chance that clinical decision-making based on a chemoresistance assay could inappropriately exclude an effective therapy. The negative predictive value will vary according to the prior probability of chemoresistance. For example, the negative predictive value in testicular cancer, typically a very chemosensitive tumor, will be lower than that associated with malignant melanoma, a very chemoresistant tumor. The Blue Cross Blue Shield Association Technology Evaluation Center Assessment concluded that chemoresistance assays have the highest clinical relevance in tumors with a low probability of response. However, it is still unclear how this information will affect clinical decision-making and whether health outcomes are improved as a result.
 
The extreme drug resistance (EDR) assay was specifically designed to produce a very high negative predictive value (>99%) such that the possibility of inappropriately excluding effective chemotherapy is remote in all clinical situations.  However, there are still inadequate clinical data to determine whether the use of EDR assays to deselect ineffective chemotherapies result in improved health benefits. While the relevant clinical outcome in chemosensitivity assays focuses on improved survival, the relevant outcome associated with chemoresistance assays is more controversial. Advocates of the EDR assay point out that avoidance of the toxicity of ineffective drugs is the relevant outcome, while others point out that this represents an intermediate outcome and that improved patient survival is the relevant outcome for chemoresistance assays.  For example, in clinical practice, deselection of one chemotherapy implies positive selection of another drug that did not show chemoresistance. Therefore, the toxicity and effectiveness of the drugs that are selected as a result of the EDR assay are relevant outcomes. Finally, a related clinical outcome is the extent to which an in vitro assay can improve on the empirical performance of the physician. For example, chemoresistance typically can be predicted without the use of an EDR assay in heavily pretreated patients with refractory tumors
 
The bulk of the literature regarding extreme drug resistance assays have focused on correlation studies that correlate results from predictive in vitro assays with observed outcomes of chemotherapy. However, in these studies, the patients do not receive assay-guided chemotherapy regimens. As discussed in a 2000 Blue Cross Blue Shield Association Technology Evaluation Center Assessment, correlational studies are inadequate for several reasons. First, such studies often aggregate patients with different tumor types, disease characteristics, chemotherapy options, and probabilities of response. This process is problematic since the accuracy of each assay used to predict in vivo response probably varies across different malignancies and patient characteristics. Second, the method by which assay results are translated into treatment decisions is not standardized. Without knowing the rules for converting assay findings into treatment choices, it is impossible to determine the effects of assay-guided treatment on health outcomes. Third, it is important to consider not only response, but also survival and adverse effects. The overall value of assay-guided therapy depends on the net balance of all health outcomes observed after treatment for all patients subjected to testing, regardless of the assay results or the accuracy of its predication for response. Examples of published correlation studies of the extreme drug resistance assay include those by Eltabbakh and Mehta.  A literature search did not find any prospective studies focusing on the use of the EDR.
 
Chemosensitivity Assays
The enthusiasm for chemosensitivity assays, in general, has diminished over the years, due to the poor positive predictive values. In other words, what is the likelihood that drugs shown to be effective in vitro will produce a positive clinical response? A meta-analysis of 54 different retrospective studies by Von Hoff reported a positive predictive value of only 69%.  The poor positive predictive value may in part be related to a variety of host factors, such as tumor vascularity. Several prospective trials have also reported technical challenges and inconclusive results, which further dampened enthusiasm.  Interpretation of other trials is flawed by methodologic issues. For example, using a chemosensitivity assay, Xu and colleagues compared outcomes for an assay-guided treatment group with outcomes for a group given contemporaneous empiric therapy.  The patient sample consisted of 156 patients with advanced breast cancer. The article stated that choice of regimen in the assay-guided group was based on assay results, but no specific decision rules were reported. Patients whose EDR results suggested resistant disease were given empiric regimens and were excluded from the analysis of outcome results. This violated principles of intention-to-treat analysis. An intention-to-treat analysis is required to assess chemotherapy sensitivity and resistance assays since resources are consumed for all tested patients. Furthermore, it permits investigators to calculate the number of patients needed to test to identify one patient whose outcomes could be improved by use of assay-guided rather than empiric therapy.
 
Kurbacher and colleagues studied 55 patients with ovarian cancer, whose tumors were evaluated with a chemosensitivity assay.  This report stated that patients treated with assay guidance received the optimal protocol indicated by assay. However the report did not include specific rules for translating assay results into treatment decisions. Patients in the empiric group were contemporaneous to the assay-guided group. However, some patients subjected to testing were added to the control group when assay results proved unevaluable or when clinicians preferred a different regimen than identified by assay results. This method of defining groups violated the intention-to-treat principle, and potentially biases outcomes estimated for assay-guided management.
 
