Surgery after primary chemoradiotherapy in squamous cancer of the esophagus: is the photon mightier than the sword?

Esophageal cancer presents medical, surgical, and radiation oncologists with one of the most difficult treatment challenges. The rarity of the disease in the West and the absence of effective screening result in patients presenting with dysphagia, weight loss, and advanced stage cancers. Squamous cancer patients are usually elderly, have a history of alcohol and tobacco abuse, and have comorbid conditions that limit therapy tolerance. Esophagectomy for local disease is fraught with significant operative morbidity and operative mortality. The loss of organ function leads to protracted nutritional compromise and a slow recovery. Primary chemoradiotherapy without surgery in the treatment of esophageal cancer emerged as a potential alternative to esophagectomy with the publication of the Radiation Therapy Oncology Group (RTOG) trial 85-01. This trial, treating mainly squamous cancers, reported 2and 5-year survival rates that were comparable with contemporary surgical series. RTOG 85-01 engendered an ongoing debate about the relative merits of esophagectomy, primary chemoradiotherapy, or multimodality therapy using preoperative chemoradiotherapy followed by surgery. The local disease recurrence rate of 45% or higher observed with primary chemoradiotherapy has led thoracic surgeons to argue that esophagectomy is required in patients undergoing chemoradiotherapy to ensure local disease control. Others argue that the addition of surgery does not improve outcome, given the overall poor prognosis, as patients with locally advanced disease ultimately develop metastatic disease in more than 50% of cases. Are the rigors of esophagectomy justified after chemoradiotherapy, if survival is defined by distant disease as well as local disease control? The report by Bedenne and colleagues in this issue of the Journal of Clinical Oncology represents a landmark in the management of locally advanced squamous esophageal cancer. The Federation de Francophone de Cancerologie Digestive (FFCD) trial 9201 compares chemoradiotherapy alone with chemoradiotherapy followed by surgery in patients with esophageal cancer who responded to chemoradiotherapy. Although both squamous cell carcinoma and adenocarcinoma histologies were accrued, squamous cancer was the most common disease treated, in nearly 90% of cases. Unlike other Western countries in which adenocarcinoma of the esophagus is now more common, squamous cancer remains the predominant histology in France and accounts for 75% of all cases. The primary end point of the trial was to demonstrate equivalence of survival in patients treated with primary chemoradiotherapy or with chemoradiotherapy followed by surgery. Secondary end points included quality of life, pattern of disease recurrence, and the need to treat subsequent dysphagia. All patients were treated with two cycles of fluorouracil and cisplatin combined with one of two schedules of radiotherapy: 30 Gy in two split courses weeks 1 and 4, or 46 Gy given continuously. Patients were assessed for response by unidimensional measurement on esophagram and by dysphagia improvement, and responding patients were then randomly assigned to surgery or to three additional cycles of chemotherapy, combined with an additional 15 Gy of radiotherapy on the split course arm and 20 Gy on the continuous arm. The investigators only randomly assigned patients responding to chemoradiotherapy to avoid continuing inactive therapy in nonresponding patients and to avoid the potential confounding of survival by crossing over of nonresponding patients to surgery. Despite the difficulty of randomly assigning patients to a surgery or no surgery treatment plan, compliance on protocol was fairly high with the majority of randomly assigned patients completing therapy on their assigned treatment arm. Compliance rates were significantly higher in the nonsurgery (97%) compared with the surgery arm (85%), as some patients assigned to surgery refused surgery or were deemed inoperable. The strengths of FFCD 9201 include adequacy of the sample size, the nearly 4-year median length of follow-up, the documentation of pattern of failure, and the long-term assessment of swallowing function. The authors reported no difference in either median survival (17.7 v 19.3 months) or 2-year survival (34% v 40%) in patients undergoing surgery or additional chemoradiotherapy. Rates of distant metastasis were also not different in the surgery and no surgery group. However, patients undergoing surgery had a lower rate of local tumor recurrence compared with the nonsurgical group (34% v 43%) and a lesser need for palliative intervention to relieve dysphagia (24% v 46%). However, these differences in local control failed to impact survival. The vast majority of recurrences occurred either in the first year (60% of recurrences) or first 2 years (80%). Conclusions from this trial may not be applicable in the small number of patients with adenocarcinoma, although a multivariate analysis did not indicate an outcome difference as a function of histology. Methodologic problems with the FFCD 9201 trial include the significant disparity between therapy arms. The chemoradiotherapy arm received additional cycles of both chemotherapy and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 10 APRIL 1 2007