This chapter focuses on second-line therapy in inoperable pancreatic cancer.
8.1 Introduction
Gemcitabine became the new standard in the treatment of advanced pancreatic cancer (APC) [1] in the late 1990s. Since then there have been no similar significant drug advances reported. In spite of this, the median survival for patients with advanced metastatic cancer has increased to 10-12 months in the last decade [2]. But this is not an effect due to new therapeutic drugs in first-line therapy; rather it is a benefit of the extensive use of second-line regimens for appropriate patients. However, no standard second-line treatment has yet been defined for these patients. Several phase II studies (see Table 8.1) refer to effective drugs and drug combinations in second-line therapy. Most drugs are adopted from salvage therapy regimens of advanced colorectal cancer or lung cancer. Trials are missing that compare the new approach with the standard procedure after failing first-line therapy. Only one small, randomized trial could show a significant improvement for a second-line regimen [3].
8.2 Second-Line Chemotherapy
Following the use of gemcitabine as a second-line drug [4], there has been a large variety of chemotherapy regimens that realize small advan-tages. The use of chemotherapy in advanced pan-creatic cancer was heavily dependent on the ex-periences of the local oncologists. Many patients were treated with individual designs. But due to there being so many different first- and second-line patient schedules, the idea of analysis was impractical. The process of the implementation of sequential therapies into the treatment of ad¬vanced pancreatic cancer led to a development of several regimens (Table 8.1).
A small study [5] with flutamide in second-line therapy after failing the current standard, 5-fluorouracil (5-FU), in the early 1990s led to a median survival of 4.7 months in this deadly dis¬ease. But with only 14 patients in this setting and no further evaluations of this drug in pancreatic cancer, we cannot assess any impact on therapy guidelines.
Irinotecan has shown activity as a second-line therapy, and a combination of irinotecan and the thymidylate synthase inhibitor raltitrexed led to a median overall survival of 6.5 months [6]. Interestingly, the addition of irinotecan to existing first-line therapy on which patients had progressed (gemcitabine/5-FU/FA/cispla-tin, G-FLIP) was associated with some benefit, and the median overall survival of patients was
10.3 months from the start of G-FLIP [7]. An¬other trial with 17 patients in refractory disease after a multiple combination in first-line therapy (gemcitabine/mitomycin/oxaliplatin) used the combination of irinotecan and 5-FU. A pro-gression-free survival of 4 months was noted. A similar result was observed with a combination of irinotecan and 5-FU/folinic acid (FolFIri) in pretreated patients with a gemcitabine-contain-ing regimen [8]. A study with paclitaxel showed second-line activity with a median survival time of 17.5 weeks from the start of therapy [9].
a Randomized study
Arsenic trioxide (AT) after a gemcitabine-containing regimen led to a median survival of 16.6 weeks and a progression-free interval of 7 weeks in 13 patients [10]. A combination of celecoxib and 5-FU continuous venous infusion (c.v.i.) after failing a gemcitabine based regime in 20 patients with advanced pancreatic or biliary tract cancer led to a median survival of 14 weeks with a progression-free survival in second-line therapy of 8 weeks [11].
The combination of oxaliplatin/folinic acid and 5-FU after failing first-line standard therapy with gemcitabine led to an overall survival of 12.5 months in 23 patients [2]. Tsavaris et al. [12] also used the combination of oxaliplatin/5-FU/FA in patients with gemcitabine refractory disease. This small phase II study used a different weekly regimen, so more neutropenia was observed and granulocyte-stimulating factor (GSF) had to given in 17 patients. The median time to progres¬sion was 22 weeks, median survival 5.5 months.
Gemcitabine and oxaliplatin in combination af¬ter failing gemcitabine monotherapy in the first line could reach an interesting median survival in the second line of 6 months. The addition of oxaliplatin may break through the first resistance of gemcitabine for any length of time [13]. Ox-aliplatin and raltitrexed in 41 patients led to a similar result [14]. Erlotinib and capecitabine are drugs that have found their employment now in primary therapy. In combination after failing a gemcitabine-containing regimen in 30 patients, we noticed a promising median survival in sec-ond-line therapy of 6.7 months [15].
The results of Oettle et al. [3] compare favour-ably with those seen in some other second-line treatments. Remarkable is the design of their study. The authors randomized the patients who failed first-line therapy into the standard pro-cedure with best supportive care and a chemo-therapy group with the combination of oxalipla-tin/5-FU and folinic acid. Sequential oxaliplatin
8 Second-Line Chemotherapy in Advanced Pancreatic Cancer
and 5-FU/FA following gemcitabine led to a me-dian overall survival of 39.6 (range 30.4-48.8) weeks from the start of first-line treatment versus 34.4 weeks without second-line chemotherapy (p = 0.03). A median time of 21 weeks in group A versus 10 weeks in group B shows a significant difference between these two groups regarding survival time after gemcitabine failure (p = 0.008). The combination of oxaliplatin and 5-FU used in this study was remarkably well tolerated. As ex¬pected, haematotoxicity and neurotoxicity were common. However, in the majority of cases, tox¬icities were WHO grade 1 or 2.
8.3 Summary
There is no established second-line therapy for patients with refractory disease under/after a gemcitabine-containing first-line chemotherapy. Therefore, a variety of different chemotherapy combinations continue to be investigated. All pa-tients with refractory disease should be recruited into clinical trials to address the question about the best effective regimen for those patients. Un-fortunately, a far too individual landscape is to be found in practice.
The CONKO 003 trial [3] was the first ran-domized study that showed a significant survival benefit for a second-line treatment with chemo-therapy in patients with advanced pancreatic cancer. This small trial answered the main ques-tion about the use of second-line therapy in prin-ciple. But urgent need for more effective drugs and designs is obvious, and many clinical trials are now in progress (Table 8.2).
