A retrospective comparison of neoadjuvant chemoradiotherapy regimens for locally advanced esophageal cancer.

Preoperative chemoradiotherapy (CRT) with carboplatin/paclitaxel has been shown to increase survival in patients with esophageal cancer, including gastroesophageal junction (GE) junction cancer, over surgery alone; however, there have been no studies comparing the different neoadjuvant CRT regimens. We retrospectively evaluated the long-term results of trimodality therapy for patients with locally advanced esophageal cancer treated on several chemotherapy regimens. Between 1999 and 2014, 215 patients with locally advanced esophageal cancer underwent neoadjuvant CRT followed by surgical resection. The median age was 62 years (range 21-84), 80.5% were men and 86% had adenocarcinoma. The following chemotherapy regimens were administered: cisplatin/5FU (14.9%), cisplatin/irinotecan (35.8%), carboplatin/paclitaxel (35.8%), and other (9.7%). The majority of patients (92.1%) received a radiation dose of 50.4 Gy. Predictors of toxicities and surgical complications were assessed using logistic regression. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method and proportional hazards regression was used to model time-to-event outcomes. The median follow-up among surviving patients was 4.1 years (range 0.4,13). The median OS was 3.0 years from time of diagnosis and OS was 36.8% at 5 years. RFS was 34.9% at 5 years. After neoadjuvant CRT, 34.7% of patients achieved a pathologic complete response including 60.7% of squamous cell carcinoma patients and 18.4% of adenocarcinoma patients (P < 0.001) and 66% were downstaged. Of the variables examined, pathologic stage, preoperative baseline cardiac comorbidity, postoperative cardiac or pulmonary complications, and chemotherapy regimen were associated with OS. Using cisplatin and 5FU as the reference regimen, patients treated with carboplatin/paclitaxel had significantly improved OS (HR = 0.47, P = 0.017 after adjusting for surgery type, radiation modality, baseline cardiac comorbidity, and preoperative stage) with 5-year OS rate of 66%. The most common surgical complications were cardiac in 61 patients (28.5%) and pulmonary in 52 patients (24.3%). Cardiac complications were associated with age (OR 1.05, P = 0.007) and cardiac comorbidity (OR 2.6, P = 0.02) and pulmonary complications with female gender (OR 3.98, P < 0.001). Forty-four patients (20.5%) required readmission within 30 days of discharge, and readmission was associated with cardiac comorbidity (OR 2.7, P = 0.017). Three patients died within 30 days of surgery. We observed an association between neoadjuvant carboplatin/paclitaxel and improved overall survival that requires confirmation in a prospective randomized trial.

A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of esophageal and gastric carcinomas. Although previous studies have examined tyrosine kinase inhibitors of EGFR, there remains limited data regarding the role of EGFR-directed monoclonal antibody therapy in these malignancies. We carried out a multi-institutional phase II study of cetuximab, a monoclonal antibody against EGFR, in patients with unresectable or metastatic esophageal or gastric adenocarcinoma. PATIENTS AND METHODS: Thirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab, at an initial dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Patients were followed for toxicity, treatment response, and survival. RESULTS: Treatment with cetuximab was well tolerated; no patients were taken off study due to drug-related adverse events. One (3%) partial treatment response was noted. Two (6%) patients had stable disease after 2 months of treatment. Median progression-free survival and overall survival were 1.6 and 3.1 months, respectively. CONCLUSION: Although well tolerated, cetuximab administered as a single agent had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Ongoing studies of EGFR inhibitors in combination with other agents may define a role for these agents in the treatment of esophageal and gastric cancer.

Weekly docetaxel, cisplatin, and irinotecan (TPC): results of a multicenter phase II trial in patients with metastatic esophagogastric cancer.

BACKGROUND: Recent studies have examined the addition of docetaxel to fluorouracil and cisplatin in advanced esophagogastric cancer. PATIENTS AND METHODS: We carried out a phase I dose-escalation study of weekly docetaxel, cisplatin, and irinotecan (TPC), given on days 1 and 8 every 3 weeks, in patients with chemonaive solid tumors. Subsequently, we completed a multiinstitutional phase II study of TPC in patients with previously untreated, metastatic esophagogastric cancer. RESULTS: Thirty-nine patients were enrolled in the phase I trial; a weekly schedule of TPC was well tolerated. On that basis, docetaxel 30 mg/m(2), cisplatin 25 mg/m(2), and irinotecan 65 mg/m(2) were selected for the phase II trial, where in the first 18 patients irinotecan 65 mg/m(2) caused too much diarrhea and was reduced to 50 mg/m(2). Among 56 eligible patients with previously untreated, metastatic esophagogastric cancer enrolled in the phase II trial, three complete and 27 partial responses were observed (overall response rate=54%), and 15 patients (30%) had stable disease. Median progression-free survival was 7.1 months, and median survival was 11.9 months. At the final irinotecan dose of 50 mg/m(2), grade 3 or higher toxicity included diarrhea (26%), neutropenia (21%), nausea (18%), fatigue (16%), anorexia (13%), and thrombosis/embolism (13%). CONCLUSIONS: Weekly TPC is an active and well-tolerated regimen for patients with esophagogastric cancer.

