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Purpose Only 25% of oesophageal adenocarcinoma (OAC) patients have a pathological response to neo-adjuvant therapy (NAT) before oesophagectomy. Early response assessment using PET imaging may help guide management of these patients. We performed a systematic review and meta-analysis to synthesise the evidence detailing response rate and diagnostic accuracy of early PET-CT assessment. Methods We systematically searched several databases including MEDLINE and Embase. Studies with mixed cohorts of histology, tumour location and a repeat PET-CT assessment after more than one cycle of NAT were excluded. Reference standard was pathological response defined by Becker or Mandard classifications. Primary outcome was metabolic response rate after one cycle of NAT defined by a reduction in maximum standardised uptake value (SUVmax) of 35%. Secondary outcome was diagnostic accuracy of treatment response prediction, defined as the sensitivity and specificity of early PET-CT using this threshold. Quality of evidence was also assessed. Random-effects meta-analysis pooled response rates and diagnostic accuracy. This study was registered with PROSPERO (CRD42019147034). Results Overall, 1341 articles were screened, and 6 studies were eligible for analysis. These studies reported data for 518 patients (aged 27-78 years; 452 [87.3%] were men) between 2005 and 2020. Pooled sensitivity of early metabolic response to predict pathological response was 77.2% (95% CI 53.2%-100%). Significant heterogeneity existed between studies (I2 = 80.6% (95% CI 38.9%-93.8%), P = .006). Pooled specificity was 75.0% (95% CI 68.2%-82.5%), however, no significant heterogeneity between studies existed (I2 = 0.0% (95% CI 0.0%-67.4%), P = .73). Conclusion High-quality evidence is lacking, and few studies met the inclusion criteria of this systematic review. The sensitivity of PET using a SUVmax reduction threshold of 35% was suboptimal and varied widely. However, specificity was consistent across studies with a pooled value of 75.0%, suggesting early PET assessment is a better predictor of treatment resistance than of pathological response. Further research is required to define optimal PET-guided treatment decisions in OAC.

Background Patients with potentially curable oesophageal adenocarcinoma have a staging positron emission tomography (PET) examination combined with a computed tomography (CT) to assess loco-regional and distant disease. Although only 20-30% of patients are suitable for surgical resection, the majority receive neo-adjuvant therapy (chemotherapy with or without radiotherapy) before their operation. However, less than 25% experience any clinically meaningful benefit from the neo-adjuvant therapy. A repeat PET/CT after one cycle of treatment can assess for early metabolic response but remains exploratory. Patients without an early response could be offered alternative treatment strategies. The purpose of this systematic review and meta-analysis is to estimate the early response rate defined by PET/CT, its diagnostic accuracy and explore associated factors. Methods Primary studies reporting response rates and diagnostic accuracy of PET/CT will be identified from MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov databases. Peer-reviewed randomised control trials, observational cohort, cross-sectional and case-control studies reporting original response rate data, published from 2005 onwards will be included. Studies recruiting mixed cohorts and with PET/CT repeated after more than one neo-adjuvant treatment cycle will be excluded. The reference standard will be pathological response, defined by either validated Becker or Mandard tumour regression grade (TRG) classifications. The primary outcome will be metabolic response rate after one neo-adjuvant treatment cycle, defined by a reduction in maximum standardised uptake value (SUVmax) of 35%. Secondary outcome will be the sensitivity and specificity of early metabolic response to predict pathological response at this SUVmax reduction threshold. Pooled early response rate, sensitivity and specificity will be calculated using a random effects model with data extracted from selected studies. Heterogeneity between studies, risk of bias and methodological quality will be assessed. Discussion This systematic review and meta-analysis will identify and synthesise evidence to determine early response rates to neo-adjuvant therapies and the corresponding diagnostic accuracy of PET/CT to guide future clinical trials. This strategy could identify patients that will not respond to neo-adjuvant therapy and to offer this group alternative treatment strategies. Systematic review registration: PROSPERO (registration number CRD42019147034)

Background Oesophageal cancer is increasing in incidence and has a poor prognosis. Patients with potentially curable disease have a staging positron emission tomography (PET) examination combined with a computed tomography (CT) to assess loco-regional and distant disease. Although a small proportion of patients are suitable for attempted surgical resection, the majority will receive neo-adjuvant therapy (chemotherapy with or without radiotherapy) before their operation. The current regimen prescribes all patients to complete the neo-adjuvant treatment prior to surgery, but some patients will not experience a beneficial response. A repeat PET/CT after one cycle of neo-adjuvant treatment may identify early response or non-response and could alter subsequent management. The purpose of this systematic review and meta-analysis is to estimate the early and completion response rate defined by fluorodeoxyglucose (FDG)-PET, its diagnostic accuracy and explore associated factors. Methods Primary studies reporting response rates and diagnostic accuracy of PET/CT will be identified from MEDLINE, Embase, Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science, International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov databases. Peer-reviewed studies published from 2005 onwards will be included. Data will be extracted from selected studies and a meta-analysis using a random effects model will be attempted. Pooled early and completion response rates, and diagnostic accuracy (sensitivity and specificity), will be calculated from available data. Heterogeneity between studies, risk of bias and methodological quality will be assessed. Discussion This systematic review and meta-analysis will identify and synthesise evidence to determine early and completion response rates to neo-adjuvant treatment and the corresponding diagnostic accuracy of PET/CT. This strategy has the potential to identify patients that will not respond to the treatment and to offer this group an alternative pre-operative treatment or proceed directly to operation, thereby avoiding a delay in surgical resection and optimising patient outcomes.

OBJECTIVE: Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers?DESIGN: Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants.RESULTS: 1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%).CONCLUSIONS: Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94-1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.

BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

Background We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. Methods The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Results Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). Conclusions The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval., published version, peerReviewed

ObjectiveEstimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.DesignWe undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affectingMLH1,MSH2,MSH6orPMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene.Results1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards inMLH1andMSH2mutation carriers, and from about 40 years inMSH6andPMS2carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% forMLH1, MSH2, MSH6andPMS2mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian.ConclusionsThe four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established athttp://LScarisk.orgenabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.