Phase I trial of concurrent stereotactic body radiotherapy and nelfinavir for locally advanced borderline or unresectable pancreatic adenocarcinoma

Abstract

Introduction: The HIV protease inhibitor nelfinavir (NFV) displays notable radiosensitizing effects. There have been no studies evaluating combined stereotactic body radiotherapy (SBRT) and NFV for borderline/unresectable pancreatic cancer. The primary objective of this phase I trial (NCT01068327) was to determine the maximum tolerated SBRT/NFV dose, and secondarily evaluate outcomes.

Methods: Following initial imaging, pathologic confirmation, and staging laparoscopy, subjects initially received three 3-week cycles of gemcitabine/leucovorin/fluorouracil; patients without radiologic progression received 5-fraction SBRT/NFV. Dose escalation was as follows: (1) 25 Gy/625 mg BID ×3wks; (2) 25 Gy/1250 mg BID ×3wks; (3) 30 Gy/1250 mg BID ×3wks; (4) 35 Gy/1250 mg BID ×3wks; (5) 35 Gy/1250 mg BID ×5wks; and (6) 40 Gy/1250 mg BID ×5wks. Pancreaticoduodenectomy was performed thereafter if resectable; if not, gemcitabine/leucovorin/fluorouracil was administered.

Results: Forty-six patients enrolled (10/2008-5/2013); 39 received protocol-directed therapy. Sixteen (41%) experienced any grade ≥2 event during and 1 month after SBRT. Four grade 3 and both grade 4 events occurred in a single patient at the initial dose level. 40 Gy/1250 mg BID ×5wks was the maximum tolerated dose. Five patients had late gastrointestinal bleeding (n = 2 superior mesenteric artery pseudo-aneurysm, n = 1 disease progression, n = 1 lower GI tract, n = 1 unknown location). The median overall survival was 14.4 months. Six (15%) patients recurred locally; median local failure-free survival was not reached. The median distant failure-free survival was 11 months, and median all failure-free survival was 10 months.

Conclusions: Concurrent SBRT (40 Gy)/NFV (1250 mg BID) for locally advanced pancreatic cancer is feasible and safe, although careful attention to treatment planning parameters is recommended to reduce the incidence of late gastrointestinal bleeding.

Keywords: Nelfinavir; Pancreas; Pancreatic cancer; Stereotactic body radiation therapy.

Conflict of interest statement

Conflicts of Interest: All authors declare no conflicts of interest.

All authors declare that conflicts of interest do not exist.

Published by Elsevier B.V.

Figures

Figure 1.

Study schema.

Figure 2.

Cumulative incidence curve of local failures (A), Kaplan-Meier survival curves of distant failure-free survival and (overall) failure-free survival (B), and Kaplan-Meier overall survival curve (C).

Figure 2.

Cumulative incidence curve of local failures (A), Kaplan-Meier survival curves of distant failure-free survival and (overall) failure-free survival (B), and Kaplan-Meier overall survival curve (C).

Figure 3.

Kaplan-Meier overall survival curves of patients having undergone surgical resection versus lack thereof (A), and unresected patients having received 7-8 Gy/fraction versus 5-6 Gy/fraction.