Improved Survival With Shorter Delays Between Diagnosis and Surgery and Before Initiating Adjuvant Chemotherapy


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The survival benefits of reducing the time to surgery following a diagnosis of breast cancer and the time to initiation of adjuvant chemotherapy following surgery were outlined in two articles and an accompanying editorial in JAMA Oncology.

Analyzing two independent population-based studies with a total of 210,334 patients with breast cancer, Richard J. Bleicher, MD, and colleagues from Fox Chase Cancer Center, Philadelphia, concluded: “Although time is required for preoperative evaluation and consideration of options such as reconstruction, efforts to reduce time to surgery should be pursued when possible to enhance survival.” Reviewing data from an observational, population-based study with 24,843 patients,
Mariana Chavez-MacGregor, MD, MSc, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues “observed that a delay in initiation of adjuvant chemotherapy of 91 or more days was associated with worse” overall survival and breast cancer–specific survival.

Time to Surgery Study

The time to surgery study was based on prospectively collected national data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare–linked database and the National Cancer Database (NCDB). The SEER-Medicare cohort included 94,544 patients 66 years or older, with a mean age of 75.2 years. The NCDB study included 115,790 patients aged 18 years to 90, with a mean age of 60.3 years.

All patients were diagnosed with noninflammatory, nonmetastatic, invasive breast cancer and had surgery as their initial treatment. “Each analysis assessed overall survival as a function of time between diagnosis and surgery by evaluating five intervals (≤ 30, 31–60, 61–90, 91–120, and 121–180 days) and disease-specific survival at 60-day intervals,” the authors explained.

In the SEER-Medicare study, 77.7% of patients had surgery within 30 days of diagnosis, but 18.3% waited 31 to 60 days, 2.7% waited 61 to 90 days, 0.7% waited 91 to 120 days, and 0.5% waited from 121 to 180 days.

Longer time to surgery was associated with lower overall survival and disease-specific survival after adjusting for patient, tumor, and treatment factors. Each increase in the interval of delay increased mortality by 9% (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.06–1.13; P < .001). “The time to surgery was statistically significant with respect to overall survival in stage I (HR, 1.13; 95% CI, 1.08–1.18; P < .001) and stage II disease (HR, 1.06; 95% CI, 1.01–1.11; P = .01) but not in stage III (HR, 1.06; 95% CI, 0.97–1.16; P = .17),” the investigators reported. Each 60-day interval increased breast cancer–specific mortality, with the association significant for stage I but not for stage II or III disease.

In the NCDB study, 69.5% of patients had surgery within 30 days of diagnosis, but 24.9% waited 31 to 60 days, 4.1% waited 61 to 90 days, 1.0% waited 91 to 120 days, and 0.5% waited from 121 to 180 days. “The added risk of death from all causes for each interval increase in time to surgery was 10% (HR, 1.10; 95% CI, 1.07–1.13; P < .001) for the entire cohort,” the researchers reported. “The time to surgery was associated with overall survival in stage I (HR, 1.16; 95% CI, 1.12–1.21; P < .001) and stage II (HR, 1.09; 95% CI, 1.05–1.13; P < .001) but not stage III (HR, 1.01; 95% CI, 0.96–1.07; P = .64).”

“The effect of time to surgery on survival is a ubiquitous concern of patients with cancer and a question frequently posed in consultations with surgeons,” the authors commented. “Elimination of undue delay is desirable to both reduce anxiety and lower risk, and we believe that this study provides clinicians needed data to answer patients’ questions about time to surgery and its effect on outcome. Although the absolute magnitude of the 5-year survival difference was small (4.6% and 3.1% for ≤ 30 days vs 91–120 days in SEER-Medicare and NCDB patients, respectively), this benefit is comparable to the addition of some standard therapies, such as the recent extension of tamoxifen therapy from 5 to 10 years, while not having the adverse effects or costs found with most interventions.”

Time to Chemotherapy Study

The time to chemotherapy study used data obtained from the California Cancer Registry on 24,843 patients with stage I to III invasive breast cancer treated with adjuvant chemotherapy. The median age at time of diagnosis was 53 years. “Time to chemotherapy was defined as the number of days between surgery and the first dose of chemotherapy, and delayed time to chemotherapy was defined as 91 or more days from surgery to the first dose of adjuvant chemotherapy,” the authors explained.

Half of all patients (12,432) started chemotherapy between 31 and 60 days, but 21% (5,224) started chemotherapy within fewer than 31 days; 19.2% (4,765) started chemotherapy between 61 and 90 days; and 9.8% (2,422) started chemotherapy 91 or more days after surgery. The median time to chemotherapy was 46 days. Patients with stage II and III disease and those with triple-negative breast cancer were less likely to experience delays, “probably because such characteristics are associated with poor prognosis,” the authors noted.

“Compared with patients receiving chemotherapy within 31 days from surgery, there was no evidence of adverse outcomes among those with time to chemotherapy of 31 to 60 or 60 to 90 days,” the researchers reported. Patients treated 91 or more days from surgery had a 34% increase in the risk of death (hazard ratio [HR], 1.34; 95% CI, 1.15–1.57) and a 27% increase in the risk of breast cancer death (HR, 1.27; 95% CI, 1.05–1.53). “In a subgroup analysis according to subtype, longer time to chemotherapy caused patients with triple-negative breast cancer to have worse overall survival (HR, 1.53; 95% CI, 1.17–2.00) and worse breast cancer–specific survival (HR, 1.53; 95% CI, 1.17–2.07),” the investigators added.

“We acknowledge that in clinical practice a number of factors determine the optimal time to chemotherapy, and that in many cases, this time frame is determined by comorbidities or complications associated with surgery,” the authors wrote. “In addition, we acknowledge that the potential determinants of chemotherapy initiation include the recommendation of the medical oncologist and the entire multidisciplinary team. Additionally, from the patient-centered care perspective, a patient’s preferences are likely to play a role, which we were unable to take into account.”

Accompanying Editorial

“The articles published in this issue of JAMA Oncology increase our confidence that avoiding delays in breast cancer care is important to ensuring the best possible outcomes for our patients,” according to an accompanying editorial by Adrienne G. Waks, MD, Tari King, MD, and Eric P. Winer, MD, of Dana-Farber Cancer Institute/Brigham and Women’s Cancer Center, Boston. “Thoughtfulness and attention to facilitate timely care is essential, and at this point it seems that some added vigilance is warranted in the triple-negative breast cancer subset.”

The SEER-Medicare study and the California Cancer Registry study identified several factors associated with delay in receiving treatment. Common factors identified in both studies were Hispanic ethnicity and black race. “These findings are troubling,” the editorialists wrote, “and are neither novel nor isolated; multiple prior studies have shown that minority race/ethnicity and lower socioeconomic status correlate with longer breast cancer treatment delays. Excessive delays may be one component of why disadvantaged groups experience worse breast cancer outcomes than comparators.”■

Bleicher RJ, et al: JAMA Oncol 2:330-339, 2016.

Chavez-MacGregor M, et al: JAMA Oncol 2:322-329, 2016.

Waks AG, et al: JAMA Oncol 2:302-304, 2016.



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