As explained in an article from MedPage Today, the study shows that initiating adjuvant chemotherapy at 61 days or later afer surgery was associated with a 19% increase in the risk of premature death, as compared with starting adjuvant therapy within 30 days of surgery. In the subgroup of patients with stage III disease, the mortality risk increased by 76%. According to Mariana Chavez-MacGregor, MD, of the University of Texas MD Anderson Cancer Center in Houston, relapse-free survival (RFS) and distant relapse-free survival (DRFS) worsened regardless of stage at diagnosis.
The authors of the study added that “among patients with stage II and III breast cancer, triple-negative breast cancer, and HER2-positive tumors, every effort should be made to avoid postponing initiation of adjuvant chemotherapy. This may lead to an improvement in outcomes for these subsets of patients.”
The heterogeneity of breast cancer must be taken into account but, in most cases, adjuvant chemotherapy begins within a few weeks of surgery. However, the potential impact of a delay in initiation of therapy is not clear, although mathematical models have suggested deleterious effects. An increased likelihood that treatment-resistant micrometastases would emerge, the authors noted, is one the most harmful effects of delaying chemo.
There is little information relative to the impact of time to chemotherapy on outcomes in different breast cancer subtypes. Trying to fill some of these information gaps, Chavez-MacGregor and her colleagues retrospectively reviewed medical records of 6,827 patients treated for early breast cancer at MD Anderson from 1997 to 2011, and followed them for a median duration of 59.3 months.
The majority of the study population, 84.5%, were patients with stage I-II disease, and the remaining 15.5% of patients had stage III disease at diagnosis. The study group comprised 2,716 (39.8%) patients who started therapy within 30 days of surgery, 2,994 (43.8%) who initiated adjuvant therapy 31 to 60 days after surgery, and 1,117 (16.4%) who initiated treatment 61 days or more after surgery.
The cohort had a 5-year overall survival (OS) of 84%, 5-year RFS of 69%, and DRFS of 72%. Patients with larger tumors and greater nodal involvement had worse OS, RFS, and DRFS, the authors noted with no surprise.
Analysis of factors that influenced outcomes of interest showed no difference in OS, RFS, or DRFS in patients with hormone receptor-positive or HER2-positive tumors, regardless of when they initiated therapy. However, the 5-year OS estimate differed among HER2-positive patients who received trastuzumab (Herceptin), as better survival was observed in patients who started therapy within 30 days of surgery (88%) compared with 31 to 60 days (87%) or ≥61 days (75%, P=0.01). The difference between ≥61 days and ≤30 days translated into a hazard ratio of 3.09 (95% CI 1.49-6.39).
Similarly, patients with triple-negative breast cancer had a 5-year OS estimate of 70% when they started chemotherapy within 30 days, 59% for therapy starting between 31 and 60 days, and 67% for therapy ≥61 days after surgery (P=0.005). Comparing the latest and earliest initiation times resulted in an HR of 1.54 (95% CI 1.09-2.18).
Neither RFS nor DRFS differed by time to chemotherapy in patients with stage I disease. Among patients with stage II disease, the hazard for DRFS increased by 18% to 20% when chemotherapy was started more than 30 days after surgery.
The subgroup of patients with stage III disease had a 76% increase in mortality risk if they started chemotherapy ≥61 days after surgery versus 30 days or less (HR 1.76, 95% CI 1.26-2.46). Risks associated with RFS and DRFS increased by 34% and 36%, respectively.
Jim Biagi, MD, of Queen’s University in Kingston, Ontario, participated in a meta-analysis of studies evaluating the impact of time to chemotherapu on survival in colorectal cancer and found a significant association between increasing time to therapy and worse OS and overall survival and disease-free survival. Biagi told MedPage Today that the study “adds to the available literature suggesting that delays may be detrimental to a patient’s cancer outcome.” In fact, he said, “patients who had the highest-risk features for breast cancer recurrence, and who would thus derive the greatest benefit from adjuvant chemotherapy, were the most vulnerable to this effect.”
“While discrepancies in their results limit our ability to make a strong statement about delays, the study is an important addition to our understanding of the impact delays might have on patient outcomes. It seems to me that if we are asking our patients to undergo 4 to 6 months of chemotherapy, that we offer the treatment in a timely manner,” Biagi concluded.