Capital Bluecross in vitro chemosensitivity Coverage

Coverage Determination

Assays considered not meeting coverage

Not covered when the following assay types are requested:

Not covered assay types: In vitro chemosensitivity assays (e.g., histoculture drug response assay, fluorescent cytoprint assay) and in vitro chemoresistance assays (e.g., extreme drug resistance [EDR] assays) do not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of an individual's illness.

Policy explicitly lists these assay categories as not meeting coverage criteria.

The policy states that in vitro chemosensitivity assays and in vitro chemoresistance assays do not meet coverage criteria. These assay categories are considered not covered because there is insufficient published scientific literature demonstrating that the tests are required and beneficial for diagnosing or treating an individual’s illness.

Examples of assay types specifically identified as not meeting coverage include the histoculture drug response assay and the fluorescent cytoprint assay (classified under in vitro chemosensitivity assays), and extreme drug resistance (EDR) assays (classified under in vitro chemoresistance assays).

Study (author, year)	Tumor type	Agents/regimens evaluated	Outcome / main findings
Tatar et al., 2016	Ovarian carcinoma	Paclitaxel; carboplatin; docetaxel; topotecan; gemcitabine; doxorubicin (assessed by MTT, ATP-TCA, and DISC assays)	All three assays correlated reasonably well with each other; authors concluded large prospective studies comparing standard versus assay-directed therapy with overall survival endpoints are required before routine clinical use.
Kwon et al., 2016	Stage II colorectal adenocarcinoma	Fluorouracil (5-FU) – chemosensitivity by ATP-CRA; cell death rate (CDR) used to define sensitivity	Patients with CDR ≥20% had better disease-free survival; authors suggested ATP-CRA may help identify patients likely to benefit from fluorouracil-based adjuvant chemotherapy.
Krivak et al., 2014	Advanced-stage (FIGO III–IV) ovarian, fallopian, and peritoneal cancers	Platinum/taxane regimens (carboplatin + paclitaxel); ChemoFx assay evaluation of platinum resistance	Assay resistance to carboplatin was strongly associated with shortened progression-free survival, supporting use of the assay to identify patients likely to experience early recurrence on standard platinum-based therapy.
Rutherford et al., 2013	Recurrent ovarian cancer	Multiple empiric treatments (15 protocol-designated treatments); ChemoFx assay used to categorize sensitivity	Patients treated with assay-sensitive regimens had significantly improved PFS and OS compared with others; no difference between intermediate and resistant groups.
Hoffman, 2018	Advanced gastric and colon cancer (and subsets evaluated)	Various regimens including mitomycin C and 5-fluorouracil (5-FU); histoculture drug response assay (HDRA)	Patients whose tumors were 'sensitive' by HDRA demonstrated higher survival rates and disease arrest compared with 'insensitive' groups across evaluated subsets.
Strickland et al., 2013	Untreated adult acute myelocytic leukemia (AML)	Idarubicin-induced apoptosis measured by MiCK assay during standard induction chemotherapy	Higher idarubicin-induced apoptosis (>3 KU) correlated with significantly higher complete remission and appeared predictive of CR and overall survival.
Howard et al., 2017	Glioblastoma	Temozolomide (TMZ); ChemoID assay assessing bulk tumor cells and cancer stem cells (CSC)	Higher CSC kill by TMZ associated with increased 12‑month nonrecurrence and longer median recurrence times; authors concluded ChemoID CSC assay has potential to improve individualized chemotherapy selection.
Chen et al., 2018	Lung cancer (adenocarcinoma and squamous)	Single agents and combination regimens assessed by ATP-TCA: PTX (paclitaxel), TXT (docetaxel), GEM (gemcitabine), PTX+DDP, TXT+L-OHP, VP16+DDP, among others	Authors reported highest in vitro chemosensitivity rates for several agents/regimens (eg, PTX, TXT, PTX+DDP, TXT+L-OHP) and noted a proportion of patients had resistance; suggested testing could help prevent primary drug resistance and inappropriate treatment.
Shuford et al., 2021	High‑grade glioma	3D live tumor cell–based assay predicting response to temozolomide and other agents; assay validated for drug concentration, timing, reproducibility	Assay predicted temozolomide response in 17/20 patients (85%); responders had longer median overall survival (11.6 vs 5.9 months); study provided analytic and clinical validation and case implementation examples.

