BlueCross and BlueShield of Montana Medical Policy/Codes
Detection of Circulating Tumor Cells in the Management of Patients with Cancer
Chapter: Medicine: Tests
Current Effective Date: October 25, 2013
Original Effective Date: December 21, 2010
Publish Date: October 25, 2013
Revised Dates: August 13, 2012; September 27, 2013
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 short survival. CTCs are malignant cells that are found in the peripheral blood and originate from primary or metastatic tumors.   The detection of CTCs might be useful for assessing prognosis and guiding cancer therapy.

Background

CTCs could potentially provide prognostic 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 women with metastatic breast cancer.  CTCs have also been investigated as an additional prognostic factor in nonmetastatic breast cancer and could be used to determine the need for additional adjuvant chemotherapy.

Detection Methods

Research over the past ten years has focused on 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 site hybridization (FISH) have been added to provide required specificity.

The CellSearch™ system (Veridex) is an example of immunofluorescent technology.  The technique involves identification of the CTCs 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.

This policy does not address techniques for the detection of disseminated tumor cells, e.g., in bone marrow.

Regulatory Status

The CellSearch™ system (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).  Veridex LLC, a Johnson & Johnson company, markets the CellSearch system.  It 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.  As of April 2011, the CellSearch system remains the only FDA-cleared system for assessing CTCs, and the indications for its use are unchanged.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

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

Rationale

This policy was originally created in 2010 and was updated with searches of the MEDLINE database.  The most recent peer reviewed literature search was performed through September 2011.  Following is a summary of the key literature to date.

The first prospective study using the CellSearch system to predict prognosis of patients with metastatic breast cancer was published by Cristofanilli and colleagues in 2004.  This multicenter study included 177 patients with measurable metastatic breast cancer who were followed up for 38.7 weeks or longer.  Using the CellSearch System (Veridex LLC), they measured the number of circulating tumor cells (CTCs) before initiating a new line of therapy and at first follow-up (4.5 +/- 2.4 weeks after baseline sample).  Also tested were 145 normal subjects and 200 patients with benign breast diseases.  The authors report detecting two or fewer epithelial cells per 7.5 milliliters (mL) of blood in all normal subjects and patients with benign breast diseases.  Using a statistically validated threshold of five cells per 7.5 mL of blood, they found that patients below threshold at baseline (n=90; 51%) had longer median progression-free survival (PFS) (7.0 vs. 2.7 months, respectively; p<0.001) and overall survival ([OS] greater than 18 months vs. 10.1 months, respectively; p<0.001) than those above threshold (n=87; 49%).  Survival duration of a subgroup (n=33) with values above threshold at baseline but below threshold at first follow-up (i.e., after the first cycle of therapy) was similar to that of patients below threshold at baseline.  This subgroup’s median survival also was significantly longer than survival of those who remained above threshold despite therapy.  Multivariate analysis showed that being below threshold for level of CTCs was the most statistically significant independent predictor of longer PFS and OS of all parameters studied, including hormone receptor status, HER-2/neu status, site of metastases, etc.

Nole and colleagues tested 80 patients with metastatic breast cancer for CTC levels before starting a new treatment and after four weeks, eight weeks, at the first clinical evaluation, and every two months thereafter.  Forty-nine patients had five or more cells at baseline.  At the multivariate analysis, baseline number of CTCs was associated with progression-free survival ([PFS] hazard ratio [HR] 2.5; 95% confidence interval [CI] 1.2–5.4).  The risk of progression for patients with five or more CTCs at the last available follow-up was five times the risk of patients with 0–4 CTCs at the same point (HR 5.3; 95% CI: 2.8–10.4).  Patients with rising or persistent counts of five or more CTCs at last available follow-up showed a statistically significant higher risk of progression with respect to patients with less than five CTCs at both times of blood sampling.  The authors concluded that circulating tumor cell basal value is a predictive indicator of prognosis that changes in CTC levels during therapy may indicate a clinical response, and that testing CTC levels during targeted treatments might substitute for other parameters to determine response to therapy.

