FOXO transcriptional activity is associated with response to chemoradiation in EAC.

In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.

Postoperative Complications and Long-Term Quality of Life After Multimodality Treatment for Esophageal Cancer: An Analysis of the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP).

BACKGROUND: Esophagectomy has major effects on health-related quality of life (HR-QoL). Postoperative complications might contribute to a decreased HR-QOL. This population-based study aimed to investigate the difference in HR-QoL between patients with and without complications after esophagectomy for cancer. METHODS: A prospective comparative cohort study was performed with data from the Netherlands Cancer Registry (NCR) and Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP). All patients with esophageal and gastroesophageal junction (GEJ) cancer after esophagectomy in the period 2015-2018 were enrolled. The study investigated HR-QoL at baseline, then 3, 6, 9, 12, 18, and 24 months postoperatively, comparing patients with and without complications as well as with and without anastomotic leakage. RESULTS: The 486 enrolled patients comprised 270 patients with complications and 216 patients without complications. Significantly more patients with complications had comorbidities (69.6% vs 57.3%; p = 0.001). No significant difference in HR-QoL was found over time between the patients with and without complications. In both groups, a significant decline in short-term HR-QoL was found in various HR-QoL domains, which were restored to the baseline level during the 12-month follow-up period. No significant difference was found in HR-QoL between the patients with and without anastomotic leakage. The patients with grades 2 and 3 anastomotic leakage reported significantly more "choking when swallowing" at 6 months (ß = 14.5; 95% confidence interval [CI], - 24.833 to - 4.202; p = 0.049), 9 months (ß = 22.4, 95% CI, - 34.259 to - 10.591; p = 0.007), and 24 months (ß = 24.6; 95% CI, - 39.494 to - 9.727; p = 0.007) than the patients with grade 1 or no anastomotic leakage. CONCLUSION: In general, postoperative complications were not associated with decreased short- or long-term HR-QoL for patients after esophagectomy for esophageal or GEJ cancer. The temporary decrease in HR-QoL likely is related to the nature of esophagectomy and reconstruction itself.

Conditional survival after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer.

BACKGROUND: Conditional survival accounts for the time already survived after surgery and may be of additional informative value. The aim was to assess conditional survival in patients with oesophageal cancer and to create a nomogram predicting the conditional probability of survival after oesophagectomy. METHODS: This retrospective study included consecutive patients with oesophageal cancer who received neoadjuvant chemoradiation followed by oesophagectomy between January 2004 and 2019. Conditional survival was defined as the probability of surviving y years after already surviving for x years. The formula used for conditional survival (CS) was: CS(x|y)  = S(x + y) /S(x) , where S(x) represents overall survival at x years. Cox proportional hazards models were used to evaluate predictors of overall survival. A nomogram was constructed to predict 5-year survival directly after surgery and given survival for 1, 2, 3 and 4 years after surgery. RESULTS: Some 660 patients were included. Median overall survival was 44·4 (95 per cent c.i. 37·0 to 51·8) months. The probability of achieving 5-year overall survival after resection increased from 45 per cent directly after surgery to 54, 65, 79 and 88 per cent given 1, 2, 3 and 4 years already survived respectively. Cardiac co-morbidity, cN category, ypT category, ypN category, chyle leakage and pulmonary complications were independent predictors of survival. The nomogram predicted 5-year survival using these predictors and number of years already survived. CONCLUSION: The probability of achieving 5-year overall survival after oesophagectomy for cancer increases with each additional year survived. The proposed nomogram predicts survival in patients after oesophagectomy, taking the years already survived into account.

