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Journal ArticleDOI

Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: Systematic review with meta-analysis combining individual patient and aggregate data

TL;DR: Preoperative chemotherapy for locoregional gastroesophageal adenocarcinoma increases survival compared to surgery alone and should be offered to all eligible patients.
About: This article is published in European Journal of Cancer.The article was published on 2013-10-01. It has received 138 citations till now. The article focuses on the topics: Chemoradiotherapy & Preoperative care.
Citations
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Journal ArticleDOI
TL;DR: In the EU, the highest age-standardised incidence rates for oesophageal cancer are in the Netherlands for men and the UK for women, and variation between countries is high and may reflect different prevalence of risk factors, use of screening and diagnostic methods.

810 citations

Journal ArticleDOI
TL;DR: Findings from the phase 2 part of the FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based doublet chemotherapy before surgical resection, suggest FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX.
Abstract: Summary Background Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection. Methods In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m 2 on day 1, intravenous cisplatin 60 mg/m 2 on day 1, and either fluorouracil 200 mg/m 2 as continuous intravenous infusion or capecitabine 1250 mg/m 2 orally (two doses of 625 mg/m 2 per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m 2 , intravenous oxaliplatin 85 mg/m 2 , intravenous leucovorin 200 mg/m 2 , and fluorouracil 2600 mg/m 2 as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644. Findings Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10–23] of 128 patients vs eight [6%; 3–11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3–4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]). Interpretation Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma. Funding None.

476 citations

Journal ArticleDOI
TL;DR: The prognosis is based on tumor stage; patients with T1a tumors have an excellent prognosis, whereas few patients with advanced disease have long-term survival.

284 citations

Journal ArticleDOI
TL;DR: The role of preoperative chemotherapy in the treatment of resectable thoracic esophageal cancer remains undefined and the total number of patients randomised to the treatment and control groups and the number of deaths in each group is determined.
Abstract: Background Carcinoma of the esophagus is a relatively uncommon but lethal cancer that continues to kill over 90% of its victims within 5 years. Surgery is the treatment of choice for most localized esophageal cancer patients. However, despite curative resection, the 5-year survival rate ranges from 15% to 39%. The failure of surgery to cure clinically localized esophageal cancer is because of the advanced state of the disease before symptoms occur, high frequency of lymph node involvement, and the common occurrence of submucosal spread and extension to surrounding structures. Preoperative chemotherapy has been used in an attempt to decrease tumour activity, increase resectability, and improve disease-free and overall survival. A number of studies have investigated whether preoperative chemotherapy followed by surgery leads to an improvement in cure rates, but the individual reports have not been encouraging. The role of preoperative chemotherapy in the treatment of resectable thoracic esophageal cancer remains undefined. Objectives The objective of this review is to determine the role of preoperative chemotherapy on overall survival and/or quality-of-life for patients with resectable thoracic esophageal carcinoma. Search strategy Trials were identified by searching the Cochrane Controlled Trials Register (Issue 2 - 2000), MEDLINE (1966 - 2000), EMBASE (1988 - 2000) and CancerLit (1993 - 2000). The references of all identified studies, review articles, and standard textbooks were examined. Members of the Cochrane UGPD Group and experts in the oncology field were contacted and asked to supply details of any outstanding clinical trials and relevant unpublished materials. There were no language restrictions. The searches were updated in June 2000. The clinical trial registers of the National Cancer Institute and the Radiation Therapy Oncology Group were consulted for ongoing trials. Selection criteria Types of studies Studies (published or unpublished) that randomised patients with potentially resectable carcinoma of the esophagus (of any histologic type) to chemotherapy or no chemotherapy before surgery were included in this review. Studies were excluded if they were not truly randomised (phase I or II trials), earlier versions of updated trials, if other treatment modalities (e.g. radiotherapy, hyperthermia) were used, or if there was not a surgery alone control arm. Types of participants The participants consisted of patients with potentially resectable thoracic esophageal carcinoma (of any histologic type). Trials involving patients with carcinoma of the cervical esophagus were excluded. Types of interventions Trials that compared chemotherapy before surgery (esophagectomy) with surgical resection alone (esophagectomy). Types of outcome measures The primary outcome was death at yearly intervals. Morbidity (complications), and quality-of-life were secondary outcomes. Data collection and analysis Overall mortality at yearly intervals was determined by extracting the total number of patients randomised to the treatment and control groups and the number of deaths in each group. All analyses were carried out on intention-to-treat that is patients were analyzed according to their allocated treatment, irrespective of whether they received that treatment. Mortality at 1, 2, 3, 4 and 5 years were used as endpoints of clinical relevance. If survival numbers at the specified time intervals were not given, they were estimated from the published survival curves. The number of deaths in the treatment groups (preoperative chemotherapy plus surgery) was compared to the number of deaths in the control groups (surgery alone). Treatment modalities as well as patient demographics and characteristics and side-effects were also recorded. Trials meeting the inclusion criteria were evaluated by two independent reviewers using the Jadad method Main results A total of 14 randomised controlled trials and 1 meta-analysis of preoperative chemotherapy versus surgery alone for esophageal carcinoma were identified to be potentially eligible for review. This review is based on 7 randomised trials and 1653 patients. At 1 year the Peto odds ratio based on the fixed-effects models showed no difference in mortality between preoperative chemotherapy and surgery alone (OR = 1.03). At 2 years there was a 20% significant decrease in mortality for preoperative chemotherapy (OR = 0.80; 95% C.I. 0.65 to 0.99) but the results were not robust. The results at 3, 4, and 5 years found odds ratios tending to favour preoperative chemotherapy, but wide confidence intervals that included 1. None of the published trials reported on quality-of-life outcomes. There appeared to be an increased risk of morbidity with chemotherapy. Reviewer's conclusions The results of this review suggest that there is no strong evidence to recommend preoperative chemotherapy in the treatment of surgically resectable carcinomas of the thoracic esophagus. (ABSTRACT TRUNCATED)

