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

Randomized trials of autologous HCT versus standard dose chemotherapy for patients with high-risk nonmetastatic or metastatic breast cancer have not shown a survival advantage with HCT and have shown greater treatment-related mortality and toxicity. Therefore, autologous HCT is considered not medically necessary for this indication. 

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

Background 
Hematopoietic cell transplantation (HCT) refers to a procedure in which hematopoietic 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 radiotherapy. Hematopoietic cells may be obtained from the transplant recipient (autologous HCT) or from a donor (allogeneic HCT). 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 "naive" and thus are associated with a lower incidence of rejection or graft-versus-host disease (GVHD). Cord blood is discussed in greater detail in evidence review 70150.

Immunologic compatibility between infused hematopoietic cells and the recipient is not an issue in autologous HCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HCT. 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).

Preparative Conditioning for HCT
The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiotherapy to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic cells obtained from the patient before undergoing bone marrow ablation. As a consequence, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.

The conventional ("classical") practice of allogeneic HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect mediated by non-self-immunologic effector cells that develop after engraftment of allogeneic cells within the patient’s bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.

Reduced-Intensity Conditioning for Allogeneic HCT
Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden and to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of nonrelapse mortality and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells.

For our purposes, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (traditional) regimens.

HCT in Solid Tumors in Adults
HCT 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 high-dose chemotherapy 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 regulates human cells and tissues intended for implantation, transplantation or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations. 

Related Policies
70150 Parental and Umbilical Cord Blood as a Source of Stem Cells

Policy:
Single or tandem autologous hematopoietic cell transplantation is considered NOT MEDICALLY NECESSARY to treat any stage of breast cancer.

Allogeneic hematopoietic cell transplantation is INVESTIGATIONAL to treat any stage of breast cancer.

Policy Guidelines
In 2003, CPT centralized codes describing allogeneic and autologous hematopoietic cell transplant services to the hematology section (CPT 38204-38242). Not all codes are applicable for each high-dose chemotherapy/stem cell support procedure. For example, Plans should determine if cryopreservation is performed. A range of codes describes services associated with cryopreservation, storage and thawing of cells (38208 – 38215).

CPT 38208 and 38209 describe thawing and washing of cryopreserved cells 
CPT 38210 – 38214 describe certain cell types being depleted 
CPT 38215 describes plasma cell concentration 

Benefit Application:
BlueCard/National Account Issues
For indications considered investigational, the following considerations may supersede this policy:

• State mandates requiring coverage for autologous bone marrow transplantation offered as part of clinical trials of autologous bone marrow transplantation approved by the National Institutes of Health (NIH).
• Some plans may participate in voluntary programs offering coverage for patients participating in NIH-approved clinical trials of cancer chemotherapies, including autologous bone marrow transplantation.
• Some contracts or certificates of coverage (e.g., FEP) may include specific conditions in which autologous bone marrow transplantation would be considered eligible for coverage.

Rationale
History of Hematopoietic Cell Transplant for Breast Cancer
In the late 1980s/early 1990s, initial results of phase 2 trials for breast cancer and autologous hematopoietic cell transplant (HCT) 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 HCT 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 HCT procedures performed for breast cancer decreased from thousands every year to only a few.¹ 

Autologous HCT
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 HCT (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 HCT arm after initial induction therapy, only 5 (7%) were converted to CR. Median survival (24 months vs. 26 months, respectively) and overall survival (OS) at 3 years (32% vs. 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 HCT, 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 HCT versus conventional-dose chemotherapy for adjuvant therapy of high-risk nonmetastatic breast cancer.^3,4,5,6 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 2,337 patients.