ANTECEDENTES: La supervivencia condicional hace referencia al tiempo ya sobrevivido tras la cirugía y esta información puede tener un valor adicional. El objetivo fue evaluar la supervivencia condicional en pacientes con cáncer de esófago y crear un nomograma para predecir la probabilidad condicional de supervivencia tras una esofaguectomía. MÉTODOS: Estudio retrospectivo incluyó pacientes consecutivos con cáncer de esófago que fueron tratados con quimiorradioterapia neoadyuvante seguida de cirugía, entre enero de 2004 a 2019, en el centro médico de la Universidad de Amsterdam (AMC) de los Países Bajos. La supervivencia condicional se definió como la probabilidad de sobrevivir y años tras haber ya sobrevivido ya durante x años. La formula utilizada fue: CS(x|y) =S(x+y) /S(x) , con S(x) representando la supervivencia global a x años. Se utilizaron modelos de riesgo proporcional de Cox para evaluar los predictores de supervivencia global. Se construyó un nomograma para predecir la supervivencia a los 5 años directamente tras la cirugía y dar la supervivencias a 1-, 2-, 3- y 4 años después de la cirugía. RESULTADOS: Se incluyeron 660 pacientes. La mediana de la supervivencia global fue de 44,4 meses (i.c. del 95% 37,0-51,8). La probabilidad de conseguir una supervivencia global a los 5 años tras la resección aumentó del 45% directamente después de la cirugía al 54%, 65%, 79% y 88% por cada año adicional sobrevivido. La comorbilidad cardiaca, estadio cN, estadio ypT, estadio ypN, quilotórax y complicaciones pulmonares fueron predictores independientes de supervivencia. El nomograma predijo la supervivencia a 5 años utilizando estos predictores y número de años ya sobrevividos. CONCLUSIÓN: La probabilidad de alcanzar una supervivencia global a los 5 años tras una esofaguectomía por cáncer aumenta por cada año adicional sobrevivido. El nomograma propuesto predice la supervivencia en pacientes después de una esofaguectomía, teniendo en cuenta los años ya sobrevividos.

Thromboembolic and bleeding complications in patients with oesophageal cancer.

BACKGROUND: In patients who undergo curative treatment for oesophageal cancer, risk estimates of venous thromboembolism (VTE), arterial thromboembolism and bleeding are needed to guide decisions about thromboprophylaxis. METHODS: This was a single-centre, retrospective cohort study of patients with stage I-III oesophageal cancer who received neoadjuvant chemoradiation followed by oesophagectomy. The outcomes VTE, arterial thromboembolism, major bleeding, clinically relevant non-major bleeding and mortality were analysed for four consecutive cancer treatment stages (from diagnosis to neoadjuvant chemoradiotherapy, during neoadjuvant treatment, 30-day postoperative period, and up to 6 months after postoperative period). RESULTS: Some 511 patients were included. The 2-year survival rate was 67·3 (95 per cent c.i. 63·2 to 71·7) per cent. During the 2-year follow-up, 50 patients (9·8 per cent) developed VTE, 20 (3·9 per cent) arterial thromboembolism, 21 (4·1 per cent) major bleeding and 30 (5·9 per cent) clinically relevant non-major bleeding. The risk of these events was substantial at all treatment stages. Despite 30-day postoperative thromboprophylaxis, 17 patients (3·3 per cent) developed VTE after surgery. Patients with VTE had worse survival (time-varying hazard ratio 1·81, 95 per cent c.i. 1·25 to 2·64). Most bleeding events occurred around the time of medical intervention, and approximately one-half during concomitant use of prophylactic or therapeutic anticoagulation. CONCLUSION: Patients with oesophageal cancer undergoing neoadjuvant chemoradiotherapy and surgery are at substantial risk of thromboembolic and bleeding events throughout all stages of treatment. Survival is worse in patients with thromboembolic events during follow-up.

ANTECEDENTES: Para tomar decisiones en cuanto a la profilaxis tromboembólica, es preciso estimar el riesgo de tromboembolismo venoso (venous thromboembolism, VTE), de tromboembolismo arterial y de hemorragia en pacientes a los que se vaya a realizar un tratamiento curativo para el cáncer de esófago. MÉTODOS: Se realizó un estudio de cohortes retrospectivo de un solo centro, de pacientes con cáncer de esófago en estadios I-III que fueron tratados con quimiorradioterapia neoadyuvante y esofagectomía. Se analizaron, en cuatro momentos del tratamiento (desde el momento del diagnóstico hasta la quimiorradioterapia neoadyuvante, durante el tratamiento neoadyuvante, en los 30 días del período postoperatorio y a los 6 meses de la cirugía) las siguientes variables: VTE, tromboembolismo arterial, hemorragia grave, hemorragia no grave clínicamente relevante y mortalidad. RESULTADOS: Se incluyeron 511 pacientes. La supervivencia a los 2 años fue del 67,3% (ic. del 95%, 63,2-71,7). Durante el seguimiento de 2 años, 50 pacientes desarrollaron un VTE (9,8%), 20 un tromboembolismo arterial (3,9%), 21 hemorragias graves (4,1%) y 30 hemorragias no graves clínicamente relevantes (5,9%). El riesgo de estos accidentes fue notable en todas las etapas del tratamiento. A pesar de la profilaxis tromboembólica posquirúrgica, a los 30 días, 17 pacientes (3,3%) desarrollaron un VTE después de la operación. Los pacientes con VTE tuvieron una supervivencia menor (cociente de riesgos instantáneos, hazard ratio en función del tiempo 1,81; i.c. del 95%, 1,25-2,64). La mayoría de los accidentes hemorrágicos ocurrieron en el contexto de una intervención médica y el 48% durante el uso concomitante de anticoagulación profiláctica o terapéutica. CONCLUSIÓN: Los pacientes con cáncer de esófago tratados con quimiorradioterapia neoadyuvante y cirugía tienen un riesgo sustancial de sufrir accidentes tromboembólicos y hemorrágicos en todas las fases del tratamiento. La supervivencia es peor en aquellos pacientes que presentan accidentes tromboembólicos durante el seguimiento.

