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Abdominal pain as a predictor of overall survival in patients with pancreatic ductal adenocarcinoma – A systematic review and meta-analysis
Electronic Poster Abstracts Massachusetts General Hospital, Harvard Medical School, 8Hematology-Oncology, Yale University School of Medicine, and 9Radiotherapy, Florida Hospital Orlando/ Altamonte, United States Introduction: Unresectable locally advanced pancreatic cancer (LAPC) represents about 40% of pancreatic cancer patients. Several studies have evaluated systemic chemotherapy with FOLFIRINOX for LAPC patients. We report a patient-level meta-analysis of survival outcomes and pooled analyses for grade 3/4 adverse events (AE) rate and resection rate after FOLFIRINOX. Methods: Studies evaluating FOLFIRINOX as first-line treatment for LAPC were included. The primary outcome measure was overall survival (OS) and secondary outcomes were progression-free survival (PFS), grade 3/4 AE rate and resection rate after FOLFIRINOX. We collected patient-level data from all studies that reported survival outcomes. Grade 3/4 AE rate and resection rates of eligible studies were pooled. Results: Eight of the thirteen included studies were eligible for patient-level meta-analysis of survival, representing 281 patients. The median OS ranged from 15.7 to 26.0 months across studies with a patient-level median OS of 24.0 months [95% CI 21.3e26.7 months]. The median PFS ranged from 7.6 to 20.4 months with a patient-level median PFS of 15.0 months [95% CI 13.6e16.4 months]. Grade 3/ 4 AE rate were reported in 372 of 490 patients (75.9%). No deaths due to FOLFIRINOX were reported. The resection rate after FOLFIRINOX was reported for 330 patients with unresectable LAPC and ranged from 0% to 42.9% with a pooled resection rate of 25.5%. Conclusion: Patients with LAPC treated with FOLFIRINOX have a median OS of 24.0 months. Prospective studies are ongoing to clarify the efficacy and tolerability of this regimen in LAPC.
EP02C-004 SYSTEMATIC REVIEW OF FOLFIRINOX IN PATIENTS WITH LOCALLY UNRESECTABLE PANCREATIC CANCER M. Walma1, S. Rombouts1, J. Vogel2, B. van Rijssen2, H. van Santvoort3, Q. Molenaar1 and M. Besselink2 1 Surgery, University Medical Center Utrecht, 2Surgery, Academic Medical Center Amsterdam, and 3Surgery, St. Antonius Hospital, Netherlands Introduction: Since FOLFIRINOX has been proven successful for the treatment of patients with metastatic pancreatic cancer, the possible applicability in patients with locally unresectable pancreatic ductal adenocarcinoma (LU-PDAC) has gained more interest. However, many studies included also patients with borderline resectable PDAC and thereby distort conclusions. This systematic review aims to provide an overview of the clinical outcomes of FOLFIRINOX, solely in patients with LUPDAC. Methods: A systematic search in PubMed, Embase and the Cochrane library was performed for clinical studies, published up to September 1 2015, concerning FOLFIRINOX treatment in LU-PDAC. Outcomes of interest were
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overall survival (OS), resection rate, toxicity and response rate. Results: Fourteen studies involving 359 patients with LUPDAC were included. These studies concerned FOLFIRINOX alone (n = 3) and FOLFIRINOX plus chemoradiotherapy (CRT) (n = 11). Six studies showed data after FOLFIRINOX treatment and before CRT separately. All studies described FOLFIRINOX modifications or dose reduction, with a minimum of 14% dose reductions. After solely (modified) FOLFIRINOX, the pooled resection rate was 12.2%, with a pooled response rate of 24.1%. Median OS was 15.7 months. Concerning (modified) FOLFIRINOX plus CRT, pooled resection rate was 30.1%, with a response rate of 33.5%. Median OS was 22 - 25 months. Toxicity was reported in 3 studies and reached a maximum of 26% grade 3e4 toxicity. Conclusion: FOLFIRINOX treatment is often modified but appears to be feasible and safe in patients with LU-PDAC leading to high resection rates with acceptable toxicity.
