Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma

Abstract

There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure. In view of the urgent need for such therapy, and since preclinical and phase I clinical data suggest an encouraging, potentially synergistic activity between raltitrexed and irinotecan, the present randomised phase II study was initiated. A total of 38 patients with metastatic pancreatic adenocarcinoma, who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine, were enrolled in this study. They were randomised to 3-weekly courses of raltitrexed 3 mg m À2 on day 1 (arm A) or irinotecan 200 mg m À2 on day 1 plus raltitrexed 3 mg m À2 on day 2 (arm B). The primary study end point was objective response, secondary end points included progression-free survival (PFS) and overall survival (OS), as well as clinical benefit response in symptomatic patients (n ¼ 28). In the combination arm, the IRC-confirmed objective response rate was 16% (three out of 19 patients had a partial remission; 95% CI, 3 -40%), which was clearly superior to that in the comparator/control arm with raltitrexed alone, in which no response was obtained. Therefore, the trial was already stopped at the first stage of accrual. Also, the secondary study end points, median PFS (2.5 vs 4.0 months), OS (4.3 vs 6.5 months), and clinical benefit response (8 vs 29%) were superior in the combination arm. The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe, clinically relevant treatment-related toxicities: gastrointestinal symptoms (42 vs 68%), partial alopecia (0 vs 42%), and cholinergic syndrome (0 vs 21%) were more commonly noted in arm B; however, grade 3 adverse events occurred in only three patients in both treatment groups. Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer. The superior response activity, PFS and OS (when compared to raltitrexed), as well as its tolerability and ease of administration suggest that future trials with this combination are warranted.

Use of gemcitabine as a second-line treatment following chemotherapy with folfirinox for metastatic pancreatic adenocarcinoma

“…The present study reports the findings on a single center cohort of patients who received second-line gemcitabine treatment for advanced-stage pancreatic adenocarcinoma. A survival of 3.6 months with second-line chemotherapy was observed, which is in agreement with previous published data (Table I) (7)(8)(9)(10)14,15,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Response to gemcitabine therapy at the first follow-up evaluation (at 2 months) impacted significantly the OS of the patients.…”

Phase II study of palliative S-1 in combination with cisplatin as second-line chemotherapy for gemcitabine-refractory pancreatic cancer patients

“…The results of previous studies concerning oxaliplatin (15), ralitrexed (16), paclitaxel (17) and pemetrexed (18) monotherapies in the second-line treatment of pancreatic cancer have revealed modest antitumor effects with no survival benefit. Studies have also reported combination chemotherapeutic regimens as second-line therapies for advanced pancreatic cancer.…”

A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer

“…Several phase II studies have evaluated different combinations of cytotoxic agents in order to improve the proportion of objective responses and the duration of survival. Numerous phase II studies have investigated combinations of these active drugs with or without gemcitabine in patients with advanced/metastatic pancreatic cancer (Rothenberg et al, 1998;Bahadori et al, 1999;Hidalgo et al, 1999;Rocha-Lima et al, 1999;Heinemann et al, 2000;Stathopoulos et al, 2001;Alberts et al, 2002;Berlin et al, 2002;Hess et al, 2003;Stathopoulos et al, 2003;Ulrich-Pur et al, 2003). The combination of gemcitabine plus irinotecan has resulted in an objective response of 25% with a median overall survival ranging from 5.7 to 7 months (Rocha-Lima et al, 2002;Stathopoulos et al, 2004).…”

“…Despite the fact that the achieved objective response rate with gemcitabine-based combinations is practically similar, there are controversial results concerning overall survival; the 1-year survival was reported to be 22% with the gemcitabine -irinotecan combination (objective response rate (ORR) 25%) whereas overall survival was found to be 34.8% with the gemcitabine -capecitabine combination (ORR 18.9%) (Stathopoulos et al, 2003;Ulrich-Pur et al, 2003).…”