Delayed Surgical Intervention After Chemoradiotherapy in Esophageal Cancer: (DICE) Study.

OBJECTIVE: To determine the impact of delayed surgical intervention following chemoradiotherapy (CRT) on survival from esophageal cancer. BACKGROUND: CRT is a core component of multimodality treatment for locally advanced esophageal cancer. The timing of surgery following CRT may influence the probability of performing an oncological resection and the associated operative morbidity. METHODS: This was an international, multicenter, cohort study, including patients from 17 centers who received CRT followed by surgery between 2010 and 2020. In the main analysis, patients were divided into 4 groups based upon the interval between CRT and surgery (0-50, 51-100, 101-200, and >200 days) to assess the impact upon 90-day mortality and 5-year overall survival. Multivariable logistic and Cox regression provided hazard ratios (HRs) with 95% CIs adjusted for relevant patient, oncological, and pathologic confounding factors. RESULTS: A total of 2867 patients who underwent esophagectomy after CRT were included. After adjustment for relevant confounders, prolonged interval following CRT was associated with an increased 90-day mortality compared with 0 to 50 days (reference): 51 to 100 days (HR=1.54, 95% CI: 1.04-2.29), 101 to 200 days (HR=2.14, 95% CI: 1.37-3.35), and >200 days (HR=3.06, 95% CI: 1.64-5.69). Similarly, a poorer 5-year overall survival was also observed with prolonged interval following CRT compared with 0 to 50 days (reference): 101 to 200 days (HR=1.41, 95% CI: 1.17-1.70), and >200 days (HR=1.64, 95% CI: 1.24-2.17). CONCLUSIONS: Prolonged interval following CRT before esophagectomy is associated with increased 90-day mortality and poorer long-term survival. Further investigation is needed to understand the mechanism that underpins these adverse outcomes observed with a prolonged interval to surgery.

Histological prognosticators in neoadjuvant naive oesophageal cancer patients.

PURPOSE: Prognosis of oesophageal cancer is primarily based upon the TNM stage of the disease. However, even in those with similar TNM staging, survival can be varied. Additional histopathological factors including venous invasion (VI), lymphatic invasion (LI) and perineural invasion (PNI) have been identified as prognostic markers yet are not part of TNM classification. The aim of this study is to determine the prognostic importance of these factors and overall survival in patients with oesophageal or junctional cancer who underwent transthoracic oesophagectomy as the unimodality treatment. METHODS: Data from patients who underwent transthoracic oesophagectomy for adenocarcinoma without neoadjuvant treatment were reviewed. Patients were treated with radical resection, with a curative intent using a transthoracic Ivor Lewis or three staged McKeown approach. RESULTS: A total of 172 patients were included. Survival was poorer when VI, LI and PNI were present (p<0.001), with the estimated survival being significantly worse (p<0.001) when patients were stratified according to the number of factors present. Univariable analysis of factors revealed VI, LI and PNI were all associated with survival. Presence of LI was independently predictive of incorrect staging/upstaging in multivariable logistic regression analysis (OR 12.9 95% CI 3.6-46.6, p<0.001). CONCLUSION: Histological factors of VI, LI and PNI are markers of aggressive disease and may have a role in prognostication and decision-making prior to treatment. The presence of LI as an independent marker of upstaging could be a potential indication for the use of neoadjuvant treatment in patients with early clinical disease.

FLOT-regimen Chemotherapy and Transthoracic en bloc Resection for Esophageal and Junctional Adenocarcinoma.