EP02C-005 ABDOMINAL PAIN AS A PREDICTOR OF OVERALL SURVIVAL IN PATIENTS WITH PANCREATIC DUCTAL ADENOCARCINOMA e A SYSTEMATIC REVIEW AND META-ANALYSIS S. Schorn, C. Schneider, I. E. Demir, H. Friess and G. O. Ceyhan Surgery, Klinikum rechts der Isar, Technische Universität München, Germany Introduction: One of the most common symptoms of patients with pancreatic ductal adenocarcinoma (PCa) is serve abdominal pain. This pain was recently identified as neuropathic due to the invasion of cancer cells into nerves. Although pain is an omnipresent symptom, the question of how far pain does predict survival hasn’t been clarified yet. Therefore, we aimed to investigate the prognostic impact of pain in PCa in a systematic meta-analysis. Methods: The databases of Scopus, Pubmed, The Cochrane library and Google Scholar were screened for the terms “pain”, “survival”, “recurrence”, “pancreatic ductal adenocarcinoma” and “pancreatic cancer”. To assess the impact of pain on OS, meta-analysis were performed by pooling univariate and multivariate odds (OR) and hazard ratios (HR). Results: By screening the data bases, more than 4000 studies were identified analyzing the impact of pain on OS. After exclusion irrelevant papers 38 studies were included in systematic review, whereas 12 papers were eligible for meta-analysis. A total of 7 univariate HR and 2 univariate OR could pooled in meta-analysis. The meta-analysis identified abdominal pain as a strong prognostic factor on OS (HR 1.63, CI: 1.18e2.24, p = 0.003; OR 2.69, CI: 1.56e4.62; p = 0.0004). Importantly, this data was confirmed by the meta-analysis of multivariate HR, which shows also an unfavorable, independent influence of pain on OS (HR 1.55, CI: 1.29e1.87, p < 0.00001). Conclusion: This is the first meta-analysis, which underlines the unfavorable impact of pain on OS in PCa. Therefore, the presence and mechanism of abdominal pain
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in PCa should receive strong attention due to its high clinical relevance.
EP02C-006 BEYOND THE DOLLAR: INFLUENCE OF SOCIODEMOGRAPHIC MARGINALIZATION ON SURVIVAL AND ADJUVANT THERAPY FOLLOWING RESECTION OF PANCREATIC CANCER D. Kagedan1, L. Abraham2, N. Goyert2, Q. Li3, L. Paszat4, A. Kiss5, C. Earle6, N. Mittmann7 and N. Coburn1,2 1 Department of Surgery, University of Toronto, 2 Department of Surgery, Sunnybrook Health Sciences Centre, 3Institute for Clinical Evaluative Sciences, 4 Department of Radiation Oncology, 5Institute of Health Policy, Management & Evaluation, 6Department of Medical Oncology, University of Toronto, and 7Health Outcomes and PharmacoEconomic (HOPE) Research Centre, Sunnybrook Research Institute, Canada Introduction: The single-payer universal healthcare system in the province of Ontario creates a setting with reduced socioeconomic barriers to treatment. We sought to elucidate the influence of sociodemographic marginalization on receipt of adjuvant treatment and overall survival (OS) following resection of pancreatic adenocarcinoma (PC) at the population level. Method: Patients undergoing PC resection in Ontario between 2005 and 10 were identified using the provincial cancer registry, and linked to databases that include all treatments received and outcomes experienced. Pathology reports were abstracted for staging and margin status. Each patient’s postal code was used to predict their median income, residential instability, material deprivation, ethnic concentration, and dependency (proportion of population aged <15, >65, or unemployed) using census data. Independent predictors of receipt of adjuvant treatment and OS were identified by logistic regression and Cox proportional hazards analysis. Results: 469 patients met inclusion criteria. Multivariable analysis did not identify a significant association between receipt of adjuvant treatment and residential instability (OR = 0.88, 95%CI = 0.69e1.14), material deprivation (OR = 0.95, 95%CI = 0.70e1.28), ethnic concentration (OR = 0.98, 95%CI = 0.78e1.22), or dependency (OR = 1.20, 95%CI = 0.94e1.52). Similarly, a significant association was not identified between survival and residential instability (HR = 1.00, 95%CI = 0.90e1.13), material deprivation (HR = 0.95, 95%CI = 0.84e1.08), ethnic concentration (HR = 1.05, 95%CI = 0.95e1.15), or dependency (HR = 0.94, 95%CI = 0.85e1.03). Compared to patients in the highest income quintile, patients in the second-highest demonstrated improved OS (HR = 0.63, 95%CI = 0.44e0.90), but those in lower income quintiles did not. Conclusions: In contrast to reports generated in other healthcare systems, measures of sociodemographic marginalization were not associated with worse processes or outcomes of care in this analysis.
