Preoperative Chemoradiation Therapy
Chemoradiation followed by surgery is a standard treatment option for patients with stages IB, II, III, and IVA esophageal cancer, based on the results of several randomized trials.
The ongoing CROSS (NCT01498289) study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks.[Level of evidence: 1iiA] The majority of the patients enrolled in the study have adenocarcinoma (75%).
With a median follow-up of 45 months, preoperative chemoradiation was found to improve median OS from 24 months in the surgery-alone group to 49.4 months (hazard ratio [HR], 0.657; 95% confidence interval [CI], 0.495–0.871, P = .003). Additionally, preoperative chemoradiation improved the rate of R0 resections (R0 is defined as complete resection with no tumor within 1 mm of resection margins, 92% vs. 69%, P < .001). A complete pathologic response was achieved in 29% of patients who underwent resection after chemoradiation therapy. Postoperative complications and in-hospital mortality were equivalent in both groups. The most common hematologic side effects in the chemoradiation group were leukopenia (6%) and neutropenia (2%). The most common nonhematologic side effects were anorexia (5%) and fatigue (3%).
Other phase III trials have compared preoperative concurrent chemoradiation therapy to surgery alone for patients with esophageal cancer.[15,16,17,18,19][Level of evidence: 1iiA] A multicenter prospective randomized trial in which preoperative combined chemotherapy (i.e., cisplatin) and radiation therapy (37 Gy in 3.7 Gy fractions) followed by surgery was compared to surgery alone in patients with squamous cell carcinoma showed no improvement in OS and a significantly higher postoperative mortality (12% vs. 4%) in the combined modality arm. In patients with adenocarcinoma of the esophagus, a single-institution phase III trial demonstrated a modest survival benefit (16 months vs. 11 months) for patients treated with induction chemoradiation therapy consisting of 5-FU, cisplatin, and 40 Gy (2.67 Gy fractions) plus surgery over resection alone. A subsequent single-institution trial randomly assigned patients (75% with adenocarcinoma) to 5-FU, cisplatin, vinblastine, and radiation therapy (1.5 Gy twice daily to a total of 45 Gy) plus resection versus esophagectomy alone. At a median follow-up of more than 8 years, there was no significant difference between the surgery alone and combined modality therapy with respect to median survival (17.6 months vs. 16.9 months), OS (16% vs. 30% at 3 years), or disease-free survival (16% vs. 28% at 3 years). An Intergroup trial (CALGB-9781) planned to randomly assign 475 patients with resectable squamous cell or adenocarcinoma of the thoracic esophagus to treatment with preoperative chemoradiation therapy (5-FU, cisplatin, and 50.4 Gy) followed by esophagectomy and nodal dissection or surgery alone.[Level of evidence: 1iiA] The trial was closed as a result of poor patient accrual; however, the results of the 56 enrolled patients, with a median follow-up of 6 years, were reported. The median survival was 4.48 years (95% CI, 2.4 years to not estimable) for trimodality therapy versus 1.79 years (95% CI, 1.41–2.59 years) for surgery alone (P = .002), with 5-year OS of 39% (95% CI, 21%–57%) versus 16% (95% CI, 5%–33%) for trimodality therapy versus surgery alone.