Procedure codes shown in this policy are provided only as a general reference and may not be all-inclusive. This section does not establish specific medical necessity rules; providers should refer to member benefit documents and applicable government program policies for coverage determinations.

Procedure Codes and Code Groups

General pathology/unlisted codesCPT

86849	Unlisted immunology procedure
88104	Cytopathology, fluids, washings or brushings, except cervical or vaginal; smears with interpretation
88199	Unlisted cytopathology procedure
88313	Special stain including interpretation and report; Group II, all other
88358	Morphometric analysis; tumor (eg, DNA ploidy)
89050	Cell count, miscellaneous body fluids
89240	Unlisted miscellaneous pathology test

Proprietary assay HCPCS/CPT-like codesHCPCS

0083U	Oncology, response to chemotherapy drugs using motility contrast tomography, fresh or frozen tissue, reported as likelihood of sensitivity or resistance to drugs or drug combinations (Onco4D™)
0248U	Oncology spheroid cell culture in 3D microenvironment, 12 drug panel, brain or brain metastasis response prediction for each drug (3D Predict Glioma)
0249U	Oncology (breast), semiquantitative analysis of 32 phosphoproteins and protein analytes, includes laser capture microdissection, with algorithmic analysis and interpretative report (Theralink® RPPA)
0435U	Oncology, chemotherapeutic drug cytotoxicity assay of cancer stem cells (CSCs), from cultured CSCs and primary tumor cells, categorical drug response reported based on cytotoxicity percentage observed, minimum of 14 drugs or drug combinations (ChemoID®)
0525U	Oncology, spheroid cell culture, 11-drug panel ovarian, fallopian, or peritoneal response prediction for each drug (3D Predict™ Ovarian)
0564T	Chemotherapeutic drug cytotoxicity assay of cancer stem cells (CSCs), categorical drug response reported based on percent of cytotoxicity observed, a minimum of 14 drugs or drug combinations (Reported for ChemoID®)

Applicable CPT/HCPCS Procedure CodesCPT

0083U	Oncology, response to chemotherapy drugs using motility contrast tomography, fresh or frozen tissue, reported as likelihood of sensitivity or resistance to drugs or drug combinations (Onco4D™)
0248U	Oncology spheroid cell culture in 3D microenvironment, 12 drug panel, brain or brain metastasis response prediction for each drug (3D Predict Glioma)
0249U	Oncology (breast), semiquantitative analysis of 32 phosphoproteins and protein analytes, includes laser capture microdissection, with algorithmic analysis and interpretative report (Theralink® RPPA)
0435U	Oncology, chemotherapeutic drug cytotoxicity assay of cancer stem cells (CSCs), from cultured CSCs and primary tumor cells, categorical drug response reported based on cytotoxicity percentage observed, minimum of 14 drugs or drug combinations (ChemoID®)
0525U	Oncology, spheroid cell culture, 11-drug panel (carboplatin, docetaxel, doxorubicin, etoposide, gemcitabine, niraparib, olaparib, paclitaxel, rucaparib, topotecan, veliparib) ovarian, fallopian, or peritoneal response prediction for each drug (3D Predict™ Ovarian)
0564T	Oncology, chemotherapeutic drug cytotoxicity assay of cancer stem cells (CSCs), from cultured CSCs and primary tumor cells, categorical drug response reported based on percent of cytotoxicity observed, a minimum of 14 drugs or drug combinations (Reported for ChemoID®)

Billing, Submission, and Provider Responsibilities

Billing Rule

Procedure coding and submission

Providers should submit the specific procedure code reported for the assay when filing claims. Use the CPT/HCPCS code that corresponds to the proprietary or unlisted assay performed; do not substitute a generic assay code if a proprietary code is available.