8.1 Introduction
Gemcitabine became the new standard in the treatment of advanced pancreatic cancer (APC) [1] in the late 1990s. Since then there have been no similar significant drug advances reported. In spite of this, the median survival for patients with advanced metastatic cancer has increased to 10-12 months in the last decade [2]. But this is not an effect due to new therapeutic drugs in first-line therapy; rather it is a benefit of the extensive use of second-line regimens for appropriate patients. However, no standard second-line treatment has yet been defined for these patients. Several phase II studies (see Table 8.1) refer to effective drugs and drug combinations in second-line therapy. Most drugs are adopted from salvage therapy regimens of advanced colorectal cancer or lung cancer. Trials are missing that compare the new approach with the standard procedure after failing first-line therapy. Only one small, randomized trial could show a significant improvement for a second-line regimen [3].
8.2 Second-Line Chemotherapy
Following the use of gemcitabine as a second-line drug [4], there has been a large variety of chemotherapy regimens that realize small advan-tages. The use of chemotherapy in advanced pan-creatic cancer was heavily dependent on the ex-periences of the local oncologists. Many patients were treated with individual designs. But due to there being so many different first- and second-line patient schedules, the idea of analysis was impractical. The process of the implementation of sequential therapies into the treatment of ad¬vanced pancreatic cancer led to a development of several regimens (Table 8.1).
A small study [5] with flutamide in second-line therapy after failing the current standard, 5-fluorouracil (5-FU), in the early 1990s led to a median survival of 4.7 months in this deadly dis¬ease. But with only 14 patients in this setting and no further evaluations of this drug in pancreatic cancer, we cannot assess any impact on therapy guidelines.
Irinotecan has shown activity as a second-line therapy, and a combination of irinotecan and the thymidylate synthase inhibitor raltitrexed led to a median overall survival of 6.5 months [6]. Interestingly, the addition of irinotecan to existing first-line therapy on which patients had progressed (gemcitabine/5-FU/FA/cispla-tin, G-FLIP) was associated with some benefit, and the median overall survival of patients was
10.3 months from the start of G-FLIP [7]. An¬other trial with 17 patients in refractory disease after a multiple combination in first-line therapy (gemcitabine/mitomycin/oxaliplatin) used the combination of irinotecan and 5-FU. A pro-gression-free survival of 4 months was noted. A similar result was observed with a combination of irinotecan and 5-FU/folinic acid (FolFIri) in pretreated patients with a gemcitabine-contain-ing regimen [8]. A study with paclitaxel showed second-line activity with a median survival time of 17.5 weeks from the start of therapy [9].
a Randomized study
Arsenic trioxide (AT) after a gemcitabine-containing regimen led to a median survival of 16.6 weeks and a progression-free interval of 7 weeks in 13 patients [10]. A combination of celecoxib and 5-FU continuous venous infusion (c.v.i.) after failing a gemcitabine based regime in 20 patients with advanced pancreatic or biliary tract cancer led to a median survival of 14 weeks with a progression-free survival in second-line therapy of 8 weeks [11].
The combination of oxaliplatin/folinic acid and 5-FU after failing first-line standard therapy with gemcitabine led to an overall survival of 12.5 months in 23 patients [2]. Tsavaris et al. [12] also used the combination of oxaliplatin/5-FU/FA in patients with gemcitabine refractory disease. This small phase II study used a different weekly regimen, so more neutropenia was observed and granulocyte-stimulating factor (GSF) had to given in 17 patients. The median time to progres¬sion was 22 weeks, median survival 5.5 months.
Gemcitabine and oxaliplatin in combination af¬ter failing gemcitabine monotherapy in the first line could reach an interesting median survival in the second line of 6 months. The addition of oxaliplatin may break through the first resistance of gemcitabine for any length of time [13]. Ox-aliplatin and raltitrexed in 41 patients led to a similar result [14]. Erlotinib and capecitabine are drugs that have found their employment now in primary therapy. In combination after failing a gemcitabine-containing regimen in 30 patients, we noticed a promising median survival in sec-ond-line therapy of 6.7 months [15].
The results of Oettle et al. [3] compare favour-ably with those seen in some other second-line treatments. Remarkable is the design of their study. The authors randomized the patients who failed first-line therapy into the standard pro-cedure with best supportive care and a chemo-therapy group with the combination of oxalipla-tin/5-FU and folinic acid. Sequential oxaliplatin
8 Second-Line Chemotherapy in Advanced Pancreatic Cancer
and 5-FU/FA following gemcitabine led to a me-dian overall survival of 39.6 (range 30.4-48.8) weeks from the start of first-line treatment versus 34.4 weeks without second-line chemotherapy (p = 0.03). A median time of 21 weeks in group A versus 10 weeks in group B shows a significant difference between these two groups regarding survival time after gemcitabine failure (p = 0.008). The combination of oxaliplatin and 5-FU used in this study was remarkably well tolerated. As ex¬pected, haematotoxicity and neurotoxicity were common. However, in the majority of cases, tox¬icities were WHO grade 1 or 2.
8.3 Summary
There is no established second-line therapy for patients with refractory disease under/after a gemcitabine-containing first-line chemotherapy. Therefore, a variety of different chemotherapy combinations continue to be investigated. All pa-tients with refractory disease should be recruited into clinical trials to address the question about the best effective regimen for those patients. Un-fortunately, a far too individual landscape is to be found in practice.
The CONKO 003 trial [3] was the first ran-domized study that showed a significant survival benefit for a second-line treatment with chemo-therapy in patients with advanced pancreatic cancer. This small trial answered the main ques-tion about the use of second-line therapy in prin-ciple. But urgent need for more effective drugs and designs is obvious, and many clinical trials are now in progress (Table 8.2).
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