Is induction therapy optimal for all patients with locally advanced distal esophagus adenocarcinoma?—The impact of age and co-morbidities on treatment and outcomes

Introduction

Esophageal adenocarcinoma presents significant clinical challenges (1,2). The estimated new cases of esophageal cancer in the United States have risen from 17,460 in 2012 to 21,560 in 2023, accompanied by 16,120 estimated deaths (3). Five-year survival rates have consistently improved from 11.5% in 1995, but still remains disappointingly low at 21.7% overall in a recent study (4). Poor outcomes are partially attributed to delayed diagnosis, as most patients do not develop symptoms until the cancer has become at least locally advanced (4). Poor outcomes observed historically with primary surgery led to many studies regarding the use of induction therapy with mixed results, but induction therapy is now accepted as an appropriate treatment prior to esophagectomy for locally advanced esophageal and esophageal-gastric junction (EGJ) adenocarcinoma (5-8).

The Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) in particular showed a survival benefit of induction chemoradiation plus surgery over surgery alone for patients with adenocarcinoma of the esophagus or EGJ (1). This landmark trial significantly impacted guideline treatment recommendations (1). Part of the induction therapy benefit may be that patients are more likely to tolerate multimodality therapy when chemotherapy is given before rather than after surgery. However, a subset of patients may not be able to tolerate full multimodality therapy secondary to factors related to age and co-morbidities. These patients’ oncologic outcomes may be better if they proceed straight to surgery without receiving induction therapy (9,10). In addition, both the pathologic response as well as the long-term survival benefit of chemoradiation for adenocarcinoma in the CROSS trial were less than that observed for squamous cell carcinoma, possibly questioning the need for routine induction therapy (5,7,11,12). This study was therefore undertaken to test the hypothesis that specific subsets of high-risk patients with locally advanced adenocarcinoma have better long-term survival with primary surgery compared to induction therapy. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2011/rc).

Methods

Data source

The National Cancer Database (NCDB) is a comprehensive collection of cancer diagnoses from over 1,500 facilities in the United States. Patients are de-identified in the database; thus, this study was exempt from Stanford Institutional Review Board approval (Protocol 35143, approved 3/7/2017), including the waiver of individual consent for this retrospective analysis. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Patient selection

Patients with 7th edition American Joint Committee on Cancer (AJCC) cT3N0M0 or cT1-3N+M0 adenocarcinoma of the mid to distal esophagus diagnosed from 2006–2019 were included for analysis (Figure 1) (13). We included only patients who had primary surgery with or without postoperative chemotherapy or radiation, patients with preoperative chemoradiation followed by surgery, or patients treated with chemoradiation alone. Patients who received either chemotherapy alone or radiation therapy were not included, as these treatment regimens are generally not considered potentially curative for locally advanced esophageal cancer. Because the predominant induction therapy practice for esophageal adenocarcinoma is induction chemoradiation, with induction chemotherapy alone being used much less frequently and induction radiation alone considered inappropriate, patients who received either only chemotherapy or only radiation therapy were not included in the study to avoid potential confounding (14-16). Only patients for whom the use and sequence of surgery, chemotherapy, and radiation were explicitly recorded in the dataset were included for analysis, and patients with any previous malignancy or incompletely recorded follow-up data were excluded.

Figure 1 Consolidated standards of reporting trials diagram outlining patient selection and volume stratification criteria.

Analysis

Because the primary goal of the study was to evaluate whether primary surgery was preferable to induction chemoradiation followed by surgery in some patients, the initial analysis performed sought to analyze all patients who either had primary surgery or had chemoradiation prior to surgery. Independent predictors of receiving preoperative chemoradiation in this group were estimated using multivariable logistic regression, looking at variables such as age, sex, race, insurance, Charlson comorbidity index, income, education, distance traveled, clinical T stage, clinical N stage, tumor location, and facility type. Because we theorized that dissemination of the CROSS findings likely impacted treatment decisions, whether patients were treated before and after 2010 was also included in this analysis to account for potential changes in clinical practice following the CROSS trial results.