Long-term health-related quality of life after McKeown and Ivor Lewis esophagectomy for esophageal carcinoma.

INTRODUCTION: Both cervical (McKeown) and intrathoracic (Ivor Lewis) anastomosis of transthoracic esophagectomy are surgical procedures that can be performed for distal esophageal or gastro-esophageal junction (GEJ) cancer. The purpose of this study was to investigate the long-term health-related quality of life (HR-QoL) after McKeown and Ivor Lewis esophagectomy in a tertiary referral center. METHODS: Disease-free patients >1 year following a McKeown or an Ivor Lewis esophagectomy with a two-field lymphadenectomy for a distal or GEJ carcinoma visiting the outpatient clinic between 2014 and 2018 were asked to complete the EORTC QLQ-C30 and EORTC QLQ-OG25 questionnaires. HR-QoL was investigated in both groups. RESULTS: A total of 89 patients were included after McKeown and 115 after Ivor Lewis esophagectomy. Median follow-up was 2.4 years (IQR 1.7-3.6). Patients after McKeown esophagectomy reported more problems with 'eating with others' compared to patients after Ivor Lewis esophagectomy (mean scores: 49.9 vs. 38.8). This difference was both clinically relevant and significant after correction for multiple testing (ß = 11.1, 95% CI 3.105-19.127, P = 0.042). Patients in both groups reported a poorer HR-QoL (≥10 points) than the general population with respect to nausea and vomiting, dyspnea, appetite loss, financial difficulties, problems with eating, reflux, eating with others, choked when swallowing, trouble with coughing, and weight loss. CONCLUSION: Long-term HR-QoL of disease-free patients following a McKeown or Ivor Lewis esophagectomy for a distal or GEJ carcinoma is largely comparable. Irrespective of the surgical technique, patients' HR-QoL following esophagectomy is compromised. When given the choice, patients should be informed that after a McKeown esophagectomy more problems while eating with others can occur.

Impact of neoadjuvant chemoradiotherapy on health-related quality of life in long-term survivors of esophageal or junctional cancer: results from the randomized CROSS trial.

Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone. Patients and methods: Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4-Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary end points. Predefined secondary end points were global quality of life and fatigue (both QLQ-C30). Results: After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL end points were found between both groups. Compared with 1-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared with pretreatment levels, eating problems had improved (Cohen's d -0.37, P = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pretreatment levels in both groups (Cohen's d -0.56 and 0.51, respectively, both P < 0.001). Conclusions: Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared with patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care. Trial registration number: Netherlands Trial Register NTR487.

Preoperative image-guided identification of response to neoadjuvant chemoradiotherapy in esophageal cancer (PRIDE): a multicenter observational study.

BACKGROUND: Nearly one third of patients undergoing neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal cancer have a pathologic complete response (pCR) of the primary tumor upon histopathological evaluation of the resection specimen. The primary aim of this study is to develop a model that predicts the probability of pCR to nCRT in esophageal cancer, based on diffusion-weighted magnetic resonance imaging (DW-MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT). Accurate response prediction could lead to a patient-tailored approach with omission of surgery in the future in case of predicted pCR or additional neoadjuvant treatment in case of non-pCR. METHODS: The PRIDE study is a prospective, single arm, observational multicenter study designed to develop a multimodal prediction model for histopathological response to nCRT for esophageal cancer. A total of 200 patients with locally advanced esophageal cancer - of which at least 130 patients with adenocarcinoma and at least 61 patients with squamous cell carcinoma - scheduled to receive nCRT followed by esophagectomy will be included. The primary modalities to be incorporated in the prediction model are quantitative parameters derived from MRI and 18F-FDG PET-CT scans, which will be acquired at fixed intervals before, during and after nCRT. Secondary modalities include blood samples for analysis of the presence of circulating tumor DNA (ctDNA) at 3 time-points (before, during and after nCRT), and an endoscopy with (random) bite-on-bite biopsies of the primary tumor site and other suspected lesions in the esophagus as well as an endoscopic ultrasonography (EUS) with fine needle aspiration of suspected lymph nodes after finishing nCRT. The main study endpoint is the performance of the model for pCR prediction. Secondary endpoints include progression-free and overall survival. DISCUSSION: If the multimodal PRIDE concept provides high predictive performance for pCR, the results of this study will play an important role in accurate identification of esophageal cancer patients with a pCR to nCRT. These patients might benefit from a patient-tailored approach with omission of surgery in the future. Vice versa, patients with non-pCR might benefit from additional neoadjuvant treatment, or ineffective therapy could be stopped. TRIAL REGISTRATION: The article reports on a health care intervention on human participants and was prospectively registered on March 22, 2018 under ClinicalTrials.gov Identifier: NCT03474341 .

