- Email: [email protected]
Preoperative Chemoradiation for Locally Advanced Pancreatic Cancer Improves Margin Negativity and Nodal Involvement at Resection
Poster Viewing Abstracts S367
Volume 90 Number 1S Supplement 2014 Materials/Methods: Charts of all consecutive PCA patients receiving SBRT followed by surgical resection from January 2007 to November 2013 were retrospectively reviewed at two major academic centers for the following information: surgical resection, lymph node status, margin status, pathologic response from SBRT, toxicity, recurrence patterns, and overall survival (OS). Planning target volume (PTV) was defined as the gross tumor volume + 2-3 mm. 95% of the PTV received a total dose of 25-33 Gy in five fractions (5-6.6 Gy/fraction), with up to 20% heterogeneity allowed. Pre- and post-surgery chemotherapy regimens included GTX, FOLFIRINOX, 5-FU, or GEM/nab-paclitaxel. Results: Eighteen patients received SBRT, with a median follow-up time of 10.7 months. Median age was 64.9 years, 39% were male, and 72% had head tumors. At initial presentation, 12 patients had locally advanced disease and 6 had borderline resectable disease. Median OS from the first day of SBRT was 20.3 mos (95% CI Z 4.56, 35.9). Of these patients, 16 (88.9%) had margin-negative resections. Twelve patients (66.7%) had lymph node-negative resections. Based on surgical pathology, 6 patients (33%) had a complete response and 12 patients (67%) had a partial response. Acute toxicity following SBRT was minimal, with most experiencing grade 1 or 2 fatigue and no grade 3-4 acute toxicity. There was no late toxicity following SBRT for these patients. There were no significant postoperative complications in this cohort. 9 patients received adjuvant chemotherapy following surgery. 5 patients had distant progression of disease following surgical resection and 1 patient suffered from local tumor bed progression following surgery. Conclusions: Acute and late toxicity following chemotherapy, SBRT, and surgery was minimal. SBRT with aggressive chemotherapy regimens may result in high complete response rates as well as margin and node negative resection rates in patients with locally advanced and borderline resectable PCA. Author Disclosure: S. Moningi: None. A.S. Dholakia: None. S. Raman: None. A. Hacker-Prietz: None. T. Pawlik: None. L. Zheng: None. E. Pollom: None. M. Weiss: None. D. Laheru: None. C. Wolfgang: None. D.T. Chang: None. A.C. Koong: None. J.M. Herman: None.
2381 Preoperative Chemoradiation for Locally Advanced Pancreatic Cancer Improves Margin Negativity and Nodal Involvement at Resection C.A. Berriochoa, A. Kumar, A.A. Khorana, R.M. Walsh, and M. AbdelWahab; Cleveland Clinic, Cleveland, OH Purpose/Objective(s): Locally advanced pancreatic cancer (LAPC) recurs frequently following surgical resection. The potential benefits of preoperative chemoradiation (preCRT) versus postoperative (poCRT) in downstaging disease and facilitating R0 resection remain uncertain. Materials/Methods: Single institution data were obtained for all patients with LAPC treated with surgical resection and/or CRT (2011-2013). Univariate analyses were run using tumor characteristics, patient demographics, and standard pathologic evaluation using CAP recommendations. Results: Forty three patients were identified; 28 were treated with neoadjuvant intent. Ultimately, 16 received pre-CRT, 17 received definitive CRT, and 10 received po-CRT. There were no significant differences in age, BMI, gender, race, or performance status among the groups studied (p Z ns). Median tumor size in the pre-CRT and po-CRT groups was 2.6 cm and 3.0 cm respectively. Pre-CRT was 36 Gy/15 fx, 36 / 20, or 50.4 / 28 with concurrent gemcitabine or 5FU. Po-CRT was 45-50.4 Gy in 1.8 Gy/fx with concurrent gemcitabine, 5FU, or capecitabine. For patients treated with neoadjuvant intent for borderline resectability, laparoscopy was performed in 71% (20/28). Four resections were aborted due to discovery of distant metastases at surgery to produce a successful resection rate of 57% after pre-CRT. Negative margin rates were significantly higher in the pre-CRT group versus those treated post-operatively (94% versus 50%, p<0.001). In
