International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationCetuximab With Concurrent Chemoradiation for Esophagogastric Cancer: Assessment of Toxicity
Introduction
The Radiation Therapy Oncology Group protocol 8,501 demonstrated that concurrent cisplatin, fluorouracil (5-FU), and radiation improved survival compared with radiation alone for patients with esophageal cancer (1). To attempt to further improve outcome, multiple combinations of paclitaxel, cisplatin, carboplatin, irinotecan, 5-FU, and concurrent radiation have been evaluated for patients with esophageal cancer 2, 3, 4. Unfortunately, none of these newer regimens has achieved a clear benefit 2, 3, 4.
Therapies that block aberrant growth factor signal transduction pathways have substantial promise in human malignancies, including esophageal cancer. The epidermal growth factor receptor (EGFR) is a tyrosine kinase cell surface receptor encoded by the c-erbB-1 protooncogene (5). The EGFR signal transduction network plays an important role in cancer growth and progression as well as protection from apoptosis (6). EGFR is expressed in 50–80% of all esophageal cancers 7, 8, 9, 10.
Cetuximab, an immunoglobulin-G1 chimerized, monoclonal antibody, binds specifically to EGFR (11). Preclinical models have suggested synergy between cetuximab, paclitaxel, cisplatin, and radiation 12, 13. For patients with locally advanced head and neck cancer, the combination of cetuximab and radiation demonstrated a survival benefit (14). However, the safety of cetuximab in combination with concurrent chemotherapy and radiation has not been established and the initial report suggested substantial toxicity (15). A Phase II study of cetuximab, paclitaxel, carboplatin, and concurrent radiation was therefore initiated. The primary endpoint was to establish the safety of this regimen. Carboplatin was used instead of cisplatin to attempt to distinguish whether nonhematologic toxicities were due to chemoradiation or the addition of cetuximab.
Section snippets
Patient eligibility
Eligible patients included those with pathologically documented adenocarcinoma or squamous cell cancer of the esophagus or adenocarcinoma of the proximal stomach with T2-T4 or nodal disease. Patients with gastric extension and adenopathy that included mediastinal, supraclavicular, celiac, and portal disease were eligible. Patients with ascites, metastatic disease to other organs, and peritoneal implants were ineligible. Surgical resection was not a required component of this study; therefore,
Patient characteristics
Between December 2004 and October 2006, 60 patients were enrolled in this study. Table 1 shows selected demographics and disease characteristics. The median age was 60 (range, 30–87) years. Fifty-seven had esophageal cancer and 3 had proximal gastric cancer. Forty-eight patients had adenocarcinoma and 12 had squamous cell cancer. Two patients had cervical esophageal cancer. Of the 48 patients with adenocarcinoma, 18 had either celiac lymphadenopathy >2 cm or gastrohepatic or supraclavicular
Discussion
This Phase II study demonstrated that cetuximab can be safely administered with paclitaxel, carboplatin, and radiation for patients with esophagogastric cancer. Cutaneous toxicities and hypersensitivity reactions were increased with the addition of cetuximab. The rates of Grades 2, 3, and 4 dermatologic toxicity were 40%, 25% and 0%, respectively. The most significant dermatologic toxicity consisted of a painful, pruritic acneiform rash on the face. Other common but less severe areas of
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Definitive chemoradiotherapy plus cetuximab for cancer in the oesophagus or gastro-oesophageal junction
2020, Cancer Treatment and Research CommunicationsCombination of novel systemic agents and radiotherapy for solid tumors – Part II: An AIRO (Italian association of radiotherapy and clinical oncology) overview focused on treatment toxicity
2019, Critical Reviews in Oncology/HematologyCitation Excerpt :Confirmatory data were provided by subsequent prospective trials in the same setting (Sun et al., 2012; Dwedney et al., 2012). In esophageal cancer two phase II trials (Safran et al., 2008; Lledo et al., 2016) evaluated the feasibility and toxicity of concomitant Cetuximab and CT-RT in locally advanced inoperable patients: (Safran et al., 2008) found no increase in esophagitis (G3 and G4 esophagitis rates of 12% and 3%, respectively) or other radiation-enhanced toxicity adding Cetuximab to Paclitaxel and Carboplatin against a 70% rate of clinical complete response, while Lledo et al. (2016) added Cetuximab to CT (FOLFOX) and RT reported G3-G4 oesophagitis rates of 12%, with one treatment related death due to esophagitis with gastrointestinal bleeding. Unfortunately, these results were not confirmed in two recent phase III studies: in a phase II-III trial by Crosby et al. (2013) a worse toxicity and decreased survival was reported when Cetuximab was added to CT-RT (Cisplatin and 5-FU).
A randomised phase II study of chemoradiotherapy with or without nimotuzumab in locally advanced oesophageal cancer: NICE trial
2018, European Journal of CancerCitation Excerpt :Indeed, several phase II trials combining chemoradiotherapy with an anti-EGFR agent, such as gefitinib, erlotinib or cetuximab, have been performed. Complete and partial response rates found in these studies varied from 44% to 78% with manageable toxicities [16–22]. Nimotuzumab (formerly known as h-R3) is a humanised monoclonal antibody that binds to the extracellular domain of EGFR with high affinity and inhibits the EGFR-dependent intracellular signalling pathway [23].
Successes and Failures of Combined Modalities in Upper Gastrointestinal Malignancies: New Directions
2016, Seminars in Radiation OncologyEGFR targeted therapies and radiation: Optimizing efficacy by appropriate drug scheduling and patient selection
2015, Pharmacology and Therapeutics
Presented in part at the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), November 5–9, 2006, Philadelphia, PA.
Dr. Safran and Dr. Mohan report receiving grant support and honoraria from Bristol-Myers in the amount of less than $100,000. No other potential conflict of interest relevant to this article was reported.