BACKGROUND AND AIMS: The FLOT4-AIO trial established the FLOT regimen as a compelling option for gastric, junctional and esophageal adenocarcinoma. Data on FLOT with en-bloc transthoracic esophagectomy (TTE) are limited. This study explored operative complications, tolerance, toxicity, physiological impact, and oncologic outcomes. STUDY DESIGN: An observational cohort study on consecutive patients at 3 tertiary centers undergoing FLOT and TTE. Toxicity, operative complications (per ECCG definitions), tumor regression grade (TRG), recurrences and survival were documented, as well as pre and post FLOT assessment of sarcopenia and pulmonary physiology. RESULTS: 175 patients (cT2-4a, Nany) commenced treatment, 84% male, median age 65, 94% cT3/T4a, 73% cN+. 89% completed 4 preoperative cycles, and 35% all cycles. Grade 3/4 toxicities included neutropenia (12%), diarrhoea (13%), and infection (15%). Sarcopenia increased from 18% to 37% (P = 0.020), and diffusion capacity (DLCO) decreased by 8% (-34% + 25%; P < 0.010). On pathology, ypT3/4 was 59%, and ypN+54%, with 10% TRG 1, 14% TRG 2, and 76% TRG3-5, and R0 95%. 161 underwent TTE, with an in-hospital mortality of 0.6%, 24%-pneumonia, 11%-anastomotic leak, and Clavien Dindo ≥III in 27%. At a median follow up of 12 months (1-85), 33 relapsed, 8 (5%) locally, and 3yr survival was 60%. CONCLUSION: FLOT and en bloc TTE was safe, with no discernible impact on operative complications, with 24% having a major pathologic response. Caveats include a limited pathologic response in the majority, and negative impact on muscle mass and lung physiology, and low use of adjuvant cycles. These data may provide a real-world benchmark for this complex care pathway.

Does Cardiopulmonary Testing Help Predict Long-Term Survival After Esophagectomy?

BACKGROUND: Esophagectomy is associated with a high rate of morbidity and mortality. Preoperative cardiopulmonary fitness has been correlated with outcomes of major surgery. Variables derived from cardiopulmonary exercise testing (CPET) have been associated with postoperative outcomes. It is unclear whether preoperative cardiorespiratory fitness of patients undergoing esophagectomy is associated with long-term survival. This study aimed to evaluate whether any of the CPET variables routinely derived from patients with esophageal cancer may aid in predicting long-term survival after esophagectomy. METHODS: Patients undergoing CPET followed by trans-thoracic esophagectomy for esophageal cancer with curative intent between January 2013 and January 2017 from single high-volume center were retrospectively analyzed. The relationship between predictive co-variables, including CPET variables and survival, was studied with a Cox proportional hazard model. Receiver operation curve (ROC) analysis was performed to find cutoff values for CPET variables predictive of 3-year survival. RESULTS: The study analyzed 313 patients. The ventilatory equivalent for carbon dioxide (VE/VCO2) at the anerobic threshold was the only CPET variable independently predictive of long-term survival in the multivariable analysis (hazard ratio [HR], 1.049; 95% confidence interval [CI], 1.011-1.088; p = 0.011). Pathologic stages 3 and 4 disease was the other co-variable found to be independently predictive of survival. An ROC analysis of the VE/VCO2 failed to demonstrate a predictive cutoff value of 3-year survival (area under the curve, 0.564; 95% CI, 0.499-0.629; p = 0.056). CONCLUSIONS: A high VE/VCO2 before esophagectomy for malignant disease is an independent predictor of long-term survival and may be an important variable for clinicians to consider when counseling patients.

Impact of Smoking Status on Perioperative Morbidity, Mortality, and Long-Term Survival Following Transthoracic Esophagectomy for Esophageal Cancer.

INTRODUCTION: Esophagectomy is a key component in the curative treatment of esophageal cancer. Little is understood about the impact of smoking status on perioperative morbidity and mortality and the long-term outcome of patients following esophagectomy. OBJECTIVE: This study aimed to evaluate morbidity and mortality according to smoking status in patients undergoing esophagectomy for esophageal cancer. METHODS: Consecutive patients undergoing two-stage transthoracic esophagectomy (TTE) for esophageal cancers (adenocarcinoma or squamous cell carcinoma) between January 1997 and December 2016 at the Northern Oesophagogastric Unit were included from a prospectively maintained database. The main explanatory variable was smoking status, defined as current smoker, ex-smoker, and non-smoker. The primary outcome was overall survival (OS), while secondary outcomes included perioperative complications (overall, anastomotic leaks, and pulmonary complications) and survival (cancer-specific survival [CSS], recurrence-free survival [RFS]). RESULTS: During the study period, 1168 patients underwent esophagectomy for cancer. Of these, 24% (n = 282) were current smokers and only 30% (n = 356) had never smoked. The median OS of current smokers was significantly shorter than ex-smokers and non-smokers (median 36 vs. 42 vs. 48 months; p = 0.015). However, on adjusted analysis, there was no significant difference in long-term OS between smoking status in the entire cohort. The overall complication rates were significantly higher with current smokers compared with ex-smokers or non-smokers (73% vs. 66% vs. 62%; p = 0.018), and there were no significant differences in anastomotic leaks and pulmonary complications between the groups. On subgroup analysis by receipt of neoadjuvant therapy and tumor histology, smoking status did not impact long-term survival in adjusted multivariable analyses. CONCLUSION: Although smoking is associated with higher rates of short-term perioperative morbidity, it does not affect long-term OS, CSS, and RFS following esophagectomy for esophageal cancer. Therefore, implementation of perioperative pathways to optimize patients may help reduce the risk of complications.

