Chemoradiotherapy Doubles Survival in Esophageal Cancer

May 30, 2012 — Preoperative chemoradiotherapy dramatically improved survival in patients with potentially curable esophageal or esophagogastric-junction cancer, according to a 366-patient randomized trial.

The study, published in the May 31 issue of the New England Journal of Medicine, breaks new ground, according to the authors.

"The observed survival in both groups was superior to the anticipated survival and to that reported in earlier randomized trials," they write.

Median overall survival was 49.4 months with chemoradiotherapy plus surgery (n = 178) and 24.0 months with surgery alone (n = 188), report the authors, led by Ate van der Gaast, MD, from Erasmus University Medical Center in Rotterdam, the Netherlands.

Patients treated with neoadjuvant chemoradiotherapy had a 34% lower risk for death during follow-up (hazard ratio, 0.657; P = .003). Median follow-up was 45.4 months.

The chemoradiotherapy approach, which featured carboplatin and paclitaxel, should be considered by other oncologists, suggested Dr. van der Gaast.

"I think that for patients with esophageal cancer, the combined modality treatment (i.e., preoperative chemoradiotherapy) can be a standard of care. Our regimen is well tolerated but not tested against, for example, chemoradiotherapy with cisplatin and 5-fluorouracil," he told Medscape Medical News in an email.

Importantly, the patients receiving preoperative treatment did not have higher postoperative morbidity or early mortality, compared with those treated with surgery. In fact, the regimen was associated with acceptable adverse-event rates, the authors note.

"The chemoradiotherapy was associated with a low frequency of high-grade toxic effects and could be given as an outpatient treatment," they write.

Bolster Choice of Chemoradiation

These results bolster arguments that favor chemoradiotherapy, the authors report.

The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer has not well established, they explain. "The role of neoadjuvant chemoradiotherapy has been debated for several decades. In most randomized trials, no survival benefit could be shown, and the trials were criticized for inadequate trial design, samples that were too small, and poor outcomes in the surgery-alone group," they write.

One of the questions that remains about treatment in this setting, note the authors, is whether or not esophageal and esophagogastric-junction tumors should be treated with preoperative chemoradiotherapy or with perioperative chemotherapy.

Two trials — the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial and the Actions Concertées dans les Cancer Colorectaux et Digestifs (ACCORD) 07 trial — found that perioperative chemotherapy provides better outcomes, the authors report. However, both trials included gastric tumors and esophagogastric-junction tumors.

The Preoperative Chemotherapy or Radiochemotherapy in Esophagogastric Adenocarcinoma Trial (POET) might be a better comparator, the authors suggest. In that trial, patients with esophagogastric-junction tumors were randomly assigned to preoperative chemotherapy or chemoradiotherapy. The researchers found a nonsignificant survival trend in favor of preoperative chemoradiotherapy.

Study Details

In their study, Dr. van der Gaast and colleagues randomly assigned patients with resectable tumors (adenocarcinoma or squamous cell carcinoma) to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg/mL per minute) and paclitaxel (50 mg/m² of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery.

Chemoradiotherapy plus surgery achieved better overall survival than surgery alone at every follow-up time point.

Median Overall Survival in the 2 Groups

Follow-Up	Chemoradiotherapy Plus Surgery, %	Surgery Alone, %
1 y	82	70
2 y	67	50
3 y	58	44
5 y	47	34

Chemoradiotherapy enabled higher-quality resections, according to the data. Complete resection with no tumor within 1 mm of the resection margins was achieved in 148 of 161 (92%) patients treated with chemoradiotherapy plus surgery, and in 111 of 161 (69%) patients treated with surgery alone (P < .001).

A pathological complete response was seen in the resection specimens from 47 patients (29%) treated with chemoradiotherapy plus surgery. A pathological complete response was observed in 28 of 121 (23%) patients with adenocarcinoma and in 18 of 37 (49%) with squamous cell carcinoma (P = .008).

Despite the higher rate of pathological complete response in patients with squamous cell carcinoma, histologic tumor type was not a prognostic factor for survival; patients with both types of cancer benefited from neoadjuvant chemoradiotherapy.

A median of 15 lymph nodes were resected in patients treated with chemoradiotherapy plus surgery, and 18 were resected in patients treated with surgery alone (P = .77). Notably, 1 or more positive lymph nodes in the resection specimen were found in 50 patients (31%) treated with chemoradiotherapy plus surgery and in 120 patients (75%) treated with surgery alone (P < .001).

The most common major hematologic toxic effects in patients treated with the chemoradiotherapy plus surgery were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%).

In patients treated with the chemoradiotherapy plus surgery, 12 of 171 (7%) patients experienced grade 3 hematologic toxic effects; 1 patient developed a grade 4 hematologic toxic effect and neutropenic fever. All other major nonhematologic toxic effects of grade 3 or higher occurred in less than 13% of patients in this group.

The study was funded by the Dutch Cancer Foundation. The authors have disclosed no relevant financial relationships.

N Engl J Med. 2012;366:2074-2084. Abstract