David Ilson, MD
Adding cetuximab to concurrent chemoradiotherapy did not improve overall survival in patients with adenocarcinoma or squamous cell carcinoma of the esophagus according to findings of RTOG 0436, a randomized phase III trial presented by David Ilson, MD, of Memorial Sloan Kettering Cancer Center, at the 16th World Congress of Gastrointestinal Cancer on June 26, 2014.
The trial evaluated adjunct cetuximab when added to concurrent chemoradiation in patients who were undergoing nonoperative management of esophageal carcinoma. Patients with squamous cell or adenocarcinoma that was proven by biopsy (T1N1M0; T2-4 AnyN M0; Any T/N M1a) were randomized to weekly concurrent cisplatin (50 mg/m2
) and paclitaxel (25 mg/m2
) for 6 weeks plus daily radiation 50.4 gy/1.8 gy fractions with or without weekly cetuximab. Patients received 400 mg/m2
of cetuximab on day 1 followed by weekly doses of 250 mg/m2
for 6 cycles.
The results demonstrate that cetuximab or other EGFR targeted therapies added to chemoradiation does not improve overall survival (OS) in unselected patients with esophageal cancer, said Ilson.
But the trial did show that “6 weeks of cisplatin/paclitaxel was sufficient to achieve clinical complete response (cCR) at 8 weeks, suggesting that the 2 additional weeks usually administered may not be necessary,” said Ilson.
Achieving cCR after 8 weeks of treatment, Zubrod performance scale score of 0, and tumor size less than 5 cm were identified as independent predictors for OS at 2 years.
Cisplatin, 5-FU, and radiotherapy were established as the standard treatment for non-operable esophageal cancer in 2003 (Cooper et al. JAMA
2003). Overexpression of EGFR has been identified by immunohistochemistry in 60% to 80% of adenocarcinoma and squamous cell cancers of the esophagus (Bonner. NEJM
2006), leading investigators to evaluate whether cetuximab, which targets EGFR, could be effective in extending OS in these patients.
The trial enrolled 344 patients, with 328 patients meeting eligibility criteria. Patients were stratified by histology, tumor size (< 5 cm versus ≥ 5cm), and the status of celiac lymph nodal involvement. Patient characteristics were similar for both treatment arms with median follow-up for all patients was 15.4 months.
Patient accrual was halted upon interim analysis in May 2012 for patients with adenocarcinoma and in January 2013 for patients with squamous cell carcinoma, and with the publication of negative results from the SCOPE trial (Crosby et al. Lancet
The trial’s primary endpoint of OS was not met: OS at 2 years was similar between treatment arms, hazard ratio (HR) = 0.92 (P = .72). The secondary endpoint was also not met; the cCR rate was 56% versus 59% without and with cetuximab, respectively (P
Results show that cCR was also similar between treatment arms by histology; patients with adenocarcinoma (n=203) had a 12 and 24 month OS of 65% and 43% with cetuximab compared with 64% and 41% with sole chemoradiotherapy, respectively (P
= .37). OS at 12 and 24 months for the 125 squamous cell carcinoma patients was 62% and 46% with cetuximab and 67% and 43% without cetuximab, respectively (P
However, when OS was evaluated by multivariate analysis, Zubrod performance score of 0 (versus 1 or 2) and cancer lesion size <5 cm (versus 5 cm or greater) was associated with prolonged OS (P
= .0015 and P
= .0002, respectively).
OS rates at 12 and 24 months for patients achieving cCR were 79% and 58% compared with 53% and 30% for patients experiencing residual disease (P
Treatment related adverse events were similar between treatment groups and consistent with previously establish profiles for each agent.
Ilson emphasized the need for identification of biomarkers in esophageal cancer and recommended that future trials of targeted agents should be conducted only in selected population of patients with esophageal cancer.
In response to an audience question, Ilson said that BRAF did not play a role in esophageal cancer, due to extremely low expression in these tumors. “It is simply not there,” he said.
The trial was supported by RTOG CA21661 and CCOP CA3742 NCI grants and Bristol Myers Squibb.
Ilson et al. A Phase III Trial of Cisplatin, Paclitaxel and Radiation with or without Cetuximab in the Nonoperative Treatment of Esophageal Cancer. Presented at: the ESMO 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain. Abstract O-0005.
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