A 2000 Blue Cross Blue Shield Association Technology Evaluation Center Assessment was used as a reference in this policy.  The assessment reviewed both chemosensitivity and chemoresistance assays and provides a detailed discussion on what type of data would be required to evaluate the clinical use of chemoresistance or chemosensitivity assays and considered the following methods:
 
Correlation studies based on in vitro prediction of in vivo response
A variety of studies have reported a correlation between in vitro prediction or response and clinical response. While these studies may have internal validity, they cannot answer the question of whether patients given assay-guided therapy or empiric therapy have different outcomes. For example, suppose that one group of patients is treated based on assay results and demonstrates an overall response rate of 75%. It is possible that a similar group of patients, matched for important prognostic factors and given a uniform empiric chemotherapy regimen, could achieve the same overall response rate. However, even if response rates are the same for the 2 groups, the assay guided group may experience more adverse effects from treatment or may have lower overall survival. To determine whether assay-guided treatment results in overall different outcomes than empiric treatment, it is important to take into account response rates, survival, and adverse effects. These effects may be assessed by decision analysis or comparative trials.
 
Decision analysis
While decision analysis is a useful tool, it may be limited when the decision tree is so complex that it is not possible to obtain evidence-based estimates for many of the probabilities in the tree. For this reason, the Blue Cross Blue Shield Association Technology Evaluation Center Assessment concluded that decision analysis would not be a useful tool for assessing the relative effectiveness of assay-guided and empiric treatment.
 
Assessment based on direct evidence
Given the limitations in the above 2 techniques, the Blue Cross Blue Shield Association Technology Evaluation Center Assessment focused on direct evidence that compared outcomes for patients treated either by assay-guided therapy or contemporaneous empiric therapy. A total of 7 studies were identified, none of which provided strong evidence to validate the clinical role of chemosensitivity or chemoresistance assays.
 
2002–2005 Update
Updates have been based on a 2002 TEC Assessment and searches of the literature for the period of 2002 through June 2005. No studies were identified that would address the limitations noted in the discussion. Specifically, no studies were identified that provided direct evidence comparing outcomes for patients treated either by assay-guided therapy or contemporaneous empiric therapy. Therefore, the policy statement is unchanged. In 2004, the American Society of Clinical Oncology (ASCO) published a technology assessment of chemotherapy sensitivity and resistance assays (CSRA) (Schrag, 2004), along with a systematic review of the literature. (Samson, 2004) The assessment concluded that “review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice.”
Parker and colleagues studied the use of an extreme drug resistance assay in 18 patients with recurrent malignant glioma who were scheduled to receive irinotecan chemotherapy. (Parker, 2004) Of the 15 with evaluable assay results, 4 were classified as extreme drug resistant. The median time to progression was 6 weeks compared to 3 months for those with indeterminate or low drug resistance. However, similar to other studies, results of drug resistance were not used to direct therapy and there was no control group, both limiting interpretation of this small case series.
 
2006 Update
A literature review was conducted for the period of June 2005 through July 2006. Results of this review did not result in any change in the policy statements. Iwahashi and colleagues reported on outcomes of chemosensitivity-guided chemotherapy (CSC) compared to standard chemotherapy and no chemotherapy in patients with advanced gastric cancer. (Iwahashi, 2005) In some subsets, survival was improved in the CSC subgroup. However, given the small sample, additional studies are needed to confirm these findings and to extend them to other malignancies. During this update, no changes were found in the ASCO technology assessment.
 
2007–2008 Update
A literature review was conducted in January 2008 using MEDLINE. One prospective, randomized study from Europe was identified for chemosensitivity. (Cree, 2007) Cree and colleagues reported on a prospective randomized trial of chemosensitivity assay-directed chemotherapy versus physician’s choice in patients with recurrent platinum-resistant ovarian cancer. The primary aim of this randomized trial was to determine response rate and progression-free survival following chemotherapy in patients who had been treated according to an ATP-based tumor chemosensitivity assay in comparison with physician's choice. A total of 180 patients were randomized to assay-directed therapy (n=94) or physician's-choice chemotherapy (n=86). Median follow-up at analysis was 18 months; response was assessable in 147 (82%) patients: 31.5% achieved a partial or complete response in the physician's-choice group compared with 40.5% in the assay-directed group (26% vs. 31% by intention-to-treat analysis, respectively). 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 (hazard ratio 0.8, not significant). No difference was seen in overall survival between the groups, although 12/39 (41%) of patients who crossed over from the physician's-choice arm obtained a response. Increased use of combination therapy was seen in the physician's-choice arm during the study as a result of the observed effects of assay-directed therapy in patients. The authors concluded that this small randomized, clinical trial documented a trend toward improved response and progression-free survival for assay-directed treatment and that chemosensitivity testing might provide useful information in some patients with ovarian cancer. They also noted that the ATP-based tumor chemosensitivity assay remains an investigational method in this condition. In another European study, Ugurel and colleagues reported on a Phase II study of 53 patients with metastatic melanoma. (Ugurel, 2006) This study found a 36% response rate in chemosensitive patients compared with 16% in chemoresistant patients. Based on these preliminary results, a Phase III study is to follow. For this update, no changes were found in the ASCO technology assessment noted previously. While these studies begin to provide needed information about the impact of these assays on clinical outcomes, the data are still limited and the policy statements are unchanged.
 
2009 Update
Studies continue to accrue demonstrating a relationship between clinical response and in vitro sensitivity.  One study in 43 patients used an ATPpbased chemotherapy response assay and found that mean cell death rate was lowere in non-responders than in responders to therapy (Kim, 2008)  However, this was an observational study only, and drugs were not chosen based upon test results.  The policy statement remains unchanged.
 