Perioperative outcomes were analyzed, stratifying the entire cohort into one group that had preoperative chemoradiation and another group that had primary surgery without any induction therapy. Univariate analysis was performed to compare the rates of mortality, as well as hospital length of stay, readmission rates, nodes examined, T and N pathological staging, margins, and adjuvant treatment. Because the NCDB does not have detailed clinical information regarding the incidence of postoperative complications, patients were considered to have suffered perioperative major morbidity if there was a 30-day death, a hospital stay after surgery >20 days, or readmission, based on a previous Society of Thoracic Surgeons General Thoracic Surgery Database study that showed a correlation between length of stay and perioperative complication occurrence and as previously described (17-19). Independent predictors of major morbidity per this definition were evaluated with multivariable logistic regression, considering age, sex, race, insurance, Charlson co-morbidity index, income, education, distance traveled, clinical T stage, clinical N stage, tumor location, facility type, and induction therapy use. Patients who had missing data for any of the potential predictor variables were excluded from these regression analyses.

Survival was evaluated using Kaplan-Meier curves, log-rank test, and Cox proportional hazards methods, with 5-year overall survival (OS) as the primary endpoint. Variables chosen a priori for inclusion in the Cox model were patient (age, sex, comorbidities) and tumor characteristics (tumor location, T stage, nodal involvement) previously shown or clinically expected to be potentially associated with survival, along with the study variable of interest: induction chemoradiation. The Cox models were adjusted for clustering by hospital by including the specific facility in the model as a random effect. Because of the method of patient selection for the cohort, none of the patients had missing data in the variables considered in the Cox analysis.

Subset analysis of high-risk patients

Additionally, therapy and outcomes were examined in subsets of patients over the age of 80 years and those with a Charlson-Deyo co-morbidity index ≥2. The subgroup analyses were performed to investigate outcomes in patients who generally would be considered higher risk for aggressive surgery, even in the absence of using preoperative treatment. Survival after primary surgery and induction chemoradiation followed by esophagectomy were estimated, and survival after chemoradiation alone in this subgroup was also estimated to allow some assessment as to whether surgery at all was reasonable to consider in these higher risk groups. For each high-risk subset, independent predictors of induction chemoradiation use in the patients that had surgery were identified with the multivariable analysis described above, though insurance was not included for either subset analyses, as very few patients were uninsured and comorbidity index was not considered in the subset where only patients with a comorbidity score ≥2 were included. Survival analyses of the subsets were also similar to that described above, except comorbid conditions were not included in the subset that had already excluded patients who had a comorbidity score of less than 2.

Statistical analysis

The data were analyzed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). Baseline demographic and preoperative clinical characteristics between groups were compared with the Wilcoxon rank-sum test for continuous variables and Pearson’s chi-squared test for discrete variables. Continuous variables are reported as median with interquartile range (IQR). The Fisher’s exact test was used for those discrete variables with fewer than 5 outcomes. A P value of <0.05 was considered statistically significant.

Results

Use and impact of induction chemoradiation

Overall, 13,985 patients were identified as meeting inclusion criteria and had surgery as part of their treatment, with the majority (n=12,999, 92.3%) receiving induction chemoradiation and only 7.0% (n=986) having primary surgery. The use of primary surgery trended down over the course of the study (Figure 2). Patients treated in the years 2006–2009, which were prior to the dissemination of the CROSS trial results, were more likely to be treated with primary surgery compared to patients treated from 2010–2019 [15.4% (429/2,789) vs. 5.0% (557/11,196), P<0.001].

Figure 2 Primary surgery percentage graph depicting a decrease in primary surgery without induction therapy over the time course of the study.

Patient characteristics stratified by the use of induction chemoradiation are shown in Table 1. Compared to those who were treated with induction chemoradiation, patients who had primary surgery were older [65 (IQR, 57–72.8) vs. 63 (IQR, 56–69) years, P<0.001] and less likely to have a Charlson comorbidity score of 0 [66.7% (658/986) vs. 71.5% (9,298/12,999), P=0.005]. In multivariable analysis, both increasing age [odds ratio (OR) per decade 0.69, 95% confidence interval (CI): 0.63–0.75, P<0.001] and higher Charlson comorbidity scores [Charlson score 1 vs. 0: OR 0.83, 95% CI: 0.70–0.99, P=0.047; Charlson score ≥2 vs. 0: OR 0.67, 95% CI: 0.52–0.87, P=0.002] were associated with a lower use of induction chemoradiation (Table 2).

Induction therapy overall was associated with significantly better survival compared to primary surgery in univariate analysis [5-year survival 40.1% (39.2–41%) vs. 32.4% (29.5–35.6%), P<0.001] (Figure 3). Induction therapy was also associated with improved survival [hazard ratio (HR) 0.69 (0.64–0.75), P<0.001] in multivariable Cox analysis (Table 3). In this multivariable analysis, both increasing age (HR/decade 1.18, 95% CI: 1.16–1.21, P<0.001; Charlson score ≥2: HR 1.26, 95% CI: 1.16–1.37, P<0.001) were associated with worse survival.

