Patterns of recurrent disease after neoadjuvant chemoradiotherapy and esophageal cancer surgery with curative intent in a tertiary referral center.

BACKGROUND: Recurrence is frequently observed after esophageal cancer surgery, with dismal post-recurrence survival. Neoadjuvant chemoradiotherapy followed by esophagectomy is the gold standard for resectable esophageal tumors in the Netherlands. This study investigated the recurrence patterns and survival after multimodal therapy. METHODS: This retrospective cohort study included patients with recurrent disease after neoadjuvant chemoradiotherapy followed by esophagectomy for an esophageal adenocarcinoma in the Amsterdam UMC between 01 and 01-2010 and 31-12-2018. Post-recurrence treatment and survival of patients were investigated and grouped by recurrence site (loco-regional, distant, or combined loco-regional and distant). RESULTS: In total, 278 of 618 patients (45.0%) developed recurrent disease after a median of 49 weeks. Thirty-one patients had loco-regional (11.2%), 145 distant (52.2%), and 101 combined loco-regional and distant recurrences (36.3%). Post-recurrence survival was superior for patients with loco-regional recurrences (33 weeks, 95%CI 7.3-58.7) compared to distant (12 weeks, 95%CI 6.9-17.1) or combined loco-regional and distant recurrent disease (18 weeks, 95%CI 9.3-26.7). Patients with loco-regional recurrences treated with curative intent had the longest survival (87 weeks, 95%CI 6.9-167.4). CONCLUSION: Recurrent disease after potentially curative treatment for esophageal cancer was most frequently located distantly, with dismal prognosis. A subgroup of patients with loco-regional recurrence was treated with curative intent and had prolonged survival. These patients may benefit from intensive surveillance protocols, and more research is needed to identify these patients.

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.

Long-Term Quality of Life Following Transthoracic and Transhiatal Esophagectomy for Esophageal Cancer.

BACKGROUND: The impact of transthoracic (TTE) and transhiatal esophagectomy (THE) on long-term health-related quality of life (HR-QoL) in patients with distal esophageal or gastro-esophageal junction (GEJ) cancer has been studied with variable results. This study investigates long-term HR-QoL in patients having undergone TTE or THE. METHODS: Disease-free patients after TTE or THE for distal esophageal or GEJ cancer with a follow-up > 2 years were included. Patients who visited the outpatient clinic of a tertiary referral center between 2014 and 2018 were asked to complete EORTC-QLQ-C30 and EORTC-QLQ-OG25 questionnaires. Uni- and multivariable linear regression analysis of HR-QoL was performed in all patients and in subgroups of minimally invasive esophagectomy and neoadjuvant therapy. RESULTS: A total of 132 patients after TTE and 56 after THE were included. When compared with the general population, all patients reported worse HR-QoL in 'role functioning' and 'social functioning' and in a range of disease- and/or treatment-specific symptoms. The only significant difference between TTE and THE was a better HR-QoL score for "hair loss" following TTE (ß = 29.4,95%CI = -49.108 - -9.671, p = 0.016). Subgroup analysis of minimally invasively operated patients showed better scores in "physical functioning" following TTE (ß = 13.8,95%CI = 2.755-24.933, p = 0.030). No significant differences in HR-QoL were found between TTE and THE after neoadjuvant therapy. CONCLUSION: Long-term HR-QoL is largely comparable in disease-free patients following TTE or THE for distal esophageal or GEJ cancer. If there were differences between the surgical groups, they were in favor of TTE. These findings may aid in preoperative counseling of patients with esophageal or GEJ cancer.

Urinary incontinence and erectile dysfunction in patients with localized or locally advanced prostate cancer: A nationwide observational study.

