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Gene expression profiling (GEP) tests have been developed and reported for use as prognostic markers in stage 2 or stage 3 colon cancer to help identify patients who are at high risk for recurrent disease and could be candidates for adjuvant chemotherapy.
Of patients with stage 2 colon cancer, 75-80% are cured by surgery alone, and the absolute benefit of chemotherapy for the overall patient population is small. Patients most likely to benefit from chemotherapy are difficult to identify by standard clinical and pathological risk factors. Genomic tests are intended to be used as an aid in indentifying those stage 2 patients most likely to experience recurrence after surgery and most likely to benefit from additional treatment.
Colorectal cancer is classified as stage 2 (also called Dukes B) when it has spread outside the colon and/or rectum to nearby tissue, but is not detectable in the lymph nodes (stage 3 disease, also called Dukes C) and has not metastasized to distant sites (stage 4 disease). Primary treatment is surgical resection of the primary cancer and colonic anastomosis. After surgery prognosis is good, with survival rates of 75% to 80% at 5 years. A 2008 meta-analysis of 50 studies of adjuvant therapy versus surgery alone in stage 2 patients found statistically significant, although small, absolute benefit of chemotherapy for disease-free survival (DFS) but not for overall survival. Therefore, adjuvant chemotherapy with 5-fluorouracil or capecitabine is recommended only as an option for resected patients with high-risk stage 2 disease (i.e. those with poor prognostic features). However, the clinical and pathological features used to identify high-risk disease are not well-established, and the patients for whom the benefits of adjuvant chemotherapy would most likely outweigh the harms cannot be identified with certainty. The current system relies on a variety of factors, including tumor substage 2B (T4A tumors that invade the muscularis propria and extend into pericolorectal tissues) or 2C (T4B tumors that invade or are adherent to other organs or structures), obstruction or bowel perforation at initial diagnosis, an inadequately low number of sampled lymph nodes at surgery (≤12), histologic features of aggressiveness, a high preoperative carcinoembryonic antigen level, and indeterminate or positive resection margins.
For patients with stage 3 colon cancer, current guidelines from the National Comprehensive Cancer Network recommend “6 months of adjuvant chemotherapy after primary surgical treatment.” However, some have questioned the benefit of adjuvant chemotherapy in subsets of patients with stage 3 disease (eg, stage 3A) whose predicted survival may actually exceed that of some stage 2 patients (eg, stage 2C).
Of interest, a recent review has noted that microsatellite instability (MSI) and mismatch repair (MMR) deficiency in colon cancer may represent confounding factors to be considered in treatment. These factors may identify a small proportion (15%-20%) of the population with improved DFS who may derive no benefit or may exhibit deleterious effects from adjuvant fluorouracil/leucovorin-based treatments. Patient MSI and MMR status may be critically important in how to study, interpret, and use a particular GEP test.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Improvement Act (CLIA). Multigene expression assay testing for predicting recurrent colon cancer is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for highcomplexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.
The Oncotype DX® breast cancer test is addressed in the Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer medical policy.
Gene expression assays (Oncotype DX® colon cancer test) for determining the prognosis of stage 2 or stage 3 colon cancer following surgery are considered investigational.
POLICY GUIDELINESInvestigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY07/22/2010: Approved by Medical Policy Advisory Committee
06/21/2011: Policy reviewed; no changes.
11/10/2011: Policy reviewed; no changes.
09/25/2012: Policy reviewed; no changes.
11/15/2013: Policy reviewed; no changes.
11/04/2014: Policy reviewed; description updated. Policy statement unchanged.
08/04/2015: Code Reference section updated for ICD-10.
11/03/2015: Policy description updated to add information regarding stage 3 colon cancer and testing. Investigational policy statement revised to include stage 3 colon cancer. It previously stated: The 12-gene expression test (Oncotype DX® colon cancer test) is considered investigational, including use for predicting the likelihood of disease recurrence for patients with stage II colon cancer following surgery. Investigative definition updated in policy guidelines section.
12/31/2015: Code Reference section updated to add new 2016 CPT code 81525.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.61
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.