Abstract: We included 14 RCTs of 5600 women randomised to receive high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. The studies were at low risk of bias in most areas. There is high-quality evidence that high-dose chemotherapy does not increase the likelihood of overall survival at any stage of follow-up (at three years: RR 1.02, 95% CI 0.95 to 1.10, 3 RCTs, 795 women, I² = 56%; at five years: RR 1.00, 95% CI 0.96 to 1.04, 9 RCTs, 3948 women, I² = 0%; at six years: RR 0.94, 95% CI 0.81 to 1.08, 1 RCT, 511 women; at eight years: RR1.17, 95% CI 0.95 to 1.43, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.99 to 1.42, 1 RCT, 382 women). There is high-quality evidence that high-dose chemotherapy improves the likelihood of event-free survival at three years (RR 1.19, 95% CI 1.06 to 1.34, 3 RCTs, 795 women, I² = 56%) but this effect was no longer apparent at longer duration of follow-up (at five years: RR 1.04, 95% CI 0.99 to 1.09, 9 RCTs, 3948 women, I² = 14%; at six years RR 1.04, 95% CI 0.87 to 1.24, 1 RCT, 511 women; at eight years: RR 1.27, 95% CI 0.99 to 1.64, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.95 to 1.45, 1 RCT, 382 women). Treatment-related deaths were much more frequent in the high-dose arm (RR 7.97, 95% CI 3.99 to 15.92, 14 RCTs, 5600 women, I² = 12%, high-quality evidence) and non-fatal morbidity was also more common and more severe in the high-dose group. There was little or no difference between the groups in the incidence of second cancers at four to nine years' median follow-up (RR 1.25, 95% CI 0.90 to 1.73, 7 RCTs, 3423 women, I² = 0%, high-quality evidence). Women in the high-dose group reported significantly worse quality-of-life scores immediately after treatment, but there were few statistically significant differences between the groups by one year. The primary studies were at low risk of bias in most areas, and the evidence was assessed using GRADE methods and rated as high quality for all comparisons. There is high-quality evidence of increased treatment-related mortality and little or no increase in survival by using high-dose chemotherapy with autograft for women with early poor prognosis breast cancer.

Plain-language summary: We included 14 randomised controlled trials (5600 women) which compared high-dose chemotherapy versus conventional chemotherapy in women with early breast cancer and with a high risk of recurrence. We defined these as women with breast cancer that has spread to multiple local lymph nodes without any evidence of spread beyond local lymph nodes. All studies reported their source of funding. Eight studies were funded by non-profit organisations, one by a public health insurance company, one by industry sources and four by a combination of non-profit organisations and industry sources. Four of the studies reported that authors had no potential conflict of interest, six reported that one or more of their authors had received some kind of support from pharmaceutical companies, and four did not mention whether any of their authors had any potential conflict of interest. Using high-dose chemotherapy has little or no effect on increasing survival. Although rates of event-free survival were higher in the high-dose arm over three-year follow-up, this effect was not apparent at longer follow-up. Treatment-related deaths were much more common in the high-dose group. Side-effects were also more common and more severe in the high-dose group. We did not find an effect on the number of women developing second cancers. The evidence was of high quality.