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FOLFIRINOX therapy in the elderly patients with unresectable pancreatic cancer
S30
Abstracts / Pancreatology 16 (2016) S1eS192 1 Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas, MD Anderson Cancer Center, USA 2 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, USA 3 Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Japan 4 Department of Surgery & Oncology, Graduate School of Medical Sciences, Kyushu University, Japan
Background: Intraductal papillary mucinous neoplasm (IPMN) has unique clinical features which can be distinguished from pancreatic ductal adenocarcinoma (PDAC), although the prevalence of KRAS mutations is high in both diseases. Recently, activating mutations in codon 201 of GNAS, which encodes for the alpha subunit of stimulatory G protein (Gas) were discovered specifically in IPMN. Gas is an important regulator of cAMP signaling pathway. The role of mutant Gas and Kras in development of IPMN largely remains to be elucidated. Methods: We generated an inducible mouse model of R201C mutant Gas using reverse Tetracycline transactivator (Linker). The Linker is conditionally expressed in exocrine pancreas under p48-Cre system with or without LSL-Kras G12D (LGKC or LGC respectively). For further mechanistic analysis, a mutant-Kras driven primary PDAC cell with inducible R201C Gas (LGKC cell) was established from the mouse model. Results: In LGC mice, induction of R201C Gas increased acinar cell proliferation but no neoplastic changes occurred up to three months of induction. In LGKC mice, one-week induction caused massive acinar to ductal metaplasia (ADM) and in a few weeks, developed cystic lesions. Age-matched LGKC mice without the induction showed only KCcompatible PanIN lesions. In LGKC cells, induction of R201C Gas followed by cAMP elevation transiently increased cell growth via Protein kinase A and Mitogen-activated protein kinase signaling pathways. However, the long-term induction attenuated cell growth and colony formation in soft agar. Among Kras-related signaling elements, Yes-associated protein was phosphorylated and inhibited. Microarray analysis revealed up-regulation of pancreatic ductal markers: Cystic fibrosis transmembrane conductance regulator, Aquaporin-1 and Aquaporin-5. Furthermore, tumor histology of subcutaneously injected LGKC cells was altered from poorly-differentiated type to well-differentiated ductal type by the induction of R201C Gas. Conclusion: Induction of R201C Gas modified mutant Kras-driven pancreatic tumorigenesis in vivo and cell growth and differentiation in vitro.
S8-1.
PubMed, Embase and Cochrane were systematically searched for studies published up to August 31st, 2015. Primary outcome was (R0) resection rate. Fourteen studies involving 365 patients with LAPC were included. A modified chemotherapy regimen was described in 3 studies and FOLFIRINOX dose reductions in up to 65% of patients. Radiotherapy was given in 57% of all patients. Total resection rate was 28% (77% R0). Median overall survival ranged from 8.9 to 25.0 months. Median survival after resection was 24.9 months. Six out of 85 (7%) resection specimens showed a complete pathologic response. Grade 3-4 toxicity occurred in 23% of patients. The resection rate of patients treated with FOLFIRINOX without radiotherapy was 12% (70% R0) with 15.7 months median overall survival and 19% grade 3-4 toxicity. FOLFIRINOX-based treatment for patients with LAPC seems safe and achieves high (R0) resection rates and overall survival, despite the frequent administered modified regimes and dose reductions during treatment.
S8-2. FOLFIRINOX therapy in the elderly patients with unresectable pancreatic cancer Yu Ishii, Katsuya Kitamura, Akira Yamamiya, Tomohiro Nomoto, Tadashi Honma, Hitoshi Yoshida Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Japan Objective: To investigate FOLFIRINOX therapy in patients of 65 years of age or older with unresectable pancreatic cancer. Methods: Of 33 patients with unresectable pancreatic cancer who received FOLFIRINOX therapy at Showa University Hospital between April 2013 and June 2015, 22 patients with pathological diagnosis of adenocarcinoma before chemotherapy were included. We retrospectively examined the safety and efficacy of FOLFIRINOX therapy in patients of 65 years of age or older with unresectable pancreatic cancer. Results: Of 22 patients who received FOLFIRINOX therapy, 10 patients were 65 years of age (A group) and 12 were <65 years of age (B group). There were no significant differences in characteristics of patients, the number of chemotherapy course, overall survival, progression-free survival and adverse events between both groups. The response rate in group A was significantly higher than that of group B (40% vs. 0% for A and B groups, respectively; p¼0.015). The rate of patients who reduced anticancer drugs in A group was significantly higher than that of B group (90% vs. 42% for A and B groups, respectively; p¼0.019) . Conclusions: FOLFIRINOX therapy in the elderly patients with unresectable pancreatic cancer may be safe and effective according to dose reductions of anticancer drug.
