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2013 RSS Meeting Abstract Submission ABSTRACT TITLE: SBRT is non-inferior to standard chemoradiation for locally advanced

, nonmetastatic pancreas cancer: A meta-analysis of published data. AUTHOR AND CO-AUTHORS: Jessica Varley, Thomas B. Daniels, MD, John J. Kresl, MD, PhD, FACRO, Chad L. Lee, PhD, and Lauren D. Stegman, MD, PhD OBJECTIVES: Image-guided body stereotactic radiosurgery (SBRT) is an emerging treatment option for definitive therapy of locally advanced pancreatic cancer. The objective of this study was to assess the efficacy of this treatment by combining data from the available small, single institution published series. METHODS: The MEDLINE database was searched to identify publications reporting on the outcomes of cohorts of at least 20 patients without imaging evidence of metastatic disease treated with body radiosurgery. The actuarial overall survival plots from these studies were digitized. Individual patient survival data were reconstructed as per the method of Guyot et al. (BMC Medical Research Methodology 2012, 12:9). The accuracy of the data reconstruction process was verified by comparing the calculated Kaplan-Meier survival probabilities from the reconstructed data with the published results. The individual patient survival data was then aggregated to create the combined actuarial survival data. Similar methodology was used to reconstruct aggregate survival data from five Phase I/II prospective trials of gemcitabine-based, standardly fractionated chemoradiation each with cohorts of 20 patients with locally advanced, non-metastatic disease. RESULTS: Seven studies of pancreatic radiosurgery were identified meeting the inclusion criteria, which included a total of 274 patients. The aggregate, actuarial median survival after radiosurgery was 12.6 months with 6 month, 1 year, and 2 year survival probabilities of 85%, 52%, and 22%, respectively. The aggregate, actuarial median survival of 199 patients treated on the prospective ECOG, Hoosier Oncology Group, Israeli, and CALGB chemoradiation therapy trials was 10.8 months with 6 month, 1 year and 2 year survival probabilities of 74%, 44%, and 15 %, respectively. This represented a non-significant trend towards better survival with SBRT as compared to chemoradiation with a HR for death of 0.89 (95% CI 0.73 – 1.08, p = 0.24). For patients treated with SBRT, overall survival was statistically improved with neoadjuvant versus adjuvant chemotherapy with a HR for death of 0.71 (95% CI 0.55 – 0.92, p = 0.01). The median survival was 13.7 months in the three studies in

which more than 90% of patients received induction chemotherapy prior to SBRT (n = 114 patients) versus 11.1 months in the four studies (n = 160 patients) in which chemotherapy was given after radiosurgery. The delivered BED varied across studies from 47.2 Gy10 - 87.5 Gy10. When treated as a continuous variable, no radiotherapy dose response was identified (HR 1.01, 95% CI 0.997 – 1.013, p = 0.17). Conclusions: Meta-analysis of published reports of SBRT for locally advanced, non-metastatic pancreatic adenocarcinoma using reconstructed individual patient survival data suggests this therapy is not inferior to standard chemoradiation therapy. The apparently equivalent outcomes indicate that future randomized trials comparing SBRT to conventional chemoradiation may need to be conducted using a noninferiority design. Patients receiving induction chemotherapy prior to SBRT appear to have more favorable outcomes than those treated with up-front radiosurgery. It is unclear if this is due to selection of favorable prognosis patients with chemosensitive disease or due to chemosensitization or another biologic interaction between the timing of systemic therapy and SBRT. There was no clear radiation dose response, although this may be confounded by the stronger effect of chemotherapy timing. These data support the development of prospective randomized trials comparing induction chemotherapy followed by SBRT versus standard chemoradiation. Character Count: 3998