Is active surveillance an alternative to surgery for some patients with esophageal cancer?

Abstract

Overall survival with active surveillance was noninferior to overall survival with surgery after 2 years for some patients with esophageal cancer who achieved a clinical complete response after neoadjuvant chemoradiotherapy, according to researchers.

Results from the phase 3, randomized study showed that the overall survival rate was 74% for patients undergoing active surveillance and 71% for patients having surgery.

The authors caution that their research will require extended follow-up to determine the long-term efficacy of active surveillance. Some esophageal surgeons have concerns about the trial’s design and findings.

Results of the Neoadjuvant Chemoradiotherapy Followed by Active Surveillance Versus Standard Surgery for Esophageal Cancer (SANO) trial appear in The Lancet (doi:10.1016/S1470-2045(25)00027-0).

Kimberly Wilson, a survivor of stage IV esophageal cancer and patient advocate who underwent surgery in 2022, supports the study’s efforts to assess all potential treatment options for the disease.

“I believe very strongly in research supporting a wide variety of patients’ needs and perspectives to draw in the medical community’s ability to provide patients with multiple options,” says Wilson, a program specialist for the Esophageal Cancer Action Network, who had a total esophagectomy in 2022 after undergoing chemotherapy, radiation, and immunotherapy.

Unable to avoid surgery because of her advanced disease, Wilson says that she fits into the rare category of stage IV esophageal cancer “thrivers” who continue to live fairly regular lives—albeit at a slower pace.

“My stomach was pulled up to make what now functions as my esophagus,” she says. “Despite how challenging the surgery was, I would do it again.”

The phase 3, randomized SANO trial is a multicenter study of patients in 12 Dutch hospitals. The research was conducted between November 2017 and January 2021. Participants had locally advanced esophageal cancer and a clinical complete response after chemoradiotherapy. After screening 1115 patients, researchers included 309 individuals: 198 participants went on active surveillance, whereas 111 had the standard surgery. The standard surgery was esophagectomy within the 2 weeks after a clinical complete response was achieved.

Seventy-eight percent of the participants were male, and 22% were female. The primary end point was overall survival, which was analyzed according to a modified intention-to-treat principle allowing crossover at the time of clinical complete response and an intention-to-treat principle. The median follow-up was 38 months. Secondary end points included progression-free survival, health-related quality of life, and treatment-related morbidity and mortality.

The 2-year overall survival rate with active surveillance (74%) was noninferior to the rate with standard surgery (71%) after the modified intention-to-treat analysis. In the intention-to-treat analysis, the overall survival rate remained noninferior with active surveillance (75%) versus surgery (70%). The frequencies of postoperative complications and postoperative mortality after standard surgery or postponed surgery after active surveillance were similar between the groups.

The trial findings could be used for patient counseling and shared decision-making, the authors noted; however, long-term follow-up is needed.

Daniela Molena, MD, director of the esophageal surgery program at Memorial Sloan Kettering Cancer Center in New York, New York, has major concerns about the study. She notes that researchers mixed participants of two studies together by including surgery patients from a retrospective pre-SANO study in the new study. Furthermore, they mixed patients with squamous esophageal cancer and patients with adenocarcinoma esophageal cancer even though the two are unique diseases and respond differently to chemotherapy and radiation. Dr Molena also expresses concern that researchers allowed crossover from one arm to another.

“If the patients were lucky enough to not develop metastatic disease, they were allowed to have surgery,” she says. “In fact, only 35% of the ‘surveillance’ patients overall, and 29% of adenocarcinoma patients, remained in remission.”

All other patients either developed systemic recurrence or underwent surgery, she adds, noting that the follow-up is too short to determine whether these delayed surgeries will have the same outcomes as those performed immediately after treatment.

“It’s hard to make sense of the results when you have so much chaos,” Dr Molena says. “If patients and providers are led to believe that surveillance is equivalent to doing surgery, the procedure is likely to be omitted in most cases. It’s a dangerous and deceiving message because most patients underwent surgery anyway but in a delayed fashion.”

Wayne L. Hofstetter, MD, director of the esophageal surgery program at MD Anderson Cancer Center in Houston, Texas, also has concerns. He notes that the trial results were highly anticipated in the esophageal surgery community because of the ongoing debate over whether to operate on this group of patients.

Dr Hofstetter says that he has been a proponent of organ-sparing therapy when appropriate in highly select individuals who appear to have complete responses to combined chemoradiotherapy (CXRT). That group includes patients who are marginal candidates for surgery and those who do not wish to undergo esophagectomy.

“The criticism of the SANO trial is that it didn’t look at the benefit of going to surgery at 6 weeks instead of 12 weeks and beyond,” Dr Hofstetter says, noting that patients who underwent surgery at 6 weeks were not included in the study.

Moreover, trial participants who were evaluated at 6 weeks underwent only endoscopy for residual disease rather than imaging as well. The latter is a key part of the diagnostic process, he adds.

“So, essentially, you’re randomizing the best of the best and then deciding whether to operate or observe,” Dr Hofstetter says.

Emphasizing the importance of including those who had surgery at 6 weeks, Dr Hofstetter points to the NeoRes II trial (doi:10.1016/j.annonc.2023.08.010), which found that a prolonged time to surgery of 10–12 weeks after CXRT did not improve complete response and showed a strong trend toward worse survival.

He also criticizes the SANO trial researchers’ randomization method, which was not a 1:1 approach. Rather, the study began with all the surgeries, which were followed by all the observations. As a result, the surgery group had a longer follow-up than the observation group.

Although researchers noted that the follow-up difference was not crucial because most recurrences occur in the first 2–3 years, Dr Hofstetter would prefer to see a follow-up at 4 years before conclusions are drawn.

The SANO trial findings may not be applicable to patients with adenocarcinoma, Dr Hofstetter adds, noting that individuals with squamous cell esophageal cancer respond much better to CXRT than those with adenocarcinoma. Both the NeoRes II and SANO studies, along with previous European studies (doi:10.1200/JCO.2005.04.7118), support the possibility of surgery as needed for patients with squamous cell cancer. The ongoing Asian SINO trial (doi:10.1200/JCO.2024.42.23_suppl.196) is attempting to answer that question directly, he says.

At the same time, 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) neoadjuvant therapy is now the standard of care, instead of CXRT, for otherwise healthy patients with operable adenocarcinoma as per findings from the ESOPEC trial (doi:10.1200/JCO.2024.42.17_suppl.LBA1). After FLOT, those patients undergo surgery; this ends the controversy of surgery after CXRT in this specific group, according to Dr Hofstetter.

Dr Molena adds that rather than offering the same treatment to all, clinicians should strive for a more personalized approach for these patients. The SANO-recommended approach may be worthwhile for patients at high risk for surgery but certainly not for all patients, she says.

Because of her many concerns about the trial, Dr Molena would not advise her otherwise healthy patients who are good surgical candidates to avoid surgery immediately after chemoradiotherapy.

“It’s a lot of risk for patients to omit surgery and wait for the disease to progress before resection,” she says. “We don’t have a lot of good treatment options, and once you miss the ball, you can’t go back.”

Both Dr Hofstetter and Dr Molena note that although the research results are important for clinicians to consider, shared decision-making is advisable for all.