A manufacturer of this test met with ABCBS in 2009 to discuss coverage.  No information was provided that resulted in a change in policy.
 
2012 Update
This policy is being updated with a literature search conducted using the MEDLINE database through March 2012.  There was no new literature identified that would prompt a change in the coverage statement. The following is a summary of the identified relevant published literature.
 
Chemoresistance Assays
 
Prospective
A study by Tiersten et al. was designed to use the Oncotech EDR assay to examine whether chemotherapy resistance was an independent predictor of progression free survival (PFS) in patients with ovarian cancer treated with neoadjuvant chemotherapy and surgical cytoreduction followed by intraperitoneal chemotherapy (Tiersten, 2009). Fifty-eight eligible women were prospectively enrolled in this study; however, results from the EDR assay were not used to direct therapy. Evaluable EDR assay results were available for 22 of the 58 patients. No difference in PFS was reported. Follow-up has not been sufficient to measure OS. These data do not provide support for use of the EDR assay in predicting outcome and guiding patient management.
 
Retrospective
In 2010, Matsuo et al. published a study examining the relevance of EDR in epithelial ovarian carcinomas (Matsuo, 2010). Two-hundred fifty-three records from the Oncotech database were identified for women with advanced stage ovarian cancer and from whom samples were collected at the time of the primary surgery. Tissue samples were cultured and tested for response to primary drugs (4 platinum- or taxane-based) and secondary drugs (e.g., gemcitabine, topotecan, doxorubicin, etoposide, 5-fluorouracil (5-FU). Paclitaxel showed the highest resistance rate. Other agents had a resistance rate of less than 20%. There was only one (0.4%) tumor that showed complete resistance to all drugs tested; and 25% of tumors showed no resistance to any of the drugs. There was no statistical correlation between assay results and response to initial chemotherapy. The investigator acknowledges that the study, due to its retrospective and noncomparative design is not sufficiently strong to validate use of this assay in managing therapy. Potential confounding factors, as described by the investigator, may have included tumor heterogeneity and the variations in resistance between primary tumor and metastases.
 
Another study by the same group (Matsuo, 2009) evaluated the role of the EDR assay to platinum- and taxane-based therapies for management of advanced epithelial ovarian, fallopian, and peritoneal cancers. From the Oncotech database, 173 cases were identified. For all cases, tissue was collected at the time of cytoreductive therapy. The EDR assay was performed on all samples, and tumors were classified as having low drug resistance (LDR), intermediate drug resistance (IDR), or extreme drug resistance (EDR). The 58 patients (33.5%) whose tumors had LDR to both platinum and taxane showed statistically improved PFS and OS compared to the 115 patients (66.5%) who demonstrated IDR or EDR to platinum and/or taxane (5-year OS rates, 41.1% vs. 30.9%, respectively; p=0.014). The 5-year OS rates for the 28 (16.2%) cases that had optimal cytoreduction with LDR to both platinum and taxane was significantly improved over the 62 (35.8%) cases that were suboptimally cytoreduced with IDR or EDR to platinum and/or taxane (54.1% vs. 20.4%, respectively; p<0.001). Although the EDR assay was predictive for survival, it is of interest that assay results did not indicate response to therapy with either taxane or cisplatin. The investigators conclude that the EDR assay may be an independent predictor of PFS and OS; however, a prospective, randomized trial would be required to further assess its clinical utility in predicting response to taxane or platinum therapies.
 
A smaller study by Matsuo et al. testing the EDR assay for prediction of uterine carcinosarcoma response to taxane and platinum was also conducted (Matsuo, 2010). Of 51 cases, 31 (60.8%) received postoperative chemotherapy with at least a single agent; and 17 (33.3%) received combination chemotherapy with platinum and taxane modalities. Overall response rate for the 17 combination chemotherapy cases was 70.6%. Presence of EDR to either platinum or taxane showed a significantly lower PFS (1-year PFS rate, 28.6% vs. 100%, respectively; p=0.01) and lower OS (5-year OS rate, 26.9% vs. 57.1%, respectively; p=0.033). These data indicate that use of an in vitro drug resistance assay may be predictive of response to chemotherapy response and survival outcome in advanced ovarian and uterine carcinosarcoma. However, larger, prospective, randomized clinical trials (RCTs) would be required to validate use of this assay for directing chemotherapy regimens.
 
Matsuo and colleagues also completed a study examining the rates of EDR after cytoreductive therapy and neoadjuvant chemotherapy versus the rates of ERD after postoperative chemotherapy (Matsuo, 2010). The goal of this study was not to test whether the EDR assay could direct therapeutic regimens. The findings suggested that platinum resistance was most common after neoadjuvant chemotherapy, while paclitaxel resistance was more prevalent after postoperative chemotherapy.
 
