Aspects of neoadjuvant therapy in the curative treatment of cancer in the esophagus or gastroesophageal junction

Malignant esophageal tumors are among the most severe cancers. Only about 30% of the patients are suitable for curative treatment at diagnosis. The treatment is extremely demanding and unfortunately has disappointing results. The staging of disease and the treatment for cancer of the esophagus and gastroesophageal junction need to be improved. It is currently well established that neoadjuvant therapy, either with chemotherapy or with combined chemo- and radiotherapy, followed by surgery, offers a better chance for a cure in stage II and III esophageal and gastroesophageal junction cancer, than surgery alone. Data directly comparing neoadjuvant chemotherapy and chemoradiotherapy are scarce and it is debatable which of these neoadjuvant treatment concepts offers the best chance for long-term survival. This thesis aims to improve the knowledge about neoadjuvant treatment in the curative treatment of esophageal cancer. Papers I and III were based on the Neoadjuvant Chemotherapy versus Chemoradiotherapy in Resectable Cancer of the Esophagus and Gastric Cardia (NeoRes) trial, which was performed in Norway and Sweden during the period 2006– 2013. Patients with resectable squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction were randomized to either preoperative chemotherapy or preoperative combined chemoradiotherapy followed by surgical resection. Paper I showed an increased risk for severe postoperative complications after chemoradiotherapy compared to chemotherapy. In paper III we found that neoadjuvant chemoradiotherapy significantly increases the proportion of complete histological response, increases the occurrence of N0 lymph-node status, and increases the R0 resection rate, but there was no difference in overall survival compared to neoadjuvant chemotherapy. Paper II is a retrospective cohort study of patients with cancer of the esophagus or gastro- esophageal junction, who was reconstructed with cervical anastomosis. The planned radiation dose to the site of the cervical anastomosis on the gastric fundus was estimated for each patient. This study suggests that nCRT exposes the future anastomotic site to doses of radiation that may impair healing of the subsequent cervical anastomosis. Our data further suggest that nCRT may increase the severity of cervical anastomotic complications. Paper IV is a prospective population-based cohort study including all patients who underwent an esophagectomy operation due to cancer in Sweden, excluding T1N0, recorded in the Swedish National Register for Esophageal and Gastric Cancer, 2006-2014. The results showed that neoadjuvant chemoradiotherapy increases local tumor control, represented by increased R0 resection rates and pathological node-negative disease both compared to surgery alone and chemotherapy. For patients with the histological subtype squamous cell carcinoma, neoadjuvant treatment increases long-term survival but also increases the risk of postoperative morbidity and mortality compared to surgery alone. Neither of the two neoadjuvant treatment options seem to improve survival in adenocarcinomas, compared to surgery alone, in an unselected population of patients

Optimized growth and reduced morbidity in preterm infants : focus on nutrition and saturation targets

Preterm birth alters the conditions during an important period of growth and organ maturation. Extremely preterm infants have a high risk of developing morbidity. Retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) originate in a disturbed retinal and pulmonary development. Associations between nutrition and risk of ROP and BPD have been demonstrated in some previous studies. Practical guidelines published 2005 included recommendations of higher early macronutrient intakes after preterm birth, compared to previous guidelines. One well known risk factor for ROP is oxygen exposure. As a result of five coordinated randomized trials, European saturation target guidelines were revised 2013. The objective of this thesis is to study neonatal practices potentially associated with the risk of developing ROP and BPD. In addition, this thesis examines the adherence to implemented new recommendations of nutritional intakes and saturation targets. The overall aim is to increase the quality of care, in order to improve outcome in the high-risk population of extremely preterm infants. Paper I examined growth patterns in a large cohort of infants born in gestational age (GA) 23 0/7 to 30 6/7 weeks. Longitudinal data were used to investigate differences in growth patterns. The results demonstrated reduced postnatal weight gain in infants who developed ROP and BPD compared to infants without these diseases. The growth patterns differed depending on gestational age and postnatal age. Paper II used detailed nutritional data from infants born between 2004 and 2011 at GA <27 weeks to study whether early energy and protein intakes were associated with initial growth and risk for ROP and BPD. The results showed that higher intakes of energy and protein were associated with improved weight development the first week of life. Increased energy intake during postnatal days 7 to 27 was associated with a reduced risk of ROP among infants with fewer than ten days of mechanical ventilation. Increased energy and protein intake during postnatal days 7 to 27 was associated with a reduced risk of BPD among infants born during 2008 to 2011. Paper III showed that nutritional intakes have increased continuously during 2004 to 2011 in Stockholm. This coincided with implementation of a bundle of interventions aiming at improved nutrition. During 2004 to 2009 the majority infants had lower protein intakes the first postnatal days than the then prevailing guidelines recommended. Paper IV studied peripheral oxygen saturation in infants born at GA 23 0/7 to 30 6/7 with two different saturation targets and alarm limits. Higher saturation target and tighter alarm limits were associated with an increased proportion of time within the target range and a reduced oxygen saturation variability. Mean oxygen saturation and the proportion of time with hyperoxia were increased with the higher target range. In conclusion, this thesis highlights the importance of neonatal practices. Increased early nutritional intakes are associated with reduced initial growth restriction and morbidity. Poor postnatal weight gain is a marker for disease. Improved nutritional regimen and enhanced focus on postnatal growth may improve outcomes for extremely preterm infants. It is important to monitor adherence to guidelines as there is room for further improvement in quality of care

