Health-related quality of life in a randomized trial of neoadjuvant chemotherapy or chemoradiotherapy plus surgery in patients with oesophageal cancer (NeoRes trial).

BACKGROUND: There are few data comparing health-related quality of life (HRQoL) after neoadjuvant chemotherapy alone (nCT) compared with neoadjuvant chemoradiotherapy (nCRT) in patients with oesophageal cancer. METHODS: In the NeoRes trial, patients were assigned randomly in a 1 : 1 ratio to receive either cisplatin 100 mg/m2 on day 1 and an infusion of 750 mg per m2 5-fluorouracil over 24 h on days 1-5 in three 21-day cycles (nCT) or the same chemotherapy regimen, but with the addition of 40 Gy radiotherapy (nCRT). HRQoL data were collected at baseline, after neoadjuvant therapy and at 1, 3 and 5 years after surgery. The European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 and disease-specific modules were used. RESULTS: Of 181 patients randomized, 165 were included in the analysis of HRQoL. In a direct comparison between the allocated treatments, odynophagia after completion of neoadjuvant therapy but before surgery (P = 0·047) and troublesome coughing at 3 years' follow-up (P = 0·011) were more pronounced in the nCRT arm. In the longitudinal analyses within each treatment arm, a large deterioration in HRQoL was noted at 1 year. Some recovery was seen in both arms over time but, after 3 and 5 years, patients in the nCRT arm reported more symptoms compared with baseline than patients in the nCT arm. CONCLUSION: HRQoL after multimodal treatment for cancer of the oesophagus or gastro-oesophageal junction was impaired and more pronounced in patients who underwent nCRT, with only partial recovery over time.

ANTECEDENTES: Se dispone de poca información sobre la calidad de vida relacionada con la salud (health-related quality of life, HRQOL) en pacientes con cáncer de esófago después de quimioterapia neoadyuvante sola en comparación con quimiorradioterapia neoadyuvante. MÉTODOS: En el ensayo NeoRes, los pacientes fueron asignados de forma aleatoria 1:1 a tratamiento con cisplatino 100 mg/m2 en el día uno y 5-Fluorouracilo 750 mg/m2 /infusión de 24 horas en los días 1-5 en tres ciclos de 21 días (nCT) o al mismo régimen de quimioterapia, pero con la adición de radioterapia 40 Gy (nCRT). Los datos de HRQOL se recogieron al inicio, tras el tratamiento neoadyuvante y al cabo de 1, 3 y 5 años tras la cirugía. Se utilizaron los cuestionarios QLQ-C30 de la European Organisation for Research and Treatment of Cancer (EORTC) y los módulos específicos para la enfermedad. RESULTADOS: De 181 pacientes aleatorizados, 165 fueron incluidos en el análisis de la HRQOL. En la comparación directa entre los tratamientos asignados, la odinofagia tras terminar nCRT pero antes de la cirugía (P = 0,047) y la tos molesta a los 3 años de seguimiento (P = 0,011), fueron más acentuadas en el brazo de nCRT. En el análisis longitudinal dentro de cada rama de tratamiento hubo un fuerte deterioro en la HRQOL al año. Se observó cierta recuperación en ambas ramas con el tiempo, pero a los 3 y 5 años de seguimiento, los pacientes de la rama de nCRT describieron más síntomas en comparación con la situación de inicio que los pacientes de la rama de nCT. CONCLUSIÓN: La HRQOL después del tratamiento multimodal del cáncer de esófago o de la unión gastroesofágica se ve afectada, siendo dicha afectación más pronunciada en pacientes que recibieron nCRT, recuperándose solo parcialmente con el tiempo.

Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or gastroesophageal junction: long-term results of a randomized clinical trial.

