Archived Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Breast Cancer

Number:SUR703.038

Effective Date:07-15-2017

End Date:06-14-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Autologous or allogeneic hematopoietic stem-cell transplantation is considered experimental, investigational and/or unproven to treat any stage of breast cancer.

NOTE: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.

Description:

Hematopoietic Stem-Cell Transplantation

Hematopoietic stem-cell transplantation (HSCT) refers to a procedure in which hematopoietic stem-cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole-body radiation therapy. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem-cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease (GVHD).

Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigen (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the Class I and Class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

HSCT in Solid Tumors in Adults

The use of high-dose chemotherapy (HDC) and HSCT, instead of standard-dose chemotherapy, has been used in an attempt to prolong survival in women with high-risk nonmetastatic and metastatic breast cancer.

HSCT is an established treatment for certain hematologic malignancies; however, its use in solid tumors in adults continues to be largely experimental. Initial enthusiasm for the use of autologous transplant with the use of HDC and stem-cells for solid tumors has waned with the realization that dose intensification often fails to improve survival, even in tumors with a linear-dose response to chemotherapy. With the advent of reduced-intensity allogeneic transplant, interest has shifted to exploring the generation of alloreactivity to metastatic solid tumors via a graft-versus-tumor effect of donor-derived T cells.

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (26) Hematopoietic stem-cells are included in these regulations.

Rationale:

High-dose chemotherapy (HDC) followed by hematopoietic stem-cell transplant (HSCT) (i.e., blood or marrow) is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, bone marrow, or umbilical cord blood stem-cells.

The literature search of the MedLine database for this medical policy was updated through May 2017. The following is a summary of the key literature to date.

History of HSCT for Breast Cancer

In the late 1980s/early 1990s, initial results of phase II trials for breast cancer and autologous HSCT were promising, showing high response rates in patients with metastatic disease who underwent high-dose consolidation, with a subset of up to 30% remaining disease-free for prolonged periods. (1) In the early 1990s, larger prospective comparisons of conventional-dose chemotherapy to high-dose therapy with HSCT were initiated but accrued slowly, with up to a decade from initiation to the reporting of results. (1) The first results from randomized trials at a single institution in early stage and metastatic disease showed survival benefits but were ultimately shown to have been based on fraudulent data. (1) In the interim, however, the treatment became almost standard of care, while many patients received high-dose therapy off protocol, further reducing accrual to ongoing randomized trials. (1) The results of the randomized trials were presented beginning in 1999 and showed little survival benefit; subsequently, the number of HSCT procedures performed for breast cancer decreased from thousands every year to only a few. (1)

Autologous HSCT

The PBT-1 trial randomly assigned patients with a complete response (CR) or partial response (PR) to induction therapy for previously untreated metastatic breast cancer to autologous HSCT (n=101) or to conventional-dose maintenance chemotherapy (n=83) for up to 2 years. (2) Of 553 patients enrolled and given initial induction therapy, only 310 achieved a PR (n=252) or CR (n=58), and only 199 were randomized. Of 72 partial responders assigned to the HSCT arm after initial induction therapy, only 5 (7%) were converted to CR. Median survival (24 months versus 26 months, respectively) and overall survival (OS) at 3 years (32% versus 38%, respectively) did not differ between arms. There also were no statistically significant differences between arms in time to progression or progression-free survival (PFS) at 3 years. While treatment duration was substantially shorter for those randomly assigned to HSCT, acute morbidity was markedly more severe than after conventional-dose maintenance.

During 2003 and 2004, 4 trials reported final outcomes analyses from randomized comparisons of autologous HSCT versus conventional-dose chemotherapy for adjuvant therapy of high-risk nonmetastatic breast cancer. (3-6) Two of the studies involved women with at least 4 positive axillary lymph nodes, and the other 2 involved at least 10 positive lymph nodes. The 4 studies pooled included 2337 patients.

