A prospective study of menopausal hormones and risk of colorectal cancer (United States)

The relation of colorectal cancer and its subsites with use ofmenopausal hormones was evaluated in the United States among 40,464postmenopausal women, 41 to 80 years of age, who initially volunteered for anationwide breast-cancer screening program and were followed for an averageof 7.7 years. Ever-use of menopausal hormones was not associated with risk oftotal colorectal cancers (relative risk [RR] = 0.99, 95 percent confidenceinterval [CI] = 0.79-1.2) or cancers of the colon (RR = 1.1, CI = 0.81-1.6)or rectum (RR = 1.1, CI = 0.59-1.9). Recent hormone users, however, had asmall nonsignificant reduction in risk of colorectal cancer (RR = 0.78, CI =0.55-1.1), which was most pronounced for distal colon (RR = 0.68, CI =0.29-1.6) and rectal tumors (RR = 0.64, CI = 0.24-1.7). No effect wasobserved for former hormone users, and risk generally did not vary by timesince last use, type of regimen, or duration of use. However, the reducedrisk for recent users was stronger for users of five or more years'duration. These data show some lowering of colorectal cancer risk amongrecent menopausal hormone users of long duration.     

Helicobacter pylori and oesophageal and gastric cancers in a prospective study in China

In a cohort of 29,584 residents of Linxian, China, followed from 1985 to 2001, we conducted a case-cohort study of the magnitude of the association of Helicobacter pylori seropositivity with cancer risk in a random sample of 300 oesophageal squamous cell carcinomas, 600 gastric cardia adenocarcinomas, all 363 diagnosed gastric non-cardia adenocarcinomas, and a random sample of the entire cohort (N=1050). Baseline serum was evaluated for IgG antibodies to whole-cell and CagA H. pylori antigens by enzyme-linked immunosorbent assay. Risks of both gastric cardia and non-cardia cancers were increased in individuals exposed to H. pylori (Hazard ratios (HRs) and 95% confidence intervals=1.64; 1.26-2.14, and 1.60; 1.15-2.21, respectively), whereas risk of oesophageal squamous cell cancer was not affected (1.17; 0.88-1.57). For both cardia and non-cardia cancers, HRs were higher in younger individuals. With longer time between serum collection to cancer diagnosis, associations became stronger for cardia cancers but weaker for non-cardia cancers. CagA positivity did not modify these associations. The associations between H. pylori exposure and gastric cardia and non-cardia adenocarcinoma development were equally strong, in contrast to Western countries, perhaps due to the absence of Barrett's oesophagus and oesophageal adenocarcinomas in Linxian, making all cardia tumours of gastric origin, rather than a mixture of gastric and oesophageal malignancies.     

ABO Blood Groups and Risk of Cancer: a Systematic Review and Meta-analysis

Background: For decades, studies have been performed to evaluate the association between ABO bloodgroups and risk of cancer. However, whether ABO blood groups are associated with overall cancer risk remainsunclear. We therefore conducted a meta-analysis of observational studies to assess this association. Materialsand Methods: A search of Pubmed, Embase, ScienceDirect, Wiley, and Web of Knowledge databases (to May2013) was supplemented by manual searches of bibliographies of key retrieved articles and relevant reviews.We included case-control studies and cohort studies with more than 100 cancer cases. Results: The searchyielded 89 eligible studies that reported 100,554 cases at 30 cancer sites. For overall cancer risk, the pooled ORwas 1.12 (95%CI: 1.09-1.16) for A vs. non- A groups, and 0.84 (95%CI: 0.80-0.88) for O vs. non-O groups. Forindividual cancer sites, blood group A was found to confer increased risk of gastric cancer (OR=1.18; 95%CI:1.13-1.24), pancreatic cancer (OR=1.23; 95%CI: 1.15-1.32), breast cancer (OR=1.12; 95%CI: 1.01-1.24), ovariancancer (OR=1.16; 95%CI: 1.04-1.27), and nasopharyngeal cancer (OR=1.17; 95%CI: 1.00-1.33). Blood groupO was found to be linked to decreased risk of gastric cancer (OR=0.84; 95%CI: 0.80-0.88), pancreatic cancer(OR=0.75; 95%CI: 0.70-0.80), breast cancer (OR=0.90; 95%CI: 0.85-0.95), colorectal cancer (OR=0.89; 95%CI:0.81-0.96), ovarian cancer (OR=0.76; 95%CI: 0.53-1.00), esophagus cancer (OR=0.94; 95%CI: 0.89-1.00), andnasopharyngeal cancer (OR=0.81; 95%CI: 0.70-0.91). Conclusions: Blood group A is associated with increasedrisk of cancer, and blood group O is associated with decreased risk of cancer.     

