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A wealth of epidemiological evidence, combined with plausible biological mechanisms, present a convincing argument for a causal relationship between excess adiposity, commonly approximated as body mass index (BMI, kg/m2), and incident cancer risk. Beyond this relationship, there are a number of challenges posed in the context of interpreting whether being overweight (BMI 25.0–29.9 kg/m2) or obese (BMI ≥ 30.0 kg/m2) adversely influences disease progression, cancer mortality and survival. Elevated BMI (≥ 25.0 kg/m2) may influence treatment selection of, for example, the approach to surgery; the choice of chemotherapy dosing; the inclusion of patients into randomised clinical trials. Furthermore, the technical challenges posed by an elevated BMI may adversely affect surgical outcomes, for example, morbidity (increasing the risk of surgical site infections), reduced lymph node harvest (and subsequent risk of under-staging and under-treatment) and increased risk of margin positivity. Suboptimal chemotherapy dosing, associated with capping chemotherapy in obese patients as an attempt to avoid excess toxicity, might be a driver of poor prognostic outcomes. By contrast, the efficacy of immune checkpoint inhibition may be enhanced in patients who are obese, although in turn, this observation might be due to reverse causality. So, a central research question is whether being overweight or obese adversely affects outcomes either directly through effects of cancer biology or whether adverse outcomes are mediated through indirect pathways. A further dimension to this complex relationship is the obesity paradox, a phenomenon where being overweight or obese is associated with improved survival where the reverse is expected. In this overview, we describe a framework for evaluating methodological problems such as selection bias, confounding and reverse causality, which may contribute to spurious interpretations. Future studies will need to focus on prospective studies with well-considered methodology in order to improve the interpretation of causality.

Background We evaluated oncological changes in patients with squamous cell carcinoma of the anus (SCCA) treated by chemoradiotherapy (CRT) from a large UK institute, to derive estimates of contemporary outcomes. Methods We performed a treatment-cohort analysis in 560 patients with non-metastatic SCCA treated with CRT over 25 years. The primary outcomes were 3-year loco-regional failure (LRF), 5-year overall survival (OS), and 5-year cancer-specific survival (CSS). We developed prediction models; and overlaid estimates on published results from historic trials. Results Age distributions, proportions by gender and cT stage remained stable over time. The median follow-up was 61 (IQR: 36–79) months. Comparing the first period (1990–1994) with the last period (2010–2014), 3-year LRF declined from 33 to 16% (Ptrends Ptrends = 0.001); and 5-year CCS increased from 62% in to 80% (Ptrends = 0.001). For 2020, the models predicted a 3-year LRF of 14.7% (95% CIs: 0–31.3); 5-year OS of 74.7% (95% CIs: 54.6–94.9); and 5-year CSS of 85.7% (95% CIs: 75.3–96.0). Reported oncological outcomes from historic trials generally underestimated contemporary outcomes. Conclusions Current and predicted rates for 3-year LRF and 5-year survivals are considerably improved compared with those in historic trials.

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to

Introduction Traditionally patients with colorectal peritoneal metastases (CRPM) were offered palliative chemotherapy and best supportive care. With the introduction of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), patients in the UK have been referred to nationally approved centres. This study describes the pattern of referral and outcomes of patients managed through one UK centre. Methods and Methods: A prospective register recorded referrals, demographics, prior treatment pathways, and specialist multidisciplinary team (MDT) decisions (2002-2015). Peritoneal cancer index (PCI) was recorded intra-operatively; complete cytoreduction was deemed when a CC0/1 was achieved. Complications were classified using NCI CTCAE. v.4. Median overall survivals (OS) were described for those treated by CRS/HIPEC and in derived estimates for patients with isolated peritoneal metastases treated by chemotherapy alone in the ARCAD trials consortium. Results Two-hundred-eighty-six patients with CRPM were referred. Despite increasing numbers of referrals annually, the proportion of patients selected for CRS/HIPEC decreased from 64.5%, to 40%, and to 37.1% for 2002–09, 2010–12, and 2013–15, respectively (p

Aims: We evaluated the relationship between body mass index (BMI) and cancer mortality in incident type 2 diabetes. Methods: We used the Clinical Practice Research Datalink GOLD (1998-2015), linked with the Office of National Statistics mortalities, and derived an incident type 2 diabetes cohort (N: 176,886; aged 30-85 years). We determined BMI ±12 months diabetes diagnosis. The primary outcome was cancer mortality, categorised into deaths from obesity-related cancers (ORCs) and non-ORCs. Secondary outcomes were site-specific cancer mortality and main causes of deaths (cancer, cardiovascular disease [CVD], non-cancer non-CVD). We developed gender-specific Cox models and expressed risk as hazard ratios (HR) and 95% confidence intervals (CIs), stratified by smoking status. Results: With 886,850 person years follow-up, 7,593 cancer deaths occurred. Among women who never smoked, there were positive associations between BMI and deaths from endometrial (HR per 5 kg/m2: 1.43 [95% CI 1.26-1.61]. Among men, associations between BMI and ORC mortality were inverse but attenuated towards null among never smokers and excluding deaths in the first 2 years. In men, the proportion of CVD deaths increased from 36.8% in BMI category 22.5 to 24.9 kg/m2 to 43.6% in BMI category ≥ 40 kg/m2 (p < 0.001).Conclusions: We found some relationships between BMI and cancer mortality in patients with type 2 diabetes, but interpretations need to account for smoking status, reverse causality, and deaths from CVD.