In 2008, Dawood and colleagues published a retrospective study to assess the prognostic value of baseline CTCs in patients with metastatic breast cancer.  The study included patients (n=185) who were newly diagnosed.  Overall survival was calculated from the date CTCs were measured.  Median OS was 28.3 months (range 27.7–36.8 months) in those with CTCs of less than 5, and 15 months (range: 12.7–18.2 months) for patients with CTCs of five or more.  The difference in one-year survival of 23.9%, favoring patients with less than five CTCs was observed, regardless of hormone receptor and HER-2/neu status, site of first metastases, or whether the patient had recurrent or de novo metastatic disease.  The authors conclude that CTCs should be considered a new stratification method for women with newly diagnosed metastatic breast cancer.  However, the impact of these data on clinical care and patient outcomes is uncertain.

In 2008, a prospective study was conducted by Yagata and colleagues to evaluate the clinical utility of CTC levels in patients with metastatic breast cancer who were being treated at three institutions in Japan.  The study included patients (n=38) with a confirmed diagnosis of progressive, metastatic breast cancer prior to initiation of new systemic therapy.  With cutoff value set at two CTCs, sensitivity to distant metastasis was 50% (19/38) and specificity was 96.7% (29/30), with a cutoff score of five CTCs, both PFS and OS were worse for this patient population than for the population with fewer than five CTCs.  The authors concluded that for patients with breast cancer, measuring CTC levels can be both an indicator of metastases and an important measure of patient prognosis.  Limitations of this study include the small sample size and the variable cutoff levels.

A prospective multicenter industry-sponsored study by Cohen and colleagues, published in 2008, examined the association of CTCs to survival in patients with metastatic colorectal cancer.  To be eligible, patients needed to be initiating any first- or second-line systemic therapy, or third-line therapy with an epidermal growth factor receptor (EGFR) inhibitor.  CTCs were assessed at baseline and at regular intervals after starting treatment.  The authors conducted a pre-planned interim analysis using data from the first 109 patients (training set) to determine the optimal cutoff for an elevated cell count and the optimal length of time after initiating therapy to measure CTC level.  They determined that levels of CTCs at the 3 to 5 week follow-up correlated most highly with response at first imaging study (6-12 weeks after initiating treatment), and that at least three CTCs per 7.5 mL blood was the optimal threshold. The primary outcome was the agreement between CTC level at the 3-5 week follow-up and response to therapy.  Agreement was defined as either a non-elevated level of CTC corresponding to lack of disease progression or an elevated level corresponding to progressive disease.  Data from the training set and from the remaining patients (validation set) were combined in the main analysis.  A total of 481 patients were enrolled; 37 were found after enrollment not to meet eligibility criteria, six withdrew consent, and eight were excluded for other reasons, leaving 430 evaluable patients.  Only 320 patients, however, were assessable for the primary outcome.  (The authors did not specify how many of these patients had been included in the training set).  One-hundred and ten patients did not have a follow-up blood analysis or imaging, and data on eight were unavailable for other reasons.  Thirty-eight of 320 (12%) had elevated levels of CTCs 3-5 weeks after starting treatment.  By the end of the study, 20 of these 38 patients (53%) had progressive disease or were unavailable because they had died before receiving a follow-up imaging study.  In comparison, 54 of the 282 (19%) patients without elevated CTCs at the 3- to 5-week follow-up had progressive disease or had died (p value not reported).  Median PFS and OS, secondary outcomes, by baseline and post-treatment initiation CTC status are shown in the table below:

Level of circulating tumor cells   

Baseline  

3-5 week follow-up 

N (%) 

Median PFS in months (95% CI) 

N (%) 

Median OS in months (95% CI) 

Not elevated 

Not elevated 

226 (72)

7.3 (6.0-7.8)

227 (71)

17.7 (14.7-19.9)  

Elevated 

Not elevated 

52 (16) 

6.2 (4.6-7.0) 

53 (17) 

11.0 (8.7-18.1)  

Not elevated 

Elevated 

9 (13) 

6.0 (0.5 to --)  

9 (3) 

10.9 (0.6 to --)  

Elevated 

Elevated 

28 (9) 

1.6 (1.2-2.7) 

30 (9) 

3.7 (2.4-8.4) 

