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Should Minimally Invasive Esophagectomy Now Be Standard?

Patients with esophageal cancer who are candidates for curative surgery are likely to have fewer intraoperative and postoperative complications if they undergo hybrid minimally invasive esophagectomy (HMIE) than if they undergo open esophagectomy (OE), as seen in data from the MIRO study.

Indeed, the risk for these complications is 69% lower compared with OE, according to conclusions from the French investigators.

Initial results, which were reported by Medscape Medical News from the 2017 annual meeting of the European Society of Medical Oncology, were published January 9 in the New England Journal of Medicine.

“In addition to a 69% reduction in major intra- and postoperative morbidity and a reduction of pulmonary complication, 3-year and 5-year overall survival (OS) was noninferior in the laparoscopic group, showing that it is an oncologic sound procedure,” corresponding author Guillaume Piessen, MD, PhD, from University Hospital C. Huriez Place de Verdun in Lille, France, told Medscape Medical News.

“The survival data are nearly significant, but clinically relevant and may hypothetically be in line with the decreased risk of severe complications,” he added.

“The data from this trial and the previously published TIME trial comparing open to totally minimally invasive esophagectomy emphasize the importance of minimally invasive approaches in patients’ outcomes,” commented Nasser Altorki, MD, cardiothoracic surgeon at Weill Cornell Medicine and New York–Presbyterian, in New York City, who was not involved with this study.

Mark Berry, MD, from the Department of Cardiothoracic Surgery at Stanford University, California, commented that the study was “impressive.”

“It is difficult to do a randomized trial with a surgical procedure in the United States,” he said. Patients want details of their surgical procedure and are not open to chance, he explained. “It is rare to evaluate a new approach with an appropriate control, especially when it involves surgery,” Berry added.

Transthoracic Esophagectomy Explained

Altorki explained the differences in the methods used for transthoracic esophagectomies. The Ivor-Lewis standard OE is performed using a long abdominal incision (8 – 10 inches long) and a similar open chest (thoracic) incision. The patient’s diseased esophagus and the top part of the stomach are removed. A segment of the stomach is then pulled into the chest and connected to the remaining normal esophagus, forming a new esophagus.

Minimally invasive approaches may be applied to either or both components of OE. These procedures use tiny incisions and a small scope connected to a video camera. Miniature surgical instruments are passed through the incisions, and the camera sends a magnified image from inside the body to a monitor, giving the surgeon a close-up view of the anatomy.

In the French study, the hybrid approach substituted the long abdominal incision with five small “holes” through which the abdominal portion of the operation was performed.

An alternative hybrid strategy, which was not tested in this trial, involves substituting the chest incision with four small holes for the chest portion. The abdominal part of the procedure is still performed through an open incision.

In totally minimally invasive esophagectomy, both the abdominal and thoracic procedures are undertaken using minimally invasive techniques.

The MIRO Study

In the MIRO study, patients with squamous cell carcinoma or adenocarcinoma of the middle or lower third of the esophagus who were eligible for surgical resection were randomly assigned to undergo HMIE (n = 103) or OE (n = 104). Use of neoadjuvant therapy was determined locally by a multidisciplinary cancer board.

The primary endpoint of the study was major complication during surgery or within 30 days after surgery. Major complication was defined as a surgical or medical complication of Clavien-Dindo grade II or higher; the most severe complication was considered as a primary endpoint.

Patients underwent follow-up assessment at 30 days after surgery and every 6 months for 3 years after surgery.

Results

Demographic and clinical characteristics of patients were well balanced in the two arms of the study. The median age of the patients was 61 years; 85% were men. Of the 59% of patients who had adenocarcinomas, 30% had middle third involvement, and 69% had lower third involvement; 74% of patients received neoadjuvant therapy.

Major complications at 30 days were reported by 36% of patients in the HMIE group and by 64% in the OE group; thus, the study met its primary endpoint of showing a clinically meaningful difference of 20% in the incidence of major complications between the two groups (odds ratio [OR]: 0.31; 95% confidence interval [95% CI]: 0.18 – 0.55; P < .001).

After adjusting for variables such as age, sex, risk score, neoadjuvant use, tumor location, histologic subtype, resection-margin status, pathologic tumor and nodal stages, and trial center, patients in the HMIE group were at a 77% lower risk for major intraoperative and postoperative complications within 30 days (OR: 0.23; 95% CI: 0.12 – 0.44; P < .001).

The rate of intraoperative complications (10% vs 11% for OE), total operative time (327 vs 330 minutes for OE), abdominal operative time (127 vs 110 minutes for OE), and length of hospital stay (14 days for each group) were similar between the groups.

