Challenges and considerations in interpreting the age-dependent benefit of neoadjuvant treatment for adenocarcinoma of the esophagus and gastroesophageal junction

We have carefully read the paper titled ‘ Age-dependent bene ﬁ t of neoadjuvant treatment in adenocarcinoma of the esophagus and gastroesophageal junction: a multicenter retrospective observational study of young versus old patients ’ by Rompen et al . [1] presents a well-executed multicenter retrospective cohort study. The authors utilized univariate and multivariate analyses to evaluate overall survival (OS) while considering confounding variables. Their objective was to provide evidence for the age-dependent use of neoadjuvant treatment by clinically comparing young ( < 56.6 years) and old ( > 71.3 years) patients with esophageal and esophagogastric-junction adenocarcinoma. Speci ﬁ cally, the study aimed to investigate the impact of age on the utilization and effectiveness of neoadjuvant treatment in these patient populations. In the methodology, patients with esophageal adenocarcinoma undergoing esophagectomy between 2001 and 2022 were retrospectively analyzed from three different centers. The study excluded patients with distant metastases or clinical UICC-stage I. The analysis utilized Cox proportional hazards regression to identify the variables associated with survival bene ﬁ ts. The key comparison was made between young and old patients, focusing on the administration of neoadjuvant treatment, survival outcomes, and histopathological regression. Through the analysis of 990 patients in different age groups who underwent neoadjuvant therapy or surgery alone, the authors found that older patients derive less bene ﬁ t from neoadjuvant treatment in terms of OS improvement compared to younger patients. Additionally, older patients are more prone to side effects necessitating dose reduction, suggesting that upfront surgery may be a more suitable treatment approach for elderly individuals. They concluded the ﬁ ndings that neoadjuvant treatment was


Dear Editor,
We have carefully read the paper titled 'Age-dependent benefit of neoadjuvant treatment in adenocarcinoma of the esophagus and gastroesophageal junction: a multicenter retrospective observational study of young versus old patients' by Rompen et al. [1] presents a well-executed multicenter retrospective cohort study.The authors utilized univariate and multivariate analyses to evaluate overall survival (OS) while considering confounding variables.Their objective was to provide evidence for the agedependent use of neoadjuvant treatment by clinically comparing young (< 56.6 years) and old ( > 71.3 years) patients with esophageal and esophagogastric-junction adenocarcinoma.Specifically, the study aimed to investigate the impact of age on the utilization and effectiveness of neoadjuvant treatment in these patient populations.In the methodology, patients with esophageal adenocarcinoma undergoing esophagectomy between 2001 and 2022 were retrospectively analyzed from three different centers.The study excluded patients with distant metastases or clinical UICC-stage I.The analysis utilized Cox proportional hazards regression to identify the variables associated with survival benefits.The key comparison was made between young and old patients, focusing on the administration of neoadjuvant treatment, survival outcomes, and histopathological regression.Through the analysis of 990 patients in different age groups who underwent neoadjuvant therapy or surgery alone, the authors found that older patients derive less benefit from neoadjuvant treatment in terms of OS improvement compared to younger patients.Additionally, older patients are more prone to side effects necessitating dose reduction, suggesting that upfront surgery may be a more suitable treatment approach for elderly individuals.They concluded the findings that neoadjuvant treatment was administered to a higher proportion of young patients compared to elderly patients.Young age was associated with a significant OS benefit after neoadjuvant treatment, with a median OS of 85.6 months versus 29.9 months for surgery alone.In contrast, elderly patients experienced a survival benefit equal to the length of neoadjuvant treatment itself, with no significant improvement in median OS.Despite differences in median OS benefit, histopathological regression was similar between the two age groups.Furthermore, it was observed that more elderly patients had a dose reduction or termination of neoadjuvant treatment, indicating a higher incidence of side effects in this group.As a conclusion, the study suggested that older patients benefit less from neoadjuvant treatment compared to younger patients in terms of gain in OS, and due to experiencing more side effects requiring dose reduction, upfront surgery should be considered as the primary treatment option in elderly patients.While the study by Rompen and colleagues is insightful, further discussion is warranted on certain aspects.
