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Medical Policy: 02.04.28
Original Effective Date: March 2010
Reviewed: August 2011
Revised:
Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Description:
Colorectal cancer is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Surgical resection cures greater than 90% of patients with stage I colon cancer. Adjuvant therapy is not recommended. Surgical resection cures approximately 80% of patients with stage II colon cancer. Adjuvant therapy has been controversial in this patient population and several chemotherapy regimens have been studied in clinical trials over the past few years. A statistically significant benefit for the use of adjuvant chemotherapy in stage II colon cancer has not yet been shown. Meta-analysis of several trials of adjuvant therapy vs. surgery alone in all stage II patients found statistically significant, although small, absolute benefit of chemotherapy for disease-free survival but not for overall survival. Therefore, many experts encourage the use of adjuvant chemotherapy in high-risk stage II patients due to their increased risk of mortality from recurrent disease. However, the clinical and pathological features used to identify high-risk disease are not well-established and patients for whom the benefits of adjuvant chemotherapy would most likely outweigh the harms are difficult to identify.
A 12-gene expression test (Oncotype DX® colon cancer test; Genomic Health, Inc., Redwood City, CA) has been developed to predict the likelihood of disease recurrence for stage II colon cancer patients following surgery. The test was launched worldwide in January, 2010. Oncotype DX® colon cancer test has not been submitted to or cleared for marketing by the U.S. Food and Drug Administration (FDA). It is offered as a laboratory-developed assay conducted in the Clinical Laboratory Improvement Amendments (CLIA)-licensed Genomic Health clinical laboratory.
Development of the 12-gene expression test has been briefly described in abstracts from meeting. A total of 761 candidate genes of possible prognostic value for recurrence or of possible predictive value for treatment were examined by correlating the genes in tumor samples with the clinical outcomes seen in 1851 patients who had surgery with or without adjuvant 5-FU-based chemotherapy. Gene expression was quantitated from microdissected fixed paraffin-embedded primary colon cancer tissue. Of the 761 candidate genes surveyed, a multivariate analysis including disease severity, stage, and nodal involvement, reduced the genes to a significant seven-gene prognostic signature and a separate six-gene predictive signature. Five reference genes were also included in the assay.
The prognostic and predictive signatures were independently evaluated using tumor samples of a stage II subset of patients from the Quick and Simple and Reliable (QUASAR) study; the subset represented 44% of the entire parent study population and included 711 patients treated with surgery alone and 725 patients treated with adjuvant 5-FU-based chemotherapy following surgery with a mean follow-up of approximately 7 years.
The seven-gene prognosis signature, reported as a recurrence score (RS), was a significant and independent predictor of 3-year recurrence risk, which increased continuously with RS. RS scores could separate patients into low-, intermediate-, and high-risk groups. Recurrence risks (95% confidence interval) of disease at 3 years for the low-, intermediate-, and high-risk groups were 12% (9-16%), 18% (13-24%), and 22% (16-29%), respectively. Additional study of the QUASAR data showed that RS and number of lymph nodes examined were independent predictors, with 3-year recurrence risk approximately 5% lower when ≥ 12 compared to when ≤ 12 nodes were examined. Another report compared pathologic markers and gene expression by stage for both stage II and III patients in the four studies conducted to develop the Oncotype DX® colon cancer test. Neither RS nor the majority of genes examined showed significant interaction with stage, indicating a need to examine predictors of recurrence risk in stage III as well as stage II disease.
The six-gene predictive signature for 5-FU chemosensitivity did not show significance in the validation study. It must be assumed this signature has been removed from the Oncotype DX® colon cancer test released in January, 2010 and that the final assay consists of the 7-gene prognostic score plus the 5 reference genes. There are no details specific to the 6-gene predictive signature in the Genomic Health website.
The review of evidence for the Oncotype DX® colon cancer test is severely limited by lack of detail because only meeting abstracts were available at the time of this writing. None of the studies referenced above have been published in a peer-reviewed journal. Based on the information available, it seems unlikely that the 12-gene expression test for predicting colon cancer recurrence risk in individual patients could guide clinical decision making because the differences between recurrence risk categories established in the validation study were not sufficiently discriminative and the associated confidence intervals overlapped considerably. For example, a RS of 33 corresponds to a recurrence risk of 16%, which could be low risk, intermediate risk, or high risk when confidence interval of the category mean estimates are considered. For interpretation, Genomic Health has established RS category ranges for low (<30), intermediate (30-40) and high (≥41) risk categories. There is also no information from the validation study on how the test adds to current methods of predicting risk, and how extensively and accurately patients are reclassified by RS after classification by current predictors and compared to their known recurrence outcomes.
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Prior Approval:
Not applicable
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Policy:
The 12-gene expression test (Oncotype DX® colon cancer test) is considered investigational for all indications, including use for predicting the likelihood of disease recurrence for stage II colon cancer patients following surgery. The evidence to date is insufficient to permit conclusions concerning the effect of the test on health outcomes.
While there is a report clearly detailing the methodology used for developing the algorithms for this test, the only fully published evidence suggesting the RS is prognostically sound is based on bootstrapping methodologies. Preliminary promising reports on the validation of this tool as a prognostic indicator of stage II tumor recurrence have appeared in abstract form and been briefly described in a review article. However, an assessment of both clinical validity and clinical utility of testing awaits publication of more detailed results.
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Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
- 84999 Unlisted chemistry procedure
- 88299 Unlisted cytogenetic study
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Selected References:
- National Comprehensive Cancer Network (NCCN) .Clinical Practice Guidelines in Oncology. Colon Cancer v.2.2010. Available at http://www.nccn.org/. Accessed March 10, 2010.
- Kerr D, gray R, Quirke P et al. A quantitative multigene RT-PCR assay for prediction if recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study. American Society of Clinical Oncology Annual Meeting, 2009, Abstract 4000.
- Gray RG, Quirke P, Handley K et al. Correlation of number of nodes examined and the 12-gene colon cancer recurrence score with recurrence in stage II colon cancer patients from QUASAR. American Society of Clinical Oncology Gastrointestinal cancers Symposium, 2010, Abstract 331.
- O’Connell MJ, Lavery IC, Gray RG et al Comparison of molecular and pathologic features of stage II and stage III colon cancer in four large studies conducted for development of the 12-gene colon cancer recurrence score. American Society of Clinical Oncology gastrointestinal Cancers Symposium, 2010, Abstract 280.
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Policy History:
Date Reason Action
August 2011 Annual review Policy renewed
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*Current Procedural Terminology © 2010 American Medical Association. All Rights Reserved.
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