Background The DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. Patients and methods Cediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. Results In case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNFα) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). Conclusions This novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNFα emerged as a potential predictive biomarker of response and warrants further evaluation.

Introduction: We assessed the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a pooled analysis of individual patient data. Methods: Nine European NSCLC CTC centres were asked to provide reported/unreported pseudo-anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 to March 2017. We used Cox regression models, stratified by centres, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinicopathological models using likelihood ratio (LR) statistics and c-indices. Results: Seven out of nine eligible centres provided data for 550 patients with prognostic information for overall survival. CTC counts of ≥2 and ≥ 5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: hazard ratio [HR] = 1.72, p < 0·001; ≥5 CTCs: HR = 2.21, p < 0·001) and overall survival (≥2 CTCs: HR = 2·18, p < 0·001; ≥5 CTCs: HR = 2·75, p < 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinicopathological models (log-transformed CTCs p < 0·001; ≥2 CTCs p < 0·001; ≥5 CTCs p ≤ 0·001 for both survival end-points), whereas moderate improvements were observed with the use of c-index models. There was some evidence of between-centre heterogeneity, especially when examining continuous counts of CTCs. Conclusions: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC and also reveal some evidence of between-centre heterogeneity. CTC count improves prognostication when added to full clinicopathological predictive models.

Background: Circulating tumour cell (CTC) number is an independent prognostic factor in patients with small cell lung cancer (SCLC) but there is no consensus on the CTC threshold for prognostic significance. We undertook a pooled analysis of individual patient data to clinically validate CTC enumeration and threshold for prognostication.Methods: Four European cancer centres, experienced in CellSearch CTC enumeration for SCLC provided pseudo anonymised data for patients who had undergone pre-treatment CTC count. Data was collated, and Cox regression models, stratified by centre, explored the relationship between CTC count and survival. The added value of incorporating CTCs into clinico-pathological models was investigated using likelihood ratio tests.Results: A total of 367 patient records were evaluated. A one-unit increase in log-transformed CTC counts corresponded to an estimated hazard ratio (HR) of 1.24 (95% CI: 1.19-1.29, PConclusions: Higher pre-treatment CTC counts are a negative independent prognostic factor in SCLC when considered as a continuous variable or dichotomised counts of ≥15 or ≥50. Incorporating CTC counts, as a continuous variable, improves clinic-pathological prognostic models.

Introduction Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an established treatment for pseudomyxoma peritonei (PMP) from perforated low-grade appendiceal mucinous neoplasms (LAMN II). In a selected group of LAMN II patients without established PMP, CRS/HIPEC can be performed laparoscopically (L-CRS/HIPEC); however the short-term benefits and safety of this approach have yet to be determined. This study aims to determine the short-term outcomes from a series of L-CRS/HIPEC LAMN II patients compared to those who have undergone a similar open operation (O-CRS/HIPEC) for low-volume PMP. Methods LAMN II patients undergoing L-CRS/HIPEC at a UK national peritoneal tumour centre were compared to O-CRS/HIPEC patients (peritoneal cancer index ≤ 7). Outcomes of interest included Clavien–Dindo complication grade, operative time, blood transfusions, high dependency unit (HDU) admission, length of hospital stay, and histopathological findings. Results 55 L-CRS/HIPEC were compared to 29 O-CRS/HIPEC patients (2003–2017). Groups were matched for age, sex, and procedures. Median operative time was 8.8 (IQR 8.1–9.5) h for L-CRS/HIPEC versus 7.3 (IQR 6.7–8) h for O-CRS/HIPEC (Mann–Whitney test p p Conclusion L-CRS/HIPEC for LAMN II takes longer; however patients have significantly reduced length of HDU and overall stay, without increased post-operative complications. A significant proportion of LAMN II patients undergoing L-CRS/HIPEC have extra-appendiceal acellular mucin with some cases demonstrating residual cellular epithelium from the LAMN II. The risk of these patients developing PMP without surgery is under current review.

AIM: Pseudomyxoma peritonei (PMP) is a rare neoplasm of the appendix, which if untreated disseminates throughout the abdominal cavity and generates considerable morbidity. Since 2002 in the UK, patients with PMP have been managed via two nationally commissioned centres. We evaluated referrals and treatment pathways over time at the Manchester centre.METHOD: Data from all patients referred with suspected PMP were prospectively collected (2002-2015). Definitive treatment was cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC). Disease burden was quantified using the Peritoneal Cancer Index (PCI: score 0-39) and complete cytoreduction (CC) defined by scores of 0/1. Novel treatment algorithms were developed for patients with low-grade appendiceal mucinous neoplasm (LAMN) localised to the peri-appendiceal tissue.RESULTS: 817 patients with confirmed PMP were referred increasing from 11 in 2002 to 103 in 2015. Disease burden was high with mean PCI of 31 in the first quartile (Q1), levelling-off to 15,15,17 thereafter (p = 0.002). The proportion of CC0/1 increased from 67% in Q1 to 77% Q2 and 74% Q3/4. Where complete cytoreduction was achieved, 5 and 10-year overall survival was 77% and 66%. The proportion of patients referred with localised LAMN increased over time reaching 25% each year since 2010 (Ptrend CONCLUSION: The establishment of a national treatment centre was associated with an initial presentation of patients with advanced disease. The programme has demonstrated a clear trend over time towards earlier referral and adoption of minimal invasive techniques for localised disease. This article is protected by copyright. All rights reserved.