Firstly, the influence of neoadjuvant therapy on patients can lead to changes in their pathological stage, rendering it less reliable compared to the clinical stage, especially when comparing the p stage with the yp stage [2,3] .In older patients receiving neoadjuvant treatment, ~83% exhibit cT3 and 9% exhibit cT4, proportions significantly higher than those undergoing surgery alone.A similar trend is observed in the cN stage.This raises the question of whether older patients if matched for comparable characteristics, could potentially benefit more from neoadjuvant therapy.
Similarly, a comparable pattern was observed in the young patients group, revealing no notable advantage for patients undergoing neoadjuvant therapy in the radio-chemotherapy and other groups.Nonetheless, the table highlights a significant disparity in the clinical stages of patients receiving neoadjuvant therapy compared to those undergoing surgery alone, indicating a disadvantaged population in the neoadjuvant therapy group.Consequently, the outcomes of neoadjuvant chemoradiotherapy could potentially be influenced by bias.
Lastly, the principal aim of this study was to determine the advisability of neoadjuvant therapy for elderly patients with adenocarcinoma of the esophagus and gastroesophageal junction.The critical question is whether OS for elderly patients is improved by neoadjuvant therapy, rather than making comparisons between younger and older groups.The findings suggest that while neoadjuvant therapy yields similar survival rates to surgery alone, it also leads to more side effects necessitating the dose reduction.Consequently, the study recommends considering upfront surgery as the initial treatment strategy for elderly patients.However, it's noteworthy that the neoadjuvant group presented with significantly more advanced disease stages than those in the surgery-alone group.This observation could imply, contrary to the study's conclusions, a potential benefit of neoadjuvant therapy for elderly patients, particularly since it was associated with a marginally extended median overall survival in a cohort with more advanced disease despite the lack of statistical significance.Given this, further analysis is required to validate the original study's conclusion.
In the realm of esophageal cancer treatment, surgical intervention remains the cornerstone, complemented by radiotherapy, chemotherapy, and increasingly, immunotherapy [4][5][6][7] .Both preoperative and postoperative treatments play a crucial role in influencing patient survival, with key surgical considerations including the extent of lymph node dissection, resection of the thoracic duct, and the choice of anastomosis sites [8][9][10][11][12] .These factors are closely linked to postoperative complications and overall survival rates.Recent studies suggest that even in elderly patients, the removal of more than 20 lymph nodes should be considered [12] .This emphasis on the elderly population has sparked a significant amount of research aimed at optimizing treatment approaches for this demographic, laying the groundwork for personalized treatment strategies.In 2023, a study investigated the efficacy of combining S-1-based chemoradiotherapy (CRTCT) with simultaneous integrated boost radiotherapy (SIB-RT) compared to SIB-RT alone in elderly patients (aged 70 years and older) with inoperable esophageal cancer.The results indicated a significant improvement in OS and progression-free survival (PFS) in patients receiving the combined treatment, without a notable increase in severe adverse effects.This suggests that S-1-based CRTCT could be a more effective and well-tolerated treatment option for this patient group, addressing the crucial need for personalized cancer therapies that take into account both effectiveness and quality of life, particularly in older individuals with potentially higher rates of comorbidities [13] .The choice of S-1 as the chemotherapeutic agent is noteworthy, as it is an orally administered drug that combines tegafur (a prodrug of 5-fluorouracil) with two modulators to enhance its antitumor effects and minimizes gastrointestinal toxicity, making it especially suitable for elderly patients who may not tolerate conventional intravenous chemotherapy regimens [13] .
