'Surgery Remains Cornerstone' for Early Esophageal Cancer

Veronica Hackethal, MD

July 03, 2014

In patients with early esophageal cancer, preoperative chemoradiotherapy (CRT) does not improve overall survival, but it does increase postoperative mortality, according to a phase 3 study. The finding is in contrast to results from previous studies in this patient population, which have shown a benefit.

Results from the FFCD 9901 trial, published online June 30 in the Journal of Clinical Oncology, raise questions about the use of preoperative CRT, and whether surgery alone is the better option.

"This randomized study is the first dedicated to stage I and II esophageal cancers, and shows that there is no role for preoperative chemoradiation in such early cancers," said researcher Christophe Mariette, MD, PhD, professor of surgery at the University Hospital Claude Huriez in Lille, France.

"Surgery remains the cornerstone for patients with localized esophageal cancer," Dr. Mariette told Medscape Medical News.

Neoadjuvant chemotherapy without radiation, though, could be an option for patients with esophageal cancer graded as stage I or as stage II with lymph node involvement, he added.

The study was conducted in 30 treatment centers from June 2000 to June 2009. The researchers randomized patients with early resectable esophageal cancer to surgery alone (n = 97) or to preoperative CRT plus surgery (n = 98). CRT consisted of 5 weeks of radiotherapy and 2 courses of fluorouracil and cisplatin. Participants were followed for more than 7 years.

Interim analyses suggested that it was unlikely that either of the treatments would prove superior, so enrolment was stopped early.

There was no difference in the complete surgical resection rate between CRT plus surgery and surgery alone (93.8% vs 92%; P = .749). There was also no difference in overall survival (hazard ratio [HR], 0.99; P = .94) or disease-free survival (HR, 0.92; P = .648).

However, postoperative mortality was 3 times higher with CRT plus surgery than with surgery alone (11.1% vs 3.4%; P = .049).<,p>

About 33% of the CRT plus surgery group experienced "significant" downstaging.

In addition, locoregional recurrence rates were lower with CRT plus surgery than with surgery alone (29% vs 15%), and 5-year disease-free survival also seemed to favor CRT plus surgery over surgery alone (35.6% vs 27.7%).

Contrast With Previous Studies

The results from this trial are unexpected, report Brian Czito, MD, and Christopher Willett, MD, both from the Duke University School of Medicine in Durham, North Carolina, in an accompanying editorial.

"The FFCD 9901 results stand in contrast to multiple contemporary trials and meta-analyses, which have demonstrated a survival benefit with the use of preoperative chemoradiotherapy," Drs. Czito and Willett told Medscape Medical News in an email.

Most recently, results from the phase 3 CROSS trial, the largest to date to look at preoperative CRT in resectable esophageal cancer, suggest that median survival doubled with preoperative CRT. In addition, there was no difference in postoperative mortality rates with preoperative CRT, in contrast to the increase in postoperative mortality seen in the FFCD 9901 trial.

The higher postoperative mortality rates in FFCD 9901 were "most likely" due to a less healthy patient population that had more medical comorbidities, Drs. Czito and Dr. Willett explain. In FFCD 9901, most patients had squamous cell esophageal cancers, whereas most patients in the CROSS trial had adenocarcinomas. There were also differences in chemotherapy regimens (fluorouracil and cisplatin in FFCD 9901 vs paclitaxel and carboplatin in CROSS) and variations in radiation techniques and doses. All of these could also have contributed to the discrepant results, they noted.

The editorialists highlight the significant improvement in local control and recurrence rates of esophageal cancer in FFCD 9901. Such benefits of preoperative CRT were likely offset, they reason, by increased postoperative deaths in the CRT group, an explanation also mentioned by the researchers.

"For early-stage esophageal cancer patients, such as those with stage I disease and no lymph node involvement, surgical resection remains one reasonable treatment option," Drs. Czito and Dr. Willett stated.

The approach could change, though, on the basis of tumor stage and type, they write.

"For medically operable patients with resectable esophageal cancers that are clinical stage II and greater, we usually recommend a course of preoperative chemoradiotherapy," Dr. Czito and Dr. Willett continued.

They based their strategy on the high rates of local and regional recurrence after surgery. Results from FFCD 9901 and other studies, they noted, suggest that clinical staging often underestimates the true stage of esophageal cancer.

Moreover, 2 separate randomized European trials have shown no survival benefit with surgery added to CRT for squamous cell carcinoma of the esophagus (J Clin Oncol2007;25:1160-1168 and2005;23:2310-2317). As in FFCD 9901, postoperative mortality rates in these 2 trials increased with surgery added to CRT.

"It appears that the addition of surgery to chemoradiotherapy, and vice versa, in patients with squamous cell carcinoma of the esophagus, while improving local control, may increase treatment-related mortality in some patients," Drs. Czito and Willett emphasized. Many institutions, they noted, now treat such patients first with CRT, reserving surgery for treatment nonresponse or tumor recurrence.

"An alternative and reasonable strategy in patients with early-stage squamous cell carcinoma would be to treat with chemoradiotherapy, followed by repeat evaluation and surgery as appropriate, based on clinical response, patient comorbidities and medical status," they added.

"A more critical question is how to best select patients for definitive surgery, definitive chemoradiotherapy, or trimodality therapy, given the high locoregional failure rates when either approach is used by itself," Drs. Czito and Willett explained. "Patient selection for trimodality therapy in these situations is paramount."

Dr. Mariette, Dr. Czito, and Dr. Willett have disclosed no relevant financial relationships. One of the study coauthors, Francoise Mornex, MD, PhD, from the University Claude Bernard in Lyon, France, reports financial relationships with Roche and Merck.

J Clin Oncol. Published online June 30, 2014. Abstract, Editorial

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