EP02C-007 NOVEL CONCEPT OF ELECTROCOAGULATION & TUMOR CELL IMPLANTATION: CREATION OF A MINIMALLY INVASIVE ORTHOTOPIC MURINE MODEL OF PANCREATIC CANCER J. Bhullar1, Y. Cozakov1, N. Varshney2, G. Subhas1, S. Bindroo1, M. Decker3, V. Anandan2, M. Jacobs1 and V. Mittal1 1 Dept of Surgery, Providence Hospital & Medical Centers, 2 Dept of Pathology, University of Toledo, and 3Dept of Patient Care Research, Providence Hospital & Medical Centers, United States Introduction: Orthotopic murine models of pancreatic cancer represent an important tool for evaluating treatment strategies. Several genetically modified mouse tumors and xenograft models have been reported. Genetic models have unpredictable growth & variable waiting period, while orthotopic models are operative ones, difficult to create and result in irregular metastasis. There is a constant endeavor to create an orthotopic model which replicates the human disease process. Methods: Orthotopic pancreatic tumors were induced in 20 SCID mice using a novel technique. Low dose electrocoagulation of pancreas under laparoscopic guidance (using Coloview-mouse colonoscope) with thin electrode, followed by injection of 0.1 cc BxPC3 pancreatic cancer cells was done (n = 12, study group). Control mice underwent electrocoagulation alone (n = 4, group 1) and tumor cell injection alone (n = 4, group 2). Mice were evaluated for tumor growth and metastasis by necropsy (4 and 8 week for experimental group; 8 weeks for control group). Results: Tumors were detected in 11/12 mice in experimental group, 1/4 in control group 2, and none in control group 1. Over time there was an increase in tumor growth, tumor volume, lymphovascular invasion of pancreas, with metastasis to lymph nodes and surrounding organ. Conclusions: We report a novel concept of tumor cell implantation at site of electrocoagulation of pancreas. Combined with the minimally invasive technique, yields a replicative orthotopic murine model of pancreatic cancer. Our model is minimally invasive, easy to create, and overcomes the limitations of the existing models while questions the possibility free floating tumor cell implantation at resection site.
EP02C-009 PROGNOSTIC VALUE OF LYMPH NODE METASTASIS DETECTED DURING SURGICAL EXPLORATION IN PATIENTS WITH PANCREATIC CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS L. van Rijssen1, P. Narwade1, D. Tseng2, H. van Santvoort3, I. Molenaar2, H. van Laarhoven4, C. van Eijck5, O. Busch1 and M. Besselink1 1 Surgery, Academic Medical Centre, 2Surgery, University Medical Centre Utrecht, 3Surgery, St. Antonius hospital,
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EP02C-004 SYSTEMATIC REVIEW OF FOLFIRINOX IN PATIENTS WITH LOCALLY UNRESECTABLE PANCREATIC CANCER M. Walma1, S. Rombouts1, J. Vogel2, B. van Rijssen2, H. van Santvoort3, Q. Molenaar1 and M. Besselink2 1 Surgery, University Medical Center Utrecht, 2Surgery, Academic Medical Center Amsterdam, and 3Surgery, St. Antonius Hospital, Netherlands Introduction: Since FOLFIRINOX has been proven successful for the treatment of patients with metastatic pancreatic cancer, the possible applicability in patients with locally unresectable pancreatic ductal adenocarcinoma (LU-PDAC) has gained more interest. However, many studies included also patients with borderline resectable PDAC and thereby distort conclusions. This systematic review aims to provide an overview of the clinical outcomes of FOLFIRINOX, solely in patients with LUPDAC. Methods: A systematic search in PubMed, Embase and the Cochrane library was performed for clinical studies, published up to September 1 2015, concerning FOLFIRINOX treatment in LU-PDAC. Outcomes of interest were
HPB 2016, 18 (S1), e1ee384
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overall survival (OS), resection rate, toxicity and response rate. Results: Fourteen studies involving 359 patients with LUPDAC were included. These studies concerned FOLFIRINOX alone (n = 3) and FOLFIRINOX plus chemoradiotherapy (CRT) (n = 11). Six studies showed data after FOLFIRINOX treatment and before CRT separately. All studies described FOLFIRINOX modifications or dose reduction, with a minimum of 14% dose reductions. After solely (modified) FOLFIRINOX, the pooled resection rate was 12.2%, with a pooled response rate of 24.1%. Median OS was 15.7 months. Concerning (modified) FOLFIRINOX plus CRT, pooled resection rate was 30.1%, with a response rate of 33.5%. Median OS was 22 - 25 months. Toxicity was reported in 3 studies and reached a maximum of 26% grade 3e4 toxicity. Conclusion: FOLFIRINOX treatment is often modified but appears to be feasible and safe in patients with LU-PDAC leading to high resection rates with acceptable toxicity.
