Neoadjuvant chemoradiotherapy fails to boost survival

Key clinical point: Don’t postpone surgery for esophageal cancer to perform chemoradiotherapy.

Major finding: Median overall survival was 31.8 months in the intervention group and 41.2 months in the surgery-only group; 3-year overall survival was 47.5% and 5-year overall survival was 41.1% in the intervention group, compared with 53% and 33.8%, respectively, in the surgery-only group. All these differences are nonsignificant.

Data source: A multicenter randomized phase III clinical trial involving 98 patients treated with neoadjuvant chemoradiotherapy and 97 treated with surgery alone for early-stage esophageal cancer, who were followed for a median of approximately 8 years.

Disclosures: This study was supported by the French National Cancer Institute’s Programme Hospitalier pour la Recherche Clinque and Lille University Hospital; it received no commercial support. Dr. Mariette reported no financial conflicts of interest; one of his associates reported ties to Roche and Merck.

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Try definitive, not adjuvant, chemoradiotherapy

Since patients with early-stage esophageal cancer don’t appear to benefit from preoperative neoadjuvant chemoradiotherapy, perhaps it is time to consider a different approach: definitive rather than neoadjuvant chemoradiotherapy as the first-line treatment, said Dr. Brian G. Czito, Dr. Manisha Palta, and Dr. Christopher G. Willett.

Some medical centers have already adopted this approach for patients with potentially curable esophageal cancer, reserving surgery as salvage treatment. Compared with surgery as first-line treatment, definitive chemoradiotherapy is associated with a lower rate of treatment-related mortality and similar survival outcomes, they noted.

Dr. Czito, Dr. Palta, and Dr. Willett are in the department of radiation oncology at Duke Cancer Institute, Durham, N.C. They reported no financial conflicts of interest. These remarks were taken from their editorial accompanying Dr. Mariette’s report (J. Clin. Oncol. 2014 June 30 [doi:10.1200/JCO.2013.53.6532]).



For patients with early-stage esophageal cancer, undergoing chemotherapy and radiotherapy before surgical excision failed to improve the rate of curative resection and, most importantly, failed to boost survival in a phase III clinical trial, according to a report published online June 30 in the Journal of Clinical Oncology.

Unfortunately this treatment strategy also tripled postoperative mortality, making the risk-benefit ratio even more lopsided for this patient population, said Dr. Christophe Mariette of the department of digestive and oncologic surgery, University Hospital Claude Huriez-Regional University Hospital Center, Lille (France), and his associates.

Clinical trials examining neoadjuvant chemoradiotherapy for esophageal cancer have produced conflicting results, with some showing that the approach is effective, in some cases doubling median survival, while others showed no benefit. Most such studies have been limited by small sample sizes, heterogeneity of tumor types, variations in radiation doses and chemotherapy regiments, and differences in preoperative staging techniques and the adequacy of surgical resections. Moreover, the number of study participants with early-stage esophageal cancer has been very small because most patients already have more advanced disease at presentation, the investigators noted.

For their study, Dr. Mariette and his associates confined the cohort to patients younger than 75 years with treatment-naive esophageal adenocarcinoma or squamous-cell carcinoma judged to be stage I or II using thoracoabdominal CT and endoscopic ultrasound; additional preoperative assessments using PET scanning, cervical ultrasound, or radionuclide bone scanning were optional. It required 9 years to enroll 195 patients at 30 French medical centers. These study participants were randomly assigned to receive either neoadjuvant chemotherapy plus radiotherapy before potentially curative surgery (98 subjects) or potentially curative surgery alone (97 subjects).

In the intervention group, radiotherapy involved a total dose of 45 Gy delivered in 25 fractions over the course of 5 weeks. Chemotherapy was administered during the same time period and involved two cycles of fluorouracil and cisplatin infusions. All patients in this group were clinically reevaluated 2-4 weeks after completing this regimen, and surgery was performed soon afterward.

Surgery comprised a transthoracic esophagectomy with extended two-field lymphadenectomy and either high intrathoracic anastomosis (for tumors with an infracarinal proximal margin) or cervical anastomosis (for tumors with a proximal margin above the carina).

Median follow-up was 7.8 years. There were 125 deaths: 62.4% of the intervention group died, as did 66% of the surgery-only group, a nonsignificant difference, the investigators said (J. Clin. Oncol. 2014 June 30 [doi:10.1200/JCO.2013.53.6532]).

Median overall survival was 31.8 months in the intervention group and 41.2 months in the surgery-only group, a nonsignificant difference. Similarly, 3-year overall survival was 47.5% and 5-year overall survival was 41.1% in the intervention group, compared with 53% and 33.8%, respectively, in the surgery-only group, which were also nonsignificant differences.

The rate of curative resection also was not significantly different between the intervention group (93.8%) and the surgery-only group (92.1%), indicating that reducing the tumor with chemotherapy and radiotherapy had no beneficial effect in these early-stage cancers. Previous studies have demonstrated that such downsizing is effective in more advanced esophageal cancers, Dr. Mariette and his associates noted.

Postoperative mortality was more than threefold higher among patients who underwent preoperative chemoradiotherapy (11.1%) than in the surgery-only group (3.4%). The causes of postoperative death included aortic rupture, uncontrollable chylothorax, anastomotic leak, gastric conduit necrosis, mesenteric and lower limb ischemia, and acute RDS in the intervention group, compared with pneumonia and acute RDS in the surgery-only group.

These findings suggest that preoperative chemoradiotherapy "is not the appropriate neoadjuvant therapeutic strategy for stage I or II esophageal cancer," the investigators said.

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