Medical Policy: 02.04.16 
Original Effective Date: March 2008 
Reviewed: September 2016 
Revised: November 2014 


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:

The prognosis of cancer patients is often determined by the occurrence of metastatic disease. Studies have suggested that the presence of circulating tumor cells (CTCs) in patients with metastatic carcinoma is associated with shortened survival. Quantifying circulating tumor cells might be a useful technique to provide an immediate assessment of response to chemotherapy rather than relying on changes in imaging studies and guiding cancer therapy.

 

Intact circulating tumor cells (CTCs) are released from a primary tumor and/or metastatic site into the bloodstream. The half-life of a CTC in the bloodstream is short (1-2 hours), and CTCs are cleared through extravasation into secondary organs. Most assays detect CTCs through the use of surface epithelial markers such as EpCAM and cytokeratins. The primary reason for detecting CTCs is prognostic, through quantification of circulating levels which could potentially provide information that could guide treatment decisions or aid in the monitoring of response to treatment. CTCs have been documented in multiple tumor types, such as breast, prostate, lung and colorectal carcinomas; the largest body of data comes from studies of geno typical women with metastatic breast cancer. CTCs have also been investigated as an additional prognostic factor in non-metastatic breast cancer and could be used to determine the need for additional adjuvant chemotherapy. Circulating tumor cells potentially offer a noninvasive alternative to tissue biopsy.

 

Research over more than 10 years has focused the development of methodologies with improved sensitivity and specificity. Physical techniques such as size filtration, density gradient centrifugation, and microscopic morphology continue to be used. However, biological techniques such as immunomagnetic isolation, flow cytometry, immunofluorescent microscopy, reverse transcriptase-polymerase chain reaction (RT-PCR), polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH) have been added to provide required specificity.

 

The CellSearch™ system (Janssen Diagnostics, formerly Veridex) is an example of immunofluorescent technology. The technique involves identification of the circulating tumor cells in blood which are tagged using antibody-coated magnetic beads that recognize cell surface antigens. The cells are then labeled with fluorescent dyes, which can then be quantified by a semiautomated fluorescent-based microscopy system.

 

Numerous studies have reported the association of circulating tumor cells (CTCs) with prognosis and/or response to treatment in patients with various types of cancer. However, despite these correctional studies, to complete the causal chain, there must be evidence that patient management decisions based on CTC levels increase the duration or quality of life or decreases adverse events. Literature searches have not identified any published studies that prospectively evaluate patient treatment decisions and/or health outcomes in patients managed with and without the monitoring of CTCs.

 

While studies have shown that the level of circulating tumor cells (CTCs) is associated with the presence of metastatic disease and prognosis, the prospective use of this information to impact care has not been demonstrated. Given that insufficient evidence is available to evaluate the impact on patient management or health outcomes and additional remaining questions (e.g. the optimal cutoff to use for various conditions) the assessment of circulating tumor cells is considered investigational.

 

Practice Guidelines and Position Statements

American Society of Clinical Oncology (ASCO):

Recommendations for the use of tumor markers in breast cancer, published in 2007, indicate that the measurement of CTCs should not be used to make the diagnosis of breast cancer or to influence any treatment decisions in those with breast cancer. They should not be used in the prevention, screening, treatment, or surveillance of breast cancer.

 

In 2015 ASCO updated their guideline, Use of Biomarkers to Guide Decisions on Systemic Therapy for Women with Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline which states: “Recommendations for circulating tumor markers: In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient’s goals for care. There is no evidence at this time that changing therapy based solely on circulating biomarkers results improves health outcomes, quality of life or cost effectiveness.” (Type: evidence based. Evidence quality: intermediate. Strength of recommendation: moderate)

 

In 2016 ASCO issued a guideline, Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women with Early Stage Invasive Breast Cancer which states: “The clinician should not use circulating tumor cells to guide decisions on adjuvant systemic therapy.” Type: Evidence based; Evidence quality: Intermediate; Strength of recommendation: strong 


Clinical interpretation of literature review. Circulating tumor cells have been shown to have prognostic value in breast cancer; however, no data are available that demonostrate that circulating tumor cell based tests have clinical utility. 

 

National Comprehensive Care Network (NCCN)

Breast Cancer Version 2.2016

Discussion Section: Monitoring Metastatic Disease
The clinical use of circulating tumor cells (CTC) in metastatic breast cancer is not yet included in the NCCN guidelines for Breast Cancer for disease assessment and monitoring. Patients with persistently increased CTC after 3 weeks of first line chemotherapy have a poor PFS (progressive free survival) and OS (overall survival). In spite of its prognostic ability, CTC count has failed to show a predictive value. A prospective, randomized phase 3 trials (SWOG S0500) evaluated the clinical utility of serial enumeration of CTC in patients with metastatic breast cancer. According to the study results, switching to an alternative cytotoxic therapy after 3 weeks of first line chemotherapy in patients with persistently increased CTC did not affect either PFS (progressive free survival) or OS (overall survival).