Appendix adenocarcinomas are rare tumors with propensity for peritoneal metastasis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is an established treatment with curative intent, but, to date, studies reporting survival have been heterogeneous with regard to their patient groups (including other tumor types), interventions (not all patients receiving intraperitoneal chemotherapy), and follow-up (varying surveillance protocols).The aim of this study is to quantify the impact of this intervention on survival in a homogeneous group of patients with appendix adenocarcinoma receiving standardized treatment and follow-up, and to determine the impact of prognostic indicators on survival.This is a retrospective analysis of a prospective database at a national peritoneal tumor center where all patients had their appendix pathology reviewed and management planned by a specialized peritoneal tumor multidisciplinary team.Data were extracted on prognostic indicators including peritoneal cancer index, completeness of cytoreduction score, preoperative tumor markers, and histological features. Overall and disease event-free survival from the date of intervention were evaluated using Kaplan Meier curves and univariate Cox proportional hazards regression analysis.A total of 65 patients underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for appendix adenocarcinoma between 2005 and 2015. Median follow-up was 44.3 months. The overall survival was 55.5% and disease event-free survival was 36.1% (5-year rate). Peritoneal Cancer Index7, complete cytoreduction score of 0, and preoperative CEA of6 were all associated with significantly higher overall and disease event-free survival. CA19-938 and CA12531 were not associated with a significantly higher overall or disease event-free survival.The sample size was limited because of the rarity of this tumor type.This study quantifies the impact of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy on overall and disease event-free survival for appendix adenocarcinoma, identifying key prognostic indicators that may guide treatment. It supports the referral of these rare tumors to specialist centers with appropriate expertise for initial management and follow-up. See Video Abstract at http://links.lww.com/DCR/A595.

AIM: Six Phase III randomized trials have determined the effectiveness of chemoradiotherapy as primary treatment for anal squamous cell carcinoma (ASCC), but outcomes reported in these trials varied widely, hindering evidence synthesis. To improve reporting in all future trials, we aim to develop a core outcomes set (COS). As the first stage of COS development, we undertook a systematic review to summarize the outcomes reported in studies evaluating chemoradiotherapy for ASCC.METHOD: Systematic literature searches identified studies evaluating radiotherapy or chemoradiotherapy for ASCC. Outcomes and accompanying definitions were extracted verbatim and categorized into domains.RESULTS: From 5170 abstracts, we identified 95 eligible studies, reporting 1192 outcomes and 533 unique terms. We collapsed these terms into 86 standardized outcomes and five domains: survival; disease activity; life impact [including quality of life (QoL)]; delivery of care; and toxicity. The most commonly reported domains were survival and disease activity, reported in 74 (86%) and 54 (62%) studies, respectively. No outcome was reported in every publication. Over half (43/86) of the standardized outcome terms were reported in fewer than five studies, and 21 (25%) were reported in a single study only. There was wide variation in definitions of disease-free survival, colostomy-free survival and progression-free survival (PFS). Anal continence was reported in only 35 (41%) studies.CONCLUSION: Outcomes reported in studies evaluating chemoradiotherapy for ASCC were heterogenous and definitions varied widely. Outcomes likely to be important to patients, such as ano-rectal function, toxicity and QoL, have been neglected. A COS for future trials will address these issues.

Background Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are an established treatment for pseudomyxoma peritonei (PMP), but it is a major surgical procedure and may be associated with long-term morbidity. To date, health-related quality-of-life (HRQL) data among survivors are lacking. Methods A two-period qualitative study investigated patients undergoing CRS-HIPEC for PMP at a national peritoneal tumor center between 2003 and 2011. First, the European Organization for Research and Treatment (EORTC)-QLQ C30 HRQL questionnaire was used longitudinally preoperatively and at postoperative months 3, 6, 9, 12, 18, and 24, then yearly thereafter. Second, it was updated in 2016 as a cross-sectional study. Both studies were compared with age- and sex-matched reference populations (one-way t tests). Results A total of 553 longitudinal HRQL questionnaires were completed for 137 patients, truncated at 60 months. In the 2016 update, 85 responses were received from 103 survivors (mean follow-up period, 8.11 years). Patients' physical, role, and social function scores were impaired until 12 months postoperatively, after which the scores did not differ significantly from those of with reference populations. Similarly, fatigue, appetite loss, insomnia, and financial difficulties worsened significantly compared with reference populations in the first 12-months and then normalized. In contrast, impaired cognitive function (82.3 vs 88.5; P = 0.017), constipation (13.7 vs 7.3; P = 0.032), and diarrheal symptoms (15.1 vs 4.9; P = 0.0006) persisted through both periods. Global health scores did not differ significantly from those of the reference population. Conclusions Beyond 12 months postoperatively, CRS-HIPEC for PMP is associated with a good quality of life except for some cognitive functional impairment and bowel disturbances.

