Irinotecan-based chemotherapeutic regimens are options in the second-line setting for patients who progressed during gemcitabine-based treatment. In Austria, Ulrich-Pur et al conducted a phase II trial involving 38 patients who were pretreated with gemcitabine.35 The patients were randomized to 3-weekly courses of irinotecan at 200 mg/m2 on Day 1 plus raltitrexed at 3 mg/m2 on Day 2, or raltitrexed at 3 mg/m2 on Day 1 only. The superior response rate in the combination group (16% vs 0%) led to the termination of the trial in the first stage of accrual. The median PFS (4.0 vs 2.5 months) and the median OS (6.5 vs 4.3 months) were also superior in the combination group. Grades 3 and 4 toxic effects were comparable between the two groups. A study in Italy evaluated the activity of mitomycin, docetaxel, and irinotecan (MDI) on metastatic pancreatic adenocarcinoma following gemcitabine-containing chemotherapy.36 The median TTP was 1.7 months, and the median OS was 6.1 months, with no objective response observed. Ko et al tested a regimen using irinotecan and docetaxel and showed a disease control rate of 21.4%. The median OS was 134 days (4.5 months), with a 6-month survival rate of 36%.37 However, 12 of the 14 patients experienced grades 3 and 4 toxic effects, with neutropenia/leukopenia (42.9%) being the most common grades 3 and 4 toxicity. The FOLFIRI regimen has also been tested in a prospective multicenter study.38 Among the 50 enrolled patients, four partial responses (8%) and 14 stable diseases (28%) were observed. The median PFS and OS were 3.2 and 5.0 months, respectively. Grades 3 and 4 neutropenia and diarrhea occurred in ten (20%) and six (12%) patients, respectively.
An open-labeled, multicenter, phase III trial (NAPOLI-1) assessed the effect of nanoliposomal irinotecan alone and in combination with FF in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy.11 Patients were randomly assigned to receive either 120 mg/m2 nanoliposomal irinotecan every 3 weeks or FF weekly for 4 weeks in a 6-week cycle. Safety data from a concurrent study in patients with metastatic colorectal cancer treated with a combination of 80 mg/m2 nanoliposomal irinotecan and FF every 2 weeks were demonstrated; thus, the study protocol was amended to add this regimen as a third arm. The median OS in patients assigned to the nanoliposomal irinotecan combination regimen was 6.1 months versus 4.2 months with FF alone (HR = 0.67; P = 0.012). The median OS did not differ between nanoliposomal irinotecan alone and FF (HR = 0.99; P = 0.94). The most frequent grades 3 and 4 adverse events in the nanoliposomal irinotecan combination group were neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%). The US Food and Drug Administration rapidly approved nanoliposomal irinotecan plus FF as second-line therapy for metastatic pancreatic ductal adenocarcinoma.
Fluorouracil in combination with oxaliplatin or irinotecan formulations has been well studied, with the combination of fluorouracil and irinotecan formulations appearing to be appropriate as second-line treatment.39 Besides, fluorouracil combined with agents other than oxaliplatin and irinotecan has also been tested. An early phase II trial assessed the combination of eniluracil – a potent irreversible inactivator of dihydropyrimidine dehydrogenase – and fluorouracil.40 Among 48 patients with gemcitabine-refractory metastatic pancreatic cancer, one patient (2%) had a confirmed partial response. The median OS was 3.4 months, and grades 3 and 4 toxicity occurred in 31 out of 48 (65%) patients. The researchers therefore concluded that fluorouracil plus eniluracil has limited activity in patients with advanced pancreatic cancer and is associated with a high frequency of grades 3 and 4 toxic effects. Kim et al studied the combination of fluorouracil and paclitaxel in 28 patients with a history of previous gemcitabine-based chemotherapy, 20 of whom were assessable.41 The study showed a partial response rate of 10% and stable disease in 20% of patients. The median TTP and OS were 2.5 and 7.6 months, respectively. Furthermore, the combination of capecitabine and docetaxel has been studied because there are preclinical data showing synergy between these agents. A phase II study that enrolled 31 patients showed that the combination of capecitabine with docetaxel was moderately active in pretreated advanced pancreatic cancer with a partial response rate of 9.7% and stable disease in 22.6% of patients.42 The median PFS and OS were 2.4 and 6.3 months, respectively. The most common grades 3 and 4 toxic effect was neutropenia (32.2%). Moreover, the researchers reported that 20% of patients had pain control, and 38.7% of patients maintained their body weight. In another phase II study, a similar regimen, but with different dosing, showed a median PFS and OS of 3.7 and 5.3 months, respectively.43 A total of 14% of patients showed an objective response, and as many as 59% of patients had stable disease for two cycles. Treatment was generally well tolerated, but one patient died, with the cause of death being possibly related to treatment.
Based on preclinical data indicating that leucovorin could enhance the efficacy of S-1, Ge et al conducted a phase II trial enrolling 92 patients with gemcitabine-refractory advanced pancreatic cancer.44 The patients were randomly assigned to S-1 in combination with leucovorin or S-1 alone. The study showed no significant differences in the median OS (5.5 vs 6.3 months), median PFS (1.9 vs 3.0 months), and overall response rate (4.7% vs 8.3%) between the two groups. Grades 3 and 4 toxic effects were significantly higher in the S-1 plus leucovorin group than in the S-1 group. Based on these efficacy data, the researchers concluded that, compared with S-1, S-1 plus leucovorin did not improve survival in this patient population. Another similar study showed a higher disease control rate in the S-1 plus leucovorin group, but comparable OS in the two groups.45 Randomized trials from Japan comparing the efficacy and safety of S-1 plus oxaliplatin (or S-1 plus irinotecan) with that of S-1 alone also showed no significant improvement in OS and PFS.46,47
Cereda et al conducted a phase II trial exploring the activity of the combination of mitomycin and ifosfamide as salvage therapy in patients with gemcitabine-resistant metastatic pancreatic cancer.48The study showed a partial response rate of 5% (one patient) and stable disease in 10% of patients. However, grades 3 and 4 toxicities, including neutropenia in 80% of patients, were poorly tolerated, leading to the premature termination of this trial. Braghiroli et al tested the combination of paclitaxel and metformin for patients with gemcitabine-refractory pancreatic cancer based on preclinical data demonstrating synergism in this combination.49 The disease control rate was 31.6% (6 patients), with a median OS and PFS of 128 and 44 days, respectively. Treatment-related grades 3 and 4 toxicities were observed in eight patients (40%), with the most common toxicity being diarrhea. The study failed to meet its primary endpoint and was, therefore, terminated in the first phase.
Second-line targeted therapy: going beyond cytotoxic chemotherapy?
Targeted agents have been extensively assessed in the first-line setting in pancreatic cancer. Disappointingly, multiple studies have failed to show any improvement in survival. One exception is the combination of gemcitabine and the EGFR tyrosine kinase inhibitor (TKI) erlotinib, which gained regulatory approval following a small but statistically significant improvement (10-day) in median survival compared with gemcitabine alone in a large, randomized phase III trial.50 Despite the lack of activity of targeted agents in the first-line setting, investigators have tested new drugs or drug combinations to improve survival for patients with advanced pancreatic cancer following first-line therapy (Table 4).
(To view a larger version of Table 4, click here.)