Original Article
Adjuvant Chemoradiotherapy in Resected Pancreatic Ductal Adenocarcinoma: Where Does the Benefit Lie? A Nomogram for Risk Stratification and Patient Selection

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Abstract

Introduction

The impact of adjuvant sequential chemoradiotherapy (CRT) on survival in resected pancreatic ductal adenocarcinoma (PDAC) remains unclear and warrants further investigation.

Methods

NCDB patients with R0/R1 resected PDAC who received adjuvant chemotherapy without CRT or followed by CRT per RTOG-0848 protocol were included. Cox regression for 5-year overall survival (OS) was performed and used to construct a pathologic nomogram in patients who did not receive CRT. A risk score was calculated and patients were divided into low-risk and high-risk groups. Patients from each risk stratum were matched for the receipt of CRT to assess the added benefit of CRT on survival. The Kaplan–Meier analysis was performed to compare OS.

Results

A total of 7146 patients were selected, 1308 (18.3%) received CRT per RTOG-0848. Cox regression concluded grade, T stage, N stage, node yield < 12, R1, and LVI as significant predictors of 5-year OS which were used to construct the risk score. Matched analysis in low-risk patients (score 0–79) showed no difference in OS between CRT vs. no CRT (47.6 ± 5.7 vs. 45.1 ± 3.9 months; p = 0.847). OS benefit was 3% at 1 year, − 4% at 2 years, and 4% at 5 years. In high-risk patients (score 80–100), median OS was higher in CRT vs. no CRT (24.8 ± 0.7 vs. 21.7 ± 0.8 months; p = 0.043). Absolute OS benefit was 13% at 1 year, 5% at 2 years, and − 1% at 5 years.

Conclusion

CRT has a short-lived impact on OS in resected PDAC that is only evident in high-risk patients. In this subset, survival benefit peaks at 1 year and subsides at 3 to 5 years following PDAC resection.

Introduction

A little over 60,000 patients are estimated to receive a new diagnosis of pancreatic cancer in the USA with pancreatic ductal adenocarcinoma (PDAC) being the dominant pathology.1 Unfortunately, all are expected to eventually succumb to this diagnosis in the following years, even those who receive a microscopically negative resection. The poor prognosis associated with resected PDAC has been attributed to the high rates of distant and local recurrence (80% and 20%, respectively) without the utilization of adjuvant therapies, which prompted several trials in the past decades to investigate the role of multimodality approaches to improve the cure rates of PDAC. The survival benefit of adjuvant chemotherapy (ACT) in resected PDAC was evident in the early CONKO-0012,3 and ESPAC-34 trials establishing the key role of gemcitabine-based ACT. Later trials demonstrated non-inferiority of other regimens such as S-1 in the JASPAC 015 and even suggested superiority of other regimens such as FOLFOIRINOX in the PRODIGE-24 trial.6 However, the additional benefit of sequential chemoradiotherapy (CRT) or adjuvant radiotherapy (ART) alone remained unclear in resected PDAC; hence, the current recommended treatment algorithms include ACT alone, ACT followed by CRT, or CRT in between cycles of ACT.7 Multiple studies have attempted to evaluate the benefit of CRT in the adjuvant setting but unfortunately, all experienced major flaws in their study design, target patient population, and analysis, which limited their interpretation and contributed to a lack of consensus.8,9 The landmark ESPAC-1 trial with its two-by-two factorial design demonstrated a clear survival benefit with adjuvant fluorouracil-based chemotherapy but an appalling deleterious impact of adjuvant CRT.10., 11., 12. This trial received several criticisms for providing liberty of protocol selection to patients and physicians, allowing background chemotherapy per physician’s preference, pooling patients by treatment received rather than the intention-to-treat leading to a significant skew toward CRT, and the regimen of CRT itself which was a split-course and did not include a post-radiation adjuvant chemotherapy. Moreover, a concern was raised about the quality of the ART delivered in this multi-center European trial. Quality assurance has been shown to correlate with survival by U.S. investigators from the Radiation Therapy Oncology Group (RTOG) 9704 trial which reported a decreased median OS when ART was not delivered per protocol. Therefore, the RTOG designed the forthcoming randomized clinical trial, RTOG 0848, to compare the addition of adjuvant CRT to ACT vs. ACT alone in patients with upfront resectable PDAC.13 Patients undergo 5 months of ACT followed by re-staging to evaluate disease progression. In the absence of progression, patients are randomized to either an additional month of gemcitabine-based ACT (arm III) or fluorouracil-based/capecitabine-based CRT for 28 fractions in 5.5 weeks (arm IV). In this study, we aim to emulate these conditions and perform a pre-emptive analysis to predict the results of the RTOG-0848 study using the National Cancer Database (NCDB) by applying similar inclusion/exclusion criteria and determine whether an additional benefit exists with the addition of CRT to ACT in patients with upfront resectable PDAC. We also aimed to use our subgroup analysis to create a clinically useful nomogram based on commonly reported pathologic data to add some clarity to patient selection for adjuvant therapies in resected PDAC.