Karam and colleagues conducted a retrospective review of 377 patients with epithelial ovarian cancer to examine the effect of EDR assay-guided therapy on outcomes in the primary and recurrent setting (Karam, 2009). The primary endpoints were time to progression (TTP), OS, and survival after recurrence (RS). The patient population was heterogeneous, with a median age of 59 years (median 24-89), tumor completely resected in 30% of patients, and varying tumor stages (Federation of Gynecologists and Obstetricians [FIGO] stages I, II, III, and IV in 7%, 4%, 78%, and 11%, respectively). Sixty-four percent of patients underwent a secondary cytoreductive surgery. Patients had an EDR assay sent either at the time of their primary cytoreductive surgery (n=217) or at the time of disease recurrence (n=160). Predictors of survival included increasing age and greater volume of residual disease after cytoreductive surgery. EDR assay results analyzed for single agents or combinations of chemotherapies failed to independently predict patient outcomes regardless of whether the assay was performed at the time of the primary surgery or at recurrence.
 
In summary, studies do not support use of the EDR assay for directing therapy or for prediction of outcome. Weaknesses in the studies have included retrospective design, noncomparative design, and small sample size. Furthermore, tissue samples are often not sufficient to achieve evaluable results. Large, randomized, prospective clinical studies would be required to justify use of the EDR assay in these patient populations. The studies would have to compare outcomes between assay-directed therapy versus physician-directed therapy. Initial response to assay-directed therapy and TTP would be interesting endpoints; however, evaluation of overall and disease-specific survival, quality of life, and adverse events would be critical to validate the clinical utility of this assay.
 
Chemosensitivity Assays
 
Comparative studies testing outcome with assay-directed therapy versus physician-chosen therapy
 
In a case-control study, Moon and colleagues retrospectively compared adenosine triphosphate (ATP) assay-based guided chemotherapy with empirical chemotherapy in unresectable non-small-cell lung cancer (Moon, 2009). All of the patients who received ATP-assay-guided platinum-based doublet chemotherapy as first-line therapy received platinum-based chemotherapy combined with a nonplatinum drug, regardless of their in vitro platinum sensitivity; 14 patients had platinum-sensitive disease and 13 were platinum-resistant. Ninety-three matched controls (matched for performance status, stage, and chemotherapy regimen) were selected from a retrospective review of a database. In the empirical group, a nonplatinum drug was chosen, depending on physicians’ discretion, along with a platinum agent determined by renal function and performance status. The primary endpoint was clinical response rate, assessed every 2 cycles of chemotherapy by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The secondary endpoints were PFS and OS. The response rate and survival in both groups were not statistically different. The platinum-sensitive subgroup by ATP assay showed a higher response rate than the empirical group (71% vs. 38%, respectively; p=0.02), but there was no statistical significance between PFS or OS.
 
Correlational studies
 
Prospective
Kim et al. reported the results of a prospective, multicenter clinical trial designed to define the accuracy of the ATP-based chemotherapy response assay in gastric cancer patients receiving paclitaxel and cisplatin chemotherapy, by comparing clinical response and the ATP-assay results (Kim, 2010). The primary endpoint of the study was to assess accuracy of the ATP-assay results, and the secondary endpoint was to find the best method of defining in vitro chemosensitivity. Forty-eight patients with chemotherapy-naïve locally advanced or metastatic gastric cancer were treated with combination chemotherapy after a tissue specimen was obtained for the ATP assay. Tumor response was assessed by World Health Organization (WHO) criteria using a computed tomography (CT) scan after every 2 cycles of chemotherapy. Both laboratory technicians and physicians were blinded to the assay or clinical results. Thirty-six patients were evaluable for both in vitro and in vivo responses. Using a chemosensitivity index method, the specificity of the ATP assay was 95.7% (95% confidence interval [CI]: 77.2-99.9%), sensitivity 46.2% (95% CI: 19.2-74.9%), PPV 85.7% (95% CI: 42.1-99.6%) and NPV was 75.9% (95% CI: 55.1-89.3%). Median PFS was 4.2 months (95% CI: 3.4-5.0) and median OS was 11.8 months (95% CI: 9.7-13.8). The in vitro chemosensitive group showed a higher response rate (85.7% vs. 24.1%, respectively; p=0.005) compared to the chemoresistant group. The authors concluded that the ATP assay could predict clinical response to paclitaxel and cisplatin chemotherapy with high accuracy in advanced gastric cancer and that the study supported the use of the ATP assay in further validation studies.
 
Retrospective
Gallion et al. conducted a retrospective study that evaluated the association of ChemoFX® test results with the treatment response of 256 patients with ovarian or peritoneal cancer who had been treated with at least one cycle of postsurgical chemotherapy (Gallion, 2006). A subset of 135 patients had an exact match between drugs assayed and received; the rest had only a partial match. Predictive values were not reported nor were they calculable. For the subset of 135, in a multivariable analysis, ChemoFX® was an independent significant predictor (p=0.006) of PFS along with 2 other clinical variables. Hazard ratio (HR) for resistant versus sensitive was 2.9 (95% CI: 1.4–6.30) and was 1.7 (95% CI: 1.2–2.5) for resistant versus intermediate. The median progression-free interval was 9 months for the resistant group, 14 months for the intermediate group, and had not been achieved for the sensitive group.
 
