Preoperative chemoradiotherapy to improve overall survival in pancreatic cancer: Long-term results of the multicenter randomized phase III PREOPANC trial.

Abstract

4016 Background: Preoperative chemoradiotherapy (CRT) may improve overall survival in resectable pancreatic cancer (RPC) and borderline resectable pancreatic cancer (BRPC). Long term results are presented. Methods: In this multicenter phase III trial, patients with RPC or BRPC were randomized between preoperative CRT, (gemcitabine 1000 mg/m2 weekly for 7 of 10 weeks, and 15x2.4 Gy radiotherapy in week 4 to 6), followed by surgery and four cycles of adjuvant gemcitabine (1000 mg/m2 weekly for 3 of 4 weeks), or immediate surgery followed by 6 cycles of adjuvant gemcitabine (1000 mg/m2 weekly for 3 of 4 weeks). Primary endpoint was overall survival by intention-to-treat (ITT). Results: From April 2013 to July 2017, 246 eligible patients were accrued by 16 Dutch centers and randomized, 119 to preoperative CRT and 127 to immediate surgery. After a median follow up of 56 months (35.3-92.0 months), 210 patients have died, 93 (78%) in the preoperative CRT arm and 117 (92%) in the immediate surgery arm. Three- and five-year overall survival ITT was 27.7% and 20.5% after preoperative CRT versus 16.5% and 6.5% after immediate surgery (HR 0.73; 95% CI 0.56 to 0.96; p = 0.025). In addition, disease-free survival (HR 0.70; p = 0.009) locoregional failure-free interval (HR 0.57; p = 0.004) and distant metastases free interval (HR 0.74; p = 0.071) improved after preoperative CRT. Also in the stratified subsets RPC and BRPC, preoperative CRT improved OS: RPC (n = 133, HR 0.79; 95% CI 0.54 to 1.16; P = 0.23). BRPC (n = 113, HR 0.67; 95% CI 0.45 to 0.99; p = 0.045). We could not demonstrate a difference in treatment effect between these subsets (interaction test p = 0.56). Conclusions: Preoperative gemcitabine-based CRT for RPC or BRPC improves long term overall survival compared to immediate surgery with adjuvant gemcitabine. Clinical trial information: NTR3709.

Prognostic Factors in Resected Pancreatic Ductal Adenocarcinoma: Is Neutrophil-Lymphocyte Ratio a Useful Marker?

“…Even though they didn't reach statistical signi cance in the primary endpoint that was overall survival, a signi cantly higher proportion of patients reached R0 resections in the neoadjuvant arm (71% vs 40%, P<0.001) and also a lower rate of perineural invasion [31]. In a posterior long-term analysis from this trial, three-and ve-year overall survival (intention-to-treat) was 27.7% and 20.5% after preoperative CRT versus 16.5% and 6.5% after immediate surgery (HR 0.73; 95% CI 0.56 to 0.96; p = 0.025), which becomes an important evidence towards neoadjuvant approach in this group [32]. This study is not free from limitations.…”

Neoadjuvant Treatment for Resectable and Borderline Resectable Pancreatic Cancer: Chemotherapy or Chemoradiotherapy?

“…In the randomized phase II ALLIANCE A021501 trial, neoadjuvant chemotherapy followed by stereotactic radiotherapy has been investigated. In this trial, patients with BRPC were randomized between neoadjuvant extended chemotherapy (eight cycles of modified FOLFIRINOX) versus chemotherapy (seven cycles of modified FOLFIRINOX) followed by stereotactic radiotherapy (33)(34)(35)(36)(37)(38)(39)(40) Gy in 5 fractions) or hypofractionated radiotherapy (25 Gy in 5 fractions) (57). Recently, the results of an interim analysis were presented after enrollment of 126 patients.…”

“…The PREOPANC trial randomized 246 patients with RPC or BRPC between neoadjuvant chemoradiotherapy and immediate surgery, both followed by adjuvant chemotherapy. In June 2021, the updated results were presented at the ASCO annual meeting ( 40 ). With a median follow-up of 59 months, a significant benefit in overall survival was found in patients treated with neoadjuvant treatment, with a 5-year overall survival (ITT) of 20.5% versus 6.5% in the patients treated with immediate surgery.…”

Neoadjuvant Treatment for Pancreatic Adenocarcinoma: A False Promise or an Opportunity to Improve Outcome?

“…The long-term results of the PREOPANC-1 trial, which is the first multicenter, randomized phase III trial investigating pre-operative chemoradiotherapy in PDAC, have been reported at the American Society of Clinical Oncology (ASCO) 2021 Meeting [72,73]. In this study, 246 patients with resectable PDAC or borderline resectable PDAC were randomly allocated to upfront surgery and adjuvant gemcitabine or pre-operative gemcitabine-based chemoradiotherapy (36 Gy in 15 fractions) and surgery followed by adjuvant gemcitabine.…”