A Phase 1/2 and Biomarker Study of Preoperative Short Course Chemoradiation With Proton Beam Therapy and Capecitabine Followed By Early Surgery for Resectable Pancreatic Ductal Adenocarcinoma

Abstract

Purpose To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. Methods and Materials Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. Results The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). Conclusions This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRASG12D status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

C-X-C motif receptor 7 in gastrointestinal cancer

“…The expression of CXCR7 was found to be associated with tumor grade and inversely correlated with tumor size in patients with pancreatic adenocarcinoma (56). In addition, stromal expression of CXCR7 was associated with significantly worse survival outcomes in pancreatic cancer patients that were treated with neoadjuvant chemoradiotherapy followed by surgery and adjuvant gemcitabine treatment (53). These observations suggest that CXCR7 has a potential role in the tumorigenesis of pancreatic adenocarcinoma, and that CXCR7 is involved in cell migration and invasion in pancreatic cancer.…”

“…CXCR7 expression has been identified in pancreatic adenocarcinoma in vitro and in vivo, along with upregulation of the CXCR7 gene on oligonucleotide microarrays (53)(54)(55)(56)(57)(58)(59). The expression of CXCR7 was found to be associated with tumor grade and inversely correlated with tumor size in patients with pancreatic adenocarcinoma (56).…”

“…In addition, Hong et al (53) reported that stromal CXCR7 expression was associated with poor survival outcomes in patients with resectable pancreatic adenocarcinoma who underwent preoperative chemoradiation with proton beam therapy and capecitabine followed by surgery and adjuvant gemcitabine. These findings suggest that CXCR7 is involved in the resistance to treatment strategies, such as radiation and chemotherapy.…”

Individualized radiotherapy (iRT) concepts for locally advanced pancreatic cancer (LAPC): indications and prognostic factors

“…Local progressionfree survival, progression-free survival, and overall survival rates were 81.7, 64.3, and 76.8 %, respectively [88]. To shorten treatment times, hypofractionated proton radiotherapy is being evaluated within clinical trials: A dosing scheme of 5×5 Gy E has shown only 4.1 % of Grade 3 side effects with favorable local control; KRAS-status and high CXCR7-expression, circulating CEA, CA 19-9 as well as HGF-levels correlated with poor outcome [89]. Randomized trials comparing with advanced photons (IMRT, SBRT, or other) are still lacking.…”

The Role of Neoadjuvant Therapy in Pancreatic Cancer: A Review

“…The major advantage of proton beam over conventional radiation is that the energy distribution of protons can be directed and deposited in tissue volumes designated by the physicians in a 3D pattern. Investigators from Massachusetts General Hospital first reported the results of a Phase I/II study of preoperative short-course proton beam radiation with capecitabine as neoadjuvant treatment for pancreatic cancer [84,85]. These results were especially promising when compared with a similar study using the same dose escalation schema and photon radiation in which unexpected intraoperative complications occurred (63 vs 27%, respectively) [86].…”