Submit the exact procedure code used to report the assay on the claim.

Billing Rule

Procedure coding for proprietary assays

When submitting claims for the proprietary assays listed below, use the specified CPT/HCPCS codes associated with each named test.

0083U — Onco4D™ (Animated Dynamics, Inc.)
0248U — 3D Predict Glioma (KIYATEC®, Inc.)
0249U — Theralink® RPPA (Theralink® Technologies, Inc.)

Definitions and Background

Background: In vitro chemosensitivity and chemoresistance assays are laboratory tests that evaluate tumor cell response to chemotherapy agents outside the patient with the intent of predicting drug sensitivity or resistance. A variety of proprietary and non‑proprietary assays exist, but the policy finds the published evidence across tumor types to be inadequate to demonstrate consistent clinical benefit; therefore, the assay categories listed are not considered to meet coverage criteria.

ATP-CRA definition — Adenosine triphosphate-based chemotherapy response assay

TermATP-CRA

DefinitionAdenosine triphosphate-based chemotherapy response assay

Source noteListed in Table of Terminology as ATP-CRA = Adenosine triphosphate-based chemotherapy response assay

EDR definition — Extreme drug resistance assay

Term

Assay-Directed Therapy Evidence Summary

Study (author, year)	Tumor types included across studies	Agents/regimens evaluated (examples)	Association between assay result and clinical outcome
Tatar et al., 2016	Ovarian carcinoma	Paclitaxel; carboplatin; docetaxel; topotecan; gemcitabine; doxorubicin	Assays (MTT, ATP-TCA, DISC) correlated with each other; authors stated prospective trials with survival endpoints are needed to establish clinical utility.
Kwon et al., 2016	Stage II colorectal cancer	Fluorouracil (5‑FU) — ATP-CRA measured cell death rate (CDR)	Higher CDR (≥20%) associated with improved disease-free survival, suggesting potential predictive value for fluorouracil benefit.
Krivak et al., 2014; Rutherford et al., 2013	Advanced/recurrent ovarian, fallopian, peritoneal cancers	Platinum/taxane regimens (carboplatin + paclitaxel) and other protocol-designated treatments evaluated by ChemoFx	ChemoFx platinum resistance associated with shortened PFS; patients treated with assay-sensitive regimens had improved PFS and OS in prospective evaluation.
Hoffman, 2018	Advanced gastric and colon cancer	Mitomycin C; 5‑fluorouracil and other agents assessed by HDRA	Patients classified as 'sensitive' by HDRA showed higher survival rates compared with 'insensitive' groups in multiple subsets.
Strickland et al., 2013	AML (initial treatment)	Idarubicin (apoptosis by MiCK assay)	Greater drug‑induced apoptosis correlated with higher complete remission rates and was predictive of outcomes.
Howard et al., 2017	Glioblastoma	Temozolomide; ChemoID assessed bulk tumor and cancer stem cell kill	Higher CSC kill percentages correlated with increased 12‑month nonrecurrence and longer median recurrence times; assay potentially identifies more optimal treatments.
Chen et al., 2018	Lung cancer (adenocarcinoma, squamous)	Single agents and regimens: PTX, TXT, GEM, PTX+DDP, TXT+L‑OHP, VP16+DDP (ATP‑TCA)	Reported in vitro sensitivity patterns with highest sensitivity rates for specified agents/regimens; authors suggested testing could reduce inappropriate treatment but did not provide definitive clinical outcome linkage.
Shuford et al., 2021	High‑grade glioma	3D ex vivo assay predicting temozolomide response; also informed use of targeted agents like dabrafenib in absence of NGS actionable results	Assay predicted temozolomide response in 85% of cases and responders had longer median overall survival; study provided analytic and clinical validation examples.

Policy Revision History

2015-09-18policy_effective

Policy initial effective date (Initial Presentation Date).

2026-04-01policy_revisionLatest

Policy revision with updated review date (Revision Date / Last review).

OpenPayer

In Vitro Chemoresistance and Chemosensitivity Assays