NeoRes I is a randomized phase II trial comparing neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy in the treatment of resectable cancer of the esophagus or gastroesophageal junction. Patients with biopsy-proven adenocarcinoma or squamous cell carcinoma, T1N1 or T2-3N0-1 and M0-M1a (AJCC 6th ed.), were randomized to receive three 3-weekly cycles of cisplatin 100 mg/m2 day 1 and fluorouracil 750 mg/m2/24 hours, days 1-5 with or without the addition of concurrent radiotherapy 40 Gy, 2 Gy/fraction, 5 days a week, followed by esophageal resection with two-field lymphadenectomy. Primary endpoint was complete histopathological response rate in the primary tumor. Survival and recurrence patterns were evaluated as secondary endpoints. Between 2006 and 2013, 181 patients were enrolled in Sweden and Norway. All three chemotherapy cycles were delivered to 73% of the patients allocated to chemoradiotherapy and to 86% of the patients allocated to chemotherapy. 87% of those allocated to chemoradiotherapy received full dose radiotherapy. 87% in the chemoradiotherapy group and 86% in the chemotherapy group underwent tumor resection. Initial results showed that patients allocated to chemoradiotherapy more often responded with complete histopathological response in the primary tumor (28% vs. 9%). Treatment-related complications were similar between the groups although postoperative complications were more severe in the chemoradiotherapy group. This article reports the long-term results. Five-year progression-free survival was 38.9% (95% CI 28.9%-48.8%) in the chemoradiotherapy group versus 33.0% (95% CI 23.6%-42.7%) in the chemotherapy group, P = 0.82. Five-year overall survival was 42.2% (95% CI 31.9%-52.1%) versus 39.6% (95% CI 29.5%-49.4%), P = 0.60. There were no differences in recurrence patterns between the treatment groups. This is to our knowledge that the largest completed randomized trial comparing neoadjuvant chemotherapy with neoadjuvant chemoradiotherapy followed by esophageal resection in patients with cancer in the esophagus or gastroesophageal junction. Despite a higher tumor tissue response in those who received neoadjuvant chemoradiotherapy, no survival advantages were seen. Consequently, the results do not support unselected addition of radiotherapy to neoadjuvant chemotherapy as a standard of care in patients with resectable esophageal cancer.

Relief of dysphagia during neoadjuvant treatment for cancer of the esophagus or gastroesophageal junction.

Dysphagia is the main symptom of cancer of the esophagus and gastroesophageal junction and causing nutritional problems and weight loss, often counteracted by insertion of self-expandable metal stents or nutrition via an enteral route. Clinical observations indicate that neoadjuvant therapy may effectively and promptly alleviate dysphagia, making such nutrition supportive interventions redundant before surgical resection. The objective of the current study was to carefully study the effects of induction neoadjuvant therapy on dysphagia and its subsequent course and thereby investigate the actual need for alimentary gateways for nutritional support. Thirty-five consecutive patients scheduled for neoadjuvant therapy were recruited and assessed regarding dysphagia and appetite at baseline, after the first cycle of preoperative treatment with either chemotherapy alone or with chemoradiotherapy and before surgery. Platinum-based therapy in combination with 5-fluorouracil was administered intravenously days 1-5 every 3 weeks and consisted of three treatments. Patients receiving combined chemoradiotherapy started radiotherapy on day one of second chemotherapy cycle. They received fractions of 2 Gy/day each up to a total dose of 40 Gy. Watson and Ogilvie dysphagia scores were used to assess dysphagia, while appetite was assessed by the Edmonton Assessment System Visual analogue scale-appetite questionnaire. Patients were evaluated at regular outpatient clinic visits or by telephone. The histological tumor response in the surgical specimen was assessed using the Chirieac scale. Ten patients scheduled for neoadjuvant chemotherapy and 25 patients scheduled for chemoradiotherapy were included in the analysis. There was a significant improvement in dysphagia in both treatment groups, according to both scales, already from baseline to the completion of the first chemotherapy cycle which remained to the end of the neoadjuvant treatment (P < 0.001). Appetite also improved after the first chemotherapy cycle (P = 0.03). Body weight did not change during any type of neoadjuvant therapy. We were unable to demonstrate any association between relief of dysphagia and the degree of histological response to neoadjuvant therapy in the surgical specimen. The present study shows that a platin - 5FU-based neoadjuvant chemotherapy, with or without concomitant radiotherapy, effectively and promptly relieves dysphagia in patients presenting with cancers of the esophagus or gastroesophageal junction already after the first cycle.

Randomised clinical trial: transoral incisionless fundoplication vs. sham intervention to control chronic GERD.

