Tumor Chemosensitivity Assays

Coverage Summary

Policy Number: 0245; Effective Date: 1998-05-26; Last Review: 2023-03-29; Next Review: 2024-02-22.

Scope summary: Defines Aetna's coverage position for tumor chemosensitivity assays (various named assays and newer platforms) as experimental/investigational and not covered because there is insufficient evidence that assay-directed therapy improves clinical outcomes. The policy lists examples of assays and related codes and summarizes background evidence and guidance on use only in clinical trials.

Key status

Policy number0245

Last review date2023-03-29

Effective date1998-05-26

Next review date2024-02-22

Evidence strengthEvidence mixed; needs validation

Number of referencesReferences: 65

Medical-Necessity / Coverage Criteria

Experimental and Investigational (Not Covered)

Aetna considers the following chemosensitivity and related assays experimental and investigational because there is insufficient evidence that these assays influence management decisions such that clinical outcomes are improved.

Chemosensitivity assays (examples) considered experimental and investigational

Example assays: ChemoFx assay
Example assays: Differential staining cytotoxicity (DiSC) assay
Example assays: Fluorescence (Cytoprint) assay

Not Covered / Experimental Assays

Aetna considers the following specific assays experimental and investigational and not covered: ChemoFx, Differential staining cytotoxicity (DiSC) assay, Fluorescence (Cytoprint) assay, Human tumor cloning assay (HTCA), Human tumor stem cell assay, MTT assay, Microculture kinetic (MiCK) apoptosis assay (CorrectChemo).

Other named platforms specifically listed as experimental and investigational include the NexGen Cancer Cytotoxicity Assay, 3D Predict Glioma (Kiyatec Inc.), and Reverse Phase Protein Array (Theralink).

Coding

Codes listed in policy (related/associated; assays not covered)mixedNot Covered

0248U	Oncology (brain), spheroid cell culture in a 3D microenvironment, 12 drug panel, tumor-response prediction for each drug.
0249U	Oncology (breast), semiquantitative analysis of 32 phosphoproteins and protein analytes, includes laser capture microdissection, with algorithmic analysis and interpretative report.
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.
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 [ChemoFX assay].
81536	Each additional single drug or drug combination (List separately in addition to code for primary procedure) [ChemoFX assay].
87230	Toxin or antitoxin assay, tissue culture (e.g., Clostridium difficile toxin).
88104	Cytopathology, fluids, washings or brushing, except cervical or vaginal; smears with interpretation.
88305	Level IV surgical pathology, gross and microscopic examination.
88313	Special stain including interpretation and report; Group II, all other (eg, iron, trichrome), except stain for microorganisms, stains for enzyme constituents, or immunocytochemistry and immunohistochemistry.
88358	Morphometric analysis; tumor (e.g., DNA ploidy).

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Provider Actions

Documentation Required

Do not use these assays to guide therapy outside clinical trials

Aetna considers the listed chemosensitivity assays experimental and investigational and not covered for routine clinical use; providers should not use these assays to guide therapy outside of clinical trials and are encouraged to enroll patients in clinical studies evaluating these technologies.

Assays listed as experimental/investigational (e.g., ChemoFx, DiSC, Cytoprint, HTCA, MiCK, NexGen, 3D Predict Glioma, RPPA).
Participation in clinical trials evaluating these technologies is encouraged.

Documentation Required

Evidence and clinical justification required

When requesting coverage for tumor chemosensitivity testing, providers must document the specific assay being used, the intended clinical use, and the supporting evidence and rationale, noting that the policy background emphasizes limited, preliminary or inconsistent data and the need for prospective validation.

Background and Evidence Summary

Background: Chemosensitivity assays aim to predict tumor sensitivity to chemotherapeutic agents to individualize therapy by isolating tumor cells, exposing them to drugs, assessing survival, and interpreting results. Multiple assay types exist (ex-vivo 3D cell culture platforms, proteomic RPPA arrays, blood-based CTIC GEP, organoid models, CSRA/IVCA approaches) with variable techniques and success rates. A lack of prospective randomized trials demonstrating improved survival and limitations such as small sample sizes, heterogeneous methods, and modest assay success rates have led professional groups (ASCO, NCCN) to conclude that CSRAs are not recommended for routine clinical use outside of clinical trials and that further prospective validation is needed.

