MP 8.01.27

Hematopoietic Stem-Cell Transplantation for Breast Cancer

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Medical Policy
Section Therapy	Original Policy Date 12/1/99	Last Review Status/Date Reviewed with literature search/12:2008
Issue 12:2008		Return to Medical Policy Index

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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

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Description

Policy

Policy Guidelines

Benefit Application

BlueCard/National Account Issues

For indications considered investigational, the following considerations may supersede this policy:

Rationale

This policy was initially based on TEC Assessments completed in 1996 and 1998. (1, 2) The 1996 TEC Assessment focused on HDC/AuSCS to treat metastatic (i.e., Stage IV) breast cancer, while the 1998 Assessment focused on HDC/AuSCS for adjuvant therapy of high-risk primary (i.e., Stage II/III) breast cancer.

Conclusions of the original TEC Assessments were as follows:

1996 TEC Assessment: Metastatic Breast Cancer (1)

The Assessment reviewed 12 studies with a total of 459 patients. These included:

The balance of evidence available in 1996 suggested that HDC/AuSCT yielded survival durations at least equivalent to those after conventional-dose therapy. Although acute treatment-related morbidity was more severe, the duration of therapy was much shorter with HDC/AuSCT. Therefore, the Medical Advisory Panel (MAP) concluded HDC/AuSCT met the TEC criteria for patients with previously untreated, responsive, or relapsed metastatic breast cancer but not for those with metastatic disease refractory to chemotherapy. Since available evidence was insufficient to determine whether outcomes of either treatment alternative were superior, patients were encouraged to seek this treatment in the context of continued clinical trials.

 

1998 TEC Assessment: Adjuvant Therapy for High-Risk Primary (Stage II/III) Breast Cancer (2)

Evidence reviewed for this Assessment, comparing HDC/AuSCS with conventional-dose chemotherapy for adjuvant treatment, included:

• 2 small randomized trials (39–41 patients per arm), a case-control study (60 patients per group), and 6 uncontrolled series (combined n=302) of patients with 10 or more positive lymph nodes;
• 2 uncontrolled series (combined n=116) of patients with 4–9 positive nodes; and
• 3 uncontrolled series (combined n=86) of patients with non-metastatic inflammatory breast cancer.

The MAP found available evidence insufficient to permit conclusions, and HDC/AuSCS did not meet the TEC criteria for adjuvant therapy of Stage II/III breast cancer in patients with 10 or more positive nodes. HDC/AuSCS also failed the TEC criteria for patients with 4–9 positive nodes or those with inflammatory breast cancer, since the lack of controlled studies, small sample sizes, and inadequate follow-up did not permit conclusions.

