Active Surveillance May Have a Role in Esophageal Cancer

Active surveillance (AS) following a complete clinical response to neoadjuvant chemoradiotherapy was noninferior to standard surgery among patients with esophageal cancer, a phase III cluster-randomized trial showed.

In a modified intention-to-treat (ITT) analysis that allowed crossover at the time of complete response, 2-year overall survival (OS) rates were 74% in the AS group and 71% in the standard surgery group (one-sided 95% boundary 7% lower, meeting the noninferiority margin of 15%), reported Berend J. van der Wilk, MD, PhD, of the Erasmus MC Cancer Institute, University Medical Centre, in Rotterdam, the Netherlands, and colleagues.

AS remained noninferior in the ITT analysis (75% vs 70%, one-sided 95% boundary 6% lower), they noted in Lancet Oncology.

There were also no significant differences in OS according to the modified ITT analysis (HR 1.14, two-sided 95% CI 0.74-1.78) or the ITT analysis (HR 0.83, two-sided 95% CI 0.53-1.31).

Neoadjuvant chemoradiotherapy followed by surgery is standard for locally advanced esophageal cancer, with nearly a quarter of patients with adenocarcinoma and nearly half of patients with squamous cell carcinoma achieving a pathologic complete response. However, 30% to 40% of patients will develop early distant metastases, throwing the benefit of standard surgery in all patients after neoadjuvant chemoradiotherapy into question.

“Active surveillance could be introduced as an alternative approach, using the present data, in patient counseling and shared decision making,” the authors wrote. “For the long-term efficacy of active surveillance, extended follow-up is required.”

In a commentary accompanying the study, Somnath Mukherjee, MD, of the Oxford University Hospitals NHS Foundation Trust in England, observed that the study is “probably” not yet practice changing, with longer-term results and validation from other surveillance studies needed.

Mukherjee said a noninferiority endpoint at 2 years may not be long enough to determine the strategy’s success, and noted that although the difference in median disease-free survival (DFS) was not statistically significant, it was numerically higher in the surgery group (49 vs 35 months; HR 1.25, 95% CI 0.83-1.89, P=0.29), suggesting that “active surveillance might yet prove inferior on extended follow-up.”

“It is not prime time yet to offer active surveillance to every individual with operable esophageal cancer, but it could be offered to selected patients who are borderline fit for surgery, as a surgery-sparing approach in individuals who are considered at high risk of relapse despite surgery, and to those who are keen to avoid surgery and willing to accept the risks,” Mukherjee wrote.

The trial included 309 patients who achieved a complete response with neoadjuvant chemoradiotherapy, with 156 assigned to AS and 153 to surgery (the ITT population). After crossovers, there were 198 in the AS group and 111 in the surgery group (the modified ITT population).

Median age of patients was 69 years in the AS group and 68 years in the surgery group, and 78% of the entire cohort were men.

Participants in the AS group underwent clinical response evaluations every 3 months in year 1, every 4 months in year 2, every 6 months in year 3, and annually in years 4-5.

Of the 198 patients undergoing AS, isolated local recurrence was picked up in 48% on follow-up, of whom 86% were able to undergo salvage esophagectomy.

Rates of postoperative complications were similar for those who had delayed surgery in the AS group and those who had upfront surgery (82% vs 84%, respectively). In addition, 90-day mortality rates after surgery were also similar (4% vs 5%).

During AS, 33 patients developed distant metastases without undergoing surgery. In 22 of these patients, the metastases were detected at the third clinical response evaluation. Another 69 patients had a persistent clinical complete response.

The authors suggested that these were the patients who appeared to derive the greatest benefit from AS, as most of those with a persistent clinical complete response remained on surveillance, while those diagnosed with distant metastases early during follow-up would have been spared futile esophagectomy “because metastatic disease strongly dictates participants’ prognosis.”

Thus, of the patients undergoing AS after clinical complete response, “almost half (91 of 198) were spared unbeneficial esophagectomy, resulting in improved short-term health-related quality of life,” they wrote.

Patients who underwent AS (including the participants with postponed esophagectomy in case of locoregional regrowth) had statistically significantly better global health-related quality of life compared with those who underwent standard surgery at 6 months and 9 months after completion of neoadjuvant chemoradiotherapy, as measured by the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire.

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