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Clin Cancer Res. 2014 Jun 15;20(12):3289-98. doi: 10.1158/1078-0432.CCR-13-3360. Epub 2014 Apr 11.

Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer.

Author information

1
Authors' Affiliations: Division of Head and Neck Surgery, Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon; Division of Hematology/Oncology, Department of Internal Medicine; Department of Pharmacology and Chemical Biology;Biostatistics Facility, University of Pittsburgh, University of Pittsburgh Cancer Institute; Departments of Otolaryngology and Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas; Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Annandale, Virginia; Division of Hematology/Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.
2
Authors' Affiliations: Division of Head and Neck Surgery, Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon; Division of Hematology/Oncology, Department of Internal Medicine; Department of Pharmacology and Chemical Biology;Biostatistics Facility, University of Pittsburgh, University of Pittsburgh Cancer Institute; Departments of Otolaryngology and Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas; Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Annandale, Virginia; Division of Hematology/Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota baumanje@upmc.edu.
3
Authors' Affiliations: Division of Head and Neck Surgery, Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon; Division of Hematology/Oncology, Department of Internal Medicine; Department of Pharmacology and Chemical Biology;Biostatistics Facility, University of Pittsburgh, University of Pittsburgh Cancer Institute; Departments of Otolaryngology and Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas; Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Annandale, Virginia; Division of Hematology/Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and Department of Pharmacology, University of Minnesota, Minneapolis, MinnesotaAuthors' Affiliations: Division of Head and Neck Surgery, Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon; Division of Hematology/Oncology, Department of Internal Medicine; Department of Pharmacology and Chemical Biology;Biostatistics Facility, University of Pittsburgh, University of Pittsburgh Cancer Institute; Departments of Otolaryngology and Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas; Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Annandale, Virginia; Division of Hematology/Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.

Abstract

PURPOSE:

The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo.

EXPERIMENTAL DESIGN:

Patients with untreated, operable stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after seven to 14 days of treatment. The primary endpoint was change in Ki67 proliferation index. We hypothesized an ordering effect in Ki67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX2 signaling intermediates.

RESULTS:

From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, P = 0.04). Wilcoxon pairwise contrasts confirmed greater Ki67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo, P = 0.043; erlotinib vs. placebo, P = 0.027). There was a significant trend in ordering of Ki67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, P = 0.0185). Low baseline pSrc correlated with greater Ki67 reduction (R(2) = 0.312, P = 0.024).

CONCLUSIONS:

Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00779389 NCT01488318.

PMID:
24727329
PMCID:
PMC4104657
DOI:
10.1158/1078-0432.CCR-13-3360
[Indexed for MEDLINE]
Free PMC Article

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