Evidence / Source	Key Finding
ASCO Technology Assessment	Found insufficient evidence to support use of CSRAs in oncology practice; recommended use only in clinical trials (ASCO working group reviews 2004 update and 2011 update).
Cree 2007 trial	Prospective randomized trial in recurrent platinum‑resistant ovarian cancer: trend toward improved response and PFS with assay‑directed therapy but no significant difference in PFS or OS; authors concluded assay remains investigational and larger trial needed.
Rutherford 2013	Prospective non‑interventional study (ChemoFx) in recurrent ovarian cancer: patients treated with assay‑sensitive regimens had significantly improved PFS and OS versus insensitive regimens; authors called for further evaluation.
MiCK studies	Mixed evidence: feasibility and observational studies show correlations between MiCK apoptosis units and clinical response/OS in some cohorts, but overall insufficient evidence that MiCK‑guided therapy improves survival.
3D Predict Glioma results	Ex‑vivo 3D assay predicted temozolomide response in 17/20 (85%) newly diagnosed high‑grade glioma patients; predicted responders had longer median OS (11.6 vs 5.9 months, p=0.0376); authors note confounding factors and need for interventional trials.
RPPA reproducibility	Multi‑platform RPPA analyses identified concordant protein/phosphorylation response profiles across platforms, demonstrating robustness and cross‑platform reproducibility of RPPA technology.
ERCC1 rs11615 meta‑analyses	ERCC1 rs11615 polymorphism meta‑analysis in ovarian cancer: pooled OR 0.92 (95% CI 0.68–1.24) overall; subgroup analyses in Asian patients showed significant associations for some genotypes.
ERCC1 protein expression (NSCLC) meta‑analysis	Meta‑analysis found ERCC1‑negative tumors associated with greater platinum sensitivity (combined OR 0.53, 95% CI 0.30–0.79), with stronger signal in Asian subgroup; authors call for prospective validation.
ChemoSensitivity PDAC (Isacoff 2022)	Retrospective single‑center pilot and validation cohorts: patients whose treatments closely matched ChemoSensitivity assay predictions had longer time on therapy and trends or significant increases in mOS (pilot mOS 16.8 months; matched MCT mOS up to 27.7 months); study limited by retrospective single‑center design.
CTIC GEP PDAC (Yu 2022)	Prospective blinded study in metastatic PDAC: patients receiving regimens predicted effective had longer mPFS (7.8 vs 4.2 months) and mOS (21.0 vs 9.7 months); authors state further prospective validation underway.

Glossary:

ChemoFx: A chemoresponse assay reporting live tumor cell culture chemotherapeutic response and a predictive algorithm drug response score.

MiCK assay: Microculture kinetic apoptosis assay reporting kinetic units (KU) of drug-induced apoptosis.

CSRA/IVCA: Chemotherapy sensitivity and resistance assay / in-vitro chemosensitivity assay.

RPPA: Reverse Phase Protein Array — a high-throughput, antibody-based proteomic platform quantifying protein expression and post-translational modifications.

3D Predict Glioma: An ex-vivo three-dimensional cell culture assay using live glioma tissue to predict drug response.

CTIC GEP: Circulating tumor and invasive cell gene expression profiling — a blood-based pharmacogenomic chemosensitivity assay.

Medicare Determinations

Name	Number	Effective Date	Type
Human tumor assay systems	CAG-00044N	2000-04-13	NCD

Revision History

1998-05-26effective_date

Policy effective date as stated in policy header.

2023-03-29last_reviewLatest

Policy last reviewed on this date (most recent review).

2024-02-22next_review

Next scheduled review date as listed in policy header.