the pre-CRT group, at diagnosis, median tumor size was 2.6 cm and decreased to 2.4 cm after CRT but was 3.5 cm on pathologic evaluation of the pre-CRT specimens. Though similar percentages of patients in both groups (31% pre-CRT; 30% po-CRT) were clinically node positive at diagnosis, post treatment nodal positivity rates were 25% and 90% in the pre-CRT and po-CRT groups respectively (p Z 0.14). Twelve of the 28 patients treated with neoadjuvant intent did not make it to surgery. Three (11%) failed due to local progression alone, 8 (29%) due to distant +/- local progression, and 1 (4%) due to medical comorbidity precluding surgery. All patients had a treatment effect in their pathology; 1 (6%) had complete response, 6 (38%) had grade 1 response, 7 (44%) had grade 2 response, and 2 (12%) had treatment response that was ungraded. Conclusions: Pre-CRT remains a promising treatment approach for LAPC to improve surgical resectability with 57% ultimately getting surgery. Neoadjuvant treatment was associated with a histologic treatment effect in all patients and a statistically significantly higher rate of negative margins. However, assessing the effectiveness of pre-CRT by primary tumor size on CT may not show the entire benefit of neoadjuvant treatment. Further investigation is warranted. Author Disclosure: C.A. Berriochoa: None. A. Kumar: None. A.A. Khorana: None. R.M. Walsh: None. M. Abdel-Wahab: None.
2382 Caveolin-1 Confers a Multimodality Therapy Resistance Phenotype in Pancreatic Cancer Cells T.M. Williams and M. Chatterjee; The Ohio State University, Columbus, OH Purpose/Objective(s): Caveolin-1 (Cav-1) is a 21kDa protein required for formation of caveolae, a subset of lipid rafts. Cav-1 is upregulated in pancreatic cancer and has been shown to be correlated with poor prognosis by our group and others. We hypothesized that Cav-1 promotes resistance to radiation and chemotherapy, and that down regulation may lead to sensitization. Materials/Methods: We employed siRNA and shRNA mediated downregulation of Cav-1 expression both for transient and prolonged stable knockdown, and tested response to radiation and various chemotherapies using diverse molecular and cellular biology in vitro assays, as well as the effect of loss of Cav-1 in xenograft tumor models. Results: In multiple pancreatic cancer cell lines, we found that radiation and chemotherapy independently up-regulate Cav-1 expression. Additionally, genetic knockdown of Cav-1 by small interfering RNA causes reduction in tumor cell proliferation, colony formation, and invasion. Furthermore, genetic down-regulation of Cav-1 induces sensitization to chemotherapeutics commonly used for the treatment of pancreatic cancer, such as gemcitabine and 5-fluorouracil. In this setting, Cav-1 loss promoted activation of apoptotic programs after treatment with gemcitabine, by increasing the levels of activated Caspase-9 and PAR. Knockdown of caveolin-1 also led to radiosensitization of tumor cells and resulted in delayed DNA repair as demonstrated by delayed pH2.AX foci resolution, increased mitotic catastrophe, as well as decreased formation of nuclear BRCA1 and DNAPK-cs foci. Lastly, knockdown of Cav-1 in vivo significantly attenuated both tumor initiation and growth. Conclusions: These results indicate that Cav-1 expression promotes survival of pancreatic cancer cells to chemotherapy and radiation through distinct mechanisms of action. Specifically, Cav-1 downregulation sensitizes cells to radiation through delayed DNA damage repair, with defects noted in homologous recombination and non-homologous end-joining repair processes. Additionally, loss of Cav-1 sensitized cells to chemotherapeutics by modulating activation of the intrinsic pathway of apoptosis. Thus, Cav-1 expression may serve as a prognostic biomarker, a predictive marker for response to chemotherapy or radiation, and serve as a potential target to sensitize cells to chemotherapy and radiation. Author Disclosure: T.M. Williams: None. M. Chatterjee: None.