Aspirin and cancer risk: an update to 2001.

Evidence of a protective role of aspirin on the risk of colorectal and other common cancers has been building up since the end of the 1980s. There are now more than 15 epidemiological (case-control and cohort) studies indicating that long-term use of aspirin is associated with a reduced risk of colorectal cancer. The overall relative risk (RR) estimate for regular aspirin users was 0.71 (95% confidence interval (CI) 0.66-0.77) from case-control studies, and 0.84 (95% CI 0.72-0.98) from cohort studies. A recent meta-analysis reported a RR of breast cancer for aspirin use of 0.70 (95% CI 0.61-0.81) in case-control studies, and of 0.79 (95% CI 0.59-1.06) in cohort studies. Furthermore, various epidemiological studies have suggested that aspirin use might have a favourable effect on ovarian cancer as well: the overall RR estimate was 0.82 (95% CI 0.69-0.99), although the evidence is too limited to permit firm conclusions. Data are more scanty, though in the same direction, for other neoplasms, including in particular stomach and oesophageal cancer.     

Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer

Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first- and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56-2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18-4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07-12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18-5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5-8%) for men and 4% (95%CI 3-6%) for women; for gastric cancer, 2% (95%CI 1-3%) for men and 0.7% (95%CI 0.5-1%) for women; for liver cancer, 1% (95%CI 0.3-3%) for men and 0.3% (95%CI 0.1-1%) for women and for endometrial cancer, 4% (95%CI 2-8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.     

Use of hormone therapy and risk of breast cancer detected at screening and between mammographic screens

Postmenopausal hormone therapy (HT) is associated with increased risk of breast cancer, but in women undergoing breast cancer screening it is not clear whether use of HT is associated with increased risk of breast cancer detected at screening or between screens (interval cancer). Further, it is unclear whether the use of the HTs that have been common in Scandinavia is associated with higher risk of breast cancer than the HTs used in other countries. Our study was based on data from 296,651 women aged 50-69 years, who participated in the Norwegian Breast Cancer Screening Program during 1995-2004. After a mean enrollment time of 3.8 years, 1,512 women were diagnosed with invasive screen detected breast cancer, and 814 with invasive interval breast cancer. Cox regression models were used to estimate hazard ratios (HRs) of breast cancer associated with HT use, after adjusting for confounders. Ever users of HT had a 58% increased risk of breast cancer, compared to never users. The HRs associated with HT use were 1.45 (95% confidence interval (CI) = 1.29-1.63) for screen detected and 1.89 (95% CI = 1.61-2.23) for interval cancer. The difference between screen detected and interval cancer was statistically significant (p = 0.011). The HR of breast cancer increased with duration of HT use, but significantly more so for interval than for screen detected cancer (use of HT for 5 or more years compared to never use; HR = 2.91, 95% CI = 2.10-4.04 and HR = 1.94, 95% CI = 1.51-2.50, respectively; p = 0.002). The population attributable fraction of breast cancer due to HT use was 19.8% overall. Ever users of HT tended to develop a cancer of lower grade. No other differences in histological tumor characteristics were observed between ever and never users of HT among screen detected or interval cancers. The estimated risks of either breast cancer overall with HT use are higher in Norway than reported in similar studies from the U.S. HT-use is a stronger risk factor for interval cancer than for screen detected cancer. The increased risk of interval cancer, which may partly be due to decreased sensitivity of mammograms in HT users, remains a challenge in breast cancer screening programs.     

