Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP-05).

Abstract

189 Background: Despite improvements of postoperative adjuvant therapy for resected pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor. A randomized controlled trial has begun to compare neoadjuvant chemotherapy using gemcitabine and S1 (NAC-GS) with upfront surgery (Up-S) for patients with PDAC planned resection. Methods: Patients were enrolled after the diagnosis of resectable PDAC with histological confirmation. They were randomly assigned as either NAC-GS or Up-S. In NAC-GS, gemcitabine was provided at a dose of 1 g/m2 on day 1 and 8 and oral S-1 was administered at a dose of 40 mg/m2 twice daily on 1-14 days. Patients received 2 cycles of this regimen. S-1 adjuvant for 6 months was administered for the patients with curative resection and fully recovered within 10 weeks after surgery in both arms. The primary endpoint for the phase III part was overall survival (OS); secondary endpoints included adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases, and tumor marker kinetics. The target sample size required 163 patients (α-error 0.05; power 0.8) in each arm. The trial was conducted by the Health Labor Sciences Research Grant (H22-009) of Japan and registered with the UMIN Clinical Trials Registry as UMIN000009634. Results: From January 2013 to January 2016, 364 patients were enrolled in 57 centers (182 to NAC-GS and 182 to Up-S). Of these, two were excluded because of ineligibility, therefore 182 patients in NAC-GS and 180 in Up-S constituted the ITT analysis-set. The median OS was 36.7 months in NAC-GS and 26.6 months in Up-S; HR 0.72 (95% confidential interval 0.55-0.94; p=0.015 [stratified log-rank test]). Grade 3 or 4 adverse events frequently (72.8%) observed in NAC-GS were leukopenia or neutropenia. However, the resection rate, R0 resection rate, and morbidity of the operation were equivalent in the two groups. There was no perioperative mortality in either group. Conclusions: This phase III study demonstrated the significant survival benefits of NAC-GS treatment. Therefore, the results indicated that neoadjuvant chemotherapy could be a new standard for patients with resectable PDAC. Clinical trial information: UMIN000009634.

Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer: A Meta-Analysis of Randomized Controlled Trials

“…Finally, Prep-02/JSAP-05 was a large multicenter Japanese RCT comparing neoadjuvant gemcitabine and S-1 with SF in patients with resectable PDAC. Although presented in conference form only, NT led to significantly improved OS compared to SF (36.7 vs. 26.6 months; p=0.02) [35].…”

“…Among 1586 articles identified, 24 were selected for full-text review, and 6 RCTs comparing SF to NT for PDAC were included ( Figure 1) [21,22,[34][35][36][37]. The characteristics of the included trials are reported in Table 1.…”

Neoadjuvant treatment for resectable pancreatic adenocarcinoma: What is the best protocol?

“…Unfortunately to BR PDAC. 35 Although the number of cases was small, which raised some criticism of their study design and conduct, 7 39,40 The resection rates of both arms were similar, with no operative mortality. A significant decrease of pathological nodal metastases and hepatic relapse after surgery was noted in the NAC-GS patients compared to upfront surgery patients.…”

“…36,37,[41][42][43][44] Considering recent progress in chemotherapy for UR PDAC, 45,46 a clinical question has been raised about the optimal protocol in the neoadjuvant setting. 24 Okano K 57 R, BR S1 + RT 91% N. R. N. R. 25 Motoi F 101 R, BR GEM/S1 73% 30.8 N. R. 26 Tsai S 130 R, BR FOLFIRINOX (n = 52) FOLFIRI (n = 26) GEM/Nab-P (n = 16) CAP/Nab-P (n = 15) *+RT (n = 83) 82% 38 45 27 Eguchi H 63 R GEM/S1 + RT 86% 55.3 NR 39,40 showed a significantly higher response rate and longer PFS than gemcitabine single-agent. 47 Ozaka et al 48 also reported similar results, with a high response rate and longer PFS, in a randomized, phase II trial.…”

“…14,15,[18][19][20][21][22]25,27,28 RCTs comparing NACRT with upfront surgery, however, have not yet been fully reported, [33][34][35][36][37] in contrast to NAC. [38][39][40] The good survival outcomes. 55 Their concept is "total neoadjuvant therapy (TNT)," an emerging approach with excellent outcomes for other cancers.…”