Volume 90 Number 1S Supplement 2014 Materials/Methods: Charts of all consecutive PCA patients receiving SBRT followed by surgical resection from January 2007 to November 2013 were retrospectively reviewed at two major academic centers for the following information: surgical resection, lymph node status, margin status, pathologic response from SBRT, toxicity, recurrence patterns, and overall survival (OS). Planning target volume (PTV) was defined as the gross tumor volume + 2-3 mm. 95% of the PTV received a total dose of 25-33 Gy in five fractions (5-6.6 Gy/fraction), with up to 20% heterogeneity allowed. Pre- and post-surgery chemotherapy regimens included GTX, FOLFIRINOX, 5-FU, or GEM/nab-paclitaxel. Results: Eighteen patients received SBRT, with a median follow-up time of 10.7 months. Median age was 64.9 years, 39% were male, and 72% had head tumors. At initial presentation, 12 patients had locally advanced disease and 6 had borderline resectable disease. Median OS from the first day of SBRT was 20.3 mos (95% CI Z 4.56, 35.9). Of these patients, 16 (88.9%) had margin-negative resections. Twelve patients (66.7%) had lymph node-negative resections. Based on surgical pathology, 6 patients (33%) had a complete response and 12 patients (67%) had a partial response. Acute toxicity following SBRT was minimal, with most experiencing grade 1 or 2 fatigue and no grade 3-4 acute toxicity. There was no late toxicity following SBRT for these patients. There were no significant postoperative complications in this cohort. 9 patients received adjuvant chemotherapy following surgery. 5 patients had distant progression of disease following surgical resection and 1 patient suffered from local tumor bed progression following surgery. Conclusions: Acute and late toxicity following chemotherapy, SBRT, and surgery was minimal. SBRT with aggressive chemotherapy regimens may result in high complete response rates as well as margin and node negative resection rates in patients with locally advanced and borderline resectable PCA. Author Disclosure: S. Moningi: None. A.S. Dholakia: None. S. Raman: None. A. Hacker-Prietz: None. T. Pawlik: None. L. Zheng: None. E. Pollom: None. M. Weiss: None. D. Laheru: None. C. Wolfgang: None. D.T. Chang: None. A.C. Koong: None. J.M. Herman: None.
2381 Preoperative Chemoradiation for Locally Advanced Pancreatic Cancer Improves Margin Negativity and Nodal Involvement at Resection C.A. Berriochoa, A. Kumar, A.A. Khorana, R.M. Walsh, and M. AbdelWahab; Cleveland Clinic, Cleveland, OH Purpose/Objective(s): Locally advanced pancreatic cancer (LAPC) recurs frequently following surgical resection. The potential benefits of preoperative chemoradiation (preCRT) versus postoperative (poCRT) in downstaging disease and facilitating R0 resection remain uncertain. Materials/Methods: Single institution data were obtained for all patients with LAPC treated with surgical resection and/or CRT (2011-2013). Univariate analyses were run using tumor characteristics, patient demographics, and standard pathologic evaluation using CAP recommendations. Results: Forty three patients were identified; 28 were treated with neoadjuvant intent. Ultimately, 16 received pre-CRT, 17 received definitive CRT, and 10 received po-CRT. There were no significant differences in age, BMI, gender, race, or performance status among the groups studied (p Z ns). Median tumor size in the pre-CRT and po-CRT groups was 2.6 cm and 3.0 cm respectively. Pre-CRT was 36 Gy/15 fx, 36 / 20, or 50.4 / 28 with concurrent gemcitabine or 5FU. Po-CRT was 45-50.4 Gy in 1.8 Gy/fx with concurrent gemcitabine, 5FU, or capecitabine. For patients treated with neoadjuvant intent for borderline resectability, laparoscopy was performed in 71% (20/28). Four resections were aborted due to discovery of distant metastases at surgery to produce a successful resection rate of 57% after pre-CRT. Negative margin rates were significantly higher in the pre-CRT group versus those treated post-operatively (94% versus 50%, p<0.001). In
