Time to initiation of adjuvant chemotherapy for early breast cancer and outcome: the earlier, the better?

The proper timing of commencement of adjuvant chemotherapy has been studied for decades. There is in fact a biologic rationale to start chemotherapy as soon as possible after the removal of the primary tumor. Since the late 1970s, there has been evidence that tumor removal as well as surgical trauma might lead to an accelerated growth of micrometastases and an increased number of circulating tumor cells. In addition, an increased probability of drug resistance in micrometastatic disease in case of delayed administration of chemotherapy has been hypothesized. Based on these assumptions, trials on perioperative chemotherapy were launched in the 1980s. A metaanalysis focusing on trials of perioperative chemotherapy showed a potential beneficial effect of early initiation of chemotherapy with a reduced risk of relapse of 11%. More recently, retrospective analyses evaluating the role of early start of chemotherapy were published reporting conflicting results. Studies differed with respect to the patient, disease and treatment characteristics included, as well as the arbitrarily selected cutoff for the definition of early versus delayed start of therapies. For example, results presented by Lohrisch et al based on a retrospective review of 2,594 patients with early-stage breast cancer treated between 1989 and 1998 suggest that adjuvant chemotherapy, mainly with regimens containing anthracyclines, is equally effective if initiated in the first 4 weeks, second 4 weeks, or third 4 weeks after definitive surgery. While these results could encourage patients and their physicians to relax and take up to 12 weeks to initiate chemotherapy after surgery, other evidence shows that early start of cyclophosphamide, methotrexate, and fluorouracil chemotherapy (within 21 days from surgery) might be beneficial for premenopausal patients with node-positive, estrogen receptor (ER) –absent disease treated within the context of several clinical trials. In addition, postmenopausal women with nodenegative disease benefited significantly and substantially from a single perioperative course of chemotherapy initiated within 36 hours of surgery compared with a randomly assigned control group receiving no adjuvant therapy exclusively for the cohort of patients with ERabsent disease. The different results observed are not surprising considering the retrospective nature of almost all of the reported series and the related potential for bias. On one hand, chemotherapy might have been selectively administered earlier in patients with poor prognostic characteristics such as nodal positivity, high number of positive nodes, large tumor size, younger age, lymphatic vascular invasion, or ER negativity. On the other hand, delayed start of chemotherapy might be due to patient-related factors that affect the outcome, such as comorbidities or delayed healing after surgery which may be indicative of overall poor health status. The issue of timing of adjuvant chemotherapy has not received much recent attention from physicians and patients and consequently practice has not changed substantially. Current guidelines from the European Society of Medical Oncology on adjuvant chemotherapy for breast cancer indicate that treatment should start preferably within 2 to 6 weeks, whereas a significant decrease in the efficacy of chemotherapy is observed when administered more than 12 weeks from surgery. The lack of change in the attitude towards timing of adjuvant chemotherapy might be related not only to the reported controversial results but also to the increased request for additional testing or procedures used to decide whether or not to offer adjuvant chemotherapy. In fact, a significant increase in time between surgery and start of first adjuvant treatment has been reported during the last 10 years. In a large, multi-institutional cohort of women with breast cancer, mean time from diagnosis to start of adjuvant chemotherapy was 12 weeks. However, the mean time increased from 10.8 to 13.3 weeks between 2003 and 2009. This increased time was mainly associated with diagnostic evaluations such as use of a multigene assay and therapeutic interventions such as immediate postmastectomy reconstruction and re-excision for adequate surgical margins. In the article that accompanies this editorial, Gagliato et al report on outcomes according to timing to initiation of adjuvant chemotherapy of 6,827 patients. Overall, no differences were seen between cohorts starting chemotherapy either 0 to 30 days, 31 to 60 days, or more than 60 days after surgery with respect to overall survival (OS), relapse-free survival (RFS), nor distant-relapse-free survival (DRFS). Patients with more advanced stage disease experienced worse outcome in terms of RFS and DRFS (stage II and III) and OS (stage III) if chemotherapy started more than 60 days from surgery. Also, patients with triple-negative disease and those with HER2-positive disease treated with trastuzumab, had a worse OS if chemotherapy JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 8 MARCH 1