Evidence from these trials did not support the conclusion that autologous HSCT improved outcomes compared with conventional-dose adjuvant therapy, because no OS difference was seen in any of the studies. An accompanying editorial briefly reviewed and commented on factors contributing to the diffusion of autologous HSCT into routine practice of the treatment of certain breast cancer patients, without adequate testing in randomized controlled trials (RCTs). (7)

A Cochrane systematic review and meta-analysis published in July 2005 pooled data from 6 RCTs on metastatic breast cancer reported through November 2004 (438 randomly assigned to autologous HSCT, 412 to conventional-dose therapy). (8) The relative risk (RR) for treatment-related mortality (TRM) was significantly higher in the arm randomly assigned to HSCT (15 deaths versus 2 deaths; RR=4.07; 95% confidence interval [CI], 1.39 to11.88). Treatment-related morbidity also was more severe among those randomly assigned to HSCT. OS did not differ significantly between groups at 1, 3, or 5 years posttreatment. Statistically significant differences in event-free survival (EFS) at 1 year (RR=1.76; 95% CI, 1.40 to 2.21) and 5 years (RR=2.84; 95% CI, 1.07 to 7.50) favored the HSCT arms. Only 1 of the 6 included trials had followed all patients for at least 5 years. Reviewers recommended further follow-up for patients randomized in the other 5 trials. They also concluded that, in the interim, patients with metastatic breast cancer should not receive HSCT outside of a clinical trial because available data showed greater TRM and toxicity without improved OS.

A second Cochrane systematic review and meta-analysis, also published in July 2005, included data from 13 RCTs on patients with high-risk (poor prognosis) early breast cancer (2535 randomly assigned to HSCT, 2529 to conventional-dose therapy). (9) TRM was significantly greater among those randomly assigned to HDC (65 deaths) than to autologous cell transplantation (4 deaths; RR=8.58; 95% CI, 4.13 to 17.80). Treatment-related morbidity also was more common and more severe in the high-dose arms. There were no significant differences between arms in OS rates at any time after treatment. EFS was significantly greater in the HSCT group than the HSCT group at 3 years (RR=1.12; 95% CI, 1.06 to 1.19) and 4 years (RR=1.30; 95% CI, 1.16 to 1.45) after treatment. However, the 2 groups did not differ significantly with respect to EFS at 5 and 6 years’ posttreatment. Quality-of-life scores were significantly worse in the HSCT arms than in controls soon after treatment, but differences were no longer statistically significant by 1 year. Reviewers concluded that available data were insufficient to support routine use of HSCT for patients with poor-prognosis early breast cancer.

Hanrahan et al., with a median follow-up of 12 years, demonstrated no recurrence-free or OS advantage for patients with high-risk primary breast cancer treated with autologous HSCT after standard-dose chemotherapy (n=39) versus standard chemotherapy alone (n=39). (10) Coombes et al. reported on autologous HSCT as adjuvant therapy for primary breast cancer in women free of metastatic disease, with a median follow-up of 68 months. (11) A total of 281 patients were randomly assigned to receive standard chemotherapy or HDC with HSCT. They found no significant difference in relapse-free survival or OS (OS hazard ratio [HR], 1.18; 95% CI, 0.80 to 1.75; p=0.40).

A systematic review and meta-analysis published in 2007 included RCTs comparing autologous HSCT with standard-dose chemotherapy in women with early, poor-prognosis breast cancer, which included 13 trials to September 2006 (total N=5064 patients). (12) Major conclusions were that, at 5 years, EFS approached statistical significance for the high-dose group, but no OS differences were seen. There were more transplant-related deaths in the high-dose group. The overall conclusion was that there was insufficient evidence to support routine use of autologous HSCT for treating early, poor-prognosis breast cancer.

Crump et al. reported the results of a randomized trial of women who had not previously been treated with chemotherapy and had metastatic breast cancer or locoregional recurrence after mastectomy. (13) After initial response to induction therapy, 112 women were allocated to standard chemotherapy and 112 to autologous HSCT. After a median follow-up of 48 months, 79 deaths were observed in the high-dose group and 77 in the standard chemotherapy group. No difference in OS was observed between groups after a median follow-up of 48 months, with a median OS of 24 months in the HSCT group (95% CI, 21 to 35 months) and 28 months for the standard chemotherapy group (95% CI, 22 to 33 months; HR=0.9; 95% CI, 0.6 to 1.2; p=0.43).