Herzog et al. included 147 patients from the above study by Gallion et al. (Gallion, 2006) and reported on a total of 192 women with advanced-stage primary ovarian cancer, 175 of whom had tumors that were tested for in vitro chemosensitivity to platinum therapy using ChemoFX (Herzog, 2010). Tumors were classified as responsive, intermediately responsive, or nonresponsive to chemotherapy. Seventy-eight percent were categorized as responsive or intermediately responsive, and 22% were nonresponsive. Median OS was 72.5 months for patients with tumors categorized as responsive, 48.6 months for intermediately responsive, and 28.2 months for nonresponsive (p=0.03; HR 0.70; 95% CI: 0.50-0.97). The authors concluded that the result of chemosensitivity testing with a drug response marker for therapy was predictive of OS in patients with primary ovarian cancer.
 
ChemoFX® assay is commercially available for breast and ovarian cancer treatment. The ChemoFX® website lists ongoing clinical trials of ChemoFX® for both breast cancer and ovarian cancer. However, none of the ongoing studies would satisfy the criteria to assess validity and clinical utility with a prospective comparative design (available online at: http://www.chemofx.com/cancer-treatment/drug-trials.html).
 
Practice Guidelines and Position Statements
 
National Comprehensive Cancer Network (NCCN) Guidelines
2012 NCCN guidelines for the treatment of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer (v 2.2012) state that chemotherapy/resistance assays are used in some NCCN centers to help select chemotherapy when multiple equivalent chemotherapy options are available; the current level of evidence (category 3) is not sufficient to supplant standard-of-care chemotherapy. The panel believes that in vitro chemosensitivity testing to help choose a che­motherapy regimen for recurrent disease situations should not be recommended because of the lack of demonstrable efficacy for this approach.
 
Summary
Through March 2012, there have been no studies published with a randomized, prospective, design to evaluate this testing. Therefore to date, 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. Most studies have been relatively small correlational designs that evaluated the association between assay results and already known patient outcomes; and most acknowledge that larger studies are needed. Furthermore, unexpected limitations have arisen including sampling bias due to heterogeneity of tumors and insufficient biospecimen processing resulting in unevaluable data.
 
2013 Update
A literature search was conducted using the MEDLINE database through the period of July 2013. There was no new literature identified that would prompt a change in the coverage statement.
 
2014 Update
A literature search was conducted through July 2014. There was no literature identified that would prompt a change in the coverage statement. Below is a summary of the key identified literature.
 
Rutherford et al reported results from a prospective, noninterventional, multicenter cohort study that was 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 (Rutherford, 2013). Three hundred thirty-five patients were enrolled and treated with 1 of 15 study protocols, with treating physicians blinded to the ChemoFX assay result. Two hundred sixty-two patients (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. Patients treated with an assay-sensitive regimen had a PFS of median 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 patients 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). Strengths of this study include its prospective design with physicians blinded to the assay results, which reduces the risk of bias in patient selection or measurement of outcomes. However, because the selection of chemotherapeutic agent was, by design, not influenced by the ChemoFX assay, the impact on health outcomes cannot be determined.
 
In a similar study design, Salom et al conducted a prospective, noninterventional, multicenter cohort study to assess whether the Microculture Kinetic (MiCK) assay was predictive of outcomes among women with epithelial ovarian cancer (Salom, 2012).  Data from 150 women with any stage of cancer with specimens suitable for MiCK assay were included. Chemosensitivity was expressed as kinetic units following each dose of drug in the MiCK assay and reported as mean, minimum, and maximum. For each patient, the “best” chemotherapy was defined as any single drug or combination of drugs in the patient’s MiCK assay that had the highest kinetic units. Patients’ regimens were at the discretion of their treating physicians, who were blinded to the MiCK assay results. OS stage III or IV disease was longer if patients received a chemotherapy that was considered “best” by the MiCK assay, compared with shorter survival in patients who received a chemotherapy that was not the best. (HR=0.23, p<0.01).
 
Jung et al conducted a single-center prospective study to determine whether sensitivity to paclitaxel and carboplatin, determined by using the Histoculture Drug Resistance Assay (HDRA), was predictive of outcomes among women with advanced epithelial ovarian cancer (Jung, 2013). The study included 104 patients with epithelial ovarian cancer, all of whom had undergone initial surgery and were treated with paclitaxel and carboplatin therapy. Tumor cells’ sensitivity to the chemotherapy agents was classified as sensitive, intermediate, or resistant to paclitaxel, carboplatin, or both, based on the HDRA. Patients whose tumors were sensitive to both drugs had a lower recurrence rate than those who had resistance to both drugs (29.2% vs 69.8%, p=0.02) and had a longer PFS (35 months vs 16 months, p=0.025).
 
While these studies establish that the results of chemosensitivity assays are correlated with outcome, they do not evaluate how the test may alter clinical decision making and whether changes in management based on the test improve outcomes.
 
Two retrospective studies were identified. In a small retrospective study, Grigsby et al conducted a retrospective analysis to assess the association of pretreatment chemosensitivity to cisplatin with clinical outcomes among 33 women with cervical cancer Grigsby, 2013). Tumor cell sensitivity to cisplatin was categorized as responsive, intermediately responsive, or nonresponsive with the ChemoFX assay. Patients with responsive or intermediately responsive tumors had a 2-year recurrence free survival of 87%, compared with 58% for those with nonresponsive tumors (p=0.036).
 
