Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression

Abstract

Purpose: This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC).

Patients and methods: Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression.

Results: Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016).

Conclusion: This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer.

Fig 1.

Median survival duration was 19.2 months (95% CI, 14.6 to 23.8 months) and 1-year, 2-year, and 4-year actuarial overall survival rates were 67.1%, 27.2%, and 12.4%, respectively. The survival duration was similar among the patients who did not undergo surgical resection.

Fig 2.

There was a statistically significant prolongation in survival duration among the patients that developed any grade acneiform rash as a result of cetuximab.

Fig 3.

Local tumor progression was uncommon before 1 year. Isolated local tumor progression leading to death occurred in seven patients between 16.1 and 31.2 months, representing a significant cause of late disease-related mortality.

Fig 4.

Representative diagnostic cytology specimens that were immunostained for Smad4(Dpc4) expression. Specimens were scored as (A) positive, (B) focal, (C) rare, and (D) negative. Positive and focal were considered to represent intact Smad4(Dpc4) expression, and rare and negative were considered to represent loss of Smad4(Dpc4) expression.