Organ Preservation vs Immediate Surgery for Esophageal Adenocarcinoma

Treatment advances in esophageal cancer have improved survival and other outcomes but have also raised new questions about how to optimize therapeutic potential. One frequent debate centers on the need for immediate surgery for locally advanced esophageal adenocarcinoma (EAC) after complete response to neoadjuvant therapy.

Proponents on both sides of the issue have made valid points to support their position.

A recent review of almost 60,000 patients with esophageal cancer diagnosed after 2004 compared mortality after upfront chemoradiation therapy (CRT) versus upfront surgery. The mortality hazard more than doubled (HR 2.15) for patients treated with CRT, with a hazard ratio of 2.39 for patients with EAC, who accounted for a majority of the study population (P<0.0001). An analysis limited to patients with resectable disease (stages T1-3) yielded hazard ratios of 1.65 to 2.70 for CRT versus upfront surgery (P<0.0001).

For cancers diagnosed after 2009, the mortality hazard increased in patients with EAC or esophageal squamous cell carcinoma (SCC) treated with CRT but decreased in both histologies with upfront surgery. Finally, in a subgroup of 2,714 patients who were offered surgery but did not have it, the hazard ratio for CRT versus surgery was 1.68 overall, 1.54 for SCC, and 1.76 for EAC.

In a recent commentary on the evolution of treatment for locally advanced esophageal/gastroesophageal junction cancer, the authors noted that all trimodality regimens by definition include surgery. Little evidence exists for a definite pathway to organ preservation, regardless of response to neoadjuvant or perioperative systemic therapy.

The authors pointed out that 60% of patients may develop “significant complications” after surgery, and perioperative mortality rates at 30 and 90 days approach 2.5% and 4.5%, respectively, even with modern treatment. Older age increases mortality risk, and long-term health-related quality of life is often impaired in this population that places a high value on quality of life.

Nonoperative management after complete response to neoadjuvant therapy has proven to be a viable option in rectal cancer, the authors said. Moreover, delaying surgery does not clearly sacrifice the likelihood of a cure.

Recently, the multicenter randomized SANO trial extended supportive evidence for nonoperative management to locally advanced esophageal cancer. Involving 309 patients (three-fourths with EAC), the trial compared surveillance versus immediate surgery in patients who achieved a clinical complete response (cCR) after neoadjuvant therapy. After a median follow-up of 38 months, the surveillance group had a 2-year overall survival (OS) rate of 74% versus 71% for the surgery group.

The surgery-versus-surveillance argument played out during an education session at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium earlier this year. Joshua E. Meyer, MD, of Fox Chase Cancer Center in Philadelphia, stated the case for an organ-preservation strategy, while Daniela Molena, MD, of Memorial Sloan Kettering Cancer Center in New York City, argued for a surgical strategy.

Meyer supported his perspective with evidence from three areas: CRT can achieve a cCR that confers local disease-free status; assessing cCR with “bite-on-bite” (BOB) biopsy more accurately confirms lack of disease; and active surveillance is a safe and effective strategy to identify patients who will benefit most from esophagectomy.

Who Should Enter Surveillance?

More than a decade ago, the CROSS trial of patients with esophageal or gastroesophageal junction cancer showed that preoperative CRT led to pathologic complete response (pCR) in 29% of patients, including a fourth of those with EAC.

“We know that pCR patients do better after chemoradiation and then surgery, but the question is, do these patients really benefit from the esophagectomy?” Meyer posed.

Esophagectomy is a high-risk procedure, associated with major complication rates of 33% to 59% and a 90-day mortality rate of 8.9%, he noted. Additionally, health-related quality of life declines in the short and long term.

“How do we know who can be observed? We need to know the risks of esophagectomy and the risks of delaying esophagectomy,” said Meyer.

PET-CT imaging has proven inadequate for identifying patients who can be followed safely after pCR, he continued. Esophagogastroduodenoscopy (EGD) plus PET-CT had good negative predictive value but did not do a good job of predicting pCR.

More recently, BOB — a second tissue sample at the site of the first biopsy — has shown promise for improving the ability to identify patients who can be safely observed after CRT. A study involving 626 endoscopies and 367 patients with esophageal cancer showed a 0.2% risk of grade ≥3 complications. BOB biopsy produced endoscopic evidence of tumor in 29% of patients, and 81% of patients with residual tumor had positive biopsies. The two biopsies combined substantially increased the rate of positivity in patients with residual disease as compared with the first or second biopsy.

Impact of Delayed Surgery

The randomized NeoRes II trial compared outcomes in patients who had surgery within 4 to 6 weeks or 10 to 12 weeks of completing CRT. Neither complication rates nor survival differed significantly. A meta-analysis of seven studies comparing active surveillance versus immediate surgery after pCR showed no difference in OS.