Evidence from these trials did not support the conclusion that autologous HCT 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 HCT 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 HCT, 412 to conventional-dose therapy).⁸ The relative risk (RR) for treatment-related mortality (TRM) was significantly higher in the arm randomly assigned to HCT (15 deaths vs. 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 HCT. OS did not differ significantly between groups at 1, 3 or 5 years post-treatment. 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 HCT 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 HCT 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 (2,535 randomly assigned to HCT, 2,529 to conventional-dose therapy).⁹ TRM was significantly greater among those randomly assigned to high-dose chemotherapy (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 HCT group than the HCT 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 post-treatment. Quality-of-life scores were significantly worse in the HCT 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 HCT 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 HCT after standard dose chemotherapy (n=39) versus standard chemotherapy alone (n = 39).¹⁰ Coombes et al. reported on autologous HCT 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 HCT. 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 HCT with standard-dose chemotherapy in women with early, poor-prognosis breast cancer, which included 13 trials to September 2006 (total N = 5,064 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 HCT 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 HCT. 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 HCT 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 HCT 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-up¹⁵ 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 HCT (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 = 6,102 patients) detected an absolute 13% EFS benefit in favor of HDC and autologous HCT (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). 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 HCT with HDC (n = 3,118) to standard chemotherapy (n = 3,092) 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. HCT 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 HCT group (6% [72/1207] deaths in these trial arms vs. 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 human epidermal growth factor receptor 2 (HER2) status impacted survival when comparing HCT to standard treatment. The authors found that HER2-negative patients receiving HCT had a 21% reduction in the risk of death and HER2-negative and hormone receptor negative patients receiving HCT 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 HCT 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 = 5,747 patients) published since March 2010.¹⁸ Clinical trials of patients receiving HCT as a first-line treatment for primary breast cancer were eligible for inclusion. A higher TRM was found among the patients who received HCT 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 HCT compared with standard treatment. Risk of secondary, non-breast cancer was higher in the HCT group (RR = 1.28; 95% CI, 0.82 to 1.98). Disease-free survival was better in the HCT group than in the chemotherapy-alone group (RR = 0.89; 95% CI, 0.79 to 0.99). Patients receiving HCT 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 HCT 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 HCT 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 HCT may have had. 

In 2014, GITMO published registry data on the use of adjuvant HDC with autologous HCT in 1,183 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 HCT. 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 post-transplantation. 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 HCT 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 HCT, median OS tended to be greater after single (29 months) versus tandem HDC (23.5 months; p = 0.4). The authors concluded that tandem HCT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter OS and higher toxicity compared with single HCT.

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 HCT.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 vs. standard arm, 23.4 months; p = 0.60).

Allogeneic HCT
To date, allogeneic HCT 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 HCT 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 HCT. Median follow-up time for survivors was 40 months (range, 3 – 64 months). TRM was lower in the RIC group (7% vs. 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 HLA-matched reduced-intensity allogeneic HCT.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: national clinical trial. 

Summary of Evidence
Randomized trials of autologous hematopoietic cell transplantation (HCT) versus standard dose chemotherapy for patients with high-risk nonmetastatic or metastatic breast cancer have not shown a survival advantage with HCT, and have shown greater treatment-related mortality and toxicity. Therefore, autologous HCT is considered not medically necessary for this indication.

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

Practice Guidelines and Position Statements
National Comprehensive Cancer Network guidelines (v.3.2014) do not address the use of HCT in the treatment of breast cancer.

U.S. Preventive Services Task Force Recommendations
Not applicable 

References 

1. Vogl DT, Stadtmauer EA. High-dose chemotherapy and autologous hematopoietic stem cell transplantation for metastatic breast cancer: a therapy whose time has passed [editorial]. Bone Marrow Transplant. Jun 2006;37(11):985-987. PMID 16708060
2. Stadtmauer EA, O'Neill A, Goldstein LJ, et al. Conventional-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):1069-1076. 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 Natl Cancer Inst. Jul 21 2004;96(14):1076-1083. 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):2273-2283. PMID 15111618
7. Hortobagyi GN. What is the role of high-dose chemotherapy in the era of targeted therapies? [editorial]. J Clin Oncol. Jun 15 2004;22(12):2263-2266. 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 metastatic breast cancer. Cochrane Database Syst Rev. 2005(3):CD003142. 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 early poor prognosis breast cancer. Cochrane Database Syst Rev. 2005(3):CD003139. 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):2327-2336. 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 randomised trial. Ann Oncol. May 2005;16(5):726-734. 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):325-337. 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):555-562. 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):1082-1089. 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):150-157. 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):3214-3223. 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):414-418. PMID 22863724
20. Pedrazzoli P, Martinelli G, Gianni AM, et al. Adjuvant high-dose chemotherapy with autologous hematopoietic stem cell support for high-risk primary breast cancer: results from the Italian national registry. Biol Blood Marrow Transplant. Apr 2014;20(4):501-506. 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):3919-3926. PMID 16921043
22. Schmid P, Schippinger 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):432-440. PMID 15659490
23. Carella AM, Bregni M. Current role of allogeneic stem cell transplantation in breast cancer. Ann Oncol. Oct 2007;18(10):1591-1593. 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):537-545. 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):464-467. PMID 19633692

Coding Section

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. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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