Strickland et al conducted a retrospective evaluation of the association between chemosensitivity to anthracyclines, measured by the drug-induced apoptosis MiCK assay, among 109 patients with adult-onset acute myelogenous leukemia (Strickland, 2013).  Patients were treated with a “7 plus 3” chemotherapy regimen. Chemosensitivity was expressed as maximal kinetic units following each dose of drug in the MiCK assay. Receiver-operator characteristic curve analysis and logistic regression were used to determine the optimal cutoff for chemosensitivity response to discriminate between chemoresponder and nonresponder. Patients determined to be chemoresponders to idarubicin were more likely to have complete response to chemotherapy (72%) than those who were nonresponders (p=0.01). Data for the patient cohort were collected over a 14 year period from 1996-2010, which may limit the generalizability of the results to currently-used chemotherapy regimens. In addition, the MiCK assay is limited by lack of standardized cutoffs to discriminate responders from nonresponders.
 
2016 Update
A literature search conducted through March 2016 did not reveal any new information that would prompt a change in the coverage statement.    
 
2017 Update
A literature search conducted through February 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Tanigawa and colleagues published a retrospective study evaluating the association between in vitro chemosensitivity results and relapse-free survival (RFS) in 206 gastric cancer patients (Tanigawa, 2016). The collagen gel droplet embedded culture drug sensitivity test (CD-DST), which is commercially available as a kit in Japan. (The test does not appear to be commercially available in the U.S.). All patients underwent surgery and were then treated with S-1 (tegafur/gimeracil/oteracil) chemotherapy. In vitro sensitivity of resected tumor specimens to 5 FU (fluorouracil) was used as a surrogate of in vitro sensitivity to S-1: this approach had been previously validated by the research group). Tumors were categorized as in vitro sensitive (responders) or in vitro insensitive (nonresponders). Median length of follow-up from the time of surgery was 3.2 years. Three-year RFS was significantly higher in the in vitro sensitive group than the in vitro insensitive group, p=0.0014. RFS rates were 82.9% (95% CI: 74.4 to 91.3%) in the responder group and 63.4% (95% CI: 54.7 to 72.1%) in the nonresponder group.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2015, Bosserman et al published a prospective nonblinded study to determine if physicians who use the results from MiCK assays on breast cancer specimens have better patient outcomes than physicians who do not (Bosserman, 2015). Tumor samples were extracted from 30 women with recurrent or metastatic breast cancer and submitted for the MiCK drug-induced apoptosis assay. Results were available to physicians within 72 hours after the biopsy. Physicians could use or not use the test results to determine therapy. Most physicians (22/30) used the assay results to select the chemotherapy regimens for their patients. Of those using the assay results, 15 physicians changed the original treatment plans for their patients. Among physicians who did not use the assay results, reasons given included: patient refused the most active drugs indicated by the assay (4 patients), the physician did not want to use most active drugs indicated by the assay (2 patients), and unstated (2 patients). Complete response, partial response, and disease control were more frequently experienced in patients whose physicians used the assay results compared with patients whose physicians did not use the assay results (p=0.04). Time to recurrence was significantly longer in patients whose physicians used the assay (7.4 months) compared with patients whose physicians did not (2.2 months). OS did not differ significantly between patients whose physicians used the assay (16.8 months) and patients whose physicians did not (13.1 months).

CPT/HCPCS:
81535Oncology (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
81536Oncology (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)
87230Toxin or antitoxin assay, tissue culture (eg, Clostridium difficile toxin)
88104Cytopathology, fluids, washings or brushings, except cervical or vaginal; smears with interpretation
88305Level IV - Surgical pathology, gross and microscopic examination Abortion - spontaneous/missed Artery, biopsy Bone marrow, biopsy Bone exostosis Brain/meninges, other than for tumor resection Breast, biopsy, not requiring microscopic evaluation of surgical margins Breast, reduction mammoplasty Bronchus, biopsy Cell block, any source Cervix, biopsy Colon, biopsy Duodenum, biopsy Endocervix, curettings/biopsy Endometrium, curettings/biopsy Esophagus, biopsy Extremity, amputation, traumatic Fallopian tube, biopsy Fallopian tube, ectopic pregnancy Femoral head, fracture Fingers/toes, amputation, non-traumatic Gingiva/oral mucosa, biopsy Heart valve Joint, resection Kidney, biopsy Larynx, biopsy Leiomyoma(s), uterine myomectomy - without uterus Lip, biopsy/wedge resection Lung, transbronchial biopsy Lymph node, biopsy Muscle, biopsy Nasal mucosa, biopsy Nasopharynx/oropharynx, biopsy Nerve, biopsy Odontogenic/dental cyst Omentum, biopsy Ovary with or without tube, non-neoplastic Ovary, biopsy/wedge resection Parathyroid gland Peritoneum, biopsy Pituitary tumor Placenta, other than third trimester Pleura/pericardium - biopsy/tissue Polyp, cervical/endometrial Polyp, colorectal Polyp, stomach/small intestine Prostate, needle biopsy Prostate, TUR Salivary gland, biopsy Sinus, paranasal biopsy Skin, other than cyst/tag/debridement/plastic repair Small intestine, biopsy Soft tissue, other than tumor/mass/lipoma/debridement Spleen Stomach, biopsy Synovium Testis, other than tumor/biopsy/castration Thyroglossal duct/brachial cleft cyst Tongue, biopsy Tonsil, biopsy Trachea, biopsy Ureter, biopsy Urethra, biopsy Urinary bladder, biopsy Uterus, with or without tubes and ovaries, for prolapse Vagina, biopsy Vulva/labia, biopsy
88313Special stain including interpretation and report; Group II, all other (eg, iron, trichrome), except stain for microorganisms, stains for enzyme constituents, or immunocytochemistry and immunohistochemistry
88358Morphometric analysis; tumor (eg, DNA ploidy)
89050Cell count, miscellaneous body fluids (eg, cerebrospinal fluid, joint fluid), except blood;
89240Unlisted miscellaneous pathology test