Given the unique physiological characteristics and increased likelihood of comorbidities in elderly patients, the surgical approach, as a primary treatment modality, requires careful consideration of the patient's overall health and ability to withstand surgery [12] .Evidence suggesting the beneficial impact of extensive lymph node dissection challenges traditional caution in subjecting older individuals to more extensive procedures, emphasizing the importance of a thorough evaluation of the patient's condition and the potential long-term survival benefits [14][15][16][17] .Integrating radiotherapy, chemotherapy, and immunotherapy into the treatment regimen for elderly patients requires a delicate balance, considering potential side effects and overall treatment tolerance.Personalizing treatment through geriatric assessment tools and predictive markers could optimize outcomes by tailoring therapies to individual health status and tumor characteristics [13,[17][18][19][20] .Recent research on elderly patients with esophageal cancer has provided valuable insights into treatment feasibility and outcomes, emphasizing the need for a multidisciplinary approach involving surgeons, medical oncologists, radiation oncologists, and geriatric specialists to develop a comprehensive and personalized treatment plan.In a phase 3 randomized clinical trial conducted in 2021, the efficacy and toxic effects of concurrent chemoradiotherapy (CCRT) with S-1 were compared to radiotherapy (RT) alone in older patients with esophageal cancer [20] .The study revealed that CCRT with S-1 was well-tolerated and provided significant benefits over RT alone in terms of OS and PFS.The primary endpoint, a 2-year overall survival rate, showed a marked improvement in the CCRT group compared to the RT alone group.Additionally, the CCRT group exhibited a higher complete response rate and better OS rates at 1, 2, and 3 years.These results indicate that CCRT with S-1 can effectively extend survival outcomes in older patients with esophageal cancer.In terms of safety, the incidence of grade 3 or higher toxic effects was similar between the CCRT and RT groups, except for a higher occurrence of grade 3 or higher leukopenia in the CCRT group.Treatment-related deaths were rare in both groups, with radiation-associated pneumonitis being the most common cause.Importantly, the overall tolerability of CCRT with S-1 suggests that this treatment regimen can be effectively managed in older patients.The treatment of esophageal cancer in elderly patients is a complex endeavor that requires a nuanced approach, balancing surgical intervention, including meticulous lymph node dissection, with the patient's overall health and the integration of other treatment modalities.This collaborative effort is essential in navigating the complexities associated with treating this vulnerable population, aiming not only for survival but also for preserving the quality of life [13,[18][19][20][21][22][23] .
In summary, the study by Rompen and colleagues offers a valuable contribution to the literature, providing evidence that could catalyze a shift towards age-specific treatment stratification in esophagus and gastroesophageal junction.Its findings have implications for the optimization of patient outcomes and the reduction of treatment-related morbidity in an elderly population that is often at a higher risk for both.While the study provides valuable insights, further discussion and analysis are warranted to address the potential biases in patient populations, the reliability of comparing clinical and pathological stages, and the potential benefits of neoadjuvant therapy for elderly patients.These considerations will contribute to a more comprehensive understanding of the age-dependent use and effectiveness of neoadjuvant treatment in patients with adenocarcinoma of the esophagus and gastroesophageal junction.healthcare professionals in the Department of Thoracic Surgery at Yunnan Cancer Hospital.Their dedication, expertise, and tireless efforts have been instrumental in the success of this research.The authors extend their sincere thanks to the research staff in the Department of Thoracic Surgery at Yunnan Cancer Hospital.Their diligent work and valuable contributions have been essential in advancing the authors' understanding of thoracic oncology.The authors express their special gratitude to Professor Lianhua Ye from the Department of Thoracic and Cardiovascular Surgery, The Third Affiliated Hospital of Kunming Medical University.Professor Ye's guidance, mentorship, and unwavering support have been invaluable throughout this research journey.The authors also extend their deep appreciation to Professor Yongchun Zhou from the Molecular Diagnosis Center, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, and the Cancer Center Office, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan.Professor Zhou's expertise and insights have greatly enriched this study.The authors extend their sincere gratitude to Professor Yujie Lei, the director of the Scientific Research Department at Yunnan Cancer Hospital.Professor Lei's guidance and assistance throughout the research process have been invaluable.Her expertise and insights have greatly enhanced the quality of this study.Professor Lei not only provided academic guidance but also offered crucial support in coordinating and managing research resources, ensuring the smooth progress of the research.The authors are thankful to the administrative staff at Yunnan Cancer Hospital for their significant contributions in logistics and administrative support.The authors express their sincerest gratitude to all the individuals and institutions that have provided support and assistance for this research.Their contributions have a profound impact on advancing scientific research and medical practice in the field of thoracic oncology.The authors will continue their efforts to improve the diagnosis, treatment, and quality of life for patients with thoracic tumors, making greater contributions to the cause of human health.