Biron et al. reported the results of a phase 3, open, multicenter, prospective trial of women with metastatic breast cancer (and/or local or regional relapse beyond curative treatment by surgery or radiotherapy). (14) After a CR or at least 50% PR to induction therapy, 88 women were randomly assigned to HSCT and 91 to no further treatment. No OS difference was seen between groups, with 3-year survival of 33.6% in the high-dose group and 27.3% in the observation group (p=0.8).

Zander et al. reported survival data after 6 years of follow-up (15) on a trial that had previously reported to 3.8 years of follow-up. (6) Women with surgically resected breast cancer and axillary lymph node dissection with 10 or more positive axillary lymph nodes but no evidence of metastatic disease were randomly assigned to standard chemotherapy (n=152) or HSCT (n=150). No difference in OS was observed; the estimated 5-year OS rate in the standard arm was 62% (95% CI, 54% to 70%) and 64% (95% CI, 56% to 72%) in the high-dose transplant group.

Nieto and Shpall (2009) performed a meta-analysis of all randomized trials published or updated since 2006, focusing on those that compared HDC with standard-dose chemotherapy for high-risk primary breast cancer. (16) The meta-analysis of 15 randomized trials involving patients with high-risk primary breast cancer or metastatic disease (total N=6102 patients) detected an absolute 13% EFS benefit in favor of HDC and autologous HSCT (p<0.001) at a median follow-up of 6 years. The absolute differences in disease-specific and OS was not statistically significant (7% and 5%, respectively). Subset analyses suggested that HDC could be particularly effective in patients with triple-negative tumors (hormone receptor and HER2-negative [human epidermal growth factor receptor 2]). The authors concluded that HDC remains a valid research strategy in certain subpopulations with high-risk primary breast cancer (e.g., those with triple-negative tumors).

Berry et al. performed a meta-analysis with individual patient data from 15 randomized trials comparing autologous HSCT with HDC (n=3118) to standard chemotherapy (n=3092) for patients with high-risk primary breast cancer. (17) A survival analysis was adjusted for trial, age, number of positive lymph nodes, and hormone receptor status. HSCT was associated with a nonsignificant 6% reduction in risk of death (HR=0.94; 95% CI, 0.87 to 1.02; p=0.13) and a significant reduction in the risk of recurrence (HR=0.87; 95% CI, 0.81 to 0.93; p<0.001). Toxic death was higher in the HSCT group (6% [72/1207] deaths in these trial arms versus 1.4% [17/1261] deaths in the standard therapy arms). In a subgroup analysis, the authors investigated whether age, number of positive lymph nodes, tumor size, histology, hormone receptor status, or HER2 status impacted survival when comparing HSCT to standard treatment. The authors found that HER2-negative patients receiving HSCT had a 21% reduction in the risk of death and HER2-negative and hormone receptor negative patients receiving HSCT had a 33% reduction in the risk of death. In their discussion, the authors noted that this relation could be spurious due to the amount of missing data on HER2 status and suggested that HSCT is unlikely to show much benefit in these subgroups of patients.

A meta-analysis by Wang et al. included aggregate data from 14 trials (total N=5747 patients) published since March 2010. (18) Clinical trials of patients receiving HSCT as a first-line treatment for primary breast cancer were eligible for inclusion. A higher TRM was found among the patients who received HSCT compared with standard chemotherapy (RR=3.42; 95% CI, 1.32 to 8.86). OS did not differ significantly between groups (HR=0.91; 95% CI, 0.82 to 1.00) for the HSCT compared with standard treatment. Risk of secondary, non-breast cancer was higher in the HSCT group (RR=1.28; 95% CI, 0.82 to 1.98). DFS was better in the HSCT group than in the chemotherapy-alone group (RR=0.89; 95% CI, 0.79 to 0.99). Patients receiving HSCT had a greater risk of dying during remission than patients treated with nonmyeloablative chemotherapy because of regimen toxicity. This increase in TRM may help explain why there was no observed OS benefit for patients receiving HSCT when disease-free survival was observed to be superior to standard chemotherapy.

