Comparative analysis of long-term oncologic outcomes for minimally invasive and open Ivor Lewis esophagectomy after neoadjuvant chemoradiation: a propensity score matched observational study

In the United States, there were an estimated 17,650 newly diagnosed cases of esophageal carcinoma in 2019 [1]. Neoadjuvant chemoradiation (CRT) and esophagectomy combined with comprehensive lymphadenectomy (trimodality therapy) is the current standard treatment for locally advanced esophageal carcinoma [2, 3]. The randomized Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) Trial demonstrated improved overall survival and disease-free survival for patients who underwent preoperative chemoradiation followed by esophagectomy for locally advanced esophageal carcinoma [2]. Esophagectomy is the mainstay surgical treatment for esophageal carcinoma; however, the complex surgical procedure has been associated with significant morbidity and mortality [4]. Some reports have demonstrated evidence that preoperative chemoradiation may increase the incidence of postoperative complications after open esophagectomy [5, 6].

In recent years, minimally invasive techniques for Ivor Lewis esophagectomy were developed with the hope of minimizing postoperative morbidity and mortality. Luketich and colleagues reported a large single cohort series of over 1000 minimally invasive esophagectomy procedures that demonstrated a low postoperative mortality rate and a relatively low rate of postoperative pulmonary complications [7]. A randomized clinical trial also demonstrated decreased rates of postoperative pulmonary complications for minimally invasive transthoracic esophagectomy compared to the open approach [8]. In addition, a single center cohort study demonstrated fewer postoperative complications and a shorter hospital length of stay for minimally invasive esophagectomy compared to the open approach [9]. The previous comparative studies between minimally invasive Ivor Lewis esophagectomy (M-ILE) and open Ivor Lewis esophagectomy (O-ILE) have mostly focused on short-term clinical outcomes [10, 11]. However, the current gold standard for oncologic outcomes remains overall survival and recurrence-free survival. Only a few studies have evaluated the long-term oncologic results of minimally invasive esophagectomy compared to open esophagectomy [12‐14]. In this study, we reported a propensity score adjusted comparison of the long-term oncologic outcomes (overall survival and recurrence-free survival) between M-ILE and O-ILE performed for patients with locally advanced esophageal carcinoma who completed neoadjuvant chemoradiation. We hypothesized that patients undergoing M-ILE after neoadjuvant chemoradiation for esophageal carcinoma will have equivalent long-term oncologic outcomes compared to a similar cohort of patients who underwent O-ILE.

A total of 318 patients who underwent esophagectomy for esophageal carcinoma were reviewed initially, but 38 patients were excluded from the study because they underwent different esophagectomy approaches other than the Ivor Lewis technique and 57 patients were excluded who did not receive neoadjuvant chemoradiation (Fig. 1). After IPTW adjustment, there were 142 patients in the M-ILE trimodality group and 68 patients in the O-ILE trimodality group who analyzed for the study. After the IPTW-adjusted analysis, the patient demographics (Table1) and the disease characteristics (Table 2) were better balanced between the M-ILE and O-ILE trimodality groups, with a similar distribution of age, gender, medical comorbidities, smoking status, BMI, radiation doses, histology, and clinical TNM stages. The R0 resection rates were 100% for both groups. The median number of lymph nodes removed during the M-ILE and O-ILE procedures after IPTW adjustment was 17 nodes [IQR: 13–21] and 16 nodes [IQR: 12–20], respectively (p = 0.822). The median follow-up period for the O-ILE trimodlaity group was 87.9 months ([IQR]: 63.3–107.5) and 46.6 months ([IQR]: 27.6–60.6) for the M-ILE trimodality group. The tumor differentiation, lymphovascular invasion, and signet ring cell features were present at similar rates in the pathologic resection specimen (Table 2). The tumor regression grades (complete, near complete, partial, or no response to neoadjuvant chemoradiation) were also similar between the study groups (Table 2).