Low-dose aspirin and risk of gastric and oesophageal cancer: A population-based study in the United Kingdom using The Health Improvement Network

There is increasing interest regarding potential protective effects of low-dose aspirin against various gastrointestinal cancers. We aimed to quantify the association between use of low-dose aspirin and risk of gastric/oesophageal cancer using a population-based primary care database in the UK. Between January 2005 and December 2015, we identified a cohort of 223 640 new users of low-dose aspirin (75-300 mg/day) and a matched cohort of nonusers at the start of follow-up from The Health Improvement Network. Cohorts were followed to identify incident cases of gastric/oesophageal cancer. Nested case-control analyses were conducted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for current vs nonuse of low-dose aspirin using logistic regression. Current use was defined as when low-dose aspirin lasted 0 to 90 days before the index date (event date for cases, random date for controls) and previous duration was ≥1 year. We identified 727 incident cases of gastric cancer and 1394 incident cases of oesophageal cancer. ORs (95% CIs) were 0.46 (0.38-0.57) for gastric cancer and 0.59 (0.51-0.69) for oesophageal cancer. The effect remained consistent with no clear change seen between previous duration of low-dose aspirin use of 1-3, 3-5 or >5 years. The reduced risks was seen with 75 mg/day, and effects were consistent in lag-time analyses. In conclusion, our results indicate that use of low-dose aspirin is associated with a 54% reduced risk of gastric cancer and a 41% reduced risk of oesophageal cancer as supported by mechanistic data.     

Exposure to oral bisphosphonates and risk of cancer

Recently, oral bisphosphonate use has increased markedly in the United States and elsewhere. Little is known about cancer risks associated with these drugs. A few studies have observed associations between bisphosphonates and the risk of breast, colorectal and esophageal cancer. However, the risk of all cancer and the risk of other cancers have not been investigated. In our study, we examined the risk of all cancer and site specific cancers in individuals taking bisphosphonates. Data were extracted from the UK General Practice Research Database to compare site-specific cancer incidence in a cohort of oral bisphosphonate users and a control cohort. Hazard ratios (HRs) were calculated using Cox regression modeling. The bisphosphonate and control cohort contained 41,826 participants (mean age 70, 81% female). Overall, the bisphosphonate cohort compared with the control cohort had a reduced risk of all cancer after any bisphosphonate usage [HR=0.87, 95% confidence interval (CI) 0.82, 0.92]. In the bisphosphonate cohort, compared with the control cohort, there was no evidence of a difference in the risk of lung (HR=1.03, 95% CI 0.88, 1.20) or prostate cancer (HR=0.86, 95% CI 0.67, 1.09) but breast (HR=0.71, 95% CI 0.62, 0.81) and colorectal cancer (HR=0.74, 95% CI, 0.60-0.91) were both reduced. Our findings indicate that bisphosphonates do not appear to increase cancer risk. Although reductions in breast and colorectal cancer incidence were observed in bisphosphonate users it is unclear, particularly for breast cancer, to what extent confounding by low bone density may explain the association.     

The effect of estrogen vs. combined estrogen-progestogen therapy on the risk of colorectal cancer

Studies suggest that estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT) may have different associations with colorectal cancer (CRC) risk, but data are conflicting. Prior meta-analyses did not distinguish between ET and EPT. We conducted a meta-analysis to summarize the relative risks (RR) of CRC due to ET versus EPT among peri- or postmenopausal women. From a total of 2,661 articles, four randomized controlled trials, eight cohort and eight case-control studies were included. Variables assessed included study characteristics, duration and recency of menopausal hormone therapy (HT) use, method of assessment of HT use, outcome definition and its ascertainment method. RRs were synthesized by random-effects models. We found that EPT ever use was associated with a decreased risk of CRC (RR 0.74, 95% CI 0.68-0.81), and so was ET ever use (RR 0.79, 95% CI 0.69-0.91). While current use of ET was associated with a significantly reduced risk of CRC (RR 0.70, 95% CI 0.57-0.85), former use was not (RR 0.86, 95%CI 0.67-1.11). Recency did not significantly modify the association between EPT and CRC risk. EPT former use was associated with a lower RR of CRC compared to ET former use (p = 0.008) but no such difference was observed between EPT and ET current use (p = 0.12). Overall, we found consistent evidence supporting the association between EPT and CRC risk reduction, regardless of recency. While literature for the association between ET and CRC risk is heterogeneous, our analyses suggest only current use of ET is associated with a decreased CRC risk.     