 

Colon Cancer Version 2.2016

The clinical use of circulating tumor cells (CTC) in colon cancer is not yet included in the NCCN guidelines for disease assessment and monitoring.

 

Prostate Cancer Version 3.2016

The clinical use of circulating tumor cells (CTC) in colon cancer is not yet included in the NCCN guidelines for disease assessment and monitoring.

 

National Academy of Clinical Biochemistry (NACB):

In 2009, NACB issued a guideline on the use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancer.

  • The panel concluded that the measurement of circulating prostate cancer cells was not sufficiently validated to recommend its application in routine clinical practice.
  • For breast cancer circulating tumor cells for assessing prognosis and monitoring therapy in advanced disease is undergoing evaluation and is available but not widely used in clinical practice. Prospective randomized trial underway. Level of evidence III (evidence from large prospective studies)
  • Colorectal and Ovarian Cancer – guidelines do not mention or indicate the use of circulating tumor cells.

 

Regulatory Status

The CellSearch™ system (Janssen Diagnostics, formerly Veridex) has received U.S. Food and Drug Administration (FDA) marketing clearance through the 510(k) process for monitoring metastatic breast cancer (January 2004), for monitoring metastatic colorectal cancer (November 2007), and for monitoring metastatic prostate cancer (February 2008). The system uses automated instruments manufactured by Immunicon Corp. for sample preparation (Cell Tracks® AutoPrep) and analysis (CellSpotterAnalyzer®), together with supplies, reagents, and epithelial cell control kits manufactured by Veridex.


Prior Approval:

 

Not applicable


Policy:

Detection and quantification of circulating tumor cells is considered investigational in the management of patients with cancer.

 

While levels of circulating tumor cells may be associated with the presence of metastatic disease and prognosis, the prospective use of this information to impact care has not been demonstrated. The clinical utility of quantifying CTCs remains unproven at this time. Published data is inadequate to determine how such measurements should guide treatment decisions and whether those treatment decisions could result in beneficial outcomes.  Given the insufficient evidence to evaluate the impact on net health outcomes, the assessment of circulating tumor cells is investigational for the management of cancer.



Procedure Codes and Billing Guidelines:

  • To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 86152 Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood).
  • 86153 Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood); physician interpretation and report, when required.

Selected References:

