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Ann Surg Oncol. 2015 Dec;22(13):4402-10. doi: 10.1245/s10434-015-4566-4. Epub 2015 Apr 24.

Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma.

Author information

1
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
2
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
3
Institute for Hepatobiliary and Pancreatic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
4
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
5
Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
6
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
7
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. lotzemt@upmc.edu.
8
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. zehxhx@upmc.edu.

Abstract

PURPOSE:

Autophagy is a cell survival mechanism that plays a critical role in pancreatic carcinogenesis. Murine studies have previously demonstrated that treatment with the late-autophagy inhibitor chloroquine in combination with chemotherapy limited tumor growth.

METHODS:

In this phase 1/2 trial, we examined treatment with hydroxychloroquine (HCQ) and gemcitabine for patients with pancreatic adenocarcinoma. The primary endpoints were safety and tolerability, evaluated by Storer's dose escalation design. Secondary endpoints were CA 19-9 biomarker response, R0 resection rates, survival, and correlative studies of autophagy.

RESULTS:

Thirty-five patients were enrolled. There were no dose-limiting toxicities and no grade 4/5 events related to treatment. Nineteen patients (61 %) had a decrease in CA 19-9 after treatment. Twenty-nine patients (94 %) underwent surgical resection as scheduled, with a 77 % R0 resection rate. Median overall survival was 34.8 months (95 % confidence interval, 11.57 to not reached). Patients who had more than a 51 % increase in the autophagy marker LC3-II in circulating peripheral blood mononuclear cells had improvement in disease-free survival (15.03 vs. 6.9 months, p < 0.05) and overall survival (34.83 vs. 10.83 months, p < 0.05). No outcome differences were demonstrated in the 81 % of patients with abnormal p53 expression assessed by immunohistochemistry in the resected specimens.

CONCLUSIONS:

Preoperative autophagy inhibition with HCQ plus gemcitabine is safe and well tolerated. Surrogate biomarker responses (CA 19-9) and surgical oncologic outcomes were encouraging. p53 status was not associated with adverse outcomes.

PMID:
25905586
PMCID:
PMC4663459
DOI:
10.1245/s10434-015-4566-4
[Indexed for MEDLINE]
Free PMC Article

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