History of high-dose chemotherapy and hematopoietic stem cell transplantation for breast cancer
In the late 1980s/early 1990s, initial results of phase II trials for breast cancer and high-dose chemotherapy with autologous SCT 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. (3) In the early 1990s, larger prospective comparisons of conventional dose chemotherapy to high-dose therapy with SCT were initiated but accrued slowly, with up to a decade from initiation to the reporting of results. (3) The first results from randomized trials at a single institution in early stage and metastatic disease showed survival benefits, but were ultimately shown to be based on fraudulent data. (3) In the interim, though, the treatment became almost standard of care, while many patients received high-dose therapy off protocol, further reducing accrual to ongoing randomized trials. (3) The results of the randomized trials were presented beginning in 1999, and showed little benefit, and the number of procedures performed has fallen from thousands every year to only a few. (3)
Most of the randomized controlled trials that have been published since the 1996 and 1998 TEC assessments are summarized below.
Autologous Stem-Cell Transplantation
The PBT-1 trial randomized patients with a complete or partial response to induction therapy for previously untreated metastatic breast cancer to HDC/AuSCT (n =101) or to conventional-dose maintenance chemotherapy (n =83) for up to 2 years. (4) Of 553 patients enrolled and given initial induction therapy, only 310 achieved a partial (n =252) or complete (n =58) response, and only 199 were randomized. Of 72 partial responders assigned to the HDC arm after initial induction therapy, only 5 (7%) were converted to complete responses. Median survival (24 vs. 26 months) and overall survival at 3 years (32% vs. 38%) did not differ between arms. There also were no statistically significant differences between arms in time to progression or progression-free survival at 3 years. While treatment duration was substantially shorter for those randomized to HDC/AuSCT, 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 HDC/AuSCT versus conventional dose for adjuvant therapy of high-risk non-metastatic breast cancer. (5-8) Two of the studies involved women with at least 4 positive axillary lymph nodes, and the other two at least 10 positive lymph nodes. The four studies pooled included 2,337 patients.
Evidence from these trials did not support the conclusion that HDC/AuSCT improved outcomes when compared with conventional-dose adjuvant therapy as no overall survival difference was seen in any of the studies. An editorial that accompanied one of the trials briefly reviewed and commented on factors contributing to the diffusion of HDC/AuSCT into routine practice of the treatment of certain breast cancer patients, without adequate testing in randomized clinical trials. (9)
A Cochrane systematic review and meta-analysis published in July 2005 pooled data from 6 randomized controlled trials (RCTs) on metastatic breast cancer reported through November 2004 (N =438 randomized to HDC/AuSCT, 412 to conventional dose therapy). (10) The relative risk (RR) for treatment-related mortality was significantly higher in the arm randomized to HDC/AuSCT (15 vs. 2 deaths; RR =4.07; 95% CI: 1.39–11.88). Treatment-related morbidity also was more severe among those randomized to HDC/AuSCT. Overall survival did not differ significantly between groups at 1, 3, or 5 years after treatment. Statistically significant differences in event-free survival at 1 year (RR=1.76; 95% CI: 1.40–2.21) and 5 years (RR =2.84; 95% CI: 1.07–7.50) favored the HDC/AuSCT arms. Only 1 of the 6 included trials had followed up 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 HDC/AuSCT outside of a clinical trial, since available data showed greater treatment-related mortality and toxicity without improved overall survival.
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 (N =2,535 randomized to HDC/AuSCT, 2,529 to conventional dose therapy). (11) Treatment-related mortality was significantly greater among those randomized to HDC/AuSCT (65 vs. 4 deaths; RR=8.58; 95% CI: 4.13, 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 overall survival rates at any time after treatment. Event-free survival was significantly greater in the HDC/AuSCT group at 3 years (RR =1.12; 95% CI: 1.06, 1.19) and 4 years (RR =1.30; 95% CI: 1.16, 1.45) after treatment. However, the 2 groups did not differ significantly with respect to event-free survival at 5 and 6 years after treatment. Quality of life scores were significantly worse in the HDC/AuSCT arms than in controls soon after treatment, but differences were no longer statistically significant by 1 year. Reviewers concluded available data were insufficient to support routine use of HDC/AuSCT for patients with poor-prognosis early breast cancer.
Hanrahan et al., with a median follow-up of 12 years, demonstrated no recurrence-free or overall survival advantage for patients with high-risk primary breast cancer treated with high-dose chemotherapy and autologous SCT after standard dose chemotherapy (n =39) versus standard chemotherapy alone (n = 39).