Elevated=at least 3 circulating tumor cells (CTC) per 7.5 mL blood

PFS=progression-free survival

OS=overall survival

Both PFS and OS were highest for patients with nonelevated CTCs at both time points, lowest for those with elevated CTCs at both timepoints, and at intermediate levels for those with elevated CTCs at only one time point.  The median PFS and median OS were significantly longer in patients who did not have elevated CTCs at either time point than the patients who had elevated CTCs at both time points.  Overall survival, but not PFS, was significantly longer in the group without elevated CTCs at either time compared to those whose CTCs were elevated at baseline and then decreased at 3 to 5 weeks.  Only nine patients experienced an increase in CTCs from baseline to 3 to 5 weeks.  Study limitations include that only 320 of 481 enrolled patients (67%) were included in the primary analysis.  Additional prospective studies using the same cutoff are needed to confirm the prognostic value of the three cells per 7.5 mL blood cutoff which differs from the five cells per 7.5 mL cutoff used in most other studies.  Moreover, as the authors state in their conclusion, this study was not designed to evaluate whether patient management decisions based on CTC level is beneficial.

Another prospective multicenter industry-sponsored study, by de Bono and colleagues, addressed CTC levels and prostate cancer.  The study included patients with castration-resistant progressive prostate cancer who were initiating a new cytotoxic therapy.  CTC levels were measured using the CellSearch system at baseline and before each course of therapy until disease progression or for up to 18 months.  A total of 276 patients were enrolled; of these, 33 were subsequently found to not meet eligibility criteria (e.g., did not have an evaluable baseline blood sample or scan or lacked progressive disease) and two patients withdrew consent, leaving 231 patients in the analysis.  At baseline, 219 patients were evaluable for CTCs; of these, 125 had elevated levels (5 or more cells per 7.5 mL of blood), and 94 had less than 5 cells per mL.  The primary study outcome was the association between elevated CTCs 2 to 5 weeks after initiating treatment and OS.  The authors did not report their reasons for selecting the 2 to 5 week follow-up point.  An evaluable CTC was available for 203 patients at the 2 to 5 week follow-up, and CTCs were elevated in 39 (19%).  The group of patients with elevated CTCs after initiating treatment had a significantly shorter median survival time (9.5 months) than those without elevated CTC (20.7 months), p<0.0001.  Moreover, patients with elevated CTCs at all time points (n=71) had the shortest median OS, 6.8 months.  Their OS was significantly shorter than other groups, specifically the group of patients with elevated baseline CTCs who converted to a nonelevated level after treatment (n=45, median OS 21.3 months) and the group of patients with nonelevated CTCs throughout the study (n=88, median OS was greater than 26 months).  There were only 26 patients who had non-elevated CTCs at baseline and elevated CTCs after treatment; this group had a mean OS of 9.3 months.  A limitation of the study was that only 203 of the 276 enrolled patients (74%) were included in the primary analysis.  Similar to the studies discussed previously on metastatic breast and colorectal cancer, the de Bono et al. study did not evaluate the role of CTC level assessment in patient management.

Studies have also been published evaluating CTC level as a diagnostic and/or prognostic marker for patients with nonmetastatic breast cancer, as well as other types of cancer including lung, bladder, and gastric cancer.  There are no FDA-cleared tests for these indications, and none of the studies evaluated patient management decisions using levels of CTCs.

Despite numerous correlational studies, to complete the causal chain, there must be evidence that patient management decisions based on CTC levels increases the duration or quality of life or decreases adverse events.  To date, no studies have been published that prospectively evaluate health outcomes in patients managed with and without the monitoring of CTCs.

Practice Guidelines and Position Statements

The American Society of Clinical Oncology recommendation for the use of tumor markers in breast cancer, published in 2007, indicates 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.  These recommendations were current as of April 2011.  No guidelines were identified on use of CTCs to aid in the management of other types of cancer.

National Comprehensive Care Network (NCCN) 2011 Clinical Practice Guidelines on Breast Cancer recommend that all patients with breast cancer be assigned a clinical stage of disease and, if possible, a pathologic stage of disease.  They cite the 2010 American Joint Commission on Cancer’s (AJCC) revision in their cancer staging manual which includes, among other specifications, a new category of metastatic disease, called cM0(i+).  This stage is defined as “no clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without signs or symptoms of metastases.”  The NCCN guideline did not recommend that any specific tests be performed.

The NCCN colon cancer and prostate cancer guidelines do not mention circulating tumor cells.

