DISCUSSION

Because complete resection is the only curative option for pancreatic adenocarcinoma, we have applied an aggressive neoadjuvant regimen of SBRT and multi-agent chemotherapy with the goal of resection of cancers initially marginal or ineligible for resection. These techniques could induce unacceptable surgical results or toxicity, and so this work analyzed outcomes for neoadjuvantly treated patients compared to those presenting with resectable pancreas cancer who underwent upfront resection without neoadjuvant chemotherapy or radiation. We found no evidence for worsened surgical or survival outcomes due to neoadjuvant therapy.

A superior negative margin rate for BRPC and LAPC treated neoadjuvantly was observed despite more use of vascular repair and higher initial clinical T and N classifications. The margin positive rates in this study are encouraging compared to other published studies of BRPC, though there is significant variability (2% to 89%) based on criteria for resectability and neoadjuvant regimen (23,24). Previously, acceptable negative margin rates and toxicities have been observed after neoadjuvant chemotherapy and SBRT in BRPC (13,20).


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The benefits of neoadjuvant therapy are partially explained by selection of patients who have good response to chemoradiotherapy prior to surgery. Attempts were made to control for other group differences, such as differences in staging and resectability definitions, by multivariate and matched time period analyses. In addition, we attempted to control for lead time bias by including in the survival analysis only upfront resection patients who received adjuvant therapy. As this study presents a non-randomized comparison of two retrospective cohorts, there may be unrecognized confounding factors that were not anticipated. For example, while pre-operative CA19-9 levels have had mixed prognostic value in pancreatic cancer, pre-operative CA19-9 was difficult to interpret in this series due to confounding from pre-operative biliary obstruction that was managed differently prior to surgery in the two cohorts (25,26).

A key rationale for SBRT is escalation of radiation therapy dose to the tumor. Attempts are made to treat the tumor-vessel abutment region with 50 Gy in 5 fractions. This is equivalent to 84.7 Gy at the typical fractionation of 1.8 Gy per fraction (α/β=10) or the biologically effective dose (BED) of 100 Gy10 suggested for optimal control of early non-small cell lung cancer (27). That dose was not always achievable in our series due to organ at risk limitations. Still, the median dose of 40 Gy in 5 fractions in this study represents a dose escalated equivalent of 61.0 Gy at 1.8 Gy per fraction. Also, alternative mechanisms of tumor killing have been observed for radiation doses of ≥8 Gy per fraction (28). These benefits are currently theoretical, and this work provides evidence for the safety of applying neoadjuvant multi-agent chemotherapy and SBRT with the goal of curative intent resection in coming randomized trials.

Acknowledgements

None.


Eric A. Mellon1, Tobin J. Strom1, Sarah E. Hoffe1, Jessica M. Frakes1, Gregory M. Springett2, Pamela J. Hodul2, Mokenge P. Malafa2, Michael D. Chuong3, Ravi Shridhar4

1Department of Radiation Oncology, 2Gastrointestinal Tumor Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL,USA; 3Department of Radiation Oncology, University of Maryland, Baltimore, MD, USA; 4Florida Hospital Cancer Institute, Orlando, FL, USA 


Contributions: (I) Conception and Design: EA Mellon, SE Hoffe, R Shridhar; (II) Administrative support: None; (III) Provision of study materials or patients: SE Hoffe, GM Springett, PJ Hodul, MP Malafa, R Shridhar; (IV) Collection and assembly of data: EA Mellon, TJ Strom, JM Frakes, MD Chuong; (V) Data analysis and interpretation: EA Mellon, SE Hoffe, GM Springett, R Shridhar; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The study was approved by the Institutional Review Board of the University of South Florida (No. Pro00003382).

Supplementary Materials

Univariate and multivariate correlations with overall survival

Univariate analysis (UVA) and multivariate analysis (MVA) for OS was performed by Cox Regression. Due to differences in imaging used for clinical staging between the two groups, clinical stage was not assigned in 40% of the upfront resection group. As such, comparison T and N classifications were used for UVA and MVA in Table S1, where clinical classification is used in the neoadjuvant therapy group and pathologic classification is used in the upfront resection group.

TABLE S1

In the UVA, N1 classification was significant for worse OS (P=0.035). Sex, tumor location, T classification, and number of lymph nodes examined were not significant (P>0.1). Trends towards significance were observed for benefit to younger age (P=0.056) and the neoadjuvant therapy group (P=0.059). On MVA, Trends remained for neoadjuvant therapy group (P=0.077) and N classification (P=0.091).

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