Cardiorespiratory comorbidity and postoperative complications following esophagectomy: a European multicenter cohort study

BACKGROUND: The impact of cardiorespiratory comorbidity on operative outcomes after esophagectomy remains controversial. This study investigated the effect of cardiorespiratory comorbidity on postoperative complications for patients treated for esophageal or gastroesophageal junction cancer. PATIENTS AND METHODS: A European multicenter cohort study from five high-volume esophageal cancer centers including patients treated between 2010 and 2017 was conducted. The effect of cardiorespiratory comorbidity and respiratory function upon postoperative outcomes was assessed. RESULTS: In total 1590 patients from five centers were included; 274 (17.2%) had respiratory comorbidity, and 468 (29.4%) had cardiac comorbidity. Respiratory comorbidity was associated with increased risk of overall postoperative complications, anastomotic leak, pulmonary complications, pneumonia, increased Clavien-Dindo score, and critical care and hospital length of stay. After neoadjuvant chemoradiotherapy, respiratory comorbidity was associated with increased risk of anastomotic leak [odds ratio (OR) 1.83, 95% confidence interval (CI) 1.11-3.04], pneumonia (OR 1.65, 95% CI 1.10-2.47), and any pulmonary complication (OR 1.52, 95% CI 1.04-2.22), an effect which was not observed following neoadjuvant chemotherapy or surgery alone. Cardiac comorbidity was associated with increased risk of cardiovascular and pulmonary complications, respiratory failure, and Clavien-Dindo score ≥ IIIa. Among all patients, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio > 70% was associated with reduced risk of overall postoperative complications, cardiovascular complications, atrial fibrillation, pulmonary complications, and pneumonia. CONCLUSIONS: The results of this study suggest that cardiorespiratory comorbidity and impaired pulmonary function are associated with increased risk of postoperative complications after esophagectomy performed in high-volume European centers. Given the observed interaction with neoadjuvant approach, these data indicate a potentially modifiable index of perioperative risk

Sex-related differences in oncologic outcomes, operative complications and health-related quality of life after curative-intent oesophageal cancer treatment: multicentre retrospective analysis.

Oesophageal cancer, in particular adenocarcinoma, has a strong male predominance. However, the impact of patient sex on operative and oncologic outcomes and recovery of health-related quality of life is poorly documented, and was the focus of this large multicentre cohort study. All consecutive patients who underwent oncological oesophagectomy from 2009 to 2015 in the 20 European iNvestigation of SUrveillance after Resection for Esophageal cancer study group centres were assessed. Clinicopathologic variables, therapeutic approach, postoperative complications, survival and health-related quality of life data were compared between male and female patients. Multivariable analyses adjusted for age, sex, tumour histology, treatment protocol and major complications. Specific subgroup analyses comparing adenocarcinoma versus squamous cell cancer for all key outcomes were performed. Overall, 3974 patients were analysed, 3083 (77.6%) male and 891 (22.4%) female; adenocarcinoma was predominant in both groups, while squamous cell cancer was observed more commonly in female patients (39.8% versus 15.1%, P &lt; 0.001). Multivariable analysis demonstrated improved outcomes in female patients for overall survival (HRmales 1.24, 95% c.i. 1.07 to 1.44) and disease-free survival (HRmales 1.22, 95% c.i. 1.05 to 1.43), which was caused by the adenocarcinoma subgroup, whereas this difference was not confirmed in squamous cell cancer. Male patients presented higher health-related quality of life functional scores but also a higher risk of financial problems, while female patients had lower overall summary scores and more persistent gastrointestinal symptoms. This study reveals uniquely that female sex is associated with more favourable long-term survival after curative treatment for oesophageal cancer, especially adenocarcinoma, although long-term overall and gastrointestinal health-related quality of life are poorer in women

Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.