BACKGROUND: Although urinary adverse events after treatment of prostate cancer (CaP) are common, population-based studies on functional outcomes are scarce. The aim of this study is to evaluate the occurrence of urinary incontinence (UI) and erectile dysfunction (ED) in daily clinical practice using a nationwide Dutch cohort of patients with localized or locally advanced CaP. BASIC PROCEDURES: Patients were invited to complete the EPIC-26 questionnaire before treatment (baseline) and at 12 and 24 months after diagnosis. We calculated the mean EPIC-26 domain scores, stratified by treatment modality (i.e., radical prostatectomy, external radiotherapy, and no active treatment), and the proportions of patients with UI (defined as ≥ 2 pads per day) and ED (defined as erections not firm enough for sexual intercourse). Logistic regression modeling was used to explore the factors related to UI and ED after surgery. MAIN FINDINGS: In total 1,759 patients participated in this study. Patients undergoing radical prostatectomy experienced clinically relevant worsening in the urinary incontinence domain. After excluding patients who reported UI at baseline, 15% of patients with prostatectomy reported UI 24 months after diagnosis. Only comorbidity was associated with UI in surgically treated patients. Regardless of treatment, patients reported a clinically significant reduced sexual functioning over time. Before treatment, 54% of patients reported ED. Among the 46% remaining patients, 87% of patients treated with radical prostatectomy reported ED 24 months after diagnosis, 41% after radiotherapy, and 46% in patients without active treatment. Bilateral nerve-sparing surgery was the only factor associated with ED after 24 months. PRINCIPAL CONCLUSIONS: UI and ED frequently occur in patients with localized and locally advanced CaP, in particular after radical prostatectomy. The higher occurrence rate of UI and ED, compared with clinical trial participants, supports the importance of real-world data, which can be used for local treatment recommendations and patient information, but also to evaluate effects of future initiatives, such as treatment centralization and research aimed at improving functional outcomes.

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.

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.

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.

[Hospital of diagnosis influences the probability of receiving curative treatment for oesophageal and gastric cancer]. / Ziekenhuis van diagnose beïnvloedt kans op curatieve behandeling voor slokdarm- en maagkanker.

OBJECTIVE: The aim of these studies was to examine the influence of hospital of diagnosis on the probability of receiving curative treatment and its impact on survival among oesophageal and gastric cancer. DESIGN: Although oesophageal and gastric cancer surgery is centralised in the Netherlands, the disease is often diagnosed in hospitals that do not perform this procedure. METHOD: Patients with potentially curable oesophageal or gastric cancer tumours diagnosed between 2005 and 2013 were selected from the Netherlands Cancer Registry. The probability to undergo curative treatment was examined for each hospital of diagnosis after adjustment for case-mix. Effects of variation in probability of undergoing curative treatment among these hospitals on survival were investigated Cox regression. RESULTS: All 13,017 patients with potentially curable oesophageal and 5,620 patients with potentially curable gastric cancer, diagnosed in 91 hospitals, were included. After adjustment, the proportion of oesophageal cancer patients receiving curative treatment ranged from 50% to 82% and from 48% to 78% for patients with gastric cancer in 2010-2013, depending on hospital of diagnosis (both P < 0.001). Furthermore, patients diagnosed in hospitals with a low probability of undergoing curative treatment had a worse overall survival in the period 2010-2013 (oesophageal cancer hazard ratio (HR): 1,15; 95%-CI: 1,07-1,24; gastric cancer HR: 1,21; 95%-CI: 1,04-1,41). CONCLUSION: The variation in probability of undergoing potentially curative treatment for oesophageal and gastric cancer between hospitals of diagnosis and its impact on survival indicates that treatment decision-making for these patients may be improved. Regional expert multidisciplinary team meetings in this field may improve the selection of patients for curative treatment.

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.

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.

Treatment strategies in recurrent esophageal or junctional cancer.

Little evidence is available about survival rates in patients with recurrent disease after potentially curative surgery for esophageal or junctional cancer. Only in limited occasions, potentially curative salvage strategies are available. The aim of this study is to analyze survival rates and patterns of dissemination, and to identify independent prognostic factors in a consecutive series of patients who develop recurrent esophageal or junctional cancer. Between 1994 and 2015, patients who developed disease recurrence after neoadjuvant chemo(radio)therapy followed by radical esophagectomy for esophageal or junctional cancer were retrospectively analyzed. The Kaplan-Meier estimates were performed to calculate and compare overall survival between patients with different patterns of dissemination and to compare between different treatment strategies. Furthermore, univariate and multivariate Cox-regression analyses were performed to identify independent prognostic factors for post recurrence survival. In this study, we included 219 patients. The median overall survival of all included patients was 3.2 months (range: 0.0-101.1 months). The median overall survival in patients with exclusively locoregional recurrence (n = 23, 10.8%) was 4.9 months (range: 0.1- 55.6) and 2.9 months (range: 0.0-101.1) in patients who had distant metastases (n = 189, 89.2%), P = 0.003. Patients who received treatment aimed at complete tumor eradication (n = 28, 13.7%) had a median overall survival of 13.6 months (range: 1.1-101.1) and palliative treated patients (n = 94, 46.1%) of 4.7 months (range: 0.3-25.6), P < 0.001. In a selected group of patients survival of more than 20 months was achieved. Univariate and multivariate Cox-regression analysis showed that a higher age at the diagnosis of recurrent disease (hazard ratio: 1.087, P ≤ 0.001), an irradical resection of the primary tumor (hazard ratio: 3.355, P = < 0.001), the number of positive lymph nodes after neoadjuvant therapy (hazard ratios: ypN2 = 1.724 (P = 0.024) and ypN3 = 2.082 (P = 0.028) and the presence of a single hematogenous distant metastases (hazard ratio: 2.281, P = 0.003) or more than one hematogenous distant metastasis (hazard ratio: 2.385, P = 0.005) were associated with a shorter postrecurrence survival. The prognosis of patients who develop recurrent esophageal or junctional cancer is poor. In a selected group of patients however relatively long survival can be achieved. This offers new perspectives to improve treatment strategies and survival rates.