BACKGROUND: Until recently only two therapeutic options have been available to control symptoms and the esophagitis in chronic gastro-oesophageal reflux disease (GERD), i.e. lifelong proton pump inhibitor (PPI) therapy or anti-reflux surgery. Lately, transoral incisionless fundoplication (TIF) has been developed and found to offer a therapeutic alternative for these patients. AIM: To perform a double-blind sham-controlled study in GERD patients who were chronic PPI users. METHODS: We studied patients with objectively confirmed GERD and persistent moderate to severe GERD symptoms without PPI therapy. Of 121 patients screened, we finally randomised 44 patients with 22 patients in each group. Those allocated to TIF had the TIF2 procedure completed during general anaesthesia by the EsophyX device with SerosaFuse fasteners. The sham procedure consisted of upper GI endoscopy under general anaesthesia. Neither the patient nor the assessor was aware of the patients' group affiliation. The primary effectiveness endpoint was the proportion of patients in clinical remission after 6-month follow-up. Secondary outcomes were: PPI consumption, oesophageal acid exposure, reduction in Quality of Life in Reflux and Dyspepsia and Gastrointestinal Symptom Rating Scale scores and healing of reflux esophagitis. RESULTS: The time (average days) in remission offered by the TIF2 procedure (197) was significantly longer compared to those submitted to the sham intervention (107), P < 0.001. After 6 months 13/22 (59%) of the chronic GERD patients remained in clinical remission after the active intervention. Likewise, the secondary outcome measures were all in favour of the TIF2 procedure. No safety issues were raised. CONCLUSION: Transoral incisionless fundoplication (TIF2) is effective in chronic PPI-dependent GERD patients when followed up for 6 months. Clinicaltrials.gov: CT01110811.

Morbidity and mortality after surgery for cancer of the oesophagus and gastro-oesophageal junction: A randomized clinical trial of neoadjuvant chemotherapy vs. neoadjuvant chemoradiation.

OBJECTIVE: To compare the incidence and severity of postoperative complications after oesophagectomy for carcinoma of the oesophagus and gastro-oesophageal junction (GOJ) after randomized accrual to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT). BACKGROUND: Neoadjuvant therapy improves long-term survival after oesophagectomy. To date, evidence is insufficient to determine whether combined nCT, or nCRT alone, is the most beneficial. METHODS: Patients with carcinoma of the oesophagus or GOJ, resectable with a curative intention, were enrolled in this multicenter trial conducted at seven centres in Sweden and Norway. Study participants were randomized to nCT or nCRT followed by surgery with two-field lymphadenectomy. Three cycles of cisplatin/5-fluorouracil was administered in all patients, while 40 Gy of concomitant radiotherapy was administered in the nCRT group. RESULTS: Of the randomized 181 patients, 91 were assigned to nCT and 90 to nCRT. One-hundred-and-fifty-five patients, 78 nCT and 77 nCRT, underwent resection. There was no statistically significant difference between the groups in the incidence of surgical or nonsurgical complications (P-value = 0.69 and 0.13, respectively). There was no 30-day mortality, while the 90-day mortality was 3% (2/78) in the nCT group and 6% (5/77) in the nCRT group (P = 0.24). The median Clavien-Dindo complication severity grade was significantly higher in the nCRT group (P = 0.001). CONCLUSION: There was no significant difference in the incidence of complications between patients randomized to nCT and nCRT. However, complications were significantly more severe after nCRT. REGISTRATION TRIAL DATABASE: The trial was registered in the Clinical Trials Database (registration number NCT01362127).

Effects of dietary nitrate on oesophageal motor function and gastro-oesophageal acid exposure in healthy volunteers and reflux patients.

