Radiochemotherapy with or without cetuximab for unresectable esophageal cancer: final results of a randomized phase 2 trial (LEOPARD-2)

Abstract

Purpose To investigate the efficacy and toxicity of cetuximab when added to radiochemotherapy for unresectable esophageal cancer. Methods This randomized phase 2 trial (clinicaltrials.gov, identifier NCT01787006) compared radiochemotherapy plus cetuximab (arm A) to radiochemotherapy (arm B) for unresectable esophageal cancer. Primary objective was 2‑year overall survival (OS). Arm A was considered insufficiently active if 2‑year OS was ≤40% (null hypothesis = H 0 ), and promising if the lower limit of the 95% confidence interval was >45%. If that lower limit was >40%, H 0 was rejected. Secondary objectives included progression-free survival (PFS), locoregional control (LC), metastases-free survival (MFS), response, and toxicity. The study was terminated early after 74 patients; 68 patients were evaluable. Results Two-year OS was 71% in arm A (95% CI: 55–87%) vs. 53% in arm B (95% CI: 36–71%); H 0 was rejected. Median OS was 49.1 vs. 24.1 months ( p = 0.147). Hazard ratio (HR) for death was 0.60 (95% CI: 0.30–1.21). At 2 years, PFS was 56% vs. 44%, LC 84% vs. 72%, and MFS 74% vs. 54%. HRs were 0.51 (0.25–1.04) for progression, 0.43 (0.13–1.40) for locoregional failure, and 0.43 (0.17–1.05) for distant metastasis. Overall response was 81% vs. 69% ( p = 0.262). Twenty-six and 27 patients, respectively, experienced at least one toxicity grade ≥3 ( p = 0.573). A significant difference was found for grade ≥3 allergic reactions (12.5% vs. 0%, p = 0.044). Conclusion Given the limitations of this trial, radiochemotherapy plus cetuximab was feasible. There was a trend towards improved PFS and MFS. Larger studies are required to better define the role of cetuximab for unresectable esophageal cancer.

Effect of perioperative flurbiprofen axetil on long‐term survival of patients with esophageal carcinoma who underwent thoracoscopic esophagectomy

“…Studies have shown that the survival rate of tumors located in the upper, middle, and lower esophagus is different, the prognosis of upper esophageal cancer is worse than that of middle esophagus and lower esophagus. 9 Fifth, in Table 1, the difference in tumor stage between the two groups was statistically significant. Similarly, in the multivariate analysis, the difference in tumor stage between the two groups was also statistically significant.…”

Progression‐free survival at 3 years is a reliable surrogate for 5‐year overall survival for patients suffering from locally advanced esophageal squamous cell carcinoma

“…We excluded one RCT because it had a sample size far below the statistical requirements and thus had a high risk of bias (Figure S1). 11 Finally, we included 7 RCTs [12][13][14][15][16][17][18] and 10 retrospective studies [19][20][21][22][23][24][25][26][27][28] for trial-and treatment armlevel analyses (Tables S1 and S2). Patient survival in the RCTs was superior to that in the retrospective studies, regardless of the time point (1-, 2-, and 3-year PFS and 5-year OS).…”

Metastasis Prevention: Focus on Metastatic Circulating Tumor Cells

“…OS of patients with HER2-positive stomach cancer is higher with trastuzumab deruxtecan (a conjugate consisting of trastuzumab and a cytotoxic topoisomerase I inhibitor) therapy than with irinotecan or paclitaxel chemotherapy (12.5 vs. 8.4 months) [20]. In patients with unresectable esophageal cancer, OS tends to be longer when treated with cetuximab in combination with radiochemotherapy compared to radiochemotherapy alone (49.1 vs. 24.1 months) [21].…”

“…However, current therapeutic strategies mainly target the primary tumor, assuming that metastatic seeds will also be killed. Indeed, several drugs, for example EGFR tyrosine kinase inhibitors and anti-HER2 monoclonal antibodies, can suppress metastasis and improve the survival of cancer patients [19,21]. Nevertheless, this is rather an exception than the rule; most anticancer therapies only indirectly affect metastasis-initiating cells.…”