Figure 3 Kaplan-Meier survival curves stratified by whether patients received induction chemoradiation or primary surgery. Table shows survival estimates (95% confidence interval). CRT, chemoradiation.

Use and impact of induction chemoradiation—subset of patients age ≥80 years

There were 1,872 patients aged 80 years or older who received either chemoradiation (84.6%, n=1,584) or surgery (15.4%, n=288) with or without induction therapy (Table 4). Of the patients who had surgery, most (71.5%, n=206) received induction chemoradiation and 28.5% (n=82) had primary surgery. Patients treated with induction chemoradiation had significantly better survival (5-year survival 20.6%) than primary surgery patients (5-year survival 17.7%) or chemoradiation alone patients (5-year survival 10.4%) (Figure 4A).

Figure 4 Kaplan-Meier survival curves for patients ≥80 years (A) stratified by induction chemoradiation, primary surgery, or chemoradiation and (B) stratified by induction chemoradiation versus primary surgery. Tables show survival estimates (95% confidence interval). CRT, chemoradiation.

Predictors of receiving induction therapy in patients aged ≥80 years of surgical patients included clinical T2 (OR 11.13, 95% CI: 1.09–100, P=0.04) and clinical T3 (OR 12.48, 95% CI: 1.51–100, P=0.02) tumors compared to T1, and being treated in the year 2010 or later (OR 10.19, 95% CI: 4.41–23.56, P<0.001). Increasing age (OR 0.038, 95% CI: 0.006–0.22, P<0.001) and being treated at an integrated network program (OR 0.22, 95% CI: 0.08–0.64, P=0.005) or academic/research program (OR 0.339, 95% CI: 0.14–0.84, P=0.02) were associated with patients less likely to get induction therapy (Table 5).

Perioperative outcomes and survival in patients aged ≥80 years

Postoperative events for the patients aged 80 years and above are shown in Table 6. Patients treated with induction therapy expectedly had a longer period between diagnosis and surgery. Patients who had primary surgery did not have significantly different 30-day or 90-day mortality rates compared to induction chemoradiation patients. Unplanned hospital readmission rates were also not significant different, but patients who had primary surgery had longer hospital stays (11 vs. 9 days, P=0.01), and higher major perioperative morbidity overall [36.6% (30/82) vs. 18.0% (37/206), P=0.001]. Patients treated with primary surgery had a significantly higher incidence of positive margins [34.1% (28/82) vs. 3.4% (7/206), P<0.001]. Postoperative chemotherapy use was uncommon in all of the patients aged ≥80 years, but patients who had primary surgery were more likely than induction chemoradiation patients to get postoperative chemotherapy [14.6% (12/82) vs. 1% (2/206), P<0.001].

Induction therapy was associated with significantly better survival compared to primary surgery for patients aged ≥80 years in univariate analysis [5-year survival 20.6% (95% CI: 15.0–28.2%) vs. 17.7% (95% CI: 10.9–28.7%), P=0.01] (Figure 4B). Induction therapy was also associated with improved survival in multivariable Cox analysis (HR 0.68, 95% CI: 0.50–0.94, P=0.02) (Table 7). In this multivariable analysis, increasing age and higher T-stage were associated with worse survival. Charlson comorbidity indices did not have a significant association with survival in this elderly subset of surgical patients.

Use and impact of induction chemoradiation—subset of patients with Charlson comorbidity score ≥2

There were 2,246 patients with a Charlson score ≥2 who received either chemoradiation (51.5%, n=1,156) or surgery (48.5%, n=1,090) with or without induction therapy (Table 8). Of the patients who had surgery, the majority (91.4%, n=996) received induction chemoradiation and only 8.6% (n=94) had primary surgery. Patients treated with induction chemoradiation had significantly better survival (5-year survival 31.9%) than primary surgery patients (5-year survival 24.8%) and chemoradiation alone patients (5-year survival 12.8%) (Figure 5A).

Figure 5 Kaplan-Meier survival curves for patients with Charlson comorbidity scores ≥2 stratified by induction chemoradiation versus primary surgery in (A) stratified by induction chemoradiation, primary surgery, or chemoradiation and (B) stratified by induction chemoradiation versus primary surgery. Tables show survival estimates (95% confidence interval). CRT, chemoradiation.