EP02C-005 ABDOMINAL PAIN AS A PREDICTOR OF OVERALL SURVIVAL IN PATIENTS WITH PANCREATIC DUCTAL ADENOCARCINOMA e A SYSTEMATIC REVIEW AND META-ANALYSIS S. Schorn, C. Schneider, I. E. Demir, H. Friess and G. O. Ceyhan Surgery, Klinikum rechts der Isar, Technische Universität München, Germany Introduction: One of the most common symptoms of patients with pancreatic ductal adenocarcinoma (PCa) is serve abdominal pain. This pain was recently identified as neuropathic due to the invasion of cancer cells into nerves. Although pain is an omnipresent symptom, the question of how far pain does predict survival hasn’t been clarified yet. Therefore, we aimed to investigate the prognostic impact of pain in PCa in a systematic meta-analysis. Methods: The databases of Scopus, Pubmed, The Cochrane library and Google Scholar were screened for the terms “pain”, “survival”, “recurrence”, “pancreatic ductal adenocarcinoma” and “pancreatic cancer”. To assess the impact of pain on OS, meta-analysis were performed by pooling univariate and multivariate odds (OR) and hazard ratios (HR). Results: By screening the data bases, more than 4000 studies were identified analyzing the impact of pain on OS. After exclusion irrelevant papers 38 studies were included in systematic review, whereas 12 papers were eligible for meta-analysis. A total of 7 univariate HR and 2 univariate OR could pooled in meta-analysis. The meta-analysis identified abdominal pain as a strong prognostic factor on OS (HR 1.63, CI: 1.18e2.24, p = 0.003; OR 2.69, CI: 1.56e4.62; p = 0.0004). Importantly, this data was confirmed by the meta-analysis of multivariate HR, which shows also an unfavorable, independent influence of pain on OS (HR 1.55, CI: 1.29e1.87, p < 0.00001). Conclusion: This is the first meta-analysis, which underlines the unfavorable impact of pain on OS in PCa. Therefore, the presence and mechanism of abdominal pain
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in PCa should receive strong attention due to its high clinical relevance.
