 Multimodality therapy of esophageal and esophagogastric junction cancer Background: The model of current therapy for carcinomas of the esophagus and esophagogastric junction was developed as a result of prior successes and failures. Surgery has been the mainstay of therapy in patients with localized disease who were candidates for aggressive treatment. Early-stage disease can be cured with surgical resection, but long-term survival is achieved in only the minority of patients with more advanced local disease at presentation. Similarly, either radiation therapy alone or surgery plus radiation therapy generally produced acceptable local control but little improvement in long-term survival for more advanced disease. The primary point of failure with esophageal carcinoma remains metastatic disease. Chemotherapy treatments: In metastatic esophageal carcinomas, combination chemotherapy regimens, generally based upon 5-fluorouracil and platinum compounds, yielded reproducible objective response rates of 20 percent to 50 percent; however, duration of response usually is less than six months. A theoretical argument could be made for systemic therapy combined with either concurrent or sequential aggressive local control measures (radiation therapy and/or surgery), as a means for addressing microscopic metastatic disease and the local disease process. The Radiation Therapy Oncology Group (RTOG) evaluated the impact of adding cisplatin-based chemotherapy to external beam radiation therapy in a randomized trial in patients who had surgically unresectable tumors or were medically not candidates for surgery.1 The results showed a survival advantage for the combined modality treatment (chemotherapy and radiation) over radiation therapy alone with median survivals of 12.5 months and 8.9 months, respectively. Recently, a randomized study compared combination chemotherapy consisting of two cycles of cisplatin plus 5-fluorouracil followed by surgery to surgery alone.2 The results of this study showed a statistically significant survival advantage for the bi-modality therapy (16 months median) over surgery alone (11 months median, p<0.01). The pathological complete response rate was 25 percent in the preoperative chemotherapy arm, and rates of positive lymph nodes were 42 percent for chemotherapy-treated patients and 82 percent for patients receiving surgery alone. As the trials above were being performed, a number of institutions were testing trimodality approaches, which integrated combination chemotherapy, radiation therapy and surgical resection. One series reported the results of preoperative, concurrent paclitaxe (taxol)/carboplatin/ 5-fluorouracil chemotherapy and radiation therapy followed by surgery. In this series, 50 percent of patients achieved pathological complete response, with 61 percent having no evidence of recurrence at a median follow-up of nine months. In addition to paclitaxel, other new agents such as vinorelbine (navelbine), docetaxel (taxotere) and gemcitabine (gemzar) are under investigation in combined modality treatment programs. Our team of medical oncologists, thoracic surgeons and radiotherapists at the Allegheny Center for Lung and Thoracic Disease is also investigating the role of multimodality therapy for esophageal carcinoma. We have combined our considerable individual experiences in the management of esophageal carcinoma to initiate a protocol including preoperative chemotherapy (oral 5-FU, taxol and carboplatin). This regimen is given over two to three cycles with concomitant intermediate dose external beam radiotherapy (40 Gy). Surgical resection of the esophageal cancer follows completion of this up-front therapy approximately two months after the program is begun. Esophagectomy is performed, and intraoperative brachy-radiotherapy is used as a local adjuvant treatment to the surgical resection. Our experience with this regimen has been very promising. Summary: The steady improvement in outcomes for localized esophageal and esophagogastric junction cancers has been the result of integrating newer strategies and chemotherapy agents into carefully designed and conducted clinical trials. The continuation of this process is certain to lead to future successes. References 1. Herskovic A, Martz K, Al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Eng J Med, 1992; 326:1593-1598. 2. Walsh TN, Noonan N, Hollywood D, et al: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Eng J Med, 1996; 335:462-467. 3. Meluch AA, Hainsworth JD, Gray JR, et al: Preoper- ative therapy with paclitaxel, carboplatin, 5-FU and radiation in the treatment of local esophageal cancer. Proc. ASCO, 1998;17:259a (abstract No. 995). 4. Urba SG, Orringer MB, Perez-Tamayo C, et al. Concurrent preoperative chemotherapy and radiation therapy in localized esophageal adenocarcinoma. Journal of Clinical Oncology 1992;69:285-291. 5. Forastiere AA. Treatment of locoregional esophageal cancer. Seminars in Oncology 1992;19:57-61. HOME
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