Predictors of receiving induction therapy in this subset of patients with higher comorbidity indices included clinical T2 (OR 3.68, 95% CI: 1.16–11.65, P=0.03) and clinical T3 (OR 8.00, 95% CI: 2.72–23.47, P<0.001) tumors compared to T1, clinical nodal disease (OR 2.06, 95% CI: 1.15–3.69, P=0.02), and being treated in the year 2010 or later (OR 8.84, 95% CI: 5.27–14.83, P<0.001). Increasing age (OR 0.66, 95% CI: 0.48–0.90, P=0.01) was associated with patients being less likely to get induction therapy (Table 5).

Perioperative outcomes and survival in patients with more co-morbidities

Postoperative events for the patients with Charlson scores 2 or higher are shown in Table 6. Patients treated with induction therapy expectedly had a longer period between diagnosis and surgery. Patients who had primary surgery did not have significantly different 30-day or 90-day mortality rates compared to induction chemoradiation patients. Unplanned hospital readmission rates were also not significant different, but patients who had primary surgery had longer hospital stays (13.5 vs. 10 days, P<0.0.001), and higher major perioperative morbidity overall [35.1% (33/94) vs. 18.0% (218/996), P=0.005]. Patients treated with primary surgery had a significantly higher incidence of positive margins [20.2% (19/94) vs. 6.4% (63/996), P<0.001]. Primary surgery patients were much more likely to be given postoperative chemotherapy as compared to the induction chemoradiation patients [46.8% (44/94) vs. 5.6% (56/996), P<0.001], though adjuvant chemotherapy was used in the minority of both groups.

Induction therapy was associated with significantly better survival compared to primary surgery for the patients with Charlson score ≥2 in univariate analysis (5-year survival, 31.9% (95% CI: 28.7–35.4%) vs. 24.8% (95% CI: 17.1–35.8%), P=0.07) (Figure 5B). Induction therapy was also associated with improved survival in multivariable Cox analysis (HR 0.73, 95% CI: 0.57–0.93, P=0.01) (Table 7). Increasing age and clinical nodal disease were also associated with worse survival in this analysis.

Discussion

This study of a national dataset of locally advanced esophageal adenocarcinoma patients across a wide variety of institutions found that survival was better if patients had induction chemoradiation prior to esophagectomy compared to primary surgery. These results are consistent with those of the influential CROSS trial that has essentially established a standard of care for these patients (7). Increasing age and higher co-morbidity scores were both associated with patients being more likely to go straight to surgery, perhaps reflecting concerns by their treatment teams regarding patients’ ability to tolerate tri-modality therapy. Increasing age and higher co-morbidity scores were also associated with worse survival in the cohort. However, subset analysis of both patients over the age of 80 and patients with Charlson comorbidity scores of 2 or higher continued to show that patients with induction chemoradiation had better survival than patients who had primary surgery. These findings suggest that a strategy utilizing induction therapy should be at least initially considered in all patients considered acceptable candidates for all three treatment modalities.

This topic is of current clinical relevance, as a high-volume esophageal cancer center has recently shown that primary surgery may be at least comparable to induction chemoradiation for esophageal adenocarcinoma patients (11). This study suggested that the CROSS trial results may not reflect a real world cohort of esophageal cancer patients, both in terms of age and co-morbid conditions, due to the trial’s inclusion criteria. Patients in the CROSS trial also may have been less likely to have a transthoracic approach to resection with an appropriate mediastinal lymph node dissection, which could have improved survival for patients treated without induction therapy (20,21). In addition, longer-term follow-up of the CROSS trial patients suggests that the benefits of the CROSS trial induction chemoradiation protocol may not persist over the long term for adenocarcinoma patients, perhaps related to the fact that the rate of a pathologic complete response after induction chemoradiation was much lower for adenocarcinoma patients compared to squamous cell carcinoma patients (5,7,12). However, our current study’s findings do support continued use of a CROSS trial regimen over primary surgery in locally advanced esophageal adenocarcinoma patients, even those who are elderly or have significant co-morbidities.