EP02C-006 BEYOND THE DOLLAR: INFLUENCE OF SOCIODEMOGRAPHIC MARGINALIZATION ON SURVIVAL AND ADJUVANT THERAPY FOLLOWING RESECTION OF PANCREATIC CANCER D. Kagedan1, L. Abraham2, N. Goyert2, Q. Li3, L. Paszat4, A. Kiss5, C. Earle6, N. Mittmann7 and N. Coburn1,2 1 Department of Surgery, University of Toronto, 2 Department of Surgery, Sunnybrook Health Sciences Centre, 3Institute for Clinical Evaluative Sciences, 4 Department of Radiation Oncology, 5Institute of Health Policy, Management & Evaluation, 6Department of Medical Oncology, University of Toronto, and 7Health Outcomes and PharmacoEconomic (HOPE) Research Centre, Sunnybrook Research Institute, Canada Introduction: The single-payer universal healthcare system in the province of Ontario creates a setting with reduced socioeconomic barriers to treatment. We sought to elucidate the influence of sociodemographic marginalization on receipt of adjuvant treatment and overall survival (OS) following resection of pancreatic adenocarcinoma (PC) at the population level. Method: Patients undergoing PC resection in Ontario between 2005 and 10 were identified using the provincial cancer registry, and linked to databases that include all treatments received and outcomes experienced. Pathology reports were abstracted for staging and margin status. Each patient’s postal code was used to predict their median income, residential instability, material deprivation, ethnic concentration, and dependency (proportion of population aged <15, >65, or unemployed) using census data. Independent predictors of receipt of adjuvant treatment and OS were identified by logistic regression and Cox proportional hazards analysis. Results: 469 patients met inclusion criteria. Multivariable analysis did not identify a significant association between receipt of adjuvant treatment and residential instability (OR = 0.88, 95%CI = 0.69e1.14), material deprivation (OR = 0.95, 95%CI = 0.70e1.28), ethnic concentration (OR = 0.98, 95%CI = 0.78e1.22), or dependency (OR = 1.20, 95%CI = 0.94e1.52). Similarly, a significant association was not identified between survival and residential instability (HR = 1.00, 95%CI = 0.90e1.13), material deprivation (HR = 0.95, 95%CI = 0.84e1.08), ethnic concentration (HR = 1.05, 95%CI = 0.95e1.15), or dependency (HR = 0.94, 95%CI = 0.85e1.03). Compared to patients in the highest income quintile, patients in the second-highest demonstrated improved OS (HR = 0.63, 95%CI = 0.44e0.90), but those in lower income quintiles did not. Conclusions: In contrast to reports generated in other healthcare systems, measures of sociodemographic marginalization were not associated with worse processes or outcomes of care in this analysis.
EP02C-007 NOVEL CONCEPT OF ELECTROCOAGULATION & TUMOR CELL IMPLANTATION: CREATION OF A MINIMALLY INVASIVE ORTHOTOPIC MURINE MODEL OF PANCREATIC CANCER J. Bhullar1, Y. Cozakov1, N. Varshney2, G. Subhas1, S. Bindroo1, M. Decker3, V. Anandan2, M. Jacobs1 and V. Mittal1 1 Dept of Surgery, Providence Hospital & Medical Centers, 2 Dept of Pathology, University of Toledo, and 3Dept of Patient Care Research, Providence Hospital & Medical Centers, United States Introduction: Orthotopic murine models of pancreatic cancer represent an important tool for evaluating treatment strategies. Several genetically modified mouse tumors and xenograft models have been reported. Genetic models have unpredictable growth & variable waiting period, while orthotopic models are operative ones, difficult to create and result in irregular metastasis. There is a constant endeavor to create an orthotopic model which replicates the human disease process. Methods: Orthotopic pancreatic tumors were induced in 20 SCID mice using a novel technique. Low dose electrocoagulation of pancreas under laparoscopic guidance (using Coloview-mouse colonoscope) with thin electrode, followed by injection of 0.1 cc BxPC3 pancreatic cancer cells was done (n = 12, study group). Control mice underwent electrocoagulation alone (n = 4, group 1) and tumor cell injection alone (n = 4, group 2). Mice were evaluated for tumor growth and metastasis by necropsy (4 and 8 week for experimental group; 8 weeks for control group). Results: Tumors were detected in 11/12 mice in experimental group, 1/4 in control group 2, and none in control group 1. Over time there was an increase in tumor growth, tumor volume, lymphovascular invasion of pancreas, with metastasis to lymph nodes and surrounding organ. Conclusions: We report a novel concept of tumor cell implantation at site of electrocoagulation of pancreas. Combined with the minimally invasive technique, yields a replicative orthotopic murine model of pancreatic cancer. Our model is minimally invasive, easy to create, and overcomes the limitations of the existing models while questions the possibility free floating tumor cell implantation at resection site.
EP02C-009 PROGNOSTIC VALUE OF LYMPH NODE METASTASIS DETECTED DURING SURGICAL EXPLORATION IN PATIENTS WITH PANCREATIC CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS L. van Rijssen1, P. Narwade1, D. Tseng2, H. van Santvoort3, I. Molenaar2, H. van Laarhoven4, C. van Eijck5, O. Busch1 and M. Besselink1 1 Surgery, Academic Medical Centre, 2Surgery, University Medical Centre Utrecht, 3Surgery, St. Antonius hospital,
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