Real-world patient outcome after esophageal cancer resection—implications and future directions

Esophageal cancer resection remains one of the most technically demanding and complex procedures in oncological surgery. Despite considerable improvements in disease staging, patient selection, multidisciplinary therapeutic approaches and decision making, prehabilitation, enhanced recovery pathways and improvements in surgical techniques and complication management during the past 10 years esophagectomy still provides substantial short- and long-term morbidity and mortality with the critical need for further optimization. In this context, the Esophageal Complications Consensus Group (ECCG) involving 24 high-volume esophageal surgical centers across the world developed a standardized platform for recording complications and quality measures associated with esophagectomy (1). Meanwhile, benchmark criteria for 30- and 90-day mortality were established with 2% and 4.5%, respectively, while time trends were further elucidated (2). Following that and in line with various international guidelines (3), robust evidence demonstrated the positive effect of centralization on patient outcomes and treatment of patients with esophageal cancer is consistently recommended at high-volume centers (4,5). However, despite the established concept of centralization over years, reliable patient and tumor associated factors influencing short- and long-term outcome remain limited. Therefore, the American College of Surgeons National Surgical Quality Improvement Program (ACS NASQIP) data are an important and valuable tool for evaluating quality of surgical care. However, the available risk calculator has never been validated for esophagectomy-specific postoperative events which may often be misclassified, underscoring the need for a specific module to better capture key outcomes in this patient population (6).

Since the identification of specific patient-related factors on perioperative morbidity and oncological mortality is crucial to further establish individual patient-centered care, Blasberg et al. addressed this clinical question in their article which accompanies this editorial (7). In their retrospective analysis of the American Society of Thoracic Surgeons (STS) Database linked Medicare data, the authors were able to include and analyze the follow-up of almost 4,800 patients from 207 participating STS sites who underwent esophagectomy in the United States (U.S.). Patients aged >65 years who underwent esophagectomy for both entities of esophageal cancer (squamous cell carcinoma or adenocarcinoma) between 2012 and 2020 were included. Interestingly, patients with all tumor sites and types of esophageal resections (transhiatal, thoracoabdominal or three-hole esophagectomy, both open and minimally invasive) were included. Blasberg et al. (7) report considerable 30- and 90-day mortality compared to the defined bench mark criteria mentioned above. Previously published health care data from insurance companies in Germany also showed similar mortality rates which could be improved if more patients were treated in hospitals with high case numbers. The observed association between case numbers and outcomes was tightly linked to failure to rescue (8). In order to better elucidate the reality of care, an analogous analysis of perioperative outcomes by case number/certification or level of care of the participating hospitals clinics would have been desirable. While the type of the procedure and surgical approach (open vs. minimally invasive) did not demonstrate any impact on short- and long-term survival rates, critical factors associated with postoperative mortality were cardiac morbidity [cardiac heart failure (CHF), atrial fibrillation], advanced age as well as reintubation and unexpected re-operation. In contrast, the most common severe complications after esophagectomy anastomotic leakage and pneumonia had no impact on short-term mortality but 90-day readmission rates. While most of those factors were also associated with long-term mortality (>90 days), further important values affecting mortality were American Society of Anesthesiologists (ASA) score > II, diabetes, hypertension and renal dysfunction. However, data on the severity of those comorbidities that impacted on mortality and readmission were not available. Interestingly, the authors demonstrated a correlation between tumor stage, particularly lymph node involvement, and increased perioperative mortality. Therefore, it is possible that this increase in 90-day mortality for stage 3 tumor patients is related to a higher proportion of patients receiving neoadjuvant treatment. However, it must be critically questioned whether tumor biology has an influence on the perioperative outcome or whether this descriptive result can be explained by a reluctance to exhaust all medical measures in the event of complications in patients diagnosed with advanced tumor stages.

