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

  • Pancreatic Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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Acknowledgment

Supported in part by training Grant T32CA113263 (BB) from the National Cancer Institute and an R01CA181450 (HJZ and MTL). This project used the UPCI Animal Research Facility and the Biostatistics Shared Resource Facility, which are supported in part by award P30CA047904. Correlative studies were supported by philanthropic donors to the UPMC Pancreatic Cancer Research Program.

Disclosure

The authors declare no conflict of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the U.S. National Institutes of Health.

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Author notes

    Authors and Affiliations

    1. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA

      Brian A. Boone MD, Amer H Zureikat MD, Phillip Bao MD, David L Bartlett MD, Patricia Loughran PhD, Michael T. Lotze MD, FACS & Herbert J. Zeh III MD, FACS

    2. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

      Nathan Bahary MD, PhD

    3. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

      Aatur D. Singhi MD, PhD

    4. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA

      Daniel P Normolle PhD & Wen-Chi Wu PhD

    5. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA

      Lance A Liotta PhD & Virginia Espina PhD

    6. Institute for Hepatobiliary and Pancreatic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

      A. James Moser MD

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    Correspondence to Michael T. Lotze MD, FACS or Herbert J. Zeh III MD, FACS.

    Additional information

    Michael T. Lotze and Herbert J. Zeh contributed equally to this work.

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    Boone, B.A., Bahary, N., Zureikat, A.H. et al. Safety and Biologic Response of Pre-operative Autophagy Inhibition in Combination with Gemcitabine in Patients with Pancreatic Adenocarcinoma. Ann Surg Oncol 22, 4402–4410 (2015). https://doi.org/10.1245/s10434-015-4566-4

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    • DOI: https://doi.org/10.1245/s10434-015-4566-4

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