Irinotecan monotherapy has been tested in patients with previously untreated advanced pancreatic cancer, and the activity observed with irinotecan was at least equivalent to, if not better than, that of gemcitabine. Based on these data, Yi et al initiated a phase II study of single-agent irinotecan as second-line chemotherapy in patients with advanced pancreatic cancer.19 Among 33 patients, three patients showed a partial response, and 13 patients with stable disease were observed. The median PFS and OS were 2.0 and 6.6 months, respectively. Toxicity profiles were generally manageable, and there was no treatment-related death. Nanoliposomal irinotecan is a liposomal nanoparticle that encapsulates free irinotecan. This structure protects the irinotecan base from being converted to its active metabolite, SN-38, which enables a longer duration of the drug in circulation – thus increasing and prolonging the intratumoral levels of irinotecan and SN-38. In a phase II study of 40 patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy, the administration of nanoliposomal irinotecan at 120 mg/m2 every 3 weeks resulted in a median OS of 5.2 months, 1-year survival of 25%, and a manageable toxicity profile.20

Capecitabine, a prodrug of fluorouracil, has shown single-agent activity in the first-line treatment of patients with advanced pancreatic cancer. Boeck et al also examined capecitabine as salvage chemotherapy in gemcitabine-pretreated patients.21 This agent was orally administered to 39 patients at a dose of 1,250 mg/m2 twice daily for 14 days, followed by 7 days of rest. After a median follow-up of 6.6 months, 27 patients were evaluated for their response: no complete or partial responses were observed, but 15 patients (39%) had stable disease. The median TTP was 2.3 months, and the median OS was 7.6 months. Predominant grades 2 and 3 toxicities included hand–foot syndrome (28%), anemia (23%), leg edema (15%), diarrhea (13%), nausea/vomiting (10%), and leukocytopenia (10%).

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Nab-paclitaxel – which can breach the blood–stroma barrier to reach tumor cells – was also tested in the second-line setting for advanced pancreatic cancer prior to the phase III MAPCT trial.22 Patients received nab-paclitaxel at 100 mg/m2 for over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Among the 19 treated patients, one patient had a confirmed partial response and 6 patients had stable disease as their best response. The median PFS and OS were 1.7 and 7.3 months, respectively. Grades 3 and 4 neutropenia, neutropenic fever, and anemia occurred in 32%, 11%, and 11% of patients, respectively.

In summary, single-agent chemotherapy may constitute a feasible treatment option with acceptable activity and tolerable toxicity for patients with gemcitabine-refractory pancreatic cancer. In view of the favorable toxicity profile, single agents combined with other agents might improve the therapeutic results.

Second-line combination chemotherapy: it takes two to tango?

As a patient’s performance status often rapidly declines when the tumor is locally or systemically progressing, it can be difficult to administer second-line combination chemotherapy in pancreatic cancer. However, it is reasonable to consider salvage chemotherapy in a selective patient population. Several clinical trials have evaluated the efficacy and safety of different combination regimens in patients with advanced pancreatic cancer previously treated with gemcitabine-based therapies, with some combinations yielding promising results (Tables 1 and 3).

(To view a larger version of Table 3, click here.)

Platinum-based regimens

Many studies have used oxaliplatin as part of a combination regimen – the most commonly used being oxaliplatin plus infusional fluorouracil. The OFF regimen administered on a 6-week cycle was feasible and active, with an acceptable toxicity profile.23 As discussed earlier, the OFF regimen as second-line therapy showed a survival benefit compared with BSC in gemcitabine-refractory disease.14 The German CONKO-study group further conducted a randomized phase III trial comparing OFF to folinic acid and fluorouracil (FF) and showed that the OFF regimen was associated with a significantly improved OS (5.9 vs 3.3 months; P = 0.010) and PFS (2.9 vs 2.0 months; P = 0.019).10 The addition of oxaliplatin to FF increased neurotoxicity (mostly, grades 1 and 2) but was well tolerated. However, the results of a more recent randomized phase III trial (PANCREOX) using a biweekly infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) schedule were disappointing, with similar PFS (3.1 vs 2.9 months; P = 0.99) and shorter OS (6.1 vs 9.9 months; P = 0.02) in the modified FOLFOX6 group versus the infusional fluorouracil/leucovorin (FU/LV) group.12 Moreover, the response rates were not significantly different between groups (13.2% vs 8.5%; P = 0.361). The tolerability of the infusional FU/LV group was remarkably better than that of the modified FOLFOX6 group, with a nearly six-fold lower incidence of grades 3/4 adverse events (11% vs 63%).