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Background: In mice models of cancer and human tissues samples, disturbance of the gut microbiota can reduce the effectiveness of chemotherapy and immunotherapy. There is limited evidence in humans whether antibiotics impact on the effectiveness of cancer treatments. We evaluated the associations between antibiotic use before cancer diagnoses and long-term mortality. Methods: Primary care data from general practices contributing to the English Clinical Practice Research Datalink (CPRD) and Welsh Secure Anonymised Information Linkage (SAIL) linked to Cancer Registries (CR) and Office for National Statistics (ONS) mortality records were used. Two cohort studies involving cancer patients (15 types) exposed to antibiotics before cancer diagnosis were identified. Recent, previous and past antibiotic users were compared using Cox regression models. Findings: 129 990 cancer patients from the National Cancer Registration and Analysis Service (NCRAS) linked to CPRD and 131 330 from the Welsh Cancer Intelligence Surveillance Unit (WCISU) were included. In comparison with past antibiotic users, patients who used antibiotics in the recent past before their cancer diagnosis and were mainly treated with chemotherapy or immunotherapy presented increased hazards ratio (HR) for mortality consistently in both cohorts; for leukaemia, the HR in NCRAS was 1·40 (95% CI 1·22-1·60), for lymphoma 1·19 (95% CI 1·06-1·33), for melanoma 1·31 (95% CI 1·12-1·54), and for myeloma 1·19 (95% CI 1·04-1·36). HR for cancer of the uterus, breast, urinary, colorectal, and kidney cancer followed the same trend in both CRs. Sensitivity analyses based on general practice records suggested comparable results to those from CRs. Interpretation: This study supports the hypothesis that prior use of antibiotics may reduce the effectiveness of chemotherapy and immunotherapy, potentially through disruption to the gut microbiota. Although not providing definitive results, the biological plausibility of the findings does support the need for judicious use of antibiotics. Funding: Department of Health and NIHR. Declaration of Interest: We declare no competing interests. Ethical Approval: The protocol was approved by the Independent Scientific Advisory Committee for CPRD research (protocol number 18_198) and SAIL’s Information Governance Protocol Review Panel (protocol number 0855).

Background In patients with rectal cancer who achieve clinical complete response after neoadjuvant chemoradiotherapy, watch and wait is a novel management strategy with potential to avoid major surgery. Study-level meta-analyses have reported wide variation in the proportion of patients with local regrowth. We did an individual participant data meta-analysis to investigate factors affecting occurrence of local regrowth.Methods We updated search results of a recent systematic review by searching MEDLINE and Embase from Jan 1,2016, to May 5,2017, and used expert knowledge to identify published studies reporting on local regrowth in patients with rectal cancer managed by watch and wait after clinical complete response to neoadjuvant chemoradiotherapy. We restricted studies to those that defined clinical complete response using criteria equivalent to Sao Paulo benchmarks (ie, absence of residual ulceration, stenosis, or mass within the rectum on clinical and endoscopic examination). The primary outcome was 2-year cumulative incidence of local regrowth, estimated with a two-stage random-effects individual participant data meta-analysis. We assessed the effects of clinical and treatment factors using Cox frailty models, expressed as hazard ratios (HRs). From these models, we derived percentage differences in mean 0 as an approximation of the effect of measured covariates on between-centre heterogeneity. This study is registered with PROSPERO, number CRD42017070934.Findings We obtained individual participant data from 11 studies, including 602 patients enrolled between March 11,1990, and Feb 13, 2017, with a median follow-up of 37.6 months (IQR 25.0-58.7). Ten of the 11 datasets were judged to be at low risk of bias. 2-year cumulative incidence of local regrowth was 21.4% (random-effects 95% CI 15.3-27.6), with high levels of between-study heterogeneity (I 2 =61%). We noted wide between-centre variation in patient, tumour, and treatment characteristics. We found some evidence that increasing cT stage was associated with increased risk of local regrowth (random-effects HR per cT stage 1.40, 95% CI 1.00-1.94; P-trend=0. 048). In a subgroup of 459 patients managed after 2008 (when pretreatment staging by MRI became standard), 2-year cumulative incidence of local regrowth was 19% (95% CI 13-28) for stage cT1 and cT2 tumours, 31% (26-37) for cT3, and 37% (21-60) for cT4 (random-effects HR per cT stage 1.50, random-effects 95% CI 1.03-247; P-trend=0. 0330). We estimated that measured factors contributed 4.8-45-3% of observed between-centre heterogeneity.Interpretation In patients with rectal cancer and clinical complete response after chemoradiotherapy managed by watch and wait, we found some evidence that increasing cT stage predicts for local regrowth. These data will inform clinician-patient decision making in this setting. Research is needed to determine other predictors of a sustained clinical complete response. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

Incidence rates for liver cancer have increased 3-fold since the mid-1970s in the United States in parallel with increasing trends for obesity and type II diabetes mellitus. We conducted an analysis of baseline body mass index (BMI), waist circumference (WC), and type II diabetes mellitus with risk of liver cancer. The Liver Cancer Pooling Project maintains harmonized data from 1.57 million adults enrolled in 14 U.S.-based prospective studies. Cox regression estimated HRs and 95% confidence intervals (CI) adjusted for age, sex, study center, alcohol, smoking, race, and BMI (for WC and type II diabetes mellitus). Stratified analyses assessed whether the BMI–liver cancer associations differed by hepatitis sera-positivity in nested analyses for a subset of cases (n = 220) and controls (n = 547). After enrollment, 2,162 incident liver cancer diagnoses were identified. BMI, per 5 kg/m2, was associated with higher risks of liver cancer, more so for men (HR = 1.38; 95% CI, 1.30–1.46) than women (HR = 1.25; 95% CI, 1.17–1.35; Pinteraction = 0.02). WC, per 5 cm, was associated with higher risks of liver cancer, approximately equally by sex (overall, HR = 1.08; 95% CI, 1.04–1.13). Type II diabetes mellitus was associated with higher risk of liver cancer (HR = 2.61; 95% CI, 2.34–2.91). In stratified analyses, there was a null association between BMI and liver cancer risk for participants who were sera-positive for hepatitis. This study suggests that high BMI, high WC, and type II diabetes mellitus are associated with higher risks of liver cancer and that the association may differ by status of viral hepatitis infection. Cancer Res; 76(20); 6076–83. ©2016 AACR.