BACKGROUND/AIMS: High concentrations of nitric oxide (NO), derived from dietary nitrite in an acid environment, have been demonstrated in the gastric fundus and in the oesophagus. The aim of this study was to investigate whether luminal NO can influence oesophageal smooth muscle performance, lower oesophageal sphincter (LOS) function or gastric and oesophageal acid exposure. METHODS: Eleven healthy volunteers and 9 patients with chronic gastro-oesophageal reflux disease (GORD) received a diet deprived of nitrate/nitrite but supplemented with placebo or potassium nitrate for 4 days in a randomised order. On day 4 in each trial period, manometry was performed including a sleeve sensor registration of the LOS followed by a simultaneous 24-hour intra-gastric and oesophageal pH registration. RESULTS: Nitrate supplementation increased the proportion of effective peristalsis when analysed for the entire study population. No other significant effects of dietary nitrate were found on oesophageal motor variables, on the sphincter resting tone or on the number or duration of transient sphincter relaxations. No effect was found on either gastric acidity or gastro-oesophageal reflux variables. Major reflux symptoms were not influenced by nitrate administration. CONCLUSION: Dietary nitrate did not significantly affect oesophageal motor or LOS function, gastro-oesophageal acid reflux or reflux symptomatology either in healthy volunteers or in GORD patients.

Sources of intra-oesophageal nitric oxide production following intraluminal acid exposure.

BACKGROUND: The aim of the present study was to assess luminal nitric oxide (NO) levels in the oesophagus during baseline and acidic conditions and to clarify the sources of such oesophageal NO formation. METHODS: Healthy volunteers received an intra-oesophageal infusion of either HCl (100 mM) or NaCl (50 mM) on two separate study days. After a low nitrate diet, nitrate load or no dietary restrictions/pretreatment, direct intraluminal measurements of NO formation were performed using a tonometric technique. Endoscopy was performed and mucosal biopsies were taken and analysed by means of immunohistochemistry, Western blot and RT-PCR. RESULTS: No intra-oesophageal NO was detected during baseline conditions with pH neutrality. During the infusion of HCI the NO levels rose dramatically to around 12000 ppb. This high rate of NO formation fell by 95% following deviation of saliva. NO formation after an acute nitrate load was almost doubled during acid perfusion compared to control. Immunohistochemistry demonstrated distinct staining for iNOS in the oesophageal squamous epithelial cells, and Western blot and RT-PCR confirmed the presence of iNOS. CONCLUSION: Two sources exist for intra-oesophageal NO formation, both dependent on the luminal acidity: 1) chemical reduction of salivary nitrite, a mechanism related to dietary intake of nitrate, and 2) NO formation within the oesophageal mucosal epithelium by enzymatic degradation of L-arginine. In the latter case, the NO synthase has antigenic characteristics, indicating the inducible isoform, although a functional behaviour suggests an unconventional subtype.

24-hour intragastric acidity and plasma gastrin during long-term treatment with omeprazole or ranitidine in patients with reflux esophagitis.

The reduction in intragastric acidity and the subsequent increase in plasma gastrin were compared during long-term treatment with either omeprazole or ranitidine in 19 patients with erosive reflux esophagitis. The patients received 40 mg omeprazole in the morning or 300 mg ranitidine twice daily. After healing, half the dose was given as maintenance treatment for 1 year. Intragastric acidity and plasma gastrin were measured 24 h before entry and monthly with the high dose and after 1, 6, and 12 months with the low dose. Omeprazole reduced intragastric acidity more effectively than ranitidine (p less than 0.001). This difference in efficacy was more pronounced during the daytime. Plasma gastrin increased more after omeprazole than after ranitidine (p less than 0.01), and both drugs showed a normal postprandial response and approached fasting levels before the next dose. During long-term treatment with 20 mg omeprazole in the morning no progressive alterations were observed in 24-h intragastric acidity or plasma gastrin.

Omeprazole or high-dose ranitidine in the treatment of patients with reflux oesophagitis not responding to 'standard doses' of H2-receptor antagonists.