Screen-detected and interval colorectal cancers in England: Associations with lifestyle and other factors in women in a large UK prospective cohort

Faecal occult blood (FOB) - based screening programmes for colorectal cancer detect about half of all cancers. Little is known about individual health behavioural characteristics which may be associated with screen-detected and interval cancers. Electronic linkage between the UK National Health Service Bowel Cancer Screening Programme (BCSP) in England, cancer registration and other national health records, and a large on-going UK cohort, the Million Women Study, provided data on 628,976 women screened using a guaiac-FOB test (gFOBt) between 2006 and 2012. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated by logistic and Cox regression for associations between individual lifestyle factors and risk of colorectal tumours. Among screened women, 766 were diagnosed with screen-detected colorectal cancer registered within 2 years after a positive gFOBt result, and 749 with interval colorectal cancers registered within 2 years after a negative gFOBt result. Current smoking was significantly associated with risk of interval cancer (RR 1.64, 95%CI 1.35–1.99) but not with risk of screen-detected cancer (RR 1.03, 0.84–1.28), and was the only factor of eight examined to show a significant difference in risk between interval and screen-detected cancers (p for difference, 0.003). Compared to screen-detected cancers, interval cancers tended to be sited in the proximal colon or rectum, to be of non-adenocarcinoma morphology, and to be of higher stage.     

Prospective study of ultraviolet radiation exposure and risk of cancer in the United States

Ecologic studies have reported that solar ultraviolet radiation (UVR) exposure is associated with cancer; however, little evidence is available from prospective studies. We aimed to assess the association between an objective measure of ambient UVR exposure and risk of total and site-specific cancer in a large, regionally diverse cohort [450,934 white, non-Hispanic subjects (50-71 years) in the prospective National Institutes of Health (NIH)-AARP Diet and Health Study] after accounting for individual-level confounding risk factors. Estimated erythemal UVR exposure from satellite Total Ozone Mapping Spectrometer (TOMS) data from NASA was linked to the US Census Bureau 2000 census tract (centroid) of baseline residence for each subject. We used Cox proportional hazards models adjusted for multiple potential confounders to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for quartiles of UVR exposure. Restricted cubic splines examined nonlinear relationships. Over 9 years of follow-up, UVR exposure was inversely associated with total cancer risk (N = 75,917; highest versus lowest quartile; HR = 0.97, 95% CI = 0.95-0.99; p-trend < 0.001). In site-specific cancer analyses, UVR exposure was associated with increased melanoma risk (highest versus lowest quartile; HR = 1.22, 95% CI = 1.13-1.32; p-trend < 0.001) and decreased risk of non-Hodgkin's lymphoma (HR = 0.82, 95% CI = 0.74-0.92) and colon (HR = 0.88, 95% CI = 0.82-0.96), squamous cell lung (HR = 0.86, 95% CI = 0.75-0.98), pleural (HR = 0.57, 95% CI = 0.38-0.84), prostate (HR = 0.91, 95% CI = 0.88-0.95), kidney (HR = 0.83, 95% CI = 0.73-0.94) and bladder (HR = 0.88, 95% CI = 0.81-0.96) cancers (all p-trend < 0.05). We also found nonlinear associations for some cancer sites, including the thyroid and pancreas. Our results add to mounting evidence for the influential role of UVR exposure on cancer.     

Hormone replacement therapy and risks of oesophageal and gastric adenocarcinomas

Oesophageal and gastric adenocarcinoma share an unexplained male predominance, which would be explained by the hypothesis that oestrogens are protective in this respect. We carried out a nested case-control study of hormone replacement therapy (HRT) among 299 women with oesophageal cancer, 313 with gastric cancer, and 3191 randomly selected control women, frequency matched by age and calendar year in the General Practitioners Research Database in the United Kingdom. Data were adjusted for age, calendar year, tobacco smoking, alcohol consumption, body mass index, hysterectomy, and upper gastrointestinal disorders. Among 1 619 563 person-years of follow-up, more than 50% reduced risk of gastric adenocarcinoma was found among users of HRT compared to nonusers (odds ratio (OR), 0.48, 95% confidence interval (CI) 0.29-0.79). This inverse association appeared to be stronger for gastric noncardia (OR 0.34, 95% CI 0.14-0.78) and weaker for gastric cardia tumours (OR 0.68, 95% CI 0.23-2.01). There was no association between HRT and oesophageal adenocarcinoma (OR 1.17, 95% CI 0.41-3.32).     