Chyle Leak Following Radical En Bloc Esophagectomy with Two-Field Nodal Dissection: Predisposing Factors, Management, and Outcomes.

BACKGROUND: Chyle leak is an uncommon complication following esophagectomy, accounting for significant morbidity and mortality; however, the optimal treatment for the chylothorax is still controversial. OBJECTIVE: The aim of this study was to evaluate the incidence, management, and outcomes of chyle leaks within a specialist esophagogastric cancer center. METHODS: Consecutive patients undergoing esophagectomy for esophageal cancers (adenocarcinoma or squamous cell carcinoma) between 1997 and 2017 at the Northern Oesophagogastric Unit were included from a contemporaneously maintained database. Primary outcome was overall survival, while secondary outcomes were overall complications, anastomotic leaks, and pulmonary complications. RESULTS: During the study period, 992 patients underwent esophagectomy for esophageal cancers, and 5% (n = 50) of them developed chyle leaks. There was no significant difference in survival in patients who developed a chyle leak compared with those who did not (median: 40 vs. 45 months; p = 0.60). Patients developing chyle leaks had a significantly longer length of stay in critical care (median: 4 vs. 2 days; p = 0.002), but no difference in total length of hospital stay. CONCLUSION: Chyle leak remains a complication following esophagectomy, with limited understanding on its pathophysiology in postoperative recovery. However, these data indicate chyle leak does not have a long-term impact on patients and does not affect long-term survival.

Prognostic Significance of Lymphatic, Venous and Perineural Invasion After Neoadjuvant Chemotherapy in Patients with Gastric Adenocarcinoma.

BACKGROUND: The significance of perineural (PNI), lymphatic (LI) and venous invasion (VI) in gastric cancer patients who have received neoadjuvant chemotherapy is unclear. The aim of this study is to determine the incidence and prognostic significance of LI, VI and PNI in these patients. PATIENTS AND METHODS: Consecutive patients treated with neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy were reviewed. Presence of LI, VI and PNI was recorded and correlated with clinical outcomes. RESULTS: A total of 243 patients underwent gastrectomy after neoadjuvant therapy for gastric adenocarcinoma. LI was identified in 129 (53%), VI in 107 (44%) and PNI in 116 (48%) of patients. Presence of LI (HR, 2.95, CI 1.91-4.56), VI (HR, 2.66, CI 1.78-3.98) and PNI (HR, 3.85, CI 2.49-5.95) was associated with poorer survival (all p < 0.001). Multivariable analysis revealed that ypT stage (HR, 1.35, CI 1.05-1.74), ypN stage (HR, 1.53, CI 1.28-1.83) and PNI (HR, 2.11, CI 1.31-3.42) were independent predictors of survival. CONCLUSIONS: LI, VI and PNI are associated with poorer survival, with PNI having prognostic significance independent of lymph node status. These factors may be useful for further prognostication, in particular when multiple factors are present, and appear especially useful for prognostic stratification in patients with no nodal involvement.

Predictors of early recurrence of oesophagogastric adenocarcinoma after neoadjuvant FLOT.