There was no statistically significant difference observed in the overall survival (log-rank test p = 0.699) and recurrence-free survival (log-rank test p = 0.357) in patients who underwent M-ILE compared to O-ILE after neoadjuvant chemoradiation (Figs. 2 and 3). The 3-year OS rate was 59.41% (95% CI, 49.82–67.76%) in the M-ILE trimodality group and 55.73% (95% CI, 39.16–69.44%) in the O-ILE trimodality group. The 5-year OS rate was 49.73% (95% CI, 38.28–60.16%) in the M-ILE trimodality group and 47.25% (95% CI, 30.58–62.22%) in the O-ILE trimodality group. The 3-year RFS rate was 59.86% (95% CI, 50.21–68.22%) for the M-ILE trimodality group and 61.57% (95% CI, 41.91–76.31%) for the O-ILE trimodality group. The 5-year RFS rate was 53.20% (95% CI, 49.81–62.54%) in the M-ILE trimodality group and 61.57% (95% CI, 41.91–76.31%) in the O-ILE trimodality group. In an IPTW adjusted multivariable Cox regression model, the variables age, body mass index, clinical N-stage, and tumor regression grade were independent predictors of overall survival (Table 3). In the RFS multivariable model, clinical N-stage, signet ring cell features, and tumor regression grade were independent predictors of recurrence-free survival (Table 4).

The short-term postoperative surgical outcomes for esophagectomy by approach are listed in Table 5. After IPTW adjustment, the 30-day mortality rate was 0.55% for the M-ILE trimodality group and 3.24% for the O-ILE trimodality group (p = 0.084), which was not statistically significant. The 90-day mortality rates were similar between the two groups. The IPTW-adjusted median hospital length of stay was significantly shorter in the M-ILE trimodality group (7.5 days [IQR: 7–8]) versus (9 days [IQR: 7–13] in the O-ILE trimodality group (p = 0.01). The overall rate of postoperative adverse events was higher after IPTW adjustment in the O-ILE trimodality group, but the difference was not statistically significant (53.39% vs. 39.19%, p = 0.089). The anastomotic leak rate was lower in the M-ILE trimodality group compared to the O-ILE trimodality group [6.41% vs 12.63% (p = 0.228)], but the difference was not statistically significant. Respiratory failure and atelectasis requiring bronchoscopy occurred at significantly higher rates in the O-ILE trimodality group in the IPTW-adjusted analyses (Table 5). The IPTW-adjusted rate of unexpected ICU admission was significantly higher in the O-ILE trimodality group (31.46%) versus (9.75%) for the M-ILE trimodality group (p < 0.001). The 30-day readmission rates for the M-ILE and O-ILE trimodality groups were not significantly different (p = 0.293).

Trimodality therapy (neoadjuvant chemoradiation followed by esophagectomy) is the current standard treatment for locally advanced esophageal carcinoma [2]. Ivor Lewis esophagectomy has become the procedure of choice for the resection of esophageal carcinoma involving the distal third of the esophagus and the gastroesophageal junction at many medical centers [18]. In an attempt to minimize the perioperative morbidity associated with O-ILE, many high volume centers have developed minimally invasive Ivor Lewis esophagectomy techniques. While the short-term postoperative outcomes for M-ILE have been extensively compared to O-ILE in multiple cohort studies and a small randomized clinical trial, the long-term oncologic outcomes for M-ILE after nedoadjuvant chemoradiation have been examined in only a single known study. Tapias and colleagues compared the long-term oncologic and short-term operative outcomes of M-ILE (N = 56) and O-ILE (N = 74) after neoadjuvant therapy in a single institution cohort study [19]. In the study, the overall survival rates at 5 years were similar between the two groups (open: 61% versus MIE: 50%, p = 0.933). The complete resection rates and the number of lymph nodes were similar for the M-ILE and O-ILE groups as well.