Constipation, laxative use and risk of colorectal cancer: The Miyagi Cohort Study

The objective of this study was to investigate the association between constipation or laxative use and the risk of colorectal cancer in Japanese men and women. In 1990, we delivered a self-administered questionnaire to 41670 subjects who were 40-64 years old. During the seven years of follow-up, 251 incident cases of colorectal cancer were documented. Constipation was defined as a bowel movement frequency of less than daily. The multivariate relative risk (RR) of colorectal cancer for constipated subjects compared with those with daily bowel movements was 1.35 (95% Confidence Interval: 0.99-1.84). The RR for laxative users over non-users was 1.31 (0.88-1.95), and for frequent users (twice a week or more) it was 2.75 (1.48-5.09). When colorectal cancers were divided into colon cancers or rectal cancers, a significant association was found with colon cancer alone. Our results support the hypothesis that constipation or laxative use increases the risk of colon cancer.     

Hormone therapy in relation to survival from large bowel cancer

Epidemiologic studies of hormone therapy (HT) and colorectal cancer incidence consistently show an inverse association; however, few studies have considered prediagnostic use of HT on mortality among colorectal cancer patients. We evaluated the relationship of HT and survival among a population-based cohort of women with large bowel cancer. Cases (n = 1,297) were newly diagnosed with invasive cancer of the colon or rectum, aged 40–74 years at diagnosis, who were identified by Wisconsin’s statewide registry (1988–1991; 1997–2001) for two case–control studies. Information on HT use and other colorectal cancer risk factors was collected by standardized interview. There were 507 deaths (274 of these attributable to colorectal cancer) over 8.4 years of follow-up through December 2005. Hormone use was not associated with colorectal cancer mortality (adjusted hazard rate ratio = 1.09, confidence interval = 0.81–1.47). Colorectal cancer specific mortality was not associated with HT when considered separately by preparation type. Stage did not modify this relationship. Long-term HT was weakly positively associated with increased mortality after diagnosis of proximal colon, but not distal colon cancer. Because we detected no differences in survival among users of HT compared to non-users, the results suggest that HT use may affect only the incidence of some colorectal tumors.     

Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis

Objective  We investigated the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) with cancer risk. Methods  We examined the associations of CRP and IL-6 with incident cancer in two prospective cohorts, the British Women’s Heart and Health Study (4,286 women aged 60–80) and the Caerphilly Cohort (2,398 men aged 45–59) using Cox regression and pooled our findings with previous prospective studies’ in fixed and random effects meta-analyses. Results  CRP and IL-6 were associated with some incident cancers in our cohorts, but the numbers of cancer cases were small. In our meta-analyses elevated CRP was associated with an increased overall risk of cancer (random effects estimate (RE): 1.10, 95% CI: 1.02, 1.18) and lung cancer (RE: 1.32, 95% CI: 1.08, 1.61). Its associations with colorectal (RE: 1.09, 95% CI: 0.98, 1.21) and breast cancer risks (RE: 1.10, 95% CI: 0.97, 1.26) were weaker. CRP appeared unrelated to prostate cancer risk (RE: 1.00 0.88, 1.13). IL-6 was associated with increased lung and breast cancer risks and decreased prostate cancer risk, and was unrelated to colorectal cancer risk. Conclusions  Our findings suggest an etiological role for CRP and IL-6 in some cancers. Further large prospective and genetic studies would help to better understand this role. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Morning chronotype and digestive tract cancers: Mendelian randomization study