Preoperative Chemoradiotherapy Versus Perioperative Chemotherapy for Patients With Resectable Esophageal or Gastroesophageal Junction Adenocarcinoma.

BACKGROUND: This study compares neoadjuvant chemoradiotherapy (nCRT) with perioperative chemotherapy (pCT) for patients with resectable esophageal or gastroesophageal junction (GEJ) adenocarcinoma in terms of toxicity, postoperative complications, pathologic response, and survival. METHODS: This study retrospectively analyzed and compared 313 patients with resectable esophageal or GEJ adenocarcinoma treated with either nCRT (carboplatin/paclitaxel 41.4 Gy, n = 176) or pCT (epirubicin, cisplatin and capecitabine, n = 137). RESULTS: The baseline and tumor characteristics were similar in both groups. The ability to deliver all planned preoperative cycles was greater in the nCRT group (92.0 vs. 76.6%). Whereas nCRT was associated with a higher rate of grades 3 and 4 esophagitis, pCT was associated with a higher rate of grades 3 and 4 thromboembolic events, febrile neutropenia, nausea, vomiting, diarrhea, hand-foot syndrome, mucositis, cardiac complications, and electrolyte imbalances. Two patients in the pCT group died during neoadjuvant treatment due to febrile neutropenia. More postoperative cardiac complications occurred in the nCRT group. All other postoperative complications and the in-hospital mortality rate (nCRT, 4.7%; pCT, 2.3%) were comparable. The pathologic complete response (pCR) rate was 15.1% after nCRT and 6.9% after pCT. Radicality of surgery was comparable (R0: 93.0 vs. 91.6%). The median overall survival was 35 months after nCRT versus 36 months after pCT. CONCLUSION: For patients with esophageal or GEJ adenocarcinoma, chemoradiotherapy with paclitaxel, carboplatin and concurrent radiotherapy, and perioperative chemotherapy with epirubicin, cisplatin, and capecitabin lead to equal oncologic outcomes in terms of radical resection rates, lymphadenectomy, patterns of recurrent disease, and (disease-free) survival. However, neoadjuvant chemoradiotherapy is associated with a considerably lower level of severe adverse events and should therefore be the preferred protocol until a well-powered randomized controlled trial provides different insights.

Influence of the Extent and Dose of Radiation on Complications After Neoadjuvant Chemoradiation and Subsequent Esophagectomy With Gastric Tube Reconstruction With a Cervical Anastomosis.

PURPOSE: To determine, in a large series, the influence of the extent and dose of radiation to the fundus of the stomach and mediastinum on the development and severity of anastomotic complications in patients with esophageal cancer treated with neoadjuvant chemoradiation followed by esophagectomy with cervical anastomosis. METHODS AND MATERIALS: Between 2005 and 2012, 364 consecutive patients with esophageal cancer treated with neoadjuvant chemoradiation (41.4 Gy combined with chemotherapy) followed by esophagectomy were included. The future anastomotic region in the fundus was determined, and the mean dose, V20-V40, and upper planning target volume border in relation to mediastinal length, expressed as the mediastinal ratio, were calculated. RESULTS: Anastomotic leakage occurred in 22% and anastomotic stenosis in 41%. Logistic regression analysis revealed no influence of age, comorbidity, mean fundus dose, V20-V40, or the mediastinal ratio on the incidence of anastomotic leakage or anastomotic stenosis. In 28% of the patients severe complications (Clavien-Dindo score of ≥IIIB) occurred. The presence of multiple comorbidities (hazard ratio 2.4 [95% confidence interval 1.3-4.5], P=.006) and a mediastinal ratio of 0.5 to 1.0 (hazard ratio 1.9 [95% confidence interval 1.0-3.5], P=.036) were both independent predictors of severe complications. CONCLUSION: With a mean radiation dose of 24.2 Gy to the future anastomotic region of the gastric fundus, the radiation dose was not associated with the incidence of anastomotic leakage or anastomotic stenosis. The incidence of severe complications was associated with a high superior mediastinal planning target volume border.

