More than 50% of patients with esophageal cancer have metastatic disease at presentation. The use of chemotherapy for this patient group is increasing with the intention of local and distant tumor control, improving quality of life and prolongation of survival. A number of agents have been investigated as sole therapy for esophageal cancer, including cisplatin, irinotecan, bleomycin, mitomycin, 5-fluorouracil, paclitaxel, methotrexate, vinorelbine, mitoguazone, vindesine, doxorubicin, and etoposide. Phase II trials have demonstrated responses of 15% to 30% for these agents, with cisplatin, mitomycin, 5-fluorouracil, paclitaxel, and vindesine being the most active. The responses have been short lived and have not led to any meaningful prolongation of survival. Five randomized controlled trials have not shown prolonged survival but occasional palliation can be achieved. There is a need for well designed, adequately powered, phase III trials comparing chemotherapy versus best supportive care for patients with metastatic esophageal cancer. Chemotherapy agents with promising response rates and tolerable toxicity are cisplatin, 5-fluorouracil (5-FU), paclitaxel and antracyclins. Combining taxotere and Xeloda is not supported by significant literature.
NCCN lists options for metastatic disease in a carefully worded way (without addressing specific protocols), with recommendations for oxaliplatin, cisplatin, 5FU, taxane or irinotecan (Camptosar) based therapy.
We eagerly await the results of the many cooperative group and single-institution clinical trials exploring the role of cetuximab in esophageal cancer. These include a South-west Oncology Group (SWOG) trial of cetuximab as second-line therapy in patients with metastatic esophageal adenocarcinoma, a Memorial Sloan-Kettering Cancer Center study of cetuximab in irinotecan/cisplatin-refractory patients with metastatic esophageal cancer and a Dana-Farber Cancer Institute preoperative trial with cisplatin, irinotecan, cetuximab, and radiation in locally advanced esophageal cancer. In two phase I studies, EGFR-directed antibodies have shown activity in patients with esophageal cancer. In the phase I study of the humanized EGFR mAb EMD72000, one patient with metastatic, pretreated squamous cell carcinoma had a durable, 6-month PR. In addition, a phase I trial with ABX-EGF, a high-affinity, fully human IgG2 EGFR mAb, reported stable disease for 7 months in one esophageal cancer patient. Two recent studies presented at the 2006 meeting of the American Society for Therapeutic Radiation and Oncology (ASTRO) suggest that Erbitux® (cetuximab) can be safely added to combination chemotherapy regimens for rectal and esophageal cancer. However, these are studies with radiation and in early phase II. At ASCO 2011, a French group rpesented a study of Folfox with Erbitux. The treatment was two cycles of FOLFOX induction therapy plus cetuximab, followed by radiotherapy at 50.4 Gy with FOLFOX. Cetuximab, 250 mg/m2, was given weekly during induction and during the three cycles of chemoradiotherapy.
Results are summarized in the table. NCCN(ESOPH-E,3) lists various irinotecan. taxane platin combinations and does list Erbitux for second line to be combined with other regimens. This is level 2B recommendation.
(The Cochrane Database of Systematic Reviews 2006 Issue 4 Chemotherapy for metastatic (spread to other parts of the body) cancer which originates in the esophagus.
Malthaner R, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev 2003;(4):CD001556.
NCCN.ORG, Esophageal Cancer
Tew, William P. , Kelsen, David P. , Ilson, David H.
Targeted Therapies for Esophageal Cancer
Oncologist 2005 10: 590-601;
Roedel C, Arnold D, Hipp M, et al. Cetuximab in combination with capecitabine, oxaliplatin and concomitant radiotherapy (Cet-Capox-RT) as preoperative therapy for rectal cancer. International Journal of Radiation Oncology* Biology*Physics. 2006;66, issue 3, Supplement:S82-S83, abstract 147.
Suntharalingam M, Dipretrillo T, Wanebo H, et al. A phase II trial evaluating the efficacy of weekly cetuximab, paclitaxel, carboplatin and daily RT in esophageal cancer. International Journal of Radiation Oncology* Biology*Physics. 2006;66, issue 3, Supplement:S22-S23, abstract 40.
Lledo G, Michel P, Dahan L, et al: Chemoradiation with FOLFOX plus cetuximab in locally advanced cardia or esophageal cancer: Final results of a GERCOR phase II trial (ERaFOX). 2011 Gastrointestinal Cancers Symposium. Abstract 8. Presented by Aimery de Gramont, MD, January 20, 2011.Figlin RA, Belldegrun AS, Crawford J et al. ABX-EGF, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with advanced cancer: phase 1 clinical results. Proc Am Soc Clin Oncol 2002;21:10a.
William P. Tew, David P. Kelsen, David H. Ilson Targeted Therapies for Esophageal Cancer The Oncologist, Vol. 10, No. 8, 590-601, September 2005;
J. Tabernero*, T. Macarulla, F. J. Ramos and J. Baselga Novel targeted therapies in the treatment of gastric and esophageal cancer Annals of Oncology 2005 16(11):1740-1748;