Morning chronotype has been associated with a reduced risk of prostate and breast cancer. However, few studies have examined whether chronotype is associated with digestive tract cancer risk. We conducted a Mendelian randomization (MR) study to assess the associations of chronotype with major digestive tract cancers. A total of 317 independent genetic variants associated with chronotype at the genome-wide significance level (P < 5 × 10⁻⁸) were used as instrumental variables from a genome-wide meta-analysis of 449 734 individuals. Summary-level data on overall and six digestive tract cancers, including esophageal, stomach, liver, biliary tract, pancreatic and colorectal cancers, were obtained from the UK Biobank (11 952 cases) and FinnGen (7638 cases) study. Genetic liability to morning chronotype was associated with reduced risk of overall digestive tract cancer and cancers of stomach, biliary tract and colorectum in UK Biobank. The associations for the overall digestive tract, stomach and colorectal cancers were directionally replicated in FinnGen. In the meta-analysis of the two sources, genetic liability to morning chronotype was associated with a decreased risk of overall digestive tract cancer (odds ratio [OR] 0.94, 95% confidence interval [CI]: 0.90-0.98), stomach cancer (OR 0.84, 95% CI: 0.73-0.97) and colorectal cancer (OR 0.92, 95% CI: 0.87-0.98), but not with the other studied cancers. The associations were consistent in multivariable MR analysis with adjustment for genetically predicted sleep duration, short sleep, insomnia and body mass index. The study provided MR evidence of inverse associations of morning chronotype with digestive tract cancer, particularly stomach and colorectal cancers.     

Vegetables and fruit intake and cancer mortality in the Hiroshima/Nagasaki Life Span Study

The association between green-yellow vegetables and fruit consumption and risk of cancer death was investigated in a prospective study of 38 540 men and women who were atomic-bomb survivors in Hiroshima and Nagasaki, Japan. Study participants completed a dietary questionnaire in 1980-1981 and were followed-up for cancer deaths until March 1998, during which time 3136 cancer deaths were identified. Daily or almost daily fruit consumption was associated with a significant 12% reduction in total cancer mortality (RR=0.88; 95% CI, 0.80-0.96 for daily intake compared with intake once per week or less). Daily or almost daily green-yellow vegetables consumption was associated with a marginally significant 8% reduction in total cancer mortality (0.92; 0.94-1.01). Green-yellow vegetables consumption was associated with a significant reduction in liver cancer mortality (0.75; 0.60-0.95). Fruit consumption was associated with a significantly reduced risk of stomach cancer and lung cancer mortality (0.80; 0.65-0.98). Green-yellow vegetables and fruit consumption was associated with a reduction in oesophageal cancer, but these associations were not statistically significant. Neither green-yellow vegetables nor fruit consumption was associated with colorectal cancer or breast cancer mortality. These results support the evidence that daily consumption of fruit and vegetables reduces the risk of total cancer, and specifically cancers of the stomach, liver, and lung.     

Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis

BACKGROUND: Resectable oesophageal cancer is often treated with surgery alone or with preoperative (neoadjuvant) chemoradiotherapy or chemotherapy. We aimed to clarify the benefits of neoadjuvant chemoradiotherapy or chemotherapy versus surgery alone by a meta-analysis of randomised trial data. METHODS: Eligible trials were identified first from earlier published meta-analyses and systematic reviews. We also used MEDLINE, Cancerlit, and EMBASE databases to identify additional studies and published abstracts from major scientific meetings since 1980. Only randomised studies with an analysis by an intention-to-treat principle were included, and searches were restricted to those databases citing articles in English. We used published hazard ratios if available or estimates from other survival data or survival curves. Treatment effects by type of tumour and treatment sequencing were also investigated. FINDINGS: Ten randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1209) and eight of neoadjuvant chemotherapy versus surgery alone (n=1724) in patients with local operable oesophageal carcinoma were identified. The hazard ratio for all-cause mortality with neoadjuvant chemoradiotherapy versus surgery alone was 0.81 (95% CI 0.70-0.93; p=0.002), corresponding to a 13% absolute difference in survival at 2 years, with similar results for different histological tumour types: 0.84 (0.71-0.99; p=0.04) for squamous-cell carcinoma (SCC), and 0.75 (0.59-0.95; p=0.02) for adenocarcinoma. The hazard ratio for neoadjuvant chemotherapy was 0.90 (0.81-1.00; p=0.05), which indicates a 2-year absolute survival benefit of 7%. There was no significant effect on all-cause mortality of chemotherapy for patients with SCC (hazard ratio 0.88 [0.75-1.03]; p=0.12), although there was a significant benefit for those with adenocarcinoma (0.78 [0.64-0.95]; p=0.014). INTERPRETATION: A significant survival benefit was evident for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the oesophagus. The findings provide an evidence-based framework for the use of neoadjuvant treatment in management decisions.