Association of Timing of Adjuvant Therapy With Survival in Patients With Resected Stage I to II Pancreatic Cancer

Abstract

Importance: Surgery followed by adjuvant chemotherapy or chemoradiation is widely used to treat resectable pancreatic cancer. Although studies suggest initiation of adjuvant therapy within 12 weeks of surgery, there is no clear time interval associated with better survival.

Objective: To evaluate the ideal timing of adjuvant therapy for patients with stage I to II resected pancreatic cancer.

Design, setting, and participants: This cohort study included 7548 patients with stage I to II resected pancreatic cancer (5453 with adjuvant therapy; 2095 without adjuvant therapy) from the National Cancer Database from 2004 to 2015. Data were collected from January 2014 to December 2015 and analyzed from December 2018 to May 2019.

Exposures: Adjuvant chemotherapy or chemoradiation at various time intervals.

Main outcomes and measures: Overall survival (OS).

Results: A total of 7548 patients (3770 male [49.9%]; median [interquartile range] age, 67 [59-74] years) were identified from the National Cancer Database. Among 5453 patients with adjuvant therapy, a Cox model with restricted cubic splines identified the lowest mortality risk when adjuvant therapy was started 28 to 59 days after surgery. Patients were divided into early (n = 269, adjuvant therapy initiated within <28 days), reference (n = 3048, adjuvant therapy initiated within 28-59 days), and late (n = 2136, adjuvant therapy initiated after >59 days) interval cohorts. Median (interquartile range) overall follow-up was 38.6 (24.6-62.0) months. Compared with the reference interval cohort on multivariable analysis, both the early cohort (hazard ratio, 1.17; 95% CI, 1.02-1.35; P = .03) and the late cohort (hazard ratio, 1.09; 95% CI, 1.02-1.17; P = .008) were associated with worse mortality. Similarly, the reference interval cohort had improved OS compared with the early cohort in 268 propensity-matched pairs (2-year OS, 52.5% [95% CI, 46.7%-59.0%] vs 45.1% [95% CI, 39.5%-51.6%]; P = .02) and compared with the late cohort in 2042 propensity-matched pairs (2-year OS, 51.3% [95% CI, 49.1%-53.6%] vs 45.4% [95% CI, 43.3%-47.7%]; P = .01). Patients who received adjuvant therapy more than 12 weeks after surgery (n = 683) had improved OS compared with surgery alone in both multivariable analysis (hazard ratio, 0.75; 95% CI, 0.66-0.85; P < .001) and 655 propensity-matched pairs (2-year OS, 47.2% [95% CI, 43.5%-51.3%] vs 38.0% [95% CI, 34.4%-42.0%]; P < .001).

Conclusions and relevance: Patients with stage I to II pancreatic cancer who commenced adjuvant therapy within 28 to 59 days after primary surgical resection had improved survival outcomes compared with those with adjuvant therapy before 28 days or after 59 days. Patients who recovered slowly from surgery still benefited from delayed adjuvant therapy initiated more than 12 weeks after surgery compared with patients who underwent surgery only.

Figure 1.. Flow Diagram for Patient Selection Criteria

Figure 2.. Restricted Cubic Spline Model to Determine Adjuvant Timing With Lowest Mortality Risk

The model was adjusted for facility type, age, sex, race/ethnicity, insurance, income, residential setting, Charlson/Deyo comorbidity score, year of diagnosis, primary tumor location within pancreas, tumor grade, tumor size, pathologic T and N stages, cancer antigen 19-9 level, surgery type, surgical margin, chemotherapy, radiation therapy, unplanned readmission within 30 days after surgery, duration of inpatient stay after surgery, and time from diagnosis to surgery. Shaded area indicates 95% CI.

Figure 3.. Kaplan-Meier Survival Curves for Early vs Reference Interval After Matching

Figure 4.. Kaplan-Meier Survival Curves for Late vs Reference Interval After Matching