Some results from our current study do suggest that a strategy of primary surgery may be appropriate in some very select patients. First, the finding that primary surgery was associated with higher perioperative morbidity in both the entire cohort as well as the subsets of patients aged ≥80 years and higher comorbidity subsets does suggests that perhaps there is some selection bias, where patients who had primary surgery did indeed have some unmeasured risk factors for poor outcomes, where their providers did not feel they could tolerate aggressive multimodality therapy and therefore believed they’d have better outcomes with proceeding straight to surgery. The finding that primary surgery patients did better than those patients treated with chemoradiation alone in both higher risk subsets does suggest that some subset of patients may indeed be better off going straight to surgery. Induction chemoradiation does have a risk of peri-treatment mortality associated with it, and approximately 20% of patients may never make it to surgery (9,10,22). However, a decision to forego induction chemoradiation can compromise survival and must consider specific patient details regarding their ability to tolerate therapy beyond generalized categories such as an age limit or the presence of co-morbidities. Overall, our results suggest that this should not be standard practice and patient management ideally would focus on supportive care that facilitates patients tolerating multimodal therapy. Proceeding with surgery without chemoradiation should only be done after careful and detailed multidisciplinary evaluation of a patient’s ability to tolerate all modalities of therapy.

However, patients who proceed with primary surgery for locally advanced esophageal adenocarcinoma have a low chance of cure with surgery alone. As these patients may benefit from adjuvant therapy, the same considerations of whether patients could tolerate surgery followed by systemic therapy must also be carefully evaluated in this situation (23). A key here is making sure the perioperative period is as uneventful as possible, as any complications or a prolonged recovery probably reduce the chance patients can ultimately tolerate additional therapy. However, survival remained generally low among patients aged ≥80 years across all treatments. Although induction therapy and surgery were still significantly better than other treatments, the 5-year survival was only 20.6%. In addition, the improved survival associated with induction therapy over primary surgery in this elderly subset was statistically significant but still somewhat modest (20.6% vs. 17.7%). This overall somewhat low survival numbers should not necessarily preclude aggressive therapy in patients over the age of 80 years, but they can be provided to patients and allow a well-informed process of shared decision-making between patients and providers regarding therapy and to establish realistic expectations regarding outcomes.

This study has the inherent limitation of conducting a retrospective analysis of a dataset that lacks granular data on both treatment decisions as well as patient’s functional status and specific co-morbid conditions. The dataset does not contain any specific information regarding potential frailty of patients that could impact both the decision to offer as well as the ability to tolerate specific treatments, including whether patients would have been judged appropriate for aggressive multimodality therapy that included esophagectomy. Data regarding specific chemotherapy and radiation regimens are also lacking, such that we don’t know for sure that all patients treated with chemoradiation received CROSS therapy, including whether they completed all planned treatments. In addition, surgical techniques and perioperative care for esophagectomy patients have improved with time, and the finding that primary surgery was more common earlier in the time course of the study could provide a bias against the primary surgery patients. Lastly, the lack of recurrence information in the NCDB precludes performing analyses of cause-specific survival or disease-free survival.

Nevertheless, we believe that this study provides important information regarding the care of esophageal adenocarcinoma patients. Although we recognize that the optimal treatment regimen may vary between patients, and that future studies may provide better direction and clarity, the current initial default consideration for treatment should probably be induction chemoradiation followed by surgery, even for higher-risk patients. Deviance from this approach should only occur after careful consideration of specific patient characteristics in a multidisciplinary forum that includes both surgeons and non-surgeons. Providers must carefully consider an individual’s ability to tolerate all aspects of aggressive therapy. Patients who are considered adequate candidates for aggressive therapy should then be provided with data that allows realistic expectations regarding their short-term and long-term outcomes for all treatment options. Patients and providers can then establish the most appropriate therapy for each specific patient using a shared-decision-making process.

Conclusions

Esophageal adenocarcinoma patients have improved survival when treated with induction chemoradiation compared to primary surgery, irrespective of age or comorbidity status. A strategy utilizing induction therapy is reasonable to consider in all patients considered acceptable candidates for all three treatment modalities.

Acknowledgments

An abstract related to this study was presented as a poster at the AATS International Thoracic Surgical Oncology Summit September 30-October 1 2022.

The data used in this study are derived from a de-identified National Cancer Database file. The American College of Surgeons has executed a Business Associate Agreement that includes a data use agreement with each of its Commission on Cancer accredited hospitals. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigators.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2011/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2011/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2011/coif). M.F.B. serves as an unpaid editorial board member of Journal of Thoracic Disease from October 2024 to September 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Patients are de-identified in the database, thus this study was exempt from Stanford Institutional Review Board approval (Protocol 35143, approved 3/7/2017), including the waiver of individual consent for this retrospective analysis. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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