High-Dose Chemotherapy With Autologous Stem-Cell Support As Adjuvant Therapy in Breast Cancer: Overview of 15 Randomized Trials

Purpose Adjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival. Individual trials have had limited power to show overall benefit or benefits within subsets. Methods We assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support. Prospectively defined primary end points were relapse-free survival (RFS) and overall survival (OS). We compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and we adjusted for clinically relevant covariates. Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status. Results Of 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69% were premenopausal, 29% were postmenopausal, and 2% were unknown menopausal status; 49.5% were HmR positive; 33.5% were HmR negative, and 17% were unknown HmR status. The median follow-up was 6 years. After analysis was adjusted for covariates, HDC was found to prolong relapse-free survival (RFS; hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P < .001) but not overall survival (OS; HR, 0.94; 95% CI, 0.87 to 1.02; P = .13). For OS, no covariates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC. Younger patients had a significantly better RFS on HDC than did older patients. Conclusion Adjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit. Whether HDC benefits patients in the context of targeted therapies is unknown.

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386 High-dose chemotherapy with stem cell support in high-risk primary breast cancer. An analysis of the effect on overall survival the Danish experience from a comparison study

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(03)90418-6 ◽

2003 ◽

Vol 1 (5) ◽

pp. S118

Author(s):

T. Palshof ◽

S. Werner Hansen ◽

C. rose ◽

S. Møller ◽

P. Hokland ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Stem Cell ◽

High Risk ◽

High Dose Chemotherapy ◽

High Dose ◽

Comparison Study ◽

Stem Cell Support ◽

Danish Experience ◽

Cell Support

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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

Journal of Clinical Oncology ◽

10.1200/jco.2004.07.026 ◽

2004 ◽

Vol 22 (12) ◽

pp. 2273-2283 ◽

Cited By ~ 61

Author(s):

A.R. Zander ◽

N. Kröger ◽

C. Schmoor ◽

W. Krüger ◽

V. Möbus ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Standard Dose ◽

High Dose Chemotherapy ◽

High Dose ◽

Event Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Stem Cell Support ◽

Cell Support

Purpose Investigation of high-dose chemotherapy (HD-CT) followed by autologous hematopoietic stem-cell support compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more positive axillary lymph nodes. Patients and Methods Between November 1993 and September 2000, 307 patients were randomized to receive (following four cycles of epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2, intravenously every 21 days) either HD-CT of cyclophosphamide 1,500 mg/m2, thiotepa 150 mg/m2, and mitoxantrone 10 mg/m2, intravenously for 4 consecutive days followed by stem-cell support; or SD-CT in three cycles of cyclophosphamide 500 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 intravenously on days 1 and 8, every 28 days. The primary end point was event-free survival. Results After a median follow-up of 3.8 years, 144 events with respect to event-free survival have been observed (HD-CT: 63 events; SD-CT: 81 events). The first event of failure (HD-CT v SD-CT) was an isolated locoregional recurrence (nine v 11), a distant failure (52 v 68), and death without recurrence (two v two). The estimated relative risk of HD-CT versus SD-CT was 0.75 (95% CI, 0.54 to 1.06; P = .095). Overall survival showed no difference (HD-CT: 40 deaths; SD-CT: 49 deaths). Conclusion There was a trend in favor of HD-CT with respect to event-free survival, but without statistical significance. Further follow-up and a meta-analysis of all randomized studies will reveal the effect of HD-CT as compared with SD-CT as adjuvant treatment in high-risk primary breast cancer.

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Prospective, Randomized Comparison of High-Dose Chemotherapy With Stem-Cell Support Versus Intermediate-Dose Chemotherapy After Surgery and Adjuvant Chemotherapy in Women With High-Risk Primary Breast Cancer: A Report of CALGB 9082, SWOG 9114, and NCIC MA-13

Journal of Clinical Oncology ◽

10.1200/jco.2005.10.202 ◽

2005 ◽

Vol 23 (10) ◽

pp. 2191-2200 ◽

Cited By ~ 82

Author(s):

William P. Peters ◽

Gary L. Rosner ◽

James J. Vredenburgh ◽

Elizabeth J. Shpall ◽

Michael Crump ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Primary Breast Cancer ◽

High Dose Chemotherapy ◽

High Dose ◽

Event Free Survival ◽

Free Survival ◽

Stem Cell Support ◽

Cell Support ◽

Intermediate Dose

Purpose The prognosis for women with primary breast cancer involving multiple axillary nodes remains poor. High-dose chemotherapy with stem-cell support produced promising results in initial clinical trials conducted at single institutions. Patients and Methods Seven hundred eighty-five women aged 22 to 66 years with stage IIA, IIB, or IIIA breast cancer involving 10 or more axillary lymph nodes were randomized after surgery and standard adjuvant chemotherapy to either high-dose cyclophosphamide, cisplatin, and carmustine (HD-CPB) with stem-cell support or intermediate-dose cyclophosphamide, cisplatin, and carmustine (ID-CPB) with G-CSF support but without stem cells. Planned treatment for all patients included locoregional radiation therapy. Hormone-receptor–positive patients were to receive 5 years of tamoxifen. Event-free survival (EFS) was the primary end point. Results Median follow-up was 7.3 years. Event-free survival was not significantly different between the two treatment groups (P = .24). The probability of being free of an event at 5 years with HD-CPB was 61% (95% CI, 56% to 65%), and was 58% (95% CI, 53% to 63%) for ID-CPB. Thirty-three patients died of causes attributed to HD-CPB, compared with no therapy-related deaths among women treated with ID-CPB. Overall survival for the two arms was identical at 71% at 5 years (P = .75). Conclusion HD-CPB with stem-cell support was not superior to ID-CPB for event-free or overall survival among all randomized women with high-risk primary breast cancer.

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