If gemcitabine-based chemotherapy is the current standard of care for first-line treatment of advanced pancreatic cancer, there are limited data to support a standard second-line chemotherapy regimen[23
]. Indeed, the true survival benefit from first-line therapy is small, and few patients can endure a second line as their performance status deteriorates with disease progression. In our study, the rate of patients treated with second-line chemotherapy was 38.8%, in accordance with most published data regarding gemcitabine-pretreated pancreatic cancer (16%-57%). Median overall survival from the start of second-line setting was 5.8 mo (4.1-6.6 mo), and median progression-free survival was 3.4 mo (2.4-4.2 mo). These results are similar to those obtained in first-line with gemcitabine by Burris et al[4
] or Heinemann et al[9
]. Moreover, patients with good performance status (0-1) and who had benefited from gemcitabine chemotherapy in first line (duration of treatment ≥ 4 mo) had a significantly greater duration of overall survival than those who had not (6.3 mo vs
1.8 mo, P <
0.001; and 7.2 mo vs
4.2 mo, P =
0.046, respectively). The rate of grade 3-4 toxicity was determined to be 33.7% (27 patients), but there were no unexpected side effects. Consequently, our experience demonstrates that a selected population of patients with good performance status can benefit from second-line chemotherapy after first-line gemcitabine-based treatment, with appreciable overall and progression-free survivals. This retrospective study included a large population, while most of data published over the last ten years involved relatively small samples in monotherapy (from 13 to 52 patients) as well as in bitherapy (from 12 to 46 patients)[24
]. The disease control rate was 40%, as described by many authors for both monotherapy and bitherapy regimens, and median overall and progression-free survivals were superior to those reported in monotherapy studies, but were not different from bitherapy[24
In daily practice, second-line therapies are regularly used in gemcitabine-pretreated patients with pancreatic carcinomas, but the efficacy and benefit in terms of survival or quality of life have never been validated. A randomized phase III trial conducted in second line was presented by Pelzer et al[25
]. One hundred and sixty-five gemcitabine-pretreated patients with pancreatic cancer were randomly assigned to receive either FF (5-FU 2 g/m² for 24 h plus folinic acid or leucovorin 200 mg/m² on days 1, 8, 15 and 22) or OFF (FF plus oxaliplatin 85 mg/m² on days 8 and 22). Median overall survival and progression-free survival were significantly improved with OFF protocol (20 wk vs
13 wk, P =
0.014; and 13 wk vs
9 wk, P =
0.012, respectively), with an acceptable tolerance profile. This study illustrated the effectiveness of this protocol which may become the standard second-line therapy. Currently, the National Comprehensive Cancer Center pancreatic cancer guidelines encourage the participation of patients with satisfactory performance status in clinical trials, and recommend the use of oxaliplatin and fluoropyrimidine if enrolment in trials is not possible[26,27
]. Finally, the XELOX regimen[28
] showed comparable efficacy to FOLFOX (or OFF) regimen, while offering the advantage of oral fluoropyrimidine treatment. Even so, more large randomized controlled trials are required in second line before a new standard of care can be established.
Interestingly, the CA 19-9 measurement was correlated with OS and PFS in our study. Patients whose level of CA 19-9 declined by more than 20% had a significantly greater duration of survival. The prognostic value of CA 19-9 level and course is well established for patients with pancreatic cancer treated with surgery[29-31
], radiotherapy and chemoradiotherapy[32,33
]. Some studies also correlated the level and the course of CA 19-9 with OS and PFS of pancreatic cancer patients treated with gemcitabine as first-line chemotherapy[3,34-36
]. These studies showed improved median OS for patients with a decrease of CA 19-9 > 20% after two months of treatment with gemcitabine. Saad et al[37
] reported an increase in the median OS for patients with a reduction of CA 19-9 at any time after treatment. In second-line, only one study demonstrated that a CA 19-9 value > 400 IU/mL was a significant independently negative prognostic factor[38
]. To our knowledge, it was the second report which showed a correlation between OS and CA 19-9 course[39
], and the first report for PFS and CA 19-9 course in second-line chemotherapy for gemcitabine-pretreated patients with pancreatic cancer.
In summary, treatment of metastatic pancreatic cancer remains a major challenge and requires new chemotherapeutic and targeted agent combination to be compared to gemcitabine in first-line. It should be noted that a new therapeutic alternative could merge in first-line for selected patients according to the recent results obtained in a randomized Phase III study comparing FOLFIRINOX regimen to gemcitabine[40
]. A significant longer overall survival, progression-free survival, and higher response rates were obtained with FOLFIRINOX than with gemcitabine alone, associated with manageable toxicities.
The present study focused on second-line therapy in gemcitabine-pretreated patients with advanced pancreatic cancer. From our experience, second-line chemotherapy is a valuable treatment option after progression on gemcitabine-based regimen, because 30% to 40% of patients could benefit from this therapy, especially those with good performance status (1-2) and who gained benefit from first-line therapy. Further randomized clinical trials are necessary to provide a standard treatment in this situation. Additionally, measurement of the CA 19-9 level was confirmed to be an efficient marker for treatment monitoring in first-line as well as in second-line treatment.