Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. METHODS: In this multicentre, randomised, open-label phase 2-3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1-21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203. FINDINGS: Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5-54·9) in the chemotherapy alone group and 48·1% (43·2-52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91-1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). INTERPRETATION: The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. FUNDING: Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.

Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.

BACKGROUND: A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. METHODS: We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. RESULTS: ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001). CONCLUSIONS: In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival. (Current Controlled Trials number, ISRCTN93793971 [controlled-trials.com].).

Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer.

Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

Risk of premature menopause after treatment for Hodgkin's lymphoma.

BACKGROUND: Modern treatment of Hodgkin's lymphoma (HL) has transformed its prognosis but causes late effects, including premature menopause. Cohort studies of premature menopause risks after treatment have been relatively small, and knowledge about these risks is limited. METHODS: Nonsurgical menopause risk was analyzed in 2127 women treated for HL in England and Wales at ages younger than 36 years from 1960 through 2004 and followed to 2003 through 2012. Risks were estimated using Cox regression, modified Poisson regression, and competing risks. All statistical tests were two-sided. RESULTS: During follow-up, 605 patients underwent nonsurgical menopause before age 40 years. Risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea [BCNU], etoposide, cytarabine, melphalan) chemotherapy for stem cell transplantation, but was not statistically significantly raised after adriamycin, bleomycin, vinblastine, dacarbazine (ABVD). Menopause generally occurred sooner after ovarian radiotherapy (62.5% within five years of ≥5 Gy treatment) and BEAM (50.9% within five years) than after alkylating chemotherapy (24.2% within five years of ≥6 cycles), and after treatment at older than at younger ages. Cumulative risk of menopause by age 40 years was 81.3% after greater than or equal to 5Gy ovarian radiotherapy, 75.3% after BEAM, 49.1% after greater than or equal to 6 cycles alkylating chemotherapy, 1.4% after ABVD, and 3.0% after solely supradiaphragmatic radiotherapy. Tables of individualized risk information for patients by future period, treatment type, dose and age are provided. CONCLUSIONS: Patients treated with HL need to plan intended pregnancies using personalized information on their risk of menopause by different future time points.

The feasibility of a randomized controlled trial of esophagectomy for esophageal cancer--the ROMIO (Randomized Oesophagectomy: Minimally Invasive or Open) study: protocol for a randomized controlled trial.

BACKGROUND: There is a need for evidence of the clinical effectiveness of minimally invasive surgery for the treatment of esophageal cancer, but randomized controlled trials in surgery are often difficult to conduct. The ROMIO (Randomized Open or Minimally Invasive Oesophagectomy) study will establish the feasibility of a main trial which will examine the clinical and cost-effectiveness of minimally invasive and open surgical procedures for the treatment of esophageal cancer. METHODS/DESIGN: A pilot randomized controlled trial (RCT), in two centers (University Hospitals Bristol NHS Foundation Trust and Plymouth Hospitals NHS Trust) will examine numbers of incident and eligible patients who consent to participate in the ROMIO study. Interventions will include esophagectomy by: (1) open gastric mobilization and right thoracotomy, (2) laparoscopic gastric mobilization and right thoracotomy, and (3) totally minimally invasive surgery (in the Bristol center only). The primary outcomes of the feasibility study will be measures of recruitment, successful development of methods to monitor quality of surgery and fidelity to a surgical protocol, and development of a core outcome set to evaluate esophageal cancer surgery. The study will test patient-reported outcomes measures to assess recovery, methods to blind participants, assessments of surgical morbidity, and methods to capture cost and resource use. ROMIO will integrate methods to monitor and improve recruitment using audio recordings of consultations between recruiting surgeons, nurses, and patients to provide feedback for recruiting staff. DISCUSSION: The ROMIO study aims to establish efficient methods to undertake a main trial of minimally invasive surgery versus open surgery for esophageal cancer. TRIAL REGISTRATION: The pilot trial has Current Controlled Trials registration number ISRCTN59036820(25/02/2013) at http://www.controlled-trials.com; the ROMIO trial record at that site gives a link to the original version of the study protocol.

Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin's lymphoma in England and Wales: a National Cohort Study.

PURPOSE: To investigate breast cancer risk after supradiaphragmatic radiotherapy administered to young women with Hodgkin's lymphoma (HL) in a much larger cohort than previously to provide data for patient follow-up and screening individualized according to treatment type, age, and time point during follow-up. PATIENTS AND METHODS: Breast cancer risk was assessed in 5,002 women in England and Wales treated for HL with supradiaphragmatic radiotherapy at age < 36 years from 1956 to 2003, who underwent follow-up with 97% completeness until December 31, 2008. RESULTS: Breast cancer or ductal carcinoma in situ developed in 373 patients, with a standardized incidence ratio (SIR) of 5.0 (95% CI, 4.5 to 5.5). SIRs were greatest for those treated at age 14 years (47.2; 95% CI, 28.0 to 79.8) and continued to remain high for at least 40 years. The maximum absolute excess risk was at attained ages 50 to 59 years. Alkylating chemotherapy or pelvic radiotherapy diminished the risk, but only for women treated at age ≥ 20 years, not for those treated when younger. Cumulative risks were tabulated in detail; for 40-year follow-up, the risk for patients receiving ≥ 40 Gy mantle radiotherapy at young ages was 48%. CONCLUSION: This article provides individualized risk estimates based on large numbers for patients with HL undergoing follow-up after radiotherapy at young ages. Follow-up of such women needs to continue for 40 years or longer and may require more-intensive screening regimens than those in national general population programs. Special consideration is needed of potential measures to reduce breast cancer risk for girls treated with supradiaphragmatic radiotherapy at pubertal ages.