217 citations

Journal ArticleDOI
TL;DR: The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen, and cannot be considered standard of care.
Abstract: Summary 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.

172 citations

References
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Journal ArticleDOI
13 Sep 1997-BMJ
TL;DR: Funnel plots, plots of the trials' effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials.
Abstract: Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

37,989 citations

Journal ArticleDOI
TL;DR: The results for 20 world regions are presented, summarizing the global patterns for the eight most common cancers, and striking differences in the patterns of cancer from region to region are observed.
Abstract: Estimates of the worldwide incidence and mortality from 27 cancers in 2008 have been prepared for 182 countries as part of the GLOBOCAN series published by the International Agency for Research on Cancer. In this article, we present the results for 20 world regions, summarizing the global patterns for the eight most common cancers. Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occur in 2008, with 56% of new cancer cases and 63% of the cancer deaths occurring in the less developed regions of the world. The most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total), breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most common causes of cancer death are lung cancer (1.38 million, 18.2% of the total), stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high-resource countries. Striking differences in the patterns of cancer from region to region are observed.

21,040 citations

BookDOI
01 Jan 1987
TL;DR: Head and Neck Tumours.- Lip and Oral Cavity.- Pharynx.- Larynx.' Maxillary Sinus.- Salivary Glands.- Thyroid Gland.- Digestive System Tumour .
Abstract: Head and Neck Tumours.- Lip and Oral Cavity.- Pharynx.- Larynx.- Maxillary Sinus.- Salivary Glands.- Thyroid Gland.- Digestive System Tumours.- Oesophagus.- Stomach.- Colon and Rectum.- Anal Canal.- Liver.- Gall Bladder.- Extrahepatic Bile Ducts.- Ampulla of Vater.- Pancreas.- Lung Tumours.- Tumours of Bone and Soft Tissues.- Bone.- Soft Tissue.- Skin Tumours.- Carcinoma of Skin.- Melanoma of Skin.- Breast Tumours.- Gynaecological Tumours.- Cervix Uteri.- Corpus Uteri.- Ovary.- Vagina.- Vulva.- Urological Tumours.- Prostate.- Testis.- Penis.- Urinary Bladder.- Kidney.- Renal Pelvis and Ureter.- Urethra.- Ophthalmic Tumours.- Carcinoma of Eyelid.- Malignant Melanoma of Eyelid.- Carcinoma of Conjunctiva.- Malignant Melanoma of Conjunctiva.- Malignant Melanoma of Uvea.- Retinoblastoma.- Sarcoma of Orbit.- Carcinoma of Lacrimal Gland.- Brain Tumours.- Hodgkin's Disease.- Non-Hodgkin's Lymphoma.- Paediatric Tumours.- Nephroblastoma (Wilms' Tumour).- Neuroblastoma.- Soft Tissue Sarcomas - Paediatric.

15,624 citations

Journal ArticleDOI
TL;DR: In this paper, an adjusted rank correlation test is proposed as a technique for identifying publication bias in a meta-analysis, and its operating characteristics are evaluated via simulations, and the test statistic is a direct statistical analogue of the popular funnel-graph.
Abstract: An adjusted rank correlation test is proposed as a technique for identifying publication bias in a meta-analysis, and its operating characteristics are evaluated via simulations. The test statistic is a direct statistical analogue of the popular "funnel-graph." The number of component studies in the meta-analysis, the nature of the selection mechanism, the range of variances of the effect size estimates, and the true underlying effect size are all observed to be influential in determining the power of the test. The test is fairly powerful for large meta-analyses with 75 component studies, but has only moderate power for meta-analyses with 25 component studies. However, in many of the configurations in which there is low power, there is also relatively little bias in the summary effect size estimate. Nonetheless, the test must be interpreted with caution in small meta-analyses. In particular, bias cannot be ruled out if the test is not significant. The proposed technique has potential utility as an exploratory tool for meta-analysts, as a formal procedure to complement the funnel-graph.

13,373 citations

Journal ArticleDOI
TL;DR: 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.
Abstract: 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.)

5,133 citations

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