Systematic review of resection rates and clinical outcomes after FOLFIRINOX-based treatment in patients with locally advanced pancreatic cancer Steffi Rombouts 1, Marieke Walma 1, Jantien Vogel 2, Lennart van Rijssen 2, Johanna Wilmink 4, Nadia Haj Mohammad 3, Hjalmar van Santvoort 5, Quintus Molenaar 1, Marc Besselink 2 1
Surgery, University Medical Center, Utrecht, Netherlands Surgery, Academic Medical Center, Amsterdam, Netherlands 3 Medical Oncology, University Medical Center, Utrecht, Netherlands 4 Medical Oncology, Academic Medical Center, Amsterdam, Netherlands 5 Surgery, Dt. Antonius Hospital, Nieuwegein, Netherlands 2
To provide an overview of the (R0) resection rate and clinical outcomes after FOLFIRINOX-based therapy for locally advanced pancreatic cancer (LAPC). FOLFIRINOX prolongs survival in patients with metastatic pancreatic cancer and may also benefit patients with LAPC of which a substantial number may convert into resectable tumors. Previous studies combined LAPC and borderline resectable pancreatic cancer, which hampers the interpretation of outcomes with FOLFIRINOX in LAPC.
S8-3. Phase II study of modified FOLFIRINOX for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC) Masato Ozaka 1, Hiroshi Ishii 2, Tosiya Sato 3, Makoto Ueno 4, Masafumi Ikeda 5, Kazuhiro Uesugi 2, Naohiro Sata 6, Kouichirou Miyashita 7, Nobumasa Mizuno 8, Kunihiro Tsuji 9, Takuji Okusaka 10, Junji Furuse 11 1
The Cancer Institute Hospital of JFCR, Japan National Hospital Organization Shikoku Cancer Center, Japan 3 Kyoto University School of Public Health, Japan 4 Kanagawa Cancer Center, Japan 5 National Cancer Center Hospital East, Japan 6 Jichi Medical University School of Medicine, Japan 7 Showa University Northern Yokohama Hospital, Japan 8 Aichi Cancer Center Hospital, Japan 9 Ishikawa Prefectural Central Hospital, Japan 10 National Cancer Center Hospital, Japan 11 Kyorin University School of Medicine, Japan 2
Abstracts / Pancreatology 16 (2016) S1eS192 1 Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas, MD Anderson Cancer Center, USA 2 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, USA 3 Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Japan 4 Department of Surgery & Oncology, Graduate School of Medical Sciences, Kyushu University, Japan
Background: Intraductal papillary mucinous neoplasm (IPMN) has unique clinical features which can be distinguished from pancreatic ductal adenocarcinoma (PDAC), although the prevalence of KRAS mutations is high in both diseases. Recently, activating mutations in codon 201 of GNAS, which encodes for the alpha subunit of stimulatory G protein (Gas) were discovered specifically in IPMN. Gas is an important regulator of cAMP signaling pathway. The role of mutant Gas and Kras in development of IPMN largely remains to be elucidated. Methods: We generated an inducible mouse model of R201C mutant Gas using reverse Tetracycline transactivator (Linker). The Linker is conditionally expressed in exocrine pancreas under p48-Cre system with or without LSL-Kras G12D (LGKC or LGC respectively). For further mechanistic analysis, a mutant-Kras driven primary PDAC cell with inducible R201C Gas (LGKC cell) was established from the mouse model. Results: In LGC mice, induction of R201C Gas increased acinar cell proliferation but no neoplastic changes occurred up to three months of induction. In LGKC mice, one-week induction caused massive acinar to ductal metaplasia (ADM) and in a few weeks, developed cystic lesions. Age-matched LGKC mice without the induction showed only KCcompatible PanIN lesions. In LGKC cells, induction of R201C Gas followed by cAMP elevation transiently increased cell growth via Protein kinase A and Mitogen-activated protein kinase signaling pathways. However, the long-term induction attenuated cell growth and colony formation in soft agar. Among Kras-related signaling elements, Yes-associated protein was phosphorylated and inhibited. Microarray analysis revealed up-regulation of pancreatic ductal markers: Cystic fibrosis transmembrane conductance regulator, Aquaporin-1 and Aquaporin-5. Furthermore, tumor histology of subcutaneously injected LGKC cells was altered from poorly-differentiated type to well-differentiated ductal type by the induction of R201C Gas. Conclusion: Induction of R201C Gas modified mutant Kras-driven pancreatic tumorigenesis in vivo and cell growth and differentiation in vitro.