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

The effect of air pockets in the urinary bladder on the temperature distribution during loco-regional hyperthermia treatment of bladder cancer patients.

PURPOSE: Loco-regional hyperthermia combined with mitomycin C is used for treatment of nonmuscle invasive bladder cancer (NMIBC). Air pockets may be present in the bladder during treatment. The aim of this study is to quantify the effect of air pockets on the thermal dose of the bladder. METHODS: We analysed 16 patients treated for NMIBC. Loco-regional hyperthermia was performed with the in-house developed 70 MHz AMC-4 hyperthermia device. We simulated treatments with the clinically applied device settings using Plan2Heat (developed in-house) including the air pockets delineated on CT scans made following treatment, and with the same volume filled with urine. Temperature distributions simulated with and without air pockets were compared. RESULTS: The average air and fluid volumes in the bladder were 6.0 ml (range 0.8 - 19.3 ml) and 183 ml (range 47-322 ml), respectively. The effect of these air pockets varied strongly between patients. Averaged over all patients, the median bladder wall temperature (T50) remained unchanged when an air pocket was present. Temperature changes exceeded ±0.2 °C in, on average, 23% of the bladder wall volume (range 1.3-59%), in 6.0% (range 0.6-20%) changes exceeded ±0.5 °C and in 3.2% (range 0.0-7.4%) changes exceeded ±1.0 °C. There was no correlation between the differences in temperature and the air pocket or bladder volume. There was a positive correlation between air pocket surface and temperature heterogeneity. CONCLUSION: Presence of air causes more heterogeneous bladder wall temperatures and lower T90, particularly for larger air pockets. The size of air pockets must therefore be minimized during bladder hyperthermia treatments.

Multimodality treatment for esophageal adenocarcinoma: multi-center propensity-score matched study.

Background: The primary aim of this study was to compare survival from neoadjuvant chemoradiotherapy plus surgery (NCRS) versus neoadjuvant chemotherapy plus surgery (NCS) for the treatment of esophageal or junctional adenocarcinoma. The secondary aims were to compare pathological effects, short-term mortality and morbidity, and to evaluate the effect of lymph node harvest upon survival in both treatment groups. Methods: Data were collected from 10 European centers from 2001 to 2012. Six hundred and eight patients with stage II or III oesophageal or oesophago-gastric junctional adenocarcinoma were included; 301 in the NCRS group and 307 in the NCS group. Propensity score matching and Cox regression analyses were used to compensate for differences in baseline characteristics. Results: NCRS resulted in significant pathological benefits with more ypT0 (26.7% versus 5%; P < 0.001), more ypN0 (63.3% versus 32.1%; P < 0.001), and reduced R1/2 resection margins (7.7% versus 21.8%; P < 0.001). Analysis of short-term outcomes showed no statistically significant differences in 30-day or 90-day mortality, but increased incidence of anastomotic leak (23.1% versus 6.8%; P < 0.001) in NCRS patients. There were no statistically significant differences between the groups in 3-year overall survival (57.9% versus 53.4%; Hazard Ratio (HR)= 0.89, 95%C.I. 0.67-1.17, P = 0.391) nor disease-free survival (52.9% versus 48.9%; HR = 0.90, 95%C.I. 0.69-1.18, P = 0.443). The pattern of recurrence was also similar (P = 0.660). There was a higher lymph node harvest in the NCS group (27 versus 14; P < 0.001), which was significantly associated with a lower recurrence rate and improved disease free survival within the NCS group. Conclusion: The survival differences between NCRS and NCS maybe modest, if present at all, for the treatment of locally advanced esophageal or junctional adenocarcinoma. Future large-scale randomized trials must control and monitor indicators of the quality of surgery, as the extent of lymphadenectomy appears to influence prognosis in patients treated with NCS, from this large multi-center European study.