Our report describes a series of M-ILE cases compared to a cohort of O-ILE cases performed after neoadjuvant chemoradiation at a single institution. This is the largest propensity score adjusted series comparing the long-term oncologic outcomes of M-ILE and O-ILE performed after the completion of neoadjuvant chemoradiation. The oncologic results of the M-ILE approach were comparable to the O-ILE technique after neoadjuvant chemoradiation in this report. The median number of lymph nodes that were dissected in the M-ILE group (17 nodes) were similar to the O-ILE group (16 nodes). Both surgical approaches yielded a median number of lymph nodes that were comparable to other reports [20, 21]. All of the patients in the O-ILE and M-ILE group underwent a complete R0 resection with negative surgical margins. The 3-year and 5-year overall survival and recurrence-free survival rates were not significantly different for the M-ILE trimodality group compared to the O-ILE trimodality group. This finding was consistent with the results of a small randomized phase III clinical trial comparing open transthoracic esophagectomy (McKeown and Ivor Lewis) to minimally invasive transthoracic esophagectomy after neoadjuvant therapy. The long-term follow up of the TIME (Traditional Invasive versus Minimally Invasive Esophagectomy) trial demonstrated no observed differences for 3-year overall survival (MIE: 50.5% versus Open: 40.4%, p = 0.207) and disease-free survival (MIE: 40.2% versus Open: 35.9%, p = 0.602) in patients who underwent minimally invasive transthoracic esophagectomy compared to open transthoracic esophagectomy [22].

In an IPTW adjusted multivariable Cox regression model, the variables age, body mass index, clinical N-stage, and tumor regression grade were independent predictors of overall survival. In the recurrence-free survival multivariable model, clinical N-stage, signet ring cell features, and tumor regression grade were independent predictors of recurrence-free survival. Tumor regression grade or the degree of pathologic response to neoadjuvant chemoradiation appeared to be a strong independent predictor for both overall and recurrence-free survival; whereas surgical approach (open versus MIE) did not demonstrate any prognostic significance. Takeda and colleagues performed a multivariable analysis on the varying degrees of pathologic response to neoadjuvant chemoradiation and demonstrated that tumor regression grade can reliably predict overall survival and systemic recurrence in patients with locally advanced esophageal cancer who were treated with trimodality therapy [23]. Similarly, Stiles and colleagues reviewed 238 patients who received neoadjuvant therapy followed by esophagectomy for locally advanced esophageal cancer. In a multivariable model, a poor clinical response to neoadjuvant therapy (HR 2.77; 95% CI: 1.14–7.15) was highly predictive of early mortality within a year of trimodality therapy [24]. These findings indicate that the tumor regression grade or response to neoadjuvant therapy has more prognostic significance than the surgical approach for esophagectomy.

Propensity score weighting and multivariable regression analysis allowed us to statistically balance baseline differences and control for confounders in the short-term perioperative outcomes and the long-term oncologic outcomes. Nonetheless, the present study has several limitations which should be considered when interpreting the results of study. The selection process for the surgical approach was determined by the surgeon based on individual preference and could include factors that were not captured in the study. Given the retrospective observational study design, we could not completely eliminate unmeasured selection bias; therefore, the results of the study are not generalizable. The follow up time for the M-ILE group was shorter, which decreased the accuracy of the survival data after the 3-year time point. However, the surveillance data for the first three years was robust and likely captured most of the recurrence cases and deaths.

In conclusion, OS and RFS rates were not significantly different between the M-ILE and O-ILE trimodality groups. Our analysis demonstrated that OS and RFS for locally advanced esophageal caracinoma are more likely determined by the degree of pathologic response to neoadjuvant chemoradiation as opposed to surgical approach for esophagectomy. The short-term surgical outcomes, such as respiratory failure and hospital length of stay, for patients undergoing M-ILE were significantly improved compared to patients undergoing O-ILE after IPTW adjustment for baseline demographic covariates. These results support the use of minimally invasive Ivor Lewis esophagectomy after neoadjuvant chemoradiation for surgical treatment of local advanced esophageal carcinoma at our institution.