Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Abstract

BACKGROUND: This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma. METHODS: Cetuximab was administered on days 1,8,15, 29, 36, 43, and 50 (400 mg/m 2 initial dose, then 250 mg/m 2 /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP 5 800/60 mg/m 2 /day and up to dose level (12) 5-FU/CP 5 1000/80 mg/m 2 /day. RESULTS: Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (12). The RP2D was 5-FU/CP 5 800/80 mg/m 2 /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%. CONCLUSIONS: Cetuximab could not be integrated with chemoradiotherapy-cisplatin-based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued. Cancer 2013;119:2973-80.

Efficacy and toxicity of chemoradiation in patients with anal cancer - a retrospective analysis

“…To the author’s knowledge no positive data exist regarding the use of cetuximab in a curative setting. One phase I trial and one phase II trial of patients with locally advanced anal cancer receiving 5-FU, cisplatin, cetuximab and radiotherapy reported inhomogeneous efficacy and a extremely high number of serious adverse effects (SAEs) [24,25]. Further studies in large population are required to identify the prognostic role of cetuximab and the influence of HPV and other biomarkers.…”

No evidence of NRAS mutation in squamous cell anal carcinoma (SCAC)

“…High toxicity was observed also in other clinical trials2021, suggesting that the relation between toxicity, chemotherapy dosage and radiation techniques should be better clarified to optimize this promising combination treatment strategy for SCAC. In addition to this data, a recent case report has shown a dramatic response to cetuximab in combination with cisplatin and 5-FU in a patient with metastatic anal cancer9.…”

Chemoradiotherapy for anal cancer: clinical trials past, present and future

“…Deutsch et al reported a Phase II study of cetuximab combined with cisplatin/5FU CRT [22], while Olivatto et al reported a Phase I trial with a fixed dose of cetuximab and escalating doses of 5FU and cisplatin [23]. Significant toxicity led to early stopping of both trials suggesting that cetuximab cannot be integrated safely into CRT regimens.…”