No Overall Survival Improvement but Some Palliative Benefit With Gefitinib vs Placebo in Esophageal Cancer Progressing After Chemotherapy
In what may be the first randomized trial of systemic therapy in this setting, Dutton and colleagues evaluated gefitinib (Iressa) vs placebo in patients with esophageal cancer progressing after chemotherapy. As reported in The Lancet Oncology, the COG trial showed no survival benefit with gefitinib but provided evidence of palliative benefit of gefitinib treatment in some patient-reported outcomes.
Study Details
In this double-blind trial, 449 adults at 48 UK centers with advanced esophageal cancer or type I/II Siewert junctional tumors and histologically confirmed squamous cell carcinoma or adenocarcinoma who had progressed after chemotherapy were randomly assigned between March 2009 and November 2011 to receive gefitinib 500 mg/d (n = 224) or placebo (n = 225). Patients had to have measurable or evaluable disease on computed tomography. All patients received best supportive care in addition to study treatment. The primary endpoint was overall survival in the intention to treat population.
The gefitinib and placebo groups were genrally balanced for age (median, 65 years in both), sex (82% and 84% men), original diagnosis (adenocarcinoma in 77% and 75%, squamous cell carcinoma in 22% and 25%), disease site (esophageal in 76% and 80%, type I junctional in 12% and 9%, type II junctional in 12% and 10%), World Health Organization performance status (0 in 25% in both, 1 in 52% and 56%, 2 in 22% and 20%), previous treatments (three in 5% and 4%, two in 35% and 33%, one in 61% in both), brain metastases (no in > 99% and 96%), and body mass index (median, 24.01 kg/m2 in both).
Survival and Disease Control
Median overall survival was 3.73 months (95% confidence interval [CI] = 3.23–4.50) in the gefitinib group vs 3.67 months (95% CI = 2.97–4.37) in the placebo group (hazard ratio [HR] = 0.90, P = .29). Median progression-free survival was significantly but minimally prolonged with gefitinib (1.57 vs 1.17 months, HR = 0.80, P = .020).
Disease control at 8 weeks was present in 24% of patients in the gefitinib group (including six partial responses) and in 16% of the placebo group (including one partial response; P = .02).
Patient-Reported Outcomes
Health-related quality of life was assessed by the generic European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the esophageal, junctional, and gastric cancer-specific EORTC QLQ-OG25. Questionnaires for prespecified patient-reported outcomes were completed at baseline and 4 weeks by 110 gefitinib patients and 121 placebo patients. Among these patients, gefitinib patients had significantly improved odynophagia (P = .004), with improvement from baseline observed in the gefitinib group. No significant differences were found in the other prespecified outcomes, consisting of global quality of life, dysphagia, and eating restriction.
Among exploratory patient-reported outcomes, the gefitinib group had significantly better outcomes in social functioning (P = .013), pain (P = .035), constipation (P = .0001), cough (P = .013), and speech function (P = .0004), with improvement or no worsening from baseline in each, whereas the placebo group reported less worsening of diarrhea (P < .0001).
Adverse Events
The most common adverse events of any grade in the gefitinib group were diarrhea (16% vs 3% in the placebo group) and skin toxicity (21% vs 1%). The most common grade 3 or 4 adverse events were fatigue (11% vs 6%) and diarrhea (6% vs 1%). Serious adverse events were reported in 49% and 45% of patients. Three fatal serious adverse events deaths, two in the placebo group and one in the gefitinib group, were considered possibly related to study treatment. Dose reduction from 500 mg to 250 mg occurred in 4% and 1% of patients.
The investigators concluded, “The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients.”
Susan J. Dutton, MSc, of University of Oxford, is the corresponding author for The Lancet Oncology article.
The study was funded by Cancer Research UK. For full disclosures of the study authors, view visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