BACKGROUND: Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. METHODS: OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 10(9) cells per L, platelet count at least 100 × 10(9) platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m(2) intravenously on day 1] and fluorouracil [1 g/m(2) per day intravenously on days 1-4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m(2)] and cisplatin [60 mg/m(2)] intravenously on day 1, and capecitabine [1250 mg/m(2)] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4-6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. FINDINGS: Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6-26·3) with CF and 26·1 months (22·5-29·7) with ECX (hazard ratio 0·90 (95% CI 0·77-1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. INTERPRETATION: Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. FUNDING: Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London

Maternal and Neonatal Polyunsaturated Fatty Acid Intake and Risk of Neurodevelopmental Impairment in Premature Infants

The N3 and N6 long chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid (DHA) and arachidonic acid (AA) are essential for proper neurodevelopment in early life. These fatty acids are passed from mother to infant via the placenta, accreting into fetal tissues such as brain and adipose tissue. Placental transfer of LCPUFA is highest in the final trimester, but this transfer is abruptly severed with premature birth. As such, efforts have been made to supplement the post-natal feed of premature infants with LCPUFA to improve neurodevelopmental outcomes. This narrative review analyzes the current body of evidence pertinent to neurodevelopmental outcomes after LCPUFA supplementation in prematurely born infants, which was identified via the reference lists of systematic and narrative reviews and PubMed search engine results. This review finds that, while the evidence is weakened by heterogeneity, it may be seen that feed comprising 0.3% DHA and 0.6% AA is associated with more positive neurodevelopmental outcomes than LCPUFA-deplete feed. While no new RCTs have been performed since the most recent Cochrane meta-analysis in 2016, this narrative review provides a wider commentary; the wider effects of LCPUFA supplementation in prematurely born infants, the physiology of LCPUFA accretion into preterm tissues, and the physiological effects of LCPUFA that affect neurodevelopment. We also discuss the roles of maternal LCPUFA status as a modifiable factor affecting the risk of preterm birth and infant neurodevelopmental outcomes. To better understand the role of LCPUFAs in infant neurodevelopment, future study designs must consider absolute and relative availabilities of all LCPUFA species and incorporate the LCPUFA status of both mother and infant in pre- and postnatal periods

Cardiorespiratory Comorbidity and Postoperative Complications following Esophagectomy: a European Multicenter Cohort Study

Contains fulltext : 206269.pdf (publisher's version ) (Open Access

Outcome of neoadjuvant therapies for cancer of the oesophagus or gastro-oesophageal junction based on a national data registry

Background: Randomized trials have shown that neoadjuvant treatment improves survival in the curative treatment of oesophageal and gastro-oesophageal junction cancer. Results from population-based observational studies are, however, sparse and ambiguous. Methods: This prospective population-based cohort study included all patients who had oesophagectomy for cancer in Sweden, excluding clinical T1 N0, recorded in the National Register for Oesophageal and Gastric Cancer, 2006–2014. Patients were stratified into three groups: surgery alone, neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy. Results: Neoadjuvant treatment was given to 521 patients (51·1 per cent) and 499 (48·9 per cent) received surgery alone. Neoadjuvant chemotherapy increased the risk of postoperative surgical complications compared with surgery alone (adjusted odds ratio 2·01, 95 per cent c.i. 1·24 to 3·25; P = 0·005). Postoperative mortality was significantly increased after neoadjuvant chemoradiotherapy compared with surgery alone (odds ratio 2·37, 1·06 to 5·29; P = 0·035). Survival improved in patients with squamous cell carcinoma after neoadjuvant chemotherapy, whereas after neoadjuvant chemoradiotherapy survival was significantly improved only in the subgroup with the highest performance status and without known co-morbidity. In adenocarcinoma there was a trend towards improved overall survival after neoadjuvant chemotherapy, but neoadjuvant chemoradiotherapy did not offer a survival benefit. Stratified analysis including only patients with adenocarcinoma in the highest performance category without known co-morbidity showed a strong trend towards improved survival after neoadjuvant chemotherapy compared with surgery alone (adjusted hazard ratio 0·47, 0·21 to 1·04; P = 0·061). Conclusion: For patients with squamous cell carcinoma of the oesophagus or gastro-oesophageal junction, neoadjuvant treatments seemed to increase long-term survival, but also the risk of postoperative morbidity and mortality, compared with surgery alone. Neither neoadjuvant treatment option seemed to improve survival significantly among patients with adenocarcinoma, compared with surgery alone