the pre-CRT group, at diagnosis, median tumor size was 2.6 cm and decreased to 2.4 cm after CRT but was 3.5 cm on pathologic evaluation of the pre-CRT specimens. Though similar percentages of patients in both groups (31% pre-CRT; 30% po-CRT) were clinically node positive at diagnosis, post treatment nodal positivity rates were 25% and 90% in the pre-CRT and po-CRT groups respectively (p Z 0.14). Twelve of the 28 patients treated with neoadjuvant intent did not make it to surgery. Three (11%) failed due to local progression alone, 8 (29%) due to distant +/- local progression, and 1 (4%) due to medical comorbidity precluding surgery. All patients had a treatment effect in their pathology; 1 (6%) had complete response, 6 (38%) had grade 1 response, 7 (44%) had grade 2 response, and 2 (12%) had treatment response that was ungraded. Conclusions: Pre-CRT remains a promising treatment approach for LAPC to improve surgical resectability with 57% ultimately getting surgery. Neoadjuvant treatment was associated with a histologic treatment effect in all patients and a statistically significantly higher rate of negative margins. However, assessing the effectiveness of pre-CRT by primary tumor size on CT may not show the entire benefit of neoadjuvant treatment. Further investigation is warranted. Author Disclosure: C.A. Berriochoa: None. A. Kumar: None. A.A. Khorana: None. R.M. Walsh: None. M. Abdel-Wahab: None.
2382 Caveolin-1 Confers a Multimodality Therapy Resistance Phenotype in Pancreatic Cancer Cells T.M. Williams and M. Chatterjee; The Ohio State University, Columbus, OH Purpose/Objective(s): Caveolin-1 (Cav-1) is a 21kDa protein required for formation of caveolae, a subset of lipid rafts. Cav-1 is upregulated in pancreatic cancer and has been shown to be correlated with poor prognosis by our group and others. We hypothesized that Cav-1 promotes resistance to radiation and chemotherapy, and that down regulation may lead to sensitization. Materials/Methods: We employed siRNA and shRNA mediated downregulation of Cav-1 expression both for transient and prolonged stable knockdown, and tested response to radiation and various chemotherapies using diverse molecular and cellular biology in vitro assays, as well as the effect of loss of Cav-1 in xenograft tumor models. Results: In multiple pancreatic cancer cell lines, we found that radiation and chemotherapy independently up-regulate Cav-1 expression. Additionally, genetic knockdown of Cav-1 by small interfering RNA causes reduction in tumor cell proliferation, colony formation, and invasion. Furthermore, genetic down-regulation of Cav-1 induces sensitization to chemotherapeutics commonly used for the treatment of pancreatic cancer, such as gemcitabine and 5-fluorouracil. In this setting, Cav-1 loss promoted activation of apoptotic programs after treatment with gemcitabine, by increasing the levels of activated Caspase-9 and PAR. Knockdown of caveolin-1 also led to radiosensitization of tumor cells and resulted in delayed DNA repair as demonstrated by delayed pH2.AX foci resolution, increased mitotic catastrophe, as well as decreased formation of nuclear BRCA1 and DNAPK-cs foci. Lastly, knockdown of Cav-1 in vivo significantly attenuated both tumor initiation and growth. Conclusions: These results indicate that Cav-1 expression promotes survival of pancreatic cancer cells to chemotherapy and radiation through distinct mechanisms of action. Specifically, Cav-1 downregulation sensitizes cells to radiation through delayed DNA damage repair, with defects noted in homologous recombination and non-homologous end-joining repair processes. Additionally, loss of Cav-1 sensitized cells to chemotherapeutics by modulating activation of the intrinsic pathway of apoptosis. Thus, Cav-1 expression may serve as a prognostic biomarker, a predictive marker for response to chemotherapy or radiation, and serve as a potential target to sensitize cells to chemotherapy and radiation. Author Disclosure: T.M. Williams: None. M. Chatterjee: None.