Irinotecan in esophageal cancer.

Irinotecan (Camptosar) has shown activity in several solid tumor malignancies, including gastric and pancreatic cancer. In vitro studies suggest antitumor activity in esophageal cancer cell lines. Sequence-dependent synergy has been demonstrated in vitro between irinotecan and cisplatin. A phase I trial conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) has demonstrated the safety and tolerability of cisplatin plus irinotecan. A phase II study of this combination in patients with previously untreated, advanced esophageal cancer, also at MSKCC, has demonstrated promising results. Current trials at MSKCC are attempting to combine this regimen with either paclitaxel (Taxol), fluorouracil (5-FU), or radiation therapy.

Chemotherapy in esophageal cancer.

The incidence of esophageal cancer continues to increase due to a rapid increase in adenocarcinoma of the distal esophagus and gastroesophageal junction. At least 50% of patients present with metastatic cancer and most patients with localized disease will develop metastases despite potentially curative local therapy. Thus, the majority of esophageal cancer patients will become candidates for palliative chemotherapy. Traditionally, single agents effective in this disease have included cisplatin, 5-fluorouracil, and mitomycin. The combination of cisplatin and continuous-infusion 5-fluorouracil is the standard for both squamous cell carcinoma and adenocarcinoma, with a 25% to 35% response rate in metastatic disease. More recently, paclitaxel has shown favorable results as a single agent or in combination with cisplatin in both disease histologies. One-hour weekly paclitaxel, a promising schedule with little toxicity, is under active investigation. Weekly irinotecan and cisplatin is a highly effective new regimen in both adenocarcinoma and squamous cell carcinoma with relatively little toxicity. Vinorelbine has demonstrated response in squamous cell carcinoma and has less toxicity than its predecessor, vindesine. Use of newer agents in combination with concurrent radiotherapy in locally advanced disease is the subject of ongoing clinical trials.

Phase II clinical trial of 13-cis-retinoic acid and interferon-alpha-2a in patients with advanced esophageal carcinoma.

BACKGROUND: Interferon in combination with 5-fluorouracil has been shown to be active in squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the esophagus. 13-cis-retinoic acid (CRA) has chemopreventive activity in SCC of the head and neck, and, in combination with interferon, has antitumor activity in SCC of the skin and cervix. METHODS: The activity and toxicity of CRA and interferon-alpha-2a (IFN) in patients with advanced esophageal carcinoma was evaluated in a Phase II single institution trial. Patients had unresectable or metastatic AC or SCC of the esophagus. One prior chemotherapy regimen was allowed. IFN was given by daily subcutaneous injection at a dose of 3 million U and CRA was taken orally at a dose of 1 mg/kg/day in 2 divided doses. Treatment was given in cycles of 4 weeks and continued until documented disease progression. RESULTS: Of the 19 patients entered, 15 were evaluable for response and toxicity. One patient was evaluable for response only and one patient was evaluable for toxicity only. Evaluable patients were predominantly male (15 patients), and had AC (13 patients). All had AJCC Stage IV disease and 12 were pretreated. Patients completed an average of two cycles of therapy (range, one to six cycles) prior to progression of disease. National Cancer Institute Common Toxicity Criteria Grade 3/4 toxicity was notable for nausea (25%) and fatigue (31%). No major objective responses were recorded. Eleven patients with AC and 3 patients with SCC had rapid progression of disease. One patient with AC was found to have a minor response for 22 weeks and 1 patient with AC had stable disease for 45 weeks. CONCLUSIONS: This regimen had no significant activity in patients with advanced AC of the esophagus. Further evaluation of IFN plus CRA, using this dose and schedule, is not recommended. In comparison with prior trials of this therapy, a surprising amount of severe nausea and fatigue was observed in this trial.

Irinotecan and cisplatin in upper gastrointestinal malignancies.

Irinotecan (CPT-11 [Camptosar]), an active agent in the treatment of fluorouacil-refractory colorectal cancer, has antitumor activity in upper gastrointestinal cancers. Clinical trials from Japan indicate antitumor responses in gastric and pancreatic cancers. Cisplatin (Platinol), a central agent in the treatment of upper gastrointestinal malignancies, is a logical drug to study in combination with irinotecan in upper gastrointestinal cancers. In vitro studies have shown important sequence-dependent synergy of cisplatin/irinotecan combination therapy. Irinotecan appears to prevent removal of cisplatin-induced DNA-interstrand cross-links. Initial phase I and III trials of cisplatin plus irinotecan appear to confirm this synergy, with Japanese trials in gastric cancer showing an encouraging rate of response with acceptable toxicity. A phase I trial conducted at Memorial Sloan-Kettering Cancer Center has demonstrated the safety and tolerability of weekly cisplatin and irinotecan. Currently, a phase II trial of this weekly regimen is under way in patients with metastatic or recurrent esophageal cancer. The response proportion compares favorably to standard therapy, with relatively mild toxicity. Other phase II studies, including single-agent irinotecan in esophageal cancer and the combination of cisplatin and irinotecan in gastric cancer, are being initiated at other US institutions.