In 2013, the Italian Group of Bone Marrow and Hematopoietic Stem-Cell Transplantation and Cellular Therapy (GITMO) published registry data on 415 patients with metastatic breast cancer who received HDC and autologous HSCT between 1990 and 2005. (19) More than 95% of the transplants performed used peripheral blood stem-cells. Sixteen percent of patients received a tandem transplant. Estrogen receptor (ER) status was known in 328 patients, 65% of whom were ER positive. HER2 expression data were insufficient for subset analysis. After a median follow-up of 27 months (range, 0-172 months), PFS at 5 and 10 years was 23% and14% and OS was 47% and 32%, respectively. The authors reported statistically significant survival benefits in patient subgroups including those with ER-positive tumors and those without visceral metastases; however, these are established positive prognostic factors compared with factors for patients with ER-negative tumors and visceral metastases, respectively. In addition, the authors did not report which patients received hormonal therapy, nor was it known if/which patients received targeted HER2 therapy, and it is unclear what impact on survival therapies other than HSCT may have had.

In 2014, GITMO published registry data on the use of adjuvant HDC with autologous HSCT in 1183 patients with high-risk primary breast cancer (≥3 involved lymph nodes), treated between 1990 and 2005. (20) Data on ER and HER2 status were available for 85% and 48% of patients, respectively. Most patients with hormone receptor-positive tumors received tamoxifen after HSCT. The median lymph node involvement at surgery was 15 (range, 4-63). More than 95% of the patients received peripheral blood-mobilized stem-cells. After a median follow-up of 7.1 years, disease-free survival was 9.6 years, with 65% of patients free of disease at 5 years. Median OS was not reached, with 75% of patients alive at 5 years posttransplantation. Subgroup analysis showed significantly better OS in endocrine responsive tumors and in patients who received multiple transplant procedures. Transplant-related mortality was 0.8% and late cardiac and secondary tumor-related mortality were approximately 1% overall.

Tandem Autologous Transplantation

Kroger et al. compared single versus tandem autologous HSCT in 187 patients with chemotherapy-sensitive metastatic breast cancer. (21) Only 52 of 85 patients completed the second HDC cycle in the tandem arm, mostly due to withdrawal of consent (most common reason), adverse effects, progressive disease, or death. The rate of CR was 33% in the single-dose arm versus 37% in the tandem arm (p=0.48). Although there was a trend toward improved PFS after tandem HSCT, median OS tended to be greater after single (29 months) versus tandem HDC (23.5 months; p=0.4). The authors concluded that tandem HSCT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter OS and higher toxicity compared with single HSCT.

Schmid et al. published results of 93 patients without prior chemotherapy for metastatic breast cancer who were randomly assigned to standard-dose chemotherapy or double HDC with autologous HSCT. (22) The primary study objective was to compare CR rates. Objective response rates for patients in the high-dose group were 66.7% versus 64.4% for the standard group (p=0.82). There were no significant differences between the 2 treatments in median time to progression, duration of response, or OS (double high-dose arm, 26.9 months versus standard arm, 23.4 months; p=0.60).

Allogeneic HSCT

To date, allogeneic HSCT for breast cancer has mostly been used in patients who have failed multiple lines of conventional chemotherapy. (23)

Ueno et al. reported the results of allogeneic HSCT in 66 women with poor-risk metastatic breast cancer from 15 centers who underwent transplantation between 1992 and 2000. (24) Thirty-nine (59%) received myeloablative and 27 (41%) received reduced-intensity conditioning (RIC) regimens. A total of 17 (26%) patients had received a prior autologous HSCT. Median follow-up time for survivors was 40 months (range, 3-64 months). TRM was lower in the RIC group (7% versus 29% at 100 days; p=0.03). PFS at 1 year was 23% in the myeloablative group and 8% in the RIC group (p=0.09). OS rates after myeloablative conditioning versus RIC were 51% (95% CI, 36% to 67%) versus 26% (95% CI, 11% to 45%; p=0.04) at 1 year, 25% (95% CI, 13% to 40%) versus 15% (95% CI, 3% to 34%; p=0.33) at 2 years, and 19% (95% CI, 8% to 33%) versus 7% (95% CI, <1% to 25%; p=0.21) at 3 years, respectively.