(12) Coombes and colleagues reported on HDC/AuSCT as adjuvant therapy for primary breast cancer in women free of metastatic disease, with a median follow-up of 68 months. (13) Two hundred and eighty one patients were randomized to receive standard or high-dose chemotherapy with SCT. They found no significant difference in relapse-free survival or overall survival (overall survival hazard ratio 1.18, 95% CI: 0.80-1.75, p =0.40).
A systematic review and meta-analysis published in 2007 included randomized controlled trials comparing high dose chemotherapy and autologous stem cell transplantation to standard dose chemotherapy in women with early, poor prognosis breast cancer, which included 13 trials to September 2006 with 5,064 patients. (14) Major conclusions were that, at 5 years, event-free survival approached statistical significance for the high dose group, but no overall survival differences were seen. There were more transplant-related deaths in the high dose group. The end conclusion was that there was insufficient evidence to support routine use of high dose chemotherapy with autologous SCT for treating early, poor prognosis breast cancer.
Tandem autologous transplantation
Kroger et al. reported on the comparison of single versus tandem high-dose chemotherapy followed by autologous stem-cell transplantation in 187 patients with chemotherapy-sensitive metastatic breast cancer. (15) 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 complete remission was 33% in the single-dose arm, versus 37% in the tandem arm (p =.48). Although there was a trend toward improved progression-free survival after tandem HDC, median overall survival tended to be greater after single versus tandem HDC (29 versus 23.5 months, respectively; p =0.4). The authors concluded that tandem HDC cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDC.
Schmid et al. published results of 93 patients without prior chemotherapy for metastatic breast cancer who were randomized to standard-dose chemotherapy or double high-dose chemotherapy with autologous SCT. (16) The primary study objective was to compare complete response (CR) rates. Objective response rates for the 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 two treatments in median time to disease progression, duration of response, or overall survival (overall survival 26.9 months versus 23.4 months for the double high-dose arm versus the standard arm, respectively [p =0.60]).
Allogeneic Stem-Cell Transplantation
To date, allogeneic stem-cell transplantation for breast cancer has mostly been utilized in patients who have failed multiple lines of conventional chemotherapy. (17) A1999 TEC Assessment found inadequate data regarding the use of HDC/AlloSCT as salvage therapy after a failed prior course of HDC/AuSCT. (18)
Ueno et al. reported the results of allogeneic transplantation in 66 women with poor-risk metastatic breast cancer from 15 centers who were transplanted between 1992 and 2000. (19) Thirty-nine (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. A total of 17 (26%) patients had received a prior autologous transplant. Median follow-up time for survivors was 40 months (range 3-64 months). Treatment-related mortality was lower in the RIC group (7% versus 29% at 100 days; p =0.03). Progression-free survival at 1 year was 23% in the myeloablative group versus 8% in the RIC group (p=0.09). Overall survival rates after myeloablative conditioning versus the RIC group were 51% (95% CI: 36–67%) versus 26% (95% CI: 11–45%) [p =0.04] at 1 year, 25% (95% CI: 13–40%) versus 15% (95% CI: 3–34%; p =0.33) at 2 years, and 19% (95% CI: 8–33%) versus 7% (95% CI: <1–25%; p =0.21) at 3 years, respectively.
2008 update
The results of three randomized controlled studies corroborate findings from earlier trials.
Crump and colleagues 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. (20) After initial response to induction therapy, 112 women were allocated to standard chemotherapy and 112 to high-dose chemotherapy with autologous SCT. After a median follow-up of 48 months, 79 deaths were observed in the high dose group and 77 in the standard. No difference in overall survival was observed between the two groups after a median follow-up of 48 months, with median overall survival being 24 months in the high-dose/SCT group (95% CI: 21–35 months) and 28 months for the standard chemotherapy group (95% CI: 22–33 months; hazard ratio: 0.9; 95% CI: 0.6–1.2; p=0.43).
Biron et al. reported the results of a Phase III, open, multicenter, prospective trial of women with metastatic breast cancer (and/or local or regional relapse beyond curative treatment by surgery or radiation). (21) After a complete or at least 50% partial response to induction therapy, 88 women were randomized to high-dose chemotherapy with autologous SCT, and 91 to no further treatment. No overall survival difference was seen between the 2 groups, with 3-year survival 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 (22) on a trial that had previously been reported after 3.8 years of follow-up. (8) 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 randomized to standard chemotherapy (n =152) or high-dose chemotherapy with autologous SCT (n =150). No difference in overall survival was observed, with the estimated 5-year overall survival rate in the standard arm was 62% (95% CI: 54-70%) and in the high-dose/transplant group 64% (95% CI: 56-72%).

National Comprehensive Cancer Network (NCCN) Guidelines
The updated NCCN guidelines do not address hematopoietic stem cell transplantation in the treatment of breast cancer. (23)

The National Cancer Institute clinical trials database (as of November 2008) showed no ongoing Phase III trials for stem cell transplantation for breast cancer.

 

References:

1. 1996 TEC Assessment; Tab 3.
2. 1998 TEC Assessment; Tab 24.
3. 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 2006; 37(11):985-7.
4. 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 2000; 342(15):1069-76.
5. 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 2004; 96(14):1076-83.
6. 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 2003; 349(1):7-16.
7. 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 2003; 349(1):17-26.
8. 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 2004; 22(12):2273-83.
9. Hortobagyi GN. What is the role of high-dose chemotherapy in the era of targeted therapies? J Clin Oncol 2004; 22(12):2263-6.
10. 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.
11. 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.
12. 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 2006; 106(11):2327-36.
13. 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 2005; 16(5):726-34.
14. Farquhar CM, Marjoribanks J, Lethaby A et al. High dose chemotherapy for poor prognosis breast cancer: systematic review and meta-analysis. Cancer Treat Rev 2007; 33(4):325-37.
15. 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 patient with chemotherapy-sensitive metastatic breast cancer. J Clin Oncol 2006; 24(24):3919-26.
16. 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 2005; 23(3):432-40.
17. Carella AM, Bregni M. Current role of allogeneic stem cell transplantation in breast cancer. Ann Oncol 2007; 18(10):1591-3.
18. 1999 TEC Assessments; Tab 11.
19. Ueno NT, Rizzo JD, Demirer T et al. Allogeneic hematopoietic cell transplantation for metastatic breast cancer. Bone Marrow Transplant 2008; 41(6):537-45.
20. 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 2008; 26(1):37-43.
21. 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 2008; 41(6):555-62.
22. 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 2008; 19(6):1082-9.
23. Breast Cancer. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.v.2.2008. Available online at http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. Last accessed December 2008.

Index

Policy History

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