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Q What are the effects of adjuvant chemotherapy, tamoxifen, and ovarian ablation or suppression on recurrence and survival 15 years after diagnosis of early breast cancer?
Clinical impact ratings GP/FP/Primary care ★★★★★★☆ Oncology ★★★★★★☆
Medline, published lists of randomised trials, hand searching selected journals, meeting abstracts, references of published trials and reviews, and contacting experts repeatedly over a 15 year period.
Study selection and assessment:
unconfounded randomised controlled trials (RCTs) of adjuvant systemic therapies for early breast cancer begun before 1995. Individual patient data and updated follow up were sought on every woman included in the studies. Analyses were by intention to treat.
main outcomes were death from breast cancer, death from other causes, breast cancer recurrence, and incidence of second cases of cancers.
194 RCTs (n = 144 939) were included and comprise about 91% of all women randomised in such trials before 2000. Standard polychemotherapy, including an anthracycline for 4–6 months (eg, fluorouracil, cyclophosphamide, and either doxorubicin [adriamycin] or epirubicin [FAC or FEC]) reduced annual breast cancer mortality rates by 38% in women <50 years and by 20% in women 50–69 years (table), and was more effective than cyclophosphamide, methotrexate, and fluorouracil (CMF) (p<0.001). These effects were independent of axillary lymph node involvement, oestrogen-receptor (ER) status, and treatment with tamoxifen. The absolute benefit of adjuvant chemotherapy at 15 years was more than double its benefit at 5 years in women <50 years of age (table). Tamoxifen for 5 years in women with ER positive disease reduced the annual breast cancer mortality rate by 31% and was more effective than tamoxifen for 1 or 2 years (p<0.001). These effects were independent of age, menopausal status, lymph node involvement, and tumour size. The absolute benefit of tamoxifen at 15 years was more than double its benefit at 5 years (table). Tamoxifen was ineffective in women with ER negative disease. Ovarian ablation or suppression reduced the annual breast cancer mortality rate by 29% in the absence of chemotherapy. Deaths from causes other than breast cancer were not affected by any of the 3 treatments.
Adjuvant chemotherapy, tamoxifen, and ovarian ablation or suppression substantially reduce mortality rates over 15 years in women with early breast cancer.
Abstract and commentary also appear in ACP Journal Club.
The EBCTCG update of previous work shows that the survival benefits of adjuvant therapy persist over time—the effect of killing or suppressing micrometastases lasts far beyond the end of treatment. In this case, the absolute benefit can be as high as 10 additional women alive per 100 treated, with no additional deaths from treatment related diseases.
These are the minimal effects of adjuvant therapy, too, because current treatments are more effective and less toxic. Recent large RCTs show that the addition of paclitaxel to 4 cycles of doxorubicin-cyclophosphamide adds another 2–3 survivors per 100 women.1 We can add 2–3 more survivors by giving the same chemotherapy every 2 weeks instead of every 3 weeks.2 The addition of trastuzumab (Herceptin) for women whose cancer over expresses human epidermal growth factor receptor-2 may provide even more benefit, based on its substantial effects on disease free survival.3 A low fat diet (about 30 g/d) may reduce relative recurrence risk a further 24% when added to these “best” therapies.4 Aromatase inhibitors improve disease free survival more than tamoxifen alone, or when given after tamoxifen, and will probably improve overall survival.5
How does one keep up with these developments? Adjuvant! (www.adjuvantonline.com) is a simple prediction tool to estimate the absolute benefits for women considering these treatments.
For correspondence: EBCTCG Secretariat, CTSU, Radcliffe Infirmary, Oxford, UK.
Source of funding: UK Medical Research Council.