BACKGROUND: Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points.METHODS: Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment.RESULTS: Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7-34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI -27.4, -7.0, P=0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls.CONCLUSIONS: Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy.

30 Background: Patients with rectal cancer and complete clinical response (cCR) after neoadjuvant chemoradiation (nCRT) have been offered non-operative management (W&W). Risk factors for local regrowth (RG) include baseline cT and type of nCRT. However, the influence of risk factors for RG over time and the extent in time that patients need to be followed with the rectum in situ after a cCR are unknown. Objective: Analyze the risk of recurrence over time through conditional survival (cDFS/cLRFS) estimates for rectal cancer patients under W&W. Methods: Retrospective analysis of all patients from the largest multicenter database of patients managed non-operatively (International Watch and Wait Database–IWWD). Only patients with cCR after nCRT and W&W with a median of >3 years of follow-up were included. cDFS was used to investigate the evolution of recurrence-odds, as patients remain disease-free after nCRT. 2-year cDFS was estimated at “x” years after nCRT based on the formula cDFS2=DFS(x+2)/DFS(x). Results: 768 patients treated between 1991-2015 were included. Using cDFSestimates, the probability of remaining disease-free for 2 additional years once cCR was achieved and sustained for 1, 3, and 5 years, were 85%, 97%, and 95%, respectively. These contrast with the actuarial DFS for similar intervals of 70%, 68% and 65% respectively. Baseline cT was associated with the risk of RG at 1 year after a cCR (cT2 aLRFS 89% vs. cT3 82%; p=0.004). However, after sustaining a cCR for 1 year, baseline cT becomes irrelevant at 2 years (cLRFS; 94% vs. 90%; |d| 0.14). Also, total dose of RT (≤50 vs >50Gy) was associated with the risk of RG (aLRFS 76% vs 85%; p=0.03) at 1 year. Dose of RT becomes irrelevant (at 2 years; cLRFS 93% vs. 90%; |d| 0.10) once patients sustained a cCR for 1 year. Conclusions: Conditional survival estimates suggests that patients have significantly lower risks (≤5%) of developing late RG (at 5 years) after sustaining cCR for 3 years. A sustained cCR over time may be more relevant for long-term risk of RG than cT-stage or RT dose. The present data can have significant consequences for the recommendation of intensive surveillance after sustaining 3ys of cCR.

Measurement of circulating insulin-like growth factors (IGFs), in particular IGF-binding protein (IGFBP)-2, at the time of diagnosis, is independently prognostic in many cancers, but its clinical performance against other routinely determined prognosticators has not been examined. We measured IGF-I, IGF-II, pro-IGF-II, IGF bioactivity, IGFBP-2, -3, and pregnancy-associated plasma protein A (PAPP-A), an IGFBP regulator, in baseline samples of 301 women with breast cancer treated on four protocols (Odense, Denmark: 1993–1998). We evaluated performance characteristics (expressed as area under the curve, AUC) using Cox regression models to derive hazard ratios (HR) with 95% confidence intervals (CIs) for 10-year recurrence-free survival (RFS) and overall survival (OS), and compared those against the clinically used Nottingham Prognostic Index (NPI). We measured the same biomarkers in 531 noncancer individuals to assess multidimensional relationships (MDR), and evaluated additional prognostic models using survival artificial neural network (SANN) and survival support vector machines (SSVM), as these enhance capture of MDRs. For RFS, increasing concentrations of circulating IGFBP-2 and PAPP-A were independently prognostic [HRbiomarker doubling: 1.474 (95% CIs: 1.160, 1.875, P = 0.002) and 1.952 (95% CIs: 1.364, 2.792, P RFS for NPI was 0.626 (Cox model), improving to 0.694 (P = 0.012) with the addition of IGFBP-2 plus PAPP-A. Derived AUCRFS using SANN and SSVM did not perform superiorly. Similar patterns were observed for OS. These findings illustrate an important principle in biomarker qualification—measured circulating biomarkers may demonstrate independent prognostication, but this does not necessarily translate into substantial improvement in clinical performance.