The SANO trial showed no difference in disease-free survival (DFS), OS, 90-day mortality, or complication rates in patients who had immediate surgery after cCR or underwent active surveillance. Patients randomized to active surveillance had evaluations at 6 and 12 weeks with imaging and BOB biopsy. More than a third of patients in the surveillance group had persistent cCR. About half had isolated local recurrence, most of whom underwent salvage surgery. Distant metastasis occurred in 17% of the patients.

Patient preferences were assessed in 104 patients who had completed CRT for esophageal cancer. They were asked to choose between active surveillance and immediate surgery. OS at 5 years, health-related quality of life, and risk of needing esophagectomy affected the choice. Patients were willing to trade 26% of 5-year OS to decrease the risk of surgery from 100% to 15% and 16-19% of 5-year OS for improved quality of life associated with avoiding surgery. A subsequent decision analysis favored surgery for survival, but when quality of life was included in modeling, active surveillance came out ahead.

“Nonoperative management is a standard-of-care goal in rectal cancer, with a clinical complete response rate of 54%,” said Meyer. “This may be a good goal for esophageal adenocarcinoma as well.”

The Case for Immediate Surgery

Molena argued that cCR is not equivalent to pCR, and no clinical tool is available to predict pCR with accuracy. Advances in surgical technique have greatly reduced the invasiveness and risk of complications, and quality of life is preserved long term after surgery at high-volume centers.

Delaying surgery leads to worse oncologic outcomes, and salvage surgery comes with an increased risk of morbidity and mortality. “If you’re lucky, the disease remains contained within the esophagus or the peri-esophageal lymph nodes,” she noted.

In contrast to cCR, true pCR occurs infrequently in EAC, said Molena. Referencing the CROSS trial cited by Meyer, she pointed to the 23% rate of pCR in patients with EAC.

“In the real-world scenario, even in a high-volume center, 23% is pretty high,” she added.

Moreover, pCR does not equal cure, Molena said. A study of 233 patients (169 with EAC) who achieved pCR after CRT and surgery showed a 5-year OS rate of 59% and a 5-year DFS rate of 53%.

“When patients do recur, we don’t have a lot of options,” she noted. “Our best chance here is at the get-go.”

As for cCR, “it’s mostly a guess” in EAC, she said, explaining that the concept originated in rectal cancer, which has more favorable biology, more accurate tools to predict response, and has been validated in large clinical trials. The concept has been adapted to esophageal cancer, which has a much worse prognosis, and is based on probabilistic assessment tools.

The preSANO trial evaluated the accuracy of BOB biopsy for detecting tumor response. The investigators concluded that the accuracy was adequate for detecting locoregional disease. However, accuracy was calculated on the basis of tumor regression groups (TRGs) 3 and 4 — groups with the highest likelihood of residual tumor, said Molena, adding that the accuracy for TRG 2 (1-10%) was “very low,” missed by EGD and BOB in 41% of cases.

Micrometastasis is the Achilles heel of EAC, she pointed out. That point has been borne out in multiple studies showing that higher pCR rates did not correlate with better disease control.

In the SANO trial, active surveillance merely delayed surgery for many patients rather than achieving organ preservation for a majority, said Molena. The trial had a questionable design, including a large noninferiority margin of 15% and a short 2-year follow-up for the primary endpoint. Results were driven primarily by the esophageal SCC subgroup, and superiority in quality of life was not clearly demonstrated. Half of the patients in the surveillance arm ultimately had surgery, and distant metastasis occurred more often with active surveillance.

Bad Rap for Surgery

Esophagectomy has a historically bad reputation that is no longer deserved, Molena noted.

“We do a lot better than we used to do with esophagectomy,” she said. “We have moved to a much more minimally invasive approach, and over the years, this has been validated in randomized controlled trials. Although patients have fewer complications and a much faster recovery, their oncological outcome has been preserved.”

An analysis of 6,022 patients treated from 2015 to 2019 showed that 79% received neoadjuvant therapy, 53% underwent minimally invasive procedures, and 93.5% had clear (R0) surgical margins. The 30-day mortality rate was 2.2%, and 90-day mortality was 4.5%. Anastomotic leak occurred in 12.5% and pneumonia in 13.9%.

Surgery too often gets the blame for adversely affecting quality of life, Molena continued. In the NeoRes II trial, neoadjuvant CRT, but not chemotherapy alone, was associated with significant declines in multiple aspects of quality of life. Assessment of patient-reported outcomes may not take into account the adverse impact of fear of cancer recurrence. Additionally, studies of surviving patients have shown that they can and do adapt to changes associated with surgery.

“The future is not doing less for these patients but doing more and potentially doing something that is more targeted and personalized, so that we can cure more patients,” said Molena.