Fleskens et al. reported the results of a phase 2 study of 15 patients with metastatic breast cancer treated with human leukocyte antigen (HLA)-matched reduced-intensity allogeneic HSCT. (25) Median patient age was 49.5 years (range, 39.7-60.8 years), and all patients had been extensively pretreated and had undergone at least 1 palliative chemotherapy regimen for metastatic disease. TRM was 2 (13%) of 15. One-year PFS was 20%, and 1- and 2-year OS were 40% and 20%, respectively. The authors noted no objective tumor responses but concluded that the relatively long PFS suggested a graft-versus-tumor effect.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01646034

High-dose Alkylating Chemotherapy in Oligo-metastatic Breast Cancer Harboring Homologous Recombination Deficiency

86

Jul 2019

NCT02670109

Autologous Hematopoietic Stem-cell Transplantation as Adjuvant Treatment for Triple Negative Breast Cancer Patients

20

Nov 2017

NCT02183805

Chemotherapy Followed by Peripheral Stem-cell Transplantation in Treating Metastatic Triple-negative Breast Cancer

30

Dec 2017

Table Key:

NCT: National Clinical Trial.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

NCCN guidelines (v2.2017 – April 6, 2017) do not address the use of HSCT in the treatment of breast cancer. (27)

Summary of Evidence

Randomized trials of autologous hematopoietic stem-cell transplantation (HSCT) versus standard dose-chemotherapy for patients with high-risk nonmetastatic or metastatic breast cancer have not shown a survival advantage with HSCT, and have shown greater treatment-related mortality and toxicity. Therefore, autologous HSCT is considered experimental, investigational and/or unproven for this indication.

Nonrandomized studies using reduced-intensity or myeloablative allogeneic HSCT for metastatic breast cancer have suggested a possible graft-versus-tumor effect, but remains experimental, investigational and/or unproven for this indication.

Contract:

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.

Coding:

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.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Vogl DT, Stadtmauer EA. Editorial: high-dose chemotherapy and autologous hematopoietic stem-cell transplantation for metastatic breast cancer: a therapy whose time has passed. Bone Marrow Transplant. Jun 2006; 37(11):985-7. PMID 16708060

2. Stadtmauer EA, O’Neill A, Goldstein LJ, et al. Convention-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med. Apr 13 2000; 342(15):1069-76. PMID 10760307

3. Leonard RC, Lind M, Twelves C, et al. Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. J Nat Canc Inst. Jul 24 2004; 96(14):1076-83. PMID 15265969

4. Rodenhuis S, Bontenbal M, Beex LV, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med. Jul 3 2003; 349(1):7-16. PMID 12840087

5. Tallman MS, Gray R, Robert NJ, et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med. Jul 3 2003; 349(1):17-26. PMID 12840088

6. Zander AR, Kroger N, Schmoor C, et al. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol. Jun 15 2004; 22(12):2273-83. PMID 15111618

7. Hortobagyi GN What is the role of high-dose chemotherapy in the era of targeted therapies? J Clin Oncol. Jun 15 2004; 22(12):2263-6. PMID 15111620

8. Farquhar C, Marjoribanks J, Basser R, et al. High dose chemotherapy and autologous bone marrow or stem-cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Data System Rev. 2005; (3):CD003139. PMID 16034887

9. Farquhar C, Marjoribanks J, Basser R, et al. High dose chemotherapy and autologous bone marrow or stem-cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. Cochrane Data System Rev. 2005; (3):CD003142. PMID 16034886

10. Hanrahan EO, Broglio K, Frye D, et al. Randomized trial of high-dose chemotherapy and autologous hematopoietic stem-cell support for high-risk primary breast carcinoma: follow-up at 12 years. Cancer. Jun 1 2006; 106(11):2327-36. PMID 16639731

11. Coombes RC, Howell A, Emson M, et al. High dose chemotherapy and autologous stem-cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomized trial. Ann Oncol. May 2005; 16(5):726-34. PMID 15817602

12. Farquhar CM, Marjoribanks J, Lethaby A, et al. High dose chemotherapy for poor prognosis breast cancer: systematic review and meta-analysis. Cancer Treat Rev. Jun 2007; 33(4):325-37. PMID 17382477

13. Crump M, Gluck S, Tu D, et al. Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem-cell support compared with standard-dose chemotherapy in women with metastatic breast cancer: NCIC MA.16. J Clin Oncol. Jan 1 2008; 26(1):37-43. PMID 18025439