S8-1.
PubMed, Embase and Cochrane were systematically searched for studies published up to August 31st, 2015. Primary outcome was (R0) resection rate. Fourteen studies involving 365 patients with LAPC were included. A modified chemotherapy regimen was described in 3 studies and FOLFIRINOX dose reductions in up to 65% of patients. Radiotherapy was given in 57% of all patients. Total resection rate was 28% (77% R0). Median overall survival ranged from 8.9 to 25.0 months. Median survival after resection was 24.9 months. Six out of 85 (7%) resection specimens showed a complete pathologic response. Grade 3-4 toxicity occurred in 23% of patients. The resection rate of patients treated with FOLFIRINOX without radiotherapy was 12% (70% R0) with 15.7 months median overall survival and 19% grade 3-4 toxicity. FOLFIRINOX-based treatment for patients with LAPC seems safe and achieves high (R0) resection rates and overall survival, despite the frequent administered modified regimes and dose reductions during treatment.
S8-2. FOLFIRINOX therapy in the elderly patients with unresectable pancreatic cancer Yu Ishii, Katsuya Kitamura, Akira Yamamiya, Tomohiro Nomoto, Tadashi Honma, Hitoshi Yoshida Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Japan Objective: To investigate FOLFIRINOX therapy in patients of 65 years of age or older with unresectable pancreatic cancer. Methods: Of 33 patients with unresectable pancreatic cancer who received FOLFIRINOX therapy at Showa University Hospital between April 2013 and June 2015, 22 patients with pathological diagnosis of adenocarcinoma before chemotherapy were included. We retrospectively examined the safety and efficacy of FOLFIRINOX therapy in patients of 65 years of age or older with unresectable pancreatic cancer. Results: Of 22 patients who received FOLFIRINOX therapy, 10 patients were 65 years of age (A group) and 12 were <65 years of age (B group). There were no significant differences in characteristics of patients, the number of chemotherapy course, overall survival, progression-free survival and adverse events between both groups. The response rate in group A was significantly higher than that of group B (40% vs. 0% for A and B groups, respectively; p¼0.015). The rate of patients who reduced anticancer drugs in A group was significantly higher than that of B group (90% vs. 42% for A and B groups, respectively; p¼0.019) . Conclusions: FOLFIRINOX therapy in the elderly patients with unresectable pancreatic cancer may be safe and effective according to dose reductions of anticancer drug.
Systematic review of resection rates and clinical outcomes after FOLFIRINOX-based treatment in patients with locally advanced pancreatic cancer Steffi Rombouts 1, Marieke Walma 1, Jantien Vogel 2, Lennart van Rijssen 2, Johanna Wilmink 4, Nadia Haj Mohammad 3, Hjalmar van Santvoort 5, Quintus Molenaar 1, Marc Besselink 2 1
Surgery, University Medical Center, Utrecht, Netherlands Surgery, Academic Medical Center, Amsterdam, Netherlands 3 Medical Oncology, University Medical Center, Utrecht, Netherlands 4 Medical Oncology, Academic Medical Center, Amsterdam, Netherlands 5 Surgery, Dt. Antonius Hospital, Nieuwegein, Netherlands 2
To provide an overview of the (R0) resection rate and clinical outcomes after FOLFIRINOX-based therapy for locally advanced pancreatic cancer (LAPC). FOLFIRINOX prolongs survival in patients with metastatic pancreatic cancer and may also benefit patients with LAPC of which a substantial number may convert into resectable tumors. Previous studies combined LAPC and borderline resectable pancreatic cancer, which hampers the interpretation of outcomes with FOLFIRINOX in LAPC.
S8-3. Phase II study of modified FOLFIRINOX for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC) Masato Ozaka 1, Hiroshi Ishii 2, Tosiya Sato 3, Makoto Ueno 4, Masafumi Ikeda 5, Kazuhiro Uesugi 2, Naohiro Sata 6, Kouichirou Miyashita 7, Nobumasa Mizuno 8, Kunihiro Tsuji 9, Takuji Okusaka 10, Junji Furuse 11 1
The Cancer Institute Hospital of JFCR, Japan National Hospital Organization Shikoku Cancer Center, Japan 3 Kyoto University School of Public Health, Japan 4 Kanagawa Cancer Center, Japan 5 National Cancer Center Hospital East, Japan 6 Jichi Medical University School of Medicine, Japan 7 Showa University Northern Yokohama Hospital, Japan 8 Aichi Cancer Center Hospital, Japan 9 Ishikawa Prefectural Central Hospital, Japan 10 National Cancer Center Hospital, Japan 11 Kyorin University School of Medicine, Japan 2