Other oxaliplatin–fluoropyrimidine combinations have also been evaluated in small phase II studies. In a comparable regimen to OFF, Tsavaris et al used weekly 50 mg/m2 oxaliplatin, 50 mg/m2 leucovorin, and 500 mg/m2 fluorouracil treatments and achieved a median OS of 25 weeks.24 Novarino et al administered 40 mg/m2 oxaliplatin, 250 mg/m2 leucovorin, and 500 mg/m2 fluorouracil weekly for a treatment period of 3 weeks on a 4-week cycle, resulting in a median OS of 17.1 weeks.25 In a similar study conducted by El-Hadaad and Wahba, the median OS was 22 weeks.26 Additionally, a small phase II trial in Korea randomly assigned patients to receive 85 mg/m2 oxaliplatin, 400 mg/m2 leucovorin, and 2,000 mg/m2 fluorouracil (modified FOLFOX) or 70 mg/m2 irinotecan, 400 mg/m2 leucovorin, and 2,000 mg/m2 fluorouracil (modified FOLFIRI.3).27 However, the efficacy was modest, and the median OS was 14.9 and 16.6 weeks for modified FOLFOX and modified FOLFIRI.3, respectively. A phase II study assessed the activity and safety profile of a combination of capecitabine and oxaliplatin.28 A total of 39 patients received this regimen as a second-line treatment. One patient (2.6%) showed a partial response, and ten patients had stable diseases (26%). The median PFS and OS were 9.9 and 23 weeks, respectively, and the toxic effects were generally manageable.

Oxaliplatin in combination with agents other than fluoropyrimidine has also been tested as a second-line regimen for advanced pancreatic cancer. A phase II trial evaluated oxaliplatin in combination with irinotecan in 30 patients.29 Three patients (10%) showed a partial response, and seven patients (23%) had stable disease. The median TTP was 4.1 months, and the median OS was 5.9 months, with a 1-year survival rate of 23.3%. Grades 3 and 4 adverse events included leukopenia (6%), neuropathy (6%), and diarrhea (3%). Reni et al treated 41 patients, who previously received gemcitabine in the first-line setting, with oxaliplatin at 130 mg/m2 and raltitrexed at 3 mg/m2 every 3 weeks as salvage chemotherapy.30 The results showed a partial response in 24% of patients and a median OS of 5.2 months. Neutropenia was the most common toxic effect, occurring in 12% of patients. Demols et al evaluated the activity and tolerability of gemcitabine and oxaliplatin (GEMOX) in patients who had progressed during or following gemcitabine therapy.31 The study showed a response rate of 22.6% in 31 assessable patients. The median response duration and TTP were 4.5 and 4.2 months, respectively, and the median OS was 6 months (range 0.5–21). Grades 3 and 4 toxicities occurred in 16 patients (48%). Recently, Ettrich et al conducted a phase II trial examining the activity of the docetaxel and oxaliplatin (DocOx) combination as a second-line treatment for advanced pancreatic cancer.32 Tumor response was achieved in 15.9% of the patients, with a disease control rate of 48% after the first two treatment cycles. The median PFS was 1.8 months, and the median OS was 10.1 months. Notably, grades 3 and 4 neutropenia developed in 63.6% of patients, and diarrhea developed in 11.4% of patients. However, all toxicities were manageable. Thus, the data obtained using the DocOx protocol were consistent with other second-line protocols, including the OFF regimen, indicating DocOx as an option for patients with chemorefractory pancreatic cancer.

Cisplatin-based regimens have also been investigated as second-line chemotherapy after gemcitabine failure. Kim et al conducted a phase II study examining cisplatin plus S-1 as a second-line palliative chemotherapy for patients with gemcitabine-refractory pancreatic cancer.33 The study was terminated early after the enrollment of 11 patients due to severe toxicity. The median TTP was 44 days (1.4 months), and the median OS was 81 days (2.7 months). The most common grades 3 and 4 toxicities included fatigue (27.3%), nausea (27.3%), and anorexia (18.2%). Stathopoulos et al tested lipoplatin – a liposomal cisplatin aimed at the avoidance of renal toxicity – combined with gemcitabine in pretreated patients with advanced pancreatic cancer.34 The objective response rate data showed a partial response in two of the 24 patients examined (8.3%) and stable disease in 14 patients (58.3%). The median survival from the beginning of second-line treatment was 4 months.