Ninety-eight patients (26 females), who presented with erosive and/or ulcerative oesophagitis, despite at least a 3-month period of treatment with standard doses of cimetidine (greater than or equal to 1200 mg daily) or ranitidine (greater than or equal to 300 mg daily), were included in a double-blind, randomized trial to compare omeprazole (40 mg o.m.) with a high dose of ranitidine (300 mg b.d.). The treatment was given for 4-12 weeks; endoscopy assessment and laboratory screening were performed on entry to the trial and thereafter every fourth week. Endoscopic healing was defined as complete epithelialization of all macroscopic erosions or ulcers in the squamous epithelium. An 'intention-to-treat' analysis of the clinical data revealed omeprazole to be superior to ranitidine: 63% of those patients who were given omeprazole were healed endoscopically after a 4-week period of treatment, compared with only 17% of those given ranitidine. This difference in healing rate persisted during the 12-week study period (90% vs 47% after 12 weeks; P less than 0.0001). Reflux symptoms were more rapidly and completely relieved with omeprazole: heartburn resolved completely in 86% of patients treated with omeprazole for 4 weeks compared with 32% in the ranitidine group (P less than 0.0001). The mean basal gastrin concentrations increased only in those given omeprazole from 18.9 pmol/L at pre-entry to a mean value of 31.7 pmol/L on the last day of omeprazole administration. In ranitidine-treated patients no significant increase in basal gastrin concentration was observed. Both drugs were well tolerated with few adverse events, which were mainly mild and transient. These results demonstrate the superiority of omeprazole over a high dose of ranitidine in the treatment of resistant reflux oesophagitis.

Zinc status and dark adaptation in patients subjected to total gastrectomy: effect of zinc supplementation.

Totally gastrectomized patients could be regarded at risk for development of nutritional deficiencies including trace elements. Sensitive indices for early detection of these deficiencies are lacking. In order to evaluate the nutritional status of trace elements in patients previously subjected to a total gastrectomy we studied the zinc status in 10 patients by determining serum zinc, urinary zinc excretion and also, by a simplified dark adaptation test, the effect on these parameters of 4 weeks of zinc supplementation. The serum zinc level but not the 24-h urinary zinc excretion was lower in gastrectomized patients compared to age-matched controls. A slower dark adaptation was observed in the former patients when measured in the non-fasting state but not when fasted. Dark adaptation was slower in the patients as well as the age-matched controls compared to younger healthy subjects. Zinc supplementation increased the serum zinc levels and the urinary zinc excretion in the gastrectomized patients but had no effect on dark adaptation.

Effect of high-dose omeprazole administration on histamine storage and formation in canine gastric mucosa.

The effect of a high dose of omeprazole on the plasma gastrin response to feeding and gastric mucosal histamine formation and storage in the dog has been studied. Tissue from the oxyntic gland area was obtained by introduction of an endoscope through a gastric fistula, and biopsies were taken before, after 4 weeks of oral administration of omeprazole and 1 month after withdrawal of the drug. Omeprazole administration increased the basal plasma concentration of gastrin and induced a substantial increase in the feeding response. Histidine-decarboxylase activity was significantly increased after 4 weeks of omeprazole administration, whereas no effect was found on histamine content and mucosal mast cell density. One month after drug withdrawal, the enzyme activity had returned to pretreatment levels.

Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats.

Unoperated female rats were subjected to daily oral treatment with omeprazole (10 or 400 mumol/kg body wt), ranitidine (175 + 175 + 350 mumol/kg body wt), or vehicle and antrectomized rats were treated with omeprazole (400 mumol/kg body wt) or vehicle. After 10 wk of treatment, plasma gastrin levels were high in unoperated rats treated with the high omeprazole dose and with ranitidine, and low in antrectomized controls. Plasma gastrin levels were slightly higher in the low-dose omeprazole group than in the intact controls. In antrectomized rats treated with the high dose of omeprazole, the plasma gastrin level was in the same range as in intact control rats. A close correlation (r = 0.89, p less than 0.0001) was found between the plasma gastrin level and the oxyntic mucosal enterochromaffinlike cell density (as well as the tissue levels of histidine decarboxylase and histamine in the oxyntic mucosa) in all groups. The somatostatin cell density in the oxyntic mucosa was not altered by the various treatments. During a recovery period of 10 wk after the 10-wk treatment, the enterochromaffinlike cell density and histamine concentration decreased by 30%-40% in the rats treated with the high dose of omeprazole, whereas the corresponding values increased by 50% and 40%, respectively, in the control rats. The difference between the two groups, however, was still statistically significant. Plasma gastrin levels and gastric histidine decarboxylase activity returned to control values during recovery. The results suggest that the observed changes in enterochromaffinlike cell density are related to the plasma gastrin levels and that they are reversible. it is concluded that neither omeprazole nor ranitidine per se is likely to induce proliferation of enterochromaffinlike cells.