Background The PLATO platform consists of 3 anal cancer trials (ACT) across the loco-regional disease spectrum (ACT3, 4 and 5). ACT5 tests the benefit of RT dose escalation using intensity modulated RT (IMRT) in locally advanced disease. We planned to analyse treatment compliance, acute toxicity and patient reported outcomes (PROs) on the first 60 patients (pts) prior to the phase II/III trial (final target n = 640) to evaluate the need for protocol modifications. Methods Pts with T2 N1-3, T3-4 N any M0 squamous cancer of the anus entered a prospective, multi-centre, open-labelled randomised 3-arm trial, and received 28 fractions (F) of IMRT at total standard dose of 53.2Gy or escalated to 58.8Gy or 61.6Gy to the gross tumour (40Gy in 28F elective nodal irradiation in all arms). All pts received concurrent mitomycin 12mg/m2 day 1 and capecitabine (CAP) 825mg/m2 twice daily (week days) or 5-fluorouracil 1000mg/m2 days 1-4 and 29-32. Compliance to RT (no delay >3 days due to toxicity) and chemotherapy, worst acute toxicity during treatment (CTCAEv4) and PROs up to 6 months (EORTC-QLQ C30 and ANL27) were analysed. Results 60 pts were enrolled from 12 UK sites (53.2Gy n = 19; 58.8Gy n = 21; 61.6Gy n = 20). 78% female, median age 61 years (36 -77), 67% T2/3 and 28% ECOG PS1. All pts received planned RT dose with no delays >3days. Chemotherapy (5FU n = 18; CAP n = 42) modifications were: 8.3% (n = 5) overall dose reductions and 35% (n = 15) temporary CAP omissions (range 1-5 days). Pts had acceptable acute toxicity/PROs for both experimental arms not requiring protocol modification. Worst reported CTCAE toxicity grade (G) per pt: G2 51.7% (n = 31), G3 47.6% (n = 28, 19 radiation dermatitis, 7 diarrhoea), G4 1.7% (n = 1; thrombocytopenia). PRO compliance was 86.7% at 6 months. Pre-specified PRO items on quality of life, pain, and bowel toxicity were worst in final treatment week, improving by 6 weeks and returned to baseline or better by 6 months. Conclusions RT dose intensification appears safe with acceptable compliance, acute toxicity and PROs at 6 months. Data Monitoring Committee approved phase II with no treatment schedule changes but included a 6 month clinician toxicity assessment. Phase II will open in June 2019.

Summary Clinically prescribed insulin analogues are putatively linked with increased cancer risk. We developed a framework for the mandated regulatory in vitro evaluation of cancer-relevant bioassays for comparisons of insulin analogues, and showed that the cell-specific IGF-IR/IR ratio is crucial for interpretation., Epidemiological and laboratory studies raise the possibility of a link between clinically prescribed insulin analogues and increased cancer risk. Accordingly, there is a regulatory mandate for cancer-related pre-clinical safety evaluation during insulin analogue development, but currently, there is no standardized framework for such in vitro evaluation. We tested human insulin; the super-mitogenic insulin, X10 and insulin-like growth factor I, in four cancer cell lines with a range of insulin-like growth factor-I receptor (IGF-IR)/IR (insulin receptor) ratios (HCT 116, HT-29, COLO 205 and MCF7) and related these to IGF-IR and IR expression in 17 human adenocarcinomas. All cell types were IR-A isoform dominant. We determined IGF-IR/IR signalling pathway endpoints in dose- and time-varying experiments, and performed mitogenic dose–response equivalent assays to derive EC50 values, and correlated these with IGF-IR/IR ratios. We superimposed relative EC50 values onto data from the literature in a meta-analysis. The IGF-IR/IR ratios varied from

Characterisation of human papilloma virus (HPV) infection in anal squamous cell carcinoma (ASCC) may have dual importance: first, aetiological; second, prognostic, informing outcome after chemo-radiotherapy (CRT). We undertook HPV genotyping, and allelic characterisations, to evaluate the aetiological role of HPV while simultaneously evaluating the impact of HPV genotyping on relapse-free (RFS) and overall survival (OS).Dual-primer HPV genotyping (subtypes 6, 11, 16, 18, 31, 33, 45, 52, 58) and DNA sequencing of HPV 16 positive tumours were analysed in 151 consecutively referred ASCCs, previously characterised by immunohistochemistry for p16 expression. In 110 patients treated with CRT, factors influencing RFS and OS were evaluated using univariate and multivariate models.HPV positivity was observed in 95%. HPV 16 accounted for 89%; of these, 64% harboured the T350G E6 variant. HPV 16 positivity was significantly correlated with improved 5-year RFS (62% versus 40%; p = 0.027) and OS (59% versus 38%; p = 0.019). p16 expression was also significantly correlated with improved 5-year RFS (positive versus negative: 65% versus 16%; p0.0001) and OS (63% versus 13%; p0.0001). In multivariable models that included HPV 16 status, p16 status, sex, and age, p16 expression remained an independent prognostic factor for RFS (p0.0001) and OS (p = 0.002).In ASCC, near-universal HPV detection rates were demonstrated, higher than generally reported in the literature, and supporting the development of multivalent HPV vaccinations for prevention. By contrast, p16 negatively, but not HPV 16 genotype, is an independent adverse prognosticator after chemo-radiotherapy in patients with ASCC.

Screening colonoscopy and flexible sigmoidoscopy (FSG) reduce the risk of colorectal cancer (CRC), but the magnitude and duration of protection, particularly against right-sided cancer, remain uncertain. We computed the incremental benefit of colonoscopy over FSG using a validated mathematical model, which reflects colorectal neoplasia growth characteristics while allowing uncertainty in endoscopic detection and removal of adenomas.We calibrated models of CRC incidence within a multistage clonal expansion framework to data from: (1) San Francisco-Oakland SEER registry (reference population) and (2) FSG long-term follow-up data from 50,757 individuals after a negative FSG in the Kaiser Permanente system. We compared the residual CRC risks after FSG with full-length colonoscopy.Our model mirrors trial data with 10-year CRC risk reductions after FSG screening at age 50 years of approximately one-third; the optimal age for a 'once-only' FSG exam was between ages 50 and 60 years; and the greater benefit was for men compared with women. There were considerable incremental gains in reduction in CRC risk by colonoscopy compared with FSG with the greatest benefit for screening colonoscopy at age 50 years. These results held up against lowering the right-sided adenoma detection sensitivity by 30%, as well as reducing the curative efficacy of polypectomy throughout the colon.Mathematical modeling of CRC screening, which takes account of important aspects of tumor biology, demonstrates superior risk reductions by colonoscopy over FSG. Our predictions provide further rationale for recommending screening colonoscopy in average-risk populations before the age of 60.