The rate of major pulmonary complications at 30 days was also significantly lower for patients in the HMIE group: 18% vs 30%. The risk for major pulmonary complications within 30 days was 50% lower for patients in the HMIE group (OR: 0.50; 95% CI: 0.26 – 0.96).

Commenting on the new results, Standford’s Berry said that, impressive as the study is in its scope and reach, the findings are not groundbreaking. “The lower rate of major complications was driven by the difference in pulmonary complications between the groups,” he said. Surgical complications were similar between the groups, he pointed out.

“It is gratifying to see HMIE provides benefits, but it is hard to translate this to better patient outcomes,” Berry said. He noted that the length of hospital stay was similar between the two groups, as were rates for 30-day (1% vs 2% for OE) and 90-day (4% vs 6% for OE) postoperative mortality.

At a median follow-up of 48.8 months, 44% of patients had died. Median OS was 52.2 months for patients in the HMIE group and 47.6 months for those in the OE group. Although not significant, 3-year OS rates (67% vs 55%) and 5-year OS rates (60% vs 40%) were higher for patients in the HMIE group (hazard ratio [HR] for death: 0.67; 95% CI: 0.44 – 1.01).

The trend for disease-free survival (DFS) was similar for that of OS. The 3-year DFS rates (57% vs 48%) and 5-year DFS rates (53% vs 43%) were higher for patients in the HMIE group (HR for first tumor recurrence, second cancer, or death: 0.76; 95% CI: 0.52 – 1.11).

The nonsignificant improvement in survival seen in this study, which was associated with the lower incidence of major complications, has also been observed in other studies, Piessen and colleagues note. The sample size calculation for this study was based on major complication as the primary endpoint. “The trial was not adequately powered to examine survival after esophagectomy,” they write. “However, given our findings, a trial design that is based on a survival end point remains an important area for future research,” they add.

Should Minimally Invasive Esophagectomy Be Standard of Care?

“Based on these results, HMIE should become the new standard operating procedure for patients with mid and low esophageal cancer,” Piessen said.

Registry data indicate that 60% to 80% of surgeries are OEs, Piessen noted.

“These results should surely convince the vast majority of surgeons who still perform OE, which represents 52% of operations even at expert centers,” he said, citing a recent study.

The study from the French investigators adds to the literature that minimally invasive esophagectomy is associated with lower rates of major complications. Lower rates of pulmonary complications were also reported with minimally invasive esophagectomy (both thoracoscopy and laparoscopy) in the TIME study.

No trials have directly compared totally minimally invasive esophagectomy with HMIE, though the magnitude of reduction in major pulmonary complications in the TIME trial appears to be equivalent to that in the MIRO trial, Altorki pointed out. “The data would suggest that the addition of any minimally invasive component to the operation is beneficial,” he said.

Piessen agreed, and noted that HMIE and totally minimally invasive esophagectomy offer a similar magnitude of benefit on morbidity (OR: 0.31 in MIRO vs 0.30 in TIME). “Totally MIE is technically demanding, with some studies suggesting a higher risk of anastomotic leakage for intrathoracic anastomoses,” Piessen said. He added that a comparison between totally minimally invasive esophagectomy and HMIE is of scientific interest, but differences between these two techniques would be small, and large numbers of patients would have to be enrolled for such a study.

Although the authors of the study conclude that minimally invasive approaches should become the standard of care for surgical resection of mid to lower esophageal cancers, the two experts approached for comment were more cautious.

“The trial establishes hybrid esophagectomy as an acceptable standard of care,” Altorki said, and he pointed out that 30-day mortality was similarly low in both arms of the trial. Berry agreed and noted that what is most important for patients is that the surgeon be a skilled operator. With such a surgeon, patients should experience less morbidity and mortality regardless of the procedure undertaken.

“This study does not indicate that everyone should change the way he or she does esophagectomies. HMIE did not translate to better outcomes compared with OE,” Berry said.

Although the procedure decreases the risk for morbidity, that does not imply that the operation can be performed anywhere, Piessen said. He explained that the learning curve for HMIE may be shorter than for totally minimally invasive esophagectomy, yet the procedure remains technically demanding and requires expert centers with dedicated surgeons, anesthetists, gastroenterologists, radiologists, and oncologists.

“These procedures should be preferably performed at high-volume centers,” Piessen said. He pointed to a previous study from their group that found that regardless of the level of comorbidity or tumor location, with respect to risk for postoperative mortality, patients benefited from undergoing treatment at a high-volume center.

In this study, for example, all participating centers recruited surgeons who were experienced in esophageal cancer surgery and in laparoscopic gastric mobilization, and each center was required to have performed at least 25 procedures before it was included in the trial.

The study authors and Dr Altorki have disclosed no relevant financial relationships.

N Engl J Med. Published online January 9, 2019.

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