BACKGROUND: Although survival of patients with oesophagogastric adenocarcinomas has improved over the years, rates of cancer recurrence remain high. There is limited research on predictors of early recurrence (ER), especially in patients receiving FLOT chemotherapy. The aim of this study was to investigate ER and survival rates and identify risk factors for ER. METHODS: Patients receiving neoadjuvant chemotherapy with FLOT for oesophagogastric adenocarcinoma at single high-volume centre between August 2018 and January 2023 were evaluated for early recurrence defined as disease present within 1 year of surgery. Multivariable analysis was conducted to identify risk factors for ER. Patients who died in-hospital or within 90 days of surgery and those with positive longitudinal margin were excluded. RESULTS: 196 patients were included. 93.3 % and 40.3 % of patients completed all four neoadjuvant and adjuvant cycles of FLOT respectively. 54 patients (27.6 %) developed recurrence in the follow up period with 27 patients (13.8 %) having ER. Recurrence free survival and overall survival at one year were 83.7 % and 90.8 % respectively. The estimated median survival after recurrence was 4.1 months. Extracapsular spread was found to be independent risk factor for ER (OR 4.565, 95 % CI 1.450-14.369, p = 0.009) in multivariable analyses together with ypN3 stage (OR 7.978, 95 % CI 1.339-47.534, p = 0.023). CONCLUSIONS: The variables identified in this study may be helpful in determining patients at a higher risk of ER following curative surgery. Understanding these predictors may help tailor the follow up care of these patients, such as regular surveillance imaging, treatment, and frequency of reviews.

Predictive Factors for the Development of Gallbladder Necrosis.

Introduction Acute cholecystitis is a common complication of gallstone disease. Likewise, gallbladder necrosis is a complication of cholecystitis associated with higher risks of morbidity and mortality. Identification of risk factors which portend to gallbladder necrosis is key in prioritizing the management of higher-risk patients. This study aimed to identify such factors that predict the development of gallbladder necrosis. Method A retrospective review of all patients undergoing emergency cholecystectomy in a tertiary hospital over a two-year period was performed. Gallbladder necrosis was diagnosed on histopathological examination of operative specimens. Multivariable logistic regression was performed to determine risk factors for gallbladder necrosis. Results A total of 163 patients underwent acute cholecystectomy and 43 (26%) had proven gallbladder necrosis. Multivariable analysis demonstrated that elevated white cell count (WCC) (OR 1.122, 95%CI 1.031-1.221, p=0.007), elevated C-reactive protein (CRP) (OR 1.004, 95%CI 1.001-1.008, p=0.022) and positive smoking status (OR 5.724, 95%CI 1.323-24.754, p=0.020) were independently predictive of gallbladder necrosis. Notably, advancing age, elevated BMI, diabetes mellitus or American Society of Anesthesiologists (ASA) grade were not found to be associated with developing necrosis. Conclusion Patients at risk of gallbladder necrosis include those with higher WCC, CRP, and active smokers. Given the increased potential complications, these risk factors should be identified early in the management of those admitted with gallstone disease to ensure such patients receive aggressive medical therapy alongside timely and guided surgical intervention.

Long-term survival is not affected by severity of complications following esophagectomy.

INTRODUCTION: Outcomes following esophagectomy for esophageal cancer have continued to improve over the last 30 years. Post-operative complications impact upon peri-operative and short-term survival but the effect on long-term survival remains debated. This study aims to investigate the effect of post-operative complications on long-term survival following esophagectomy. MATERIALS AND METHODS: All patients who underwent an esophagectomy between January 2010 and January 2019 were included from a single high-volume center. Data was collected contemporaneously. Patients were separated into three groups; those who experienced no, or very minor complications (Clavien-Dindo 0 or 1), minor complications (Clavien-Dindo 2), and major complications (Clavien-Dindo 3-4), at 30 days. To correct for short-term mortality effects, those who died during the index hospital admission were excluded. Overall survival was analyzed using Kaplan-Meier and log rank testing. RESULTS: The study cohort comprised 721 patients. There were 42.4% (306/721), 29.5% (213/721) and 25.7% (185/721) in the Clavien-Dindo 0-1, Clavien-Dindo 2, and Clavien-Dindo 3-4 group respectively. Seventeen patients (2.4%) died during their index hospital admission and were therefore excluded. There was no significant difference between median survival across the 3 groups (50, 57 and 52 months). Across all 3 groups, overall long-term survival rates were equivalent at 1 (87.5%, 84.9%, 83.2%), 3 (59.7%, 59.6%, 54.2%), and 5 years (43.9%, 48.9%, 45.7%) (p = 0.806). The only factors independently associated with survival in this cohort, were male gender, Charlson comorbidity index, and overall pathological stage of disease. CONCLUSION: Long-term survival is not affected by peri-operative complications, irrespective of severity, following esophagectomy. Further study into the long-term quality of life is required.