BACKGROUND: In patients with squamous cell carcinoma of the anus (SCCA), lymph node positivity (LNP) indicates poor prognosis for survival and is central to radiotherapy planning. Over the past three decades, LNP proportion has increased, mainly reflecting enhanced detection with newer imaging modalities; a process known as nodal stage migration. If accompanied by constant T stage distributions, prognosis for both lymph node-positive and lymph node-negative groups may improve without any increase in overall survival for individual patients; a paradox termed the Will Rogers phenomenon. Here, we aim to systematically evaluate the impact of nodal stage migration on survival in SCCA and address a novel hypothesis that this phenomenon results in reduced prognostic discrimination.METHODS: We did a systematic review and meta-regression to quantify changes in LNP over time and the impact of this change on survival and prognostic discrimination. We searched MEDLINE, Embase, and the Cochrane Library to identify randomised trials and observational studies in patients with SCCA published between Jan 1, 1970, and Oct 11, 2016. Studies were eligible if patients received chemoradiotherapy or radiotherapy as the main treatment, reported LNP proportions (all studies), and reported overall survival (not necessarily present in all studies). We excluded studies with fewer than 50 patients. We extracted study-level data with a standardised, piloted form. The primary outcome measure was 5-year overall survival. To investigate scenarios in which reduced prognostic discrimination might occur, we simulated varying true LNP proportions and true overall survival, and compared these with expected observed outcomes for varying levels of misclassification of true nodal state.FINDINGS: We identified 62 studies reporting LNP proportions, which included 10 569 patients. From these, we included 45 studies (6302 patients) with whole cohort 5-year overall survival, 11 studies with 5-year survival stratified by nodal status, and 20 studies with hazard ratios in our analyses of temporal changes. In 62 studies, the LNP proportions increased from a mean estimate of 15·3% (95% CI 10·5-20·1) in 1980 to 37·1% (34·0-41·3) in 2012 (pINTERPRETATION: We describe a consequence of staging misclassification in anal cancer that we have termed reduced prognostic discrimination. We used this new observation to infer that the LNP proportions of more than 30% seen in modern clinical series (11 out of 15 studies with a median year since 2007) are higher than the true LNP proportion. The introduction of new staging technologies in oncology might misclassify true disease stage, spuriously informing disease management and ultimately increasing the risk of overtreatment.FUNDING: Bowel Disease Research Foundation.

As colorectal cancers have a long latency period, their origins may lie early in life. Therefore childhood body mass index (BMI; kg/m2) and height may be associated with adult colorectal cancer. Using a cohort design, 257,623 children from The Copenhagen School Health Records Register born from 1930 to 1972 with measured heights and weights at ages 7 to 13 years were followed for adult colon and rectal adenocarcinomas by linkage to the Danish Cancer Registry. Hazard ratios (HRs) with 95% confidence intervals (CI) were estimated by Cox proportional hazard regressions. During follow-up, 2676 colon and 1681 rectal adenocarcinomas were diagnosed. No sex differences were observed in the associations between child BMI or height and adult colon or rectal cancers. Childhood BMI and height were positively associated with colon cancer; at age 13 years the HRs were 1.09 (95% CI 1.04–1.14) and 1.14 (95% CI 1.09–1.19) per z-score, respectively. Children who were persistently taller or heavier than average, had increased risk of colon cancer. Similarly, growing taller or gaining more weight than average was positively associated with colon cancer. No associations were observed between BMI or height and rectal cancer. Childhood BMI and height, along with above average change during childhood are significantly and positively associated with adult colon cancers, but not with rectal cancer, suggesting different etiologies.

Background Excess adiposity is a risk factor for incidence of several gastrointestinal cancers, but it is unclear how these epidemiological observations translate into clinical practice. Methods Critical appraisals and updated analyses of published systematic reviews were undertaken to quantify cancer risk associations better and to assess the impact of weight-reducing strategies (surgical and non-surgical) on cancer prevention. Results and conclusion A large volume of evidence demonstrates that body mass index (BMI), as an approximation for general adiposity, is a risk factor for the development of oesophageal adenocarcinoma, and colorectal, hepatocellular, gallbladder and pancreatic cancers. A smaller volume of evidence demonstrates that indices of increased central adiposity (such as waist circumference) are associated with increased risk of oesophageal adenocarcinoma and colorectal cancer, but these indices are not necessarily better predictors of risk compared with BMI. Several biological mechanisms may explain these associations but each hypothesis has several caveats and weaknesses. There are few data that convincingly demonstrate significant reductions in risk of gastrointestinal cancers following weight-reducing strategies. In turn, there are many methodological pitfalls in this literature, which prevent conclusive interpretation. The lack of robust intermediary obesity-related biomarkers is an additional unresolved challenge for prevention trials. Novel underpinning mechanisms (for example, local ectopic fat) and more accurate methods to measure these intermediaries are sought and explored as the most optimistic research strategies for the future.

