Effect of Interval between Neoadjuvant Chemotherapy and Radiation Therapy on Metastasis Risk for Inoperable Non-Metastatic Pancreatic Adenocarcinoma

Abstract

In inoperable pancreatic cancer patients requiring radiotherapy (RT) after neoadjuvant chemotherapy (CT), there can be delays in starting radiation due to multiple complications. However, pancreatic cancer can progress rapidly during short intervals without treatment. We hypothesize that longer intervals between neoadjuvant chemotherapy and radiation could expediate the development of metastatic disease. We identified patients with inoperable non-metastatic borderline resectable or locally advanced pancreatic cancer treated with neoadjuvant CT followed by RT from 2011 to 2021 at a single institution. Patients who completed palliative RT as defined by a biologic effective dose (BED) of less than 50 Gy, or those who were lost to follow-up within 3 months after completing RT without documented disease progression were excluded. The interval between RT and CT was defined as the time between last date of CT administration and initiation of RT. The primary endpoint was metastasis-free survival (MFS) after RT completion. Differences in MFS between patients who started RT within or after 4, 6, and 8 weeks of completing CT were examined utilizing log rank analysis of MFS generated via the Kaplan-Meier method. At a median follow-up of 5.45 months, twenty-three patients were included. Most patients were male (61%) with cT4 (61%), cN0 (83%) pancreatic adenocarcinoma. Almost all patients completed combination neoadjuvant CT (91%) followed by either intensity modulated RT to 50.4 Gy in 28 fractions with capecitabine (n = 9) or stereotactic body RT to 33-40 Gy in 5 fractions (n = 14). Eleven (48%) patients received adjuvant CT after radiation therapy. The median time between last CT and RT initiation was 34 days (range 13-142). The MFS of patients who initiated RT within 4 weeks of CT compared to after was higher but not significant (16.8 vs 9.9 months, p = 0.144). Those who received RT within 6 or 8 weeks of completing CT exhibited significantly longer MFS compared to later than 6 (16.0 vs 6.9 mo, p = 0.016) or 8 weeks (15.1 vs 2.1 mo, p = 0.004). There was no statistical correlation between MFS and other variables (CA 19-9 before radiation, T-stage, receipt of adjuvant CT, BED). These results suggest that a longer interval between CT and RT is associated with the risk of developing metastatic disease sooner but requires validation in a prospective cohort. Root causes of delays in starting radiation (e.g., insurance authorization) should be investigated as well.