References: 1995 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 22.

2000 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 11.

Anticancer I.(2014) HISTOCULTURE DRUG RESPONSE ASSAY - HDRA. Available online at: http://www.anticancer.com/HDRA_ref.html. Last accessed March, 2014.

Bird MC, Godwin VA, Antrobus JH et al.(1987) Comparison of in vitro drug sensitivity by the differential staining cytotoxicity (DiSC) and colony-forming assays. Br. J. Cancer 1987; 55(4):429-31.

Blue Cross Blue Shield Association Technology Evaluation Center Assessments: Tab 12.

Bosserman L, Rogers K, Willis C, et al.(2015) Application of a drug-induced apoptosis assay to identify treatment strategies in recurrent or metastatic breast cancer. PLoS One. 2015;10(5):e0122609. PMID 26024531

Brown E, Markman M.(1996) Tumor chemosensitivity and chemoresistance assays. Cancer 1996; 77(6):1020-5.

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

Elledge RM.(1995) Rapid in vitro assay for predicting response to fluorouracil in patients with metastatic breast cancer. J Clin Oncol 1995; 13:419-423.

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

Eltabbakh GH, Piver MS, Hempling RE, et al.(1998) Correlation between extreme drug resistance assay and response to primary paclitaxel and cisplatin in patients with epithelial ovarian cancer. Gynecol Oncol 1998; 70(3):392-7.

Eltabbakh GH.(2000) Extreme drug resistance assay and response to chemotherapy in patients with primary peritoneal carcinoma. J Surg Oncol 2000; 73(3):148-52.

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

Gazdar AF, Steinberg SM, Russell EK, et al.(1990) 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 1990; 82(2):117-24.

Grigsby PW, Zighelboim I, Powell MA et al.(2013) In vitro chemoresponse to cisplatin and outcomes in cervical cancer. Gynecol. Oncol. 2013; 130(1):188-91.

Herzog TJ, Krivak TC, Fader AN et al.(2010) Chemosensitivity testing with ChemoRx and overall survival in primary ovarian cancer. Am J Obstet Gynecol 2010; 203(1):68.e1-6.

Hetland TE, Kaern J, Skrede M et al.(2012) Predicting platinum resistance in primary advanced ovarian cancer patients with an in vitro resistance index. Cancer Chemother Pharmacol 2012; 69(5):1307-14.

Holloway RW, Mehta RS, Finkler NJ, et al.(2002) Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients. Gynecol Oncol 2002; 87(1):8-16.

Iwahashi M, Nakamori M, Nakamura M et al.(2005) Individualized adjuvant chemotherapy guided by chemosensitivity test sequential to extended surgery for advanced gastric cancer. Anticancer Res 2005; 25(5):3453-3459.

Jung PS, Kim DY, Kim MB et al.(2013) 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. 2013; 33(3):1029-34.

Karam AK, Chiang JW, Fung E et al.(2009) Extreme drug resistance assay results do not influence survival in women with epithelial ovarian cancer. Gynecol Oncol 2009; 114(2):246-52.

Kern DH, Weisenthal LM.(1990) Highly specific prediction of antineoplastic drug resistance with an in vitro assay using suprapharmacologic drug exposures. J Natl Cancer Inst 1990; 82(7):582-8.

Kern DH, Weisenthal LM.(1990) Highly specific prediction of antineoplastic drug resistance with an in vitro assay using suprapharmacologic drug exposures. J. Natl. Cancer Inst. 1990; 82(7):582-8.

Kim HA, Yom CK, Moon BI et al.(2008) The use of an in vitro adenosine triphosphate-based chemotherapy response assay to predict chemotherapeutic response in breast cancer. Breast; 2008 Feb;17(1):10-26.

Kim JH, Lee KW, Kim YH et al.(2010) Individualized tumor response testing for prediction of response to paclitaxel and cisplatin chemotherapy in patients with advanced gastric cancer. J Korean Med Sci 2010; 25(5):684-90.

Kurbacher CM, Cree IA, Bruckner HW, et al.(1998) Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer. Anticancer Drugs 1998; 9(1):51-7.

Larsson R.(1993) Prediction of individual patient response to chemotherapy by the fluorometric microculture cytotoxicity assay (FMCA) using drug specific cut-off limits and a Bayesian model. Anticancer Res 1993; 13:1825-1830.