Ongoing Clinical Trials

A search of ClinicalTrials.gov (available online) in April 2011 identified one study underway that is evaluating treatment decisions made based on the levels of CTCs.  This study, sponsored by the National Cancer Institute, is a randomized controlled trial of patients with metastatic breast cancer beginning first-line chemotherapy.  Patients who have elevated levels (5 or more cells per 7.5 mL of blood) of CTCs after their first round of chemotherapy will be randomized to stay on their current treatment or switch to a different treatment regimen.  Patients without elevated levels of CTCs will remain on their current treatment.  The primary outcomes are progression-free survival and survival.  The study is currently recruiting participants, and the expected date for completing data collection is September 2011.

Summary

While levels of CTCs may be associated with the presence of metastatic disease and prognosis, the prospective use of this information to impact care has not been demonstrated. Given the insufficient evidence to evaluate the impact on net health outcome, the assessment of CTCs is experimental, investigational and unproven for the management of cancer.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

Experimental, Investigational and Unproven for all diagnosis codes.

ICD-10 Codes

Experimental, Investigational and Unproven for all diagnosis codes.

Procedural Codes: 86152, 86153
References
  1. Cristofanilli M, Budd GT, Ellis MJ et al.  Circulating tumor cells, disease progression and survival in metastatic breast cancer.  N Engl J Med 2004; 351(8):781-91.
  2. 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; 25(33):5287-312.
  3. Nole F, Munzone E, Zorzino L et al.  Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications.  Ann Oncol 2008; 19(5):891-7.
  4. Dawood S, Broglio K, Valero V et al.  Circulating tumor cells in metastatic breast cancer: from prognostic stratification to modification of the staging system.  Cancer 2008; 113(9):2422-30.
  5. Yagata H, Nakamura S, Toi M et al.  Evaluation of circulating tumor cells in patients with breast cancer: multi-institutional clinical trial in Japan.  Int J Clin Oncol 2008; 13(3):252-6
  6. Cohen SJ, Punt CJ, Iannotti N et al.  Relationship of circulating tumor cells to tumor response, progression-free survival and overall survival in patients with metastatic colorectal cancer.  J Clin Oncol 2008; 26(19):3213-21.
  7. de Bono JS, Scher HI, Montgomery RB et al.  Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.  Clin Cancer Res 2008; 14(19):6302-9.
  8. 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.
  9. Guzzo TJ, McNeil BK, Bivalacqua TJ et al.  The presence of circulating tumor cells does not predict extravesical disease in bladder cancer patients prior to radical cystectomy.  Urol Oncol 2009 [Epub ahead of print].
  10. Bidard FC, Mathiot C, Delaloge S et al.  Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer.  Ann Oncol 2010; 21(4):729-33.
  11. Rink M, Chun FK, Minner S et al.  Detection of circulating tumor cells in peripheral blood of patients with advanced non-metastatic bladder cancer.  BJU Intl (2010 May) 107 (10):1668-75.   [Epub ahead of print].
  12. Matsusaka S, Chin K, Ogura M et al.  Circulating tumor cells as a surrogate marker for determining response to chemotherapy in patients with advanced gastric cancer.  Cancer Sci 2010; 101(4):1067-71.
  13. Serrano MJ, Lorente JA, Rodriguez MD et al.  Circulating tumour cells in peripheral blood: potential impact on breast cancer outcome.  Clin Transl Oncol 2011; 13(3):204-8.
  14. 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; 29(12):1556-63.
  15. National Comprehensive Care Network (NCCN) Clinical Practice Guidelines in Oncology.  Available online at: http://www.nccn.org .  Last accessed April 2011.
  16. Treatment decision making based on blood levels of tumor cells in women with metastatic breast cancer receiving chemotherapy (NCT00382018).  Sponsored by the National Cancer Institute. Last updated March 31, 2011.  Available online at: ClinicalTrials.gov .  Last accessed April 2011.
  17. Detection of Circulating Tumor Cells in the Management of Patients with Cancer.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference manual (2011 May) Medicine 2.04.37.
History
August 2012  Policy reviewed with literature search through March 2012. The policy statement is unchanged; reference numbers 1, 4, 5, 9, 13, 15 and 19 added; other references re-numbered/removed. 
October 2013 Policy formatting and language revised.  Policy statement unchanged.  Removed codes 0279T, 0280T, and S3711.
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Detection of Circulating Tumor Cells in the Management of Patients with Cancer