Anastomotic stricture after Ivor Lewis esophagectomy: An evaluation of incidence, risk factors, and treatment.

BACKGROUND: Anastomotic stricture is a recognized complication after esophagectomy. It can impact the patient's quality of life and may require recurrent dilatations. Thus, the aim of this study was to evaluate the frequency of strictures, contributing factors, and long-term outcomes of management in patients undergoing esophagectomy with thoracic anastomosis using a standardized circular stapled technique. METHODS: All patients who underwent a 2-stage transthoracic esophagectomy with curative intent between January 2010 and December 2019 at NOGU, Newcastle upon Tyne, UK were included. All patients who underwent a stapled (circular) intrathoracic anastomosis using gastric conduits were included. Stricture incidence, number of dilatations to resolve strictures, and refractory stricture rate were recorded. RESULTS: Overall, 705 patients were included with 192 (27.2%) developing strictures. Refractory strictures occurred in 38 patients (5.4%). One, 2, and 3 dilatations were needed for resolution of symptoms in 46 (37.4%), 23 (18.7%), and 20 (16.3%) patients, respectively. Multivariable analysis identified the occurrence of an anastomotic leak (odds ratio 1.906, 95% confidence interval 1.088-3.341, P = .024) and circular staple size <28 mm (odds ratio 1.462, 95% confidence interval 1.033-2.070, P = .032) as independent predictors of stricture occurrence. Patients with anastomotic leaks were more likely to develop refractory strictures (13.1% vs 4.7%, odds ratio 3.089, 95% confidence interval 1.349-7.077, P = .008). CONCLUSION: This study highlights that nearly 30% of patients having a circular stapled anastomosis will require dilatation after surgery. Although the majority will completely resolve after 2 dilatations, 5% will have longer-term problems with refractory strictures.

A feasibility trial of prehabilitation before oesophagogastric cancer surgery using a multi-component home-based exercise programme: the ChemoFit study.

BACKGROUND: Treatment for locally advanced oesophagogastric adenocarcinoma involves neoadjuvant chemotherapy which has a negative impact on patient fitness. Using 'prehabilitation' to increase activity levels and fitness may affect physiology, postoperative outcomes and improve patient wellbeing and quality of life. The aims of the trial were to address the feasibility and acceptability of recruiting participants to a home-based prehabilitation programme and provide data to allow design of future studies. METHODS: We recruited patients to a single-arm feasibility trial of home-based exercise prehabilitation. Eligible patients were aged ≥18years, had operable oesophageal or gastric adenocarcinoma and were receiving neoadjuvant chemotherapy at our tertiary referral hospital. All participants commenced a home-based exercise programme utilising pedometers and step counting to target daily aerobic exercise sessions alongside daily strengthening exercises. A weekly telephone consultation directed the exercise programme and facilitated weekly data collection. The primary (feasibility) outcomes for the trial were (a) recruitment rate, (b) completion rate, (c) engagement with the programme (use of pedometers, recording step counts, telephone consultations) and (d) compliance with exercise sessions, exercise intensity and strengthening exercises. RESULTS: There were 42 patients recruited, and the recruitment rate was 72.4% (42/58). 92.3% (36/39) of patients completed the exercise programme. There was 98.7% (IQR 93.2-100.0%) compliance with wearing a pedometer and recording data, and 100.0% (IQR 93.1-100.0%) compliance with a weekly telephone consultation. Exercise sessions and strengthening exercises were completed 70.2% (IQR 53.1-88.9%) and 69.4% (IQR 52.1-84.3%) of the time, respectively. Appropriate exercise intensity was recorded 96% (IQR 85.4-99.4%) of the time. There were no adverse events. Participants were enrolled in the exercise programme for a median of 91 days (IQR 84 to 105 days). CONCLUSIONS: The results of this trial support the feasibility and acceptability of recruiting participants to an appropriately powered randomised controlled trial of prehabilitation. TRIAL REGISTRATION: Clinicaltrials.gov NCT04194463 . Registered on 11th December 2019-retrospectively registered.