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.

Definitive chemoradiation for locoregional recurrences of esophageal cancer after primary curative treatment.

The aim of this study was to determine the outcome of salvage definitive chemoradiation (dCRT) for a locoregional recurrence after any prior curative treatment outside previously irradiated areas. Thirty-nine patients treated between January 2005 and December 2014 were reviewed for locoregional recurrent esophageal cancer outside previously irradiated areas. All patients received salvage treatment with external beam radiotherapy (50.4 Gy in 28 fractions) combined with weekly concurrent paclitaxel and carboplatin. The median follow-up period was 15 months (range 1.7-120). The median overall survival (OS) for all patients after salvage dCRT was 22 months (95% CI 6.2-37.6). The 1-, 3-, and 5-year OS was 72%, 31%, and 28%, respectively. Median survival after salvage dCRT for a regional lymph node recurrence was 33 months (95% CI 5.8-60.3) versus 14 months (95% CI 6.8-21.6) for a recurrence at the anastomosis (P = 0.022, logrank). Median OS was 35 months for the squamous cell carcinoma group and 19 months for the adenocarcinoma group (P = 0.67). Sixteen of 39 patients developed a locoregional recurrence after salvaged dCRT. The median locoregional recurrence-free survival (LRFS) was 24 months. The 1-, 3-, and 5-year LRFS was 79%, 36%, and 36%, respectively. Median disease-free survival (DFS) was 15 months. The 1-, 3-, and 5-year DFS was 66%, 27%, and 27%, respectively. Of 16 patients, 8 (50%) with a primary failure at the site of the anastomosis developed a local recurrence after salvaged dCRT compared to 7 of 22 patients (32%) with a primary recurrence in a lymph node. Definitive chemoradiation is a feasible and effective treatment for locoregional recurrent esophageal cancer outside a previously irradiated area, and should be given with a curative intent. This holds true for recurrence of both squamous cell carcinoma and adenocarcinoma. Lymph node recurrences have a markedly better prognosis than recurrences at the site of the anastomosis.

Improving hyperthermia treatment planning for the pelvis by accurate fluid modeling.

PURPOSE: Hyperthermia is an established (neo)adjuvant treatment modality for a number of pelvic malignancies. Optimal treatment of these tumors requires robust treatment planning, but up until now, the urinary bladder was not modeled accurately, making current simulations less reliable. The authors improved the dielectric and thermophysical model of the urinary bladder in their treatment planning system, and showed the improvements using phantom experiments. METHODS: The authors suspended a porcine bladder in muscle tissue equivalent gel and filled it with 120 ml 0.9% saline. The authors heated the phantom during 15 min with their deep hyperthermia device, using clinical settings, and measured the temperature both inside and outside the bladder. The authors simulated the experiment, both using the clinically used treatment planning system, and using the improved model featuring correct dielectric properties for the bladder content and an enhanced thermophysical model, enabling the simulation of convection. RESULTS: Although the dielectric changes have an impact throughout the phantom, the dominant effect is a higher net heat absorption in the bladder. The effects of changing the thermophysical model are limited to the bladder and its surroundings, but result in a very different temperature profile. The temperatures predicted by the simulations using the new bladder model were in much better agreement with the measurements than those predicted by currently used treatment planning system. CONCLUSIONS: Modeling convection in the urinary bladder is very important for accurate hyperthermia treatment planning in the pelvic area.

Chemoradiotherapy in tumours of the oesophagus and gastro-oesophageal junction.

Oesophageal cancer remains a malignancy with a poor prognosis. However, in the recent 10-15 years relevant progress has been made by the introduction of chemoradiotherapy (CRT) for tumours of the oesophagus or gastro-oesophageal junction. The addition of neo-adjuvant CRT to surgery has significantly improved survival and locoregional control, for both adenocarcinoma and squamous cell carcinoma. For irresectable or medically inoperable patients, definitive CRT has changed the treatment intent from palliative to curative. Definitive CRT is a good alternative for radical surgery in responding patients with squamous cell carcinoma and those running a high risk of surgical morbidity and mortality. For patients with an out-of-field solitary locoregional recurrence after primary curative treatment, definitive CRT can lead to long term survival.