Search strategy and selection criteria

The data for this review were identified through searches of PubMed and references from relevant articles published in the English language using the following search terms: “advanced pancreatic cancer”, “inoperable pancreatic adenocarcinoma”, “gemcitabine-refractory pancreatic cancer”, “second-line therapy”, “second-line treatment”, and “second-line chemotherapy”. Abstracts from the annual meetings of the American Society of Clinical Oncology and European Society of Medical Oncology were also screened for additional studies. Only prospective clinical trials published between 1997 and 2017 were included. Studies were also required to meet the inclusion criteria that the first-line therapy was either a gemcitabine-based regimen (gemcitabine monotherapy or gemcitabine-containing combination therapy) or FOLFIRINOX. Abstracts and reports from meetings were included only when they directly associated with previously published work. The PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) flow diagram for this review is shown in Figure 1.


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(To view a larger version of Figure 1, click here.)

Second-line chemotherapy in advanced pancreatic cancer: yes or no?

Does the benefit of chemotherapy continue with disease progression during or after first-line treatment? Two randomized phase III trials compared second-line treatments with best supportive care (BSC). In the first study by Ciuleanu et al, 303 patients with previously gemcitabine-treated metastatic pancreatic adenocarcinoma were randomized to glufosfamide or BSC.13 The median survival was 105 days (3.5 months) for glufosfamide and 84 days (2.8 months) for BSC, with an 18% increase in OS for glufosfamide, which was not statistically significant (HR 0.85; 95% CI 0.66–1.08; P = 0.19), suggesting low activity of glufosfamide in this refractory patient population. The second study by the German CONKO-study group randomized patients in a 1:1 ratio to oxaliplatin plus folinic acid and 5-fluorouracil (OFF) or BSC.14 Calculations were undertaken with a total of 165 patients to demonstrate a doubling of survival time after progression on first-line gemcitabine therapy. However, after inclusion of 46 patients (23 in each arm), the trial was terminated early due to insufficient accrual (lack of acceptance of BSC by patients and physicians). Although no confirmed response better than stable disease was observed, OFF as second-line chemotherapy significantly prolonged survival time compared to BSC alone (4.82 vs 2.30 months, P = 0.008; Table 1).

(To view a larger version of Table 1, click here.)

These two studies did not yield sufficient evidence to demonstrate the necessity of second-line chemotherapy (partly because one study used glufosfamide, which was not commonly used in the treatment of pancreatic cancer, and the other study was prematurely closed); however, this treatment may have a survival benefit in this patient population. Further trials in the second-line setting are needed, comparing active treatment with BSC to ensure that patients do not receive unnecessary toxicity without any benefit. That is, from an ethical perspective, patient-centered decision-making becomes the highest priority. Therefore, a comprehensive assessment considering performance status, comorbidities, expected toxicities, cost-effectiveness, and patient preference is required.

Second-line single-agent chemotherapy: one is all?

A summary of the prospective clinical trials on second-line single-agent chemotherapy is shown in Table 2. All of these trials were phase II studies. Although few patients showed an objective response (range 0–15%), the disease control rate ranged from 16.7% to 58%, and the median second-line survival ranged from 3.5 to 7.6 months.

(To view a larger version of Table 2, click here.)

Based on the data of increased cytotoxic activity of oxaliplatin in pancreatic cell lines with microsatellite instability, Androulakis et al conducted a phase II trial that enrolled 18 advanced pancreatic cancer patients with a previous history of gemcitabine-based chemotherapy treatment.15Oxaliplatin was administered at 130 mg/m2 every 3 weeks. The study failed to induce an objective response, and three patients had stable disease for over 2 months. Hematological toxicity was mild, with no grade 3 or 4 toxic effects reported.

In patients with advanced pancreatic cancer, first-line chemotherapy with pemetrexed has shown clinical activity as a single agent as well as in combination with gemcitabine. Based on this result, a multicenter phase II trial was conducted to evaluate the efficacy and safety of pemetrexed as a second-line treatment in patients with advanced pancreatic cancer who had progressed on single-agent gemcitabine or gemcitabine-based first-line chemotherapy.16 A total of 52 patients received pemetrexed at 500 mg/m2 intravenously every 3 weeks. The response rate was 3.8% (95% CI 0.5%–13.2%). At a median follow-up of 20 weeks, the median time to progression (TTP) was 7 weeks, and the median OS was 20 weeks. The most frequent hematological grades 3 and 4 toxic effects included neutropenia (17.3%), thrombocytopenia (5.8%), and anemia (3.8%). The most frequent non-hematological toxic effects (any grade) were diarrhea, nausea, and stomatitis/pharyngitis (23.1% each). The authors concluded that pemetrexed is a safe treatment option with limited activity in the second-line setting after gemcitabine failure.

Second-line chemotherapy with single-agent tegafur/gimeracil/oteracil (S-1) in patients with gemcitabine-resistant advanced pancreatic cancer has also been assessed. Morizane et al examined S-1 treatment at 40 mg/m2 twice a day for 4 weeks on a 6-week cycle and showed that the response rate was 15% with a median progression-free survival (PFS) of 2.0 months and a median OS of 4.5 months.17 The toxicity was tolerable, and no life-threatening toxicities were observed. Another study using the same regimen showed a similar response rate of 9.5%, and PFS and OS were 4.1 and 6.3 months, respectively.18 Moreover, the toxicity profile was similar.