14. Biron P, Durand M, Roche H, et al. Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem-cell transplantation in first-line treatment of metastatic breast cancer. Bone Marrow Transplant. Mar 2008; 41(6):555-62. PMID 18037940

15. Zander AR, Schmoor C, Kroger N, et al. Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: overall survival after 6 years of follow-up. Ann Oncol. Jun 2008; 19(6):1082-9. PMID 18304964

16. Nieto Y, Shpall EJ. High-dose chemotherapy for high-risk primary and metastatic breast cancer: is another look warranted? Curr Opin Oncol. Mar 2009; 21(2):150-7. PMID 19532017

17. Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials. J. Clin Oncol. Aug 20 2011; 29(24):3214-23. PMID 21768471

18. Wang J, Zhang Q, Zhou R, et al. High-dose chemotherapy followed by autologous stem-cell transplantation as a first-line therapy for high-risk primary breast cancer: a meta-analysis. PLoS One. 2012; 7(3):e33388. PMID 22428041

19. Martino M, Ballestrero A, Zambelli A, et al. Long-term survival in patients with metastatic breast cancer receiving intensified chemotherapy and stem-cell rescue: data from the Italian registry. Bone Marrow Transplant. Mar 2013; 48(3):414-8. PMID 22863724

20. Pedrazzoli P, Martinelli G, Gianni AM, et al. Adjuvant High-Dose Chemotherapy with Autologous Hematopoietic Stem-cell Support For1183 High-Risk Primary Breast Cancer: Results From The Italian National Registry. Biol Blood Marrow Transplant. Apr 2013; 20(4):501-6. PMID 24374214

21. Kroger N, Frick M, Gluz, O, et al. Randomized trial of single compared with tandem high-dose chemotherapy followed by autologous stem-cell transplantation in patients with chemotherapy-sensitive metastatic breast cancer. J Clin Oncol. Aug 20 2006; 24(24):1919-26. PMID 16921043

22. Schmid P, Schippinge W, Nitsch T, et al. Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. J Clin Oncol. Jan 20 2005; 23(3):432-40. PMID 15659490

23. Carella AN, Bregni M. Current role of allogeneic stem-cell transplantation in breast cancer. Ann Oncol. Oct 2007; 18(10):1591-3. PMID 17846023

24. Ueno NT, Rizzo JD, Demirer T, et al. Allogeneic hematopoietic cell transplantation for metastatic breast cancer. Bone Marrow Transplant. Mar 2008; 41(6):537-45. PMID 18084340

25. Fleskens AJ, Lalisang RI, Bos GM, et al. HLA-matched allo-SCT after reduced intensity conditioning with fludarabine/CY in patients with metastatic breast cancer. Bone Marrow Transplant. Mar 2010; 45(3):464-7. PMID 19633692

26. Food and Drug Administration (FDA). Tissue and Tissue Products. Available at <http://www.fda.gov> (accessed September 22, 2015).

27. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Breast Cancer V.2.2017 – April 6, 2017. Available at <http://www.nccn.org> (accessed June 16, 2017).

28. Hematopoietic Stem-Cell Transplantation for Breast Cancer. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2015 February) Therapy 8.01.27 (Archived).

Policy History:

Date Reason
7/15/2017 Document updated with literature review. Coverage unchanged.
6/1/2016 Reviewed. No changes.
1/1/2015 Document updated with literature review. Coverage language modified, without change to coverage position. CPT/HCPCS code(s) updated. Title changed from: Stem-Cell Transplant for Breast Cancer.
10/15/2013 Document updated with literature review. The following was added: 1) Donor leukocyte infusion and hematopoietic progenitor cell boost are considered experimental, investigational and unproven; and 2) Any related services for the treatment of breast cancer, such as short tandem repeat (STR) markers, are considered experimental, investigational and unproven. O therwise, coverage unchanged. Description and Rationale significantly revised.
4/1/2010 New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem-cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies. Stem-cell transplant remains experimental, investigational and unproved when used to treat breast cancer. [NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; Cord Blood as a Source of Stem-cells; Donor Leukocyte Infusion (DLI); and Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies.

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