Lee JH, Um JW, Lee JH et al.(2012) Can immunohistochemistry of multidrug-resistant proteins replace the histoculture drug response assay in colorectal adenocarcinomas? Hepatogastroenterology 2012; 59(116):1075-8.

Lee JH, Um JW, Lee JH et al.(2012) Can immunohistochemistry of multidrug-resistant proteins replace the histoculture drug response assay in colorectal adenocarcinomas? Hepatogastroenterology. 2012; 59(116):1075-8.

Maenpaa JU, Heinonen E, Hinkka SM, et al.(1995) The subrenal capsule assay in selecting chemotherapy for ovarian cancer: a prospective randomized trial. Gynecol Oncol 1995; 57(3) 294-8.

Matsuo K, Bond VK, Eno ML et al.(2009) 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 2009; 125(11):2721-7.

Matsuo K, Bond VK, Im DD et al.(2010) 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 2010; 33(4):358-63.

Matsuo K, Eno ML, Im DD et al.(2010) Chemotherapy time interval and development of platinum and taxane resistance in ovarian, fallopian, and peritoneal carcinomas. Arch Gynecol Obstet 2010; 281(2):325-8.

Matsuo K, Eno ML, Im DD et al.(2010) Clinical relevance of extent of extreme drug resistance in epithelial ovarian carcinoma. Gynecol Oncol 2010; 116(1):61-5.

Mehta RS, Bornstein R, Yu IR.(2000) Extreme drug resistance assay and response to chemotherapy in patients with primary peritoneal carcinoma. Breast Cancer Res Treat 2000; 66(3):225-37.

Mehta RS, Bornstein R, Yu IR.(2001) Breast cancer survival and in vitro tumor response in the extreme drug resistance assay. Breast Cancer Res Treat 2001; 66(3):225-37.

Moon YW, Sohn JH, Kim YT et al.(2009) Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided versus empirical chemotherapy in unresectable non-small cell lung cancer. Anticancer Res 2009; 29(10):4243-50.

Nagourney RA, Blitzer JB, Shuman RL et al.(2012) Functional profiling to select chemotherapy in untreated, advanced or metastatic non-small cell lung cancer. Anticancer Res 2012; 32(10):4453-60.

Nagourney RA, Blitzer JB, Shuman RL et al.(2012) Functional profiling to select chemotherapy in untreated, advanced or metastatic non-small cell lung cancer. Anticancer Res. 2012; 32(10):4453-60.

Nagourney RA.(2006) Ex vivo programmed cell death and the prediction of response to chemotherapy. Curr Treat Options Oncol 2006; 7(2):103-10.

Nagourney RA.(2006) Ex vivo programmed cell death and the prediction of response to chemotherapy. Curr Treat Options Oncol 2006; 7(2):103-10.

Oncology D.(2014) MiCK Assay. Available online at: http://diatech-oncology.com/MiCK_Assay/. Last accessed March, 2014.

Parker Rj, Fruehauf JP, Mehta R et al.(2004) A prospective blinded study of the predictive value of an extreme drug resistance assay in patients receiving CPT-111 for recurrent glioma. J Neurooncol 2004; 66(3):365-375.

Rutherford T, Orr J, Jr., Grendys E, Jr. et al.(2013) A prospective study evaluating the clinical relevance of a chemoresponse assay for treatment of patients with persistent or recurrent ovarian cancer. Gynecol. Oncol. 2013; 131(2):362-7.

Salom E, Penalver M, Homesley H et al.(2012) Correlation of pretreatment drug induced apoptosis in ovarian cancer cells with patient survival and clinical response. Journal of translational medicine 2012; 10:162.

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

Schrag D, Garewal HS, Burstein HJ, et a.(2004) American Society of Clinical Oncology Technology Assessment: chemotherapy sensitivity and resistance assays. J Clin Oncol 2004; 22(17):3631-8.

Schrag D, Garewal HS, et al.(2004) American Society of Clinical Oncology Technology Assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 2004; 22:3631-38.

Schraq D, Garewal HS, Burstein HJ et al.(2004) American Society of clinical Oncology Technology Assessment: chemotherapy sensitivity and resistance assays. J Clin Oncol 2004; 22(17):3631-3638.

Strickland SA, Raptis A, Hallquist A et al.(2013) Correlation of the microculture-kinetic drug-induced apoptosis assay with patient outcomes in initial treatment of adult acute myelocytic leukemia. Lymphoma 2013; 54(3):528-34.

Tanigawa N, Yamaue H, Ohyama S, et al.(2016) 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. Apr 2016;19(2):350-360. PMID 26385385

Therapeutics P.(2014) ChemoFx. Available online at: http://www.chemofx.com/index.html. Last accessed March, 2014.

Tiersten AD, Moon J, Smith HO et al.(2009) 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.

Ugurel S, Schadendorf D, Pfohler C et al.(2006) 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):5454-5463.

Von Hoff DD, Sandbach JF, Clark GM, et al.(1990) Selection of cancer chemotherapy for a patient by an in vitro assay versus a clinician. J Natl Cancer Inst 1990; 82(2):110-6.

Von Hoff DD.(1990) He’s not going to talk about in vitro predictive assays again, is he. J Natl Cancer Inst 1990; 82(2):96-101.

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

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


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.