Exploring factors influencing uptake and adherence to a home-based prehabilitation physical activity and exercise intervention for patients undergoing chemotherapy before major surgery (ChemoFit): a qualitative study.

OBJECTIVES: Preoperative exercise training can improve cardiorespiratory fitness before major surgery. However, little is known about what influences participation and adherence in high-risk patient groups. We identified barriers and facilitators to uptake, engagement and adherence to a presurgical, home-based physical activity and exercise intervention called ChemoFit delivered during chemotherapy and before major oesophagogastric surgery. DESIGN: A qualitative study using focus group discussions and individual semi-structured interviews was conducted. All were audio-recorded, transcribed verbatim and data thematically analysed. SETTING: Northern Oesophagogastric Unit, Royal Victoria Infirmary, Newcastle upon Tyne NHS Hospitals Foundation Trust. PARTICIPANTS: Patients with oesophagogastric cancer who participated in the ChemoFit intervention recruited between March 2020 and January 2021. INTERVENTION: A home-based physical activity and exercise intervention involving cardiovasular and strength exercise using resistance bands and pedometers to monitor step count. Weekly telephone calls provided feedback, support and positive reinforcement. RESULTS: Twenty-two participants (18 men, 4 women; aged 67±8 years old) took part in a focus group discussion (n=17) or a semi-structured interview (n=5). Fifteen themes were identified from the data generated. Participants reported that the intervention was physically and mentally beneficial, and data highlighted features of the intervention that influenced uptake and adherence. An opportunity to increase the likelihood of surviving the pending operation was reported by participants as the most salient factor to engagement, and using the intervention as a distraction from illness and taking steps to positively influence the situation were the most salient factors to adherence. CONCLUSIONS: Uptake to the ChemoFit intervention was encouraged by provision of information that participation could reduce surgical risk and that participants could play an active role in risk reduction. Adherence was facilitated by the intervention being considered a positive distraction and participants being able to do something that could ultimately provide benefit. While participants reported difficulties and avoidance with some of the exercises recommended, understanding the importance of physical activity and exercise as part of their treatment regimen led to individual adaptations to intervention components to reach individual goals. TRIAL REGISTRATION NUMBER: NCT04194463.

Recipient outcomes in total laparoscopic live donor nephrectomy with multiple renal vessels.

INTRODUCTION: In kidney transplantation, total laparoscopic live donor nephrectomy (TLLDN) in the presence of multiple renal arteries (MRA) is technically challenging and has traditionally been associated with higher complication rates. We report our experience of using MRA grafts procured by TLLDN. MATERIALS AND METHODS: Patients undergoing TLLDN at our center (2004-2014) was identified from a prospectively maintained database and divided into single renal arteries (SRA) or MRA groups. Recipient perioperative parameters, postoperative complications, and long-term graft survival were analyzed. RESULTS: Of 465 patients, 106 had MRA and 359 had an SRA. There were six vascular complications in the SRA group and two in the MRA group (1.7% vs. 1.8%). There were eight ureteric complications requiring intervention in the SRA group compared to three in the MRA group (4% vs. 3%; P = 0.45). Acute rejection was observed in 12% of the SRA group compared to 9% in the MRA group (P = 0.23). One-, 5- and 10-year graft survivals were 98.2%, 91.3%, and 89.8% in the MRA group versus 98.0%, 90.4%, and 77.5% in the SRA group (log-rank P = 0.13). CONCLUSION: The use of MRA grafts procured by TLLDN has comparable complication rates to SRA grafts and should not preclude selection for renal transplantation.