Section snippets

Patient Selection and Study Design

The NCDB for pancreatic malignancies 2010–2017 was utilized. Patients reported in the original database between 2004 and 2009 were missing standard pathologic reporting elements, such as lymphovascular invasion (LVI) and perineural invasion (PNI), thus were not considered for the analysis. We used the Collaborative Staging (CS) data addressing tumor size, extension, metastasis, clinical nodal assessment, number of examined nodes, and number of positive nodes on the final pathology report to

Results

The original NCDB for pancreas malignancies 2010–2017 included 274,056 patients. After applying the selection criteria, 7146 patients who had stage T1–T3 N0-2 M0 PDAC, treated with upfront oncologic surgical resection followed by ACT and no CRT or sequential CRT per the RTOG 0848 protocol, were included. Figure 1 demonstrates a flow diagram of the selection criteria and study design. In the selected population of 7146 patients, 3756 (50.3%) were males, and the mean age at diagnosis was 66.24 ± 

Discussion

In the current age of PDAC multidisciplinary therapy, the utility of sequential CRT after chemotherapy in the adjuvant setting for patients with resected PDAC remains a dilemma due to the palpable absence of randomized data. Our study attempted to answer this clinical question using the NCDB with stringent selection criteria to emulate the forthcoming RTOG 0848 randomized clinical trial. The inclusion/exclusion criteria were designed to include upfront resectable patients and exclude patients

Conclusion

We outline in this study that higher PDAC grade, advanced T and N stages, positive margins (R1), LVI, and LND < 12 represent risk feature with different weights on the survival outcome. In the absence of randomized data, our study shows that adjuvant sequential CRT has a marginal short-term benefit in OS compared to ACT alone. This benefit is only demonstrated in patients deemed high-risk based on a risk profile as opposed to a single-risk feature. Therefore, our analysis suggests that CRT in

Author Contribution

Study conception and design: SN, AS, JF, SH.

Acquisition of data: SN, AS

Analysis and interpretation of data: SN, AS, JF, SH

Drafting of the manuscript: SN, AS, JF, SH

Critical revision: SN, AS, DWK, EC, JF, PH, JD, MM, JF, SH

All authors have read and approved the manuscript.

This manuscript is not under consideration elsewhere. Data acquisition in this work was completed via an approved access to the NCDB Participant User File (PUF). The authors are not authorized to release data to third parties

Competing Interests

The authors declare no competing interests.

Publisher’s note

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The role of adjuvant radiation in resected pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this work, we use the NCDB to emulate the settings of arm IV in the RTOG 0848 to study the influence of the added adjuvant radiation in patients who received surgical resection of PDAC and completed adjuvant chemotherapy. Our analysis concludes a “high-risk pathologic profile”

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