As noted, the limitations include the lack of specific information about additional systemic treatment as well as the exclusion of all patients of aged <65 years. Furthermore, another unexpected observation of this real-world data set is that no benefit of minimal-invasive esophagectomy on short- and long-term postoperative outcome could be identified. This is a finding to be discussed further since technical evolution has been one of the most visible and relevant changes in esophageal cancer surgery in recent years. While minimally-invasive and hybrid esophagectomy techniques have increasingly replaced open approaches in specialized high-volume centers, randomized trials and large observational studies demonstrated significant reductions in pulmonary complications, blood loss, and length of hospital stay without compromising oncologic outcomes (9-11). Therefore, the results of the study by Blasberg et al. (7) raise further questions on the implications of those highly-specified procedures which include a steep learning curve and increased costs. The observations might demonstrate real-world heterogeneity in surgical expertise, learning curves, and case selection rather than compromising benefits of minimal-invasive esophagectomy in experienced hands. In addition, no specific differentiation for robotic-assisted esophagectomy is performed in the article, thus, limiting the final conclusion on the impact of the surgical approach on short- and long-term mortality rates after esophagectomy. While the results remain inconclusive, surgical innovation should remain evidence-driven rather than technology-focused in general. Furthermore, Blasberg et al. (7) also observed and confirmed aspects of nutritional findings in their analysis. Most notably, a moderately increased body mass index (BMI) of 30–35 kg/m² was associated with a relevantly decreased mortality risk in the short- and long-term. In line with that, various studies identified a reduced BMI and preoperative albumin as independent risk factors for poor short-term outcome and long-term quality of life (12,13). Those results including the present work underline the importance of enhanced recovery after surgery (ERAS) and prehabilitation programs with a specific focus on preoperative rehabilitation. While patients suffering from esophageal cancer usually undergo neoadjuvant treatment, this window of time of several months during neoadjuvant treatment is critical to optimize individual patient-related risk factors such as body weight, nutrition including smoking and alcohol habits as well as individual performance before esophagectomy is performed. With this in mind, it is critical to identify individual risk factors of patients not only when they are evaluated for surgery but already in advance when the tumor is initially diagnosed, patients presented at specialized centers and neoadjuvant treatment is started. This principle emphasizes the term ‘patient-centered care’ and suggests a very close collaboration between oncologists, surgeons, physical therapists and nutritionists. Since the current standard of care even in specialized high-volume centers is to evaluate and address individual risk-factors just before surgery, this field provides a large area of improvement in multimodal treatment regimens.

In conclusion, esophageal cancer resection remains a pivotal but evolving component of curative therapy with an increased focus on patient-centered care. Overall, Blasberg et al. (7) have shown that higher tumor stages—especially stage those with lymph node involvement/persistence after neoadjuvant therapy—show 3-year survival rates of less than 30%. Given these poor survival rates and the high perioperative morbidity and mortality, careful consideration of the cost-benefit ratio for each individual patient seems essential. However, several studies have repeatedly shown a huge variation in biological behavior of patients who have been managed within classically defined disease entities. In the near future, improved postoperative outcomes can be expected as a result of improved neoadjuvant therapeutic regimes and more available adjuvant immunotherapies (14,15). In addition, a relevant proportion of patients (16–49%) might achieve a complete response after neoadjuvant therapy and could potentially be placed on a watch-and-wait strategy receiving surgery only as needed (16,17). In this context, definitive chemoradiotherapy with salvage esophagectomy in cases of tumor persistence or regrowth has become the standard treatment for patients with squamous cell carcinoma of the esophagus in many countries. However, whether this will be incorporated into clinical practice for both tumor entities is currently being investigated in ongoing randomized controlled trials (RCTs) (ESORES) (18). While the future of esophageal cancer resection will focus on precision, this includes not only aspects such as molecular profiling and improved imaging but also individualized (perioperative) risk prediction models. Taking those factors and the close collaboration between surgeons and oncologists into account, they will significantly refine and improve surgical and non-surgical decision-making and outcome. In line with that, surgical approaches will likely become more tailored, less invasive, and better integrated into personalized treatment pathways. At the same time, transparent reporting of outcomes including functional recovery and patient-reported measures must become standard to not only evaluate oncological outcome but also quality of life. Since we rely on valuable data as shared in the presented article, the latter will help on multiple levels to further improve patient-centered care in multimodal settings for patients suffering from esophageal cancer not only in the U.S. but beyond.

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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.