  • Cristofanilli M, Budd GT, Ellis MJ et al. Circulating tumor cells, disease progression and survival in metastatic breast cancer. NEJM 2004; 351:781-91.
  • Harris L, Fritsche H, Mennel R et al. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007 Nov 20;25(33):5287-312.
  • Budd GT, Cristofanilli M, Ellis MJ et al. Circulating tumor cells versus imaging-predicting overall survival in metastatic breast cancer. Clin Cancer Res. 2006  Nov 1;12(21):6321-2.
  • Hayes DF, Cristofanilli M, Budd GT et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predicts progression-free and overall survival. Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4218-24.
  • Liu MC, Shields PG, Warren RD et al. Circulating Tumor Cells: A Useful Predictor of Treatment Efficacy in Metastatic Breast Cancer. J Clin Oncol. 2009 Sep 14. [Epub ahead of print]
  • Cohen SJ, Punt CJA, Iannotti N et al. Relationship of Circuating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients with Metastatic Colorectal Cancer. J Clin Oncol. 2008 Jul 1; 26(19): 3213-3221.
  • Serrano Fernadez MJ, Alvarez Merino JC, Martinez Zubiaurre I et al. Clinical relevance associated to the analysis of circulating tumour cells in patients with solid tumours. Clin Transl Oncol. 2009 Oct; 11(10):659-68.
  • Gazzaniga P, Naso G, Gradilone A et al. Chemosensitivity profile assay of circulating cancer cells (CTCs): prognostic and predictive value in epithelial tumors. In J Cancer. 2009 Oct 9. [Epub ahead of print]
  • Nakamura S, Yagata H, Ohno S et al. Multi-center study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer. Breast Cancer. 2009 Aug 1. [Epub ahead of print]
  • Mostert B, Sleijfer S, Foekens JA et al. Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer. Cancer treat Rev. 2009 Aug; 35(5): 463-74.
  • Helo P, Cronin AM, Danila DC et al. Circulating prostate tumor cells detected by reverse transcription-PCR in men with localized or castration-refractory prostate cancer: concordance with CellSearch assay and association with bone metastases and with survival. Clin Chem. 2009 Apr;55(4):765-73.
  • Iinuma H, Watanabe T, Mimori K et al. Clinical significance of circulating tumor cells, including cancer stem-like cells, in peripheral blood for recurrence and prognosis in patients with Dukes' Stage B and C colorectal cancer. J Clin Oncol 2011 Apr 20; 29(12): 1547-55. Epub 2011 Mar 21.
  • Krebs MG, Sloane R, Priest L et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol 2011 Apr 20; 29(12): 1556-63. Epub 2011 Mar 21.
  • Tanaka F, Yoneda K, Kondo N et al. Circulating tumor cells as a diagnostic marker in primary lung cancer. Clin Cancer Res 2009; 15(22):6980-6.
  • Pierga JY, Hajage D, Bachelot T, Delaloge S, et al. High independent prognostic and predictive value of circulating tumor cells compared with serum tumor markers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients. Ann Oncol. 2012 Mar;23(3):618-24.
  • Zhang L, Riethdorf S, Wu G, Wang T, et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res. 2012 Oct 15;18(20):5701-10.
  • American Society of Clinical Oncology (ASCO), American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. Published in Journal of Clinical Oncology, Vol 25, Issue 33 (November), 2007: 5287-5312.
  • American Cancer Society External SiteWhat's New in Breast Cancer Research and Treatment?  New Laboratory Tests, Circulating Tumor Cells.
  • Canadian Agency for Drugs and Technologies in Health. The CellSearch System for Detecting Circulating Tumor Cells in Advanced Ovarian Cancer: Clinical Benefit and Cost Effectiveness. November 16, 2012.
  • Agency for Healthcare Research and Quality (AHRQ). Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast and Ovarian Cancers. 2009.
  • British Journal of Cancer. A Direction Comparison of CellSearch and ISET for Circulating Tumor Cell Detection in Patients with Metastatic Carcinomas. September 6, 2011; 105(6): 847-853
  • UpToDate External SiteSystemic Treatment for Metastatic Breast Cancer: General Principles. Daniel F. Hayes, M.D. Topic last updated September 2, 2015.
  • UpToDate External SiteProstate Cancer: Risk Stratification and Choice of Treatment. Eric A. Klein, M.D. Topic last updated November 14, 2013.
  • National Comprehensive Cancer Network (NCCN) External SiteVersion 2.2016 Breast Cancer; Version 2.2016 Colon cancer; Version 3.2016 Prostate Cancer.
  • National Academy of Clinical Biochemistry (NACB). The use of tumor markers in testicular, prostate, colorectal, breast and ovarian cancer. 2009. National Guideline Clearinghouse External Site
  • UpToDate External SitePrognostic and Predictive Factors in Metastatic Breast Cancer, Stephen Chia, M.D., FRCPC, Topic last updated November 3, 2014.
  • UpToDate External SiteOverview of the Treatment of Disseminated Prostate Cancer, Nancy A. Dawson, M.D., Topic last updated March 8, 2016.
  • American Society of Clinical Oncology (ASCO), Use of Biomarkers to Guide Decisions on Systemic Therapy for Women with Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline, Journal of Clinical Oncology, J Clin Oncol 33 2015.
  • UpToDate External SitePrognostic and Predictive Factors in Early, Non-Metastatic Breast Cancer, Theodoros Foukakis M.D., PhD, Jonas Bergh, M.D., PhD, FRCP. Topic last updated March 26, 2016.
  • Janssen Diagnostics. CellSearch. Also available at www/cellsearchctc.com
  • Harris L, Ismaila N, McShane L, et. al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women and Early Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology Volume 34, Number 10 Aprila 1, 2016
  • Huang X, Gao P, Song Y, et. al. Meta-analysis of the prognostic value of circulating tumor cells detected with CellSearch System in colorectal cancer. BMC Cancer. 2015;15:202. PMID 25880692
  • Bork U, Rahbari NN, Scholch S, et. al. Circulating tumor cells and outcome on non-metastatic colorectal cancer: a prospective study. Br J Cancer. Apr 14 2015;112(8):1306-1313. PMID 25867263
  • Okabe H, Tsunoda S, Hosogi H, et. al. Circulating tumor cells as an independent predictor of survival in advanced gastric cancer. Ann Surg Oncol. Mar 17 2015. PMID 25777087
  • Schulze K, Gash C, Staufer K, et. al. Presence of EpCAM-positive circulating tumor cells in advanced head and neck cancer using the CellSearch system. Had Nec. Oct 2012;34(10):1440-1444. PMID 22076949
  • Khoja L, Lorigan P, Zhou C, et. al. Biomarker utility of circulating tumor cells in metastatic cutaneous melanoma. J Invest Dermatol. Dec 6 2013;133(6):1582-1590. PMID 23223143
  • Smerage JB, Barlow WE, Hortobagyi GN, et. al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer. SWOG S0500. J Clin Oncol. Nov 1 2014;32(31):3483-3489

Policy History:

  • September 2016 - Annual Review, Policy Renewed
  • October 2015 - Annual Review, Policy Renewed
  • November 2014 - Annual Review, Policy Revised
  • January 2014 - Annual Review, Policy Renewed
  • January 2013 - Annual Review, Policy Renewed
  • January 2012 - Annual Review, Policy Renewed
  • January 2011 - Annual Review, Policy Renewed

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.