Health-related quality of life among patients cured by surgery for esophageal cancer.

BACKGROUND: Little is known regarding the long-term, health-related quality of life (HRQL) of survivors of esophagectomy for cancer. METHODS: Consecutive patients completed the validated European Organization for Research and Treatment of Cancer general quality-of life-questionnaire (QLQ-C30) and the esophageal-specific module (QLQ-OES18) before surgery and regularly thereafter for at least 3 years. Mean scores with 95% confidence intervals were calculated. The Student t test for paired data was used to determine differences between baseline and 3-year HRQL scores in which scores differed by >or=5 points. RESULTS: Of 90 patients who underwent surgery, 47 patients (52%) survived for >or=3 years. In this group, most aspects of HRQL recovered to preoperative levels by the 3-year assessment, except that scores for physical function, breathlessness, diarrhea, and reflux were significantly worse than at baseline (P < .01). However, patients reported significantly better emotional function 3 years after surgery than before treatment (P = .0008). CONCLUSIONS: Even after 3 years, patients who underwent esophagectomy suffered persistent problems with physical function and specific symptoms. These findings may be used to inform patients of the long-term consequences of surgery.

Health-related quality of life during neoadjuvant treatment and surgery for localized esophageal carcinoma.

BACKGROUND: Esophagectomy has a negative influence on health-related quality of life (HRQL) during the first postoperative year, but it is not known how chemotherapy or chemoradiotherapy treatment before surgery affects HRQL. The current study examined HRQL during preoperative chemotherapy/chemoradiotherapy treatment and compared postoperative recovery of HRQL in patients undergoing combined treatment with patients undergoing surgery alone. METHODS: One hundred three patients completed standardized HRQL measures before and during neoadjuvant treatment and before and after surgery. Mean HRQL scores were calculated and preoperative scores were used to model postoperative ratings using linear regression. RESULTS: Deterioration in most aspects of HRQL occurred during preoperative chemotherapy. Patients proceeding to concomitant radiotherapy further deteriorated with specific problems with reflux symptoms and role function (difference between means >15, P < 0.01). After neoadjuvant treatment, but before surgery, HRQL returned to baseline levels. Six weeks after surgery, patients reported marked reductions in physical, role, and social function (difference between means > 30, P < 0.01) and increase in fatigue, nausea and emesis, pain, dyspnea, appetite loss, and coughing (difference between means > 15, P < 0.01). Recovery of HRQL was not hampered by preoperative treatment, and fewer problems with postoperative nausea, emesis, and dysphagia were reported by patients who had undergone neoadjuvant treatment compared with patients who had undergone surgery alone. CONCLUSIONS: Preoperative chemotherapy or chemoradiotherapy had a negative impact on HRQL that was restored in patients proceeding to surgery. Recovery of HRQL after esophagectomy was not impaired by neoadjuvant treatment. These results supported the use of neoadjuvant treatment before surgery.

Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and minimal thoracic symptoms: randomised controlled trial.

OBJECTIVE: To determine whether patients with locally advanced non-small cell lung cancer unsuitable for resection or radical radiotherapy, and with minimal thoracic symptoms, should be given palliative thoracic radiotherapy immediately or as needed to treat symptoms. DESIGN: Multicentre randomised controlled trial. SETTING: 23 centres in the United Kingdom, Ireland, and South Africa. PARTICIPANTS: 230 patients with previously untreated, non-small cell lung cancer that is locally too advanced for resection or radical radiotherapy with curative intent, with minimal thoracic symptoms, and with no indication for immediate thoracic radiotherapy. INTERVENTIONS: All patients were given supportive treatment and were randomised to receive palliative thoracic radiotherapy either immediately or delayed until needed to treat symptoms. The recommended regimens were 17 Gy in two fractions one week apart or 10 Gy as a single dose. MAIN OUTCOME MEASURES: Primary--patients alive and without moderate or severe cough, chest pain, haemoptysis, or dyspnoea six months from randomisation, as recorded by clinicians. Secondary--quality of life, adverse events, survival. RESULTS: From December 1992 to May 1999, 230 patients were randomised. 104/115 of the patients in the immediate treatment group received thoracic radiotherapy (90 received one of the recommended regimens). In the delayed treatment group, 48/115 (42%) patients received thoracic radiotherapy (29 received one of the recommended regimens); 64 (56%) died without receiving thoracic radiotherapy; the remaining three (3%) were alive at the end of the study without having received the treatment. For patients who received thoracic radiotherapy, the median time to start was 15 days in the immediate treatment group and 125 days in the delayed treatment group. The primary outcome measure was achieved in 28% of the immediate treatment group and 26% of patients from the delayed treatment group (27/97 and 27/103, respectively; absolute difference 1.6%, 95% confidence interval -10.7% to 13.9%). No evidence of a difference was observed between the two treatment groups in terms of activity level, anxiety, depression, and psychological distress, as recorded by the patients. Adverse events were more common in the immediate treatment group. Neither group had a survival advantage (hazard ratio 0.95, 0.73 to 1.24; P=0.71). Median survival was 8.3 months and 7.9 months, and the survival rates were 31% and 29% at 12 months, for the immediate and delayed treatment groups, respectively. CONCLUSION: In minimally symptomatic patients with locally advanced non-small cell lung cancer, no persuasive evidence was found to indicate that giving immediate palliative thoracic radiotherapy improves symptom control, quality of life, or survival when compared with delaying until symptoms require treatment.