OBJECTIVE: To report a simplified and effective method for substratification of M1 castrate resistant prostate cancer by correlating progression free and overall survival with simple numeric quantification of skeletal metastases. PATIENTS AND METHODS: 561 men with M1 CRPC were studied longitudinally Individual bone scan disease burden, quantified by counting bone metastasis number, was correlated with clinical outcome using specific cut off points of 1-4, 5-20 and >20 detectable lesions RESULTS: Patients with a higher metastasis number had a shorter progression free (PFS) and overall (OS) survival (HR=2.0 (95% CI: 1.7-2.4) p 20 metastases were shorter still (median 5.3 (95% CI: 3.4-6.9) and 13.3 (95% CI: 11.3-17.6months respectively). Dichotomising into cohorts with 1-4 and ?5 metastases, the latter group had considerably poorer PFS (8.4 (95% CI: 6.8-10.3) p

Summary Excess adiposity is an established risk factor for incident colorectal cancer (CRC) but whether this association extrapolates to poorer survival is unclear. We undertook a systematic review to examine relationships between measures of adiposity and survival in patients with CRC. For distinction, we included pre-diagnosis exposure and CRC-related mortality. We performed dose-response meta-analyses and assessed study quality using eight domains of bias. Six study categories were identified based on (i) timing of adiposity measurement relative to survival analysis time zero and (ii) clinical setting. Several types of adiposity measurements were reported; body mass index (BMI) was the commonest. For pre-diagnosis cohorts, baseline BMI negatively impacted on CRC-related mortality in men only (risk estimate per 5 kg m−2 = 1.19, 95% confidence intervals: 1.14–1.25). The other groups were pre-diagnosis BMI but diagnosis as time zero; population-based cohorts; treatment cohorts; observational analyses within adjuvant chemotherapy trials; patients with metastatic CRC – each had several biases (e.g. treatment selection, reverse causality) and sources of confounding (e.g. chemotherapy ‘capping’). Overall, there was insufficient evidence for a strong link between adiposity and survival. These findings demonstrate an important principle: an established link between an exposure (here, adiposity) and increased cancer incidence does not necessarily extrapolate into an inferior post-treatment outcome.

Purpose Obesity (body mass index [BMI] ≥ 30 kg/m2) is common among patients with cancer. We reviewed management issues in the obese patient with cancer, focusing on how obesity influences treatment selection (including chemotherapy dosing), affects chemotherapy toxicity and surgical complications, and might be a treatment effect modifier. Methods The majority of evidence is drawn from observational studies and secondary analyses of trial data, typically analyzed in N × 3 BMI categories (normal weight, overweight, and obese) matrix structures. We propose a methodological framework for interpretation focusing on sample size and composition, nonlinearity, and unmeasured confounding. Results There is a common perception that obesity is associated with increased treatment-related toxicity. Accordingly, cytotoxic chemotherapy dose reduction is common in patients with elevated BMI. Contrary to this, there is some evidence that full dosing in obese patients does not result in increased toxicity. However, these data are from a limited number of regimens, and fail to fully capture cytotoxic drug pharmacodynamics and pharmacokinetic variability in obese patients. Among patients undergoing surgery, there is evidence that elevated BMI is associated with increased perioperative mortality and increased rates of infectious complications. A novel finding is that these relationships hold after surgery for malignancy, but not for benign indications. There are biologic plausibilities that obesity might be an effect modifier of treatment, but supporting evidence from clinical studies is inconsistent. Conclusion In line with the ASCO 2012 guidelines, chemotherapy dosing is probably best performed using actual body weight in obese patients. However, specific regimens known to be associated with increased toxicity in this group should be used with caution. There is no guidance on dose for obese patients treated with biologic agents. Currently, there are no specific recommendations for the surgical management of the obese patient with cancer.

This article is featured in Highlights of This Issue, [p. 661][1] For over a decade, excess body weight, commonly categorized as overweight [body mass index (BMI): 25.0–29.9 kg/m2] and obesity (BMI: ≥30 kg/m2), has been an established incidence risk factor for several adult cancers ([1][2]).

Paulus and colleagues ([1][1]) reported that “among colorectal cancer patients with diabetes, metformin users had a 13% improved overall survival …….” and proposed that these data lend “support to ………randomized studies of …… metformin among patients with colorectal cancer.” We

Purpose/Objective(s) Randomized controlled trials for patients with squamous cell carcinoma of the anus have been successfully performed, despite the rarity of the disease. The RTOG 9811 and ACT2 trials demonstrated no improvement in cancer outcomes when neoadjuvant or adjuvant cisplatin 5FU chemotherapy was used. To capture as many anal cancer patients as possible in future clinical trials, we developed an umbrella of trials testing efficacy and acceptable morbidity across different loco-regional risk strata. Materials/Methods We formed a network of UK and international multi-disciplinary trialists and identified the following priorities:- i] the need for national consensus guidance for the introduction of intensity modulated radiation therapy (IMRT) based on the successful principles and fractionation used in the ACT2 protocol prior to future trials; ii] to evaluate a strategy using selective chemoradiation therapy (CRT) after local excision of anal margin tumors; iii] to evaluate reduced dose CRT to the primary tumor in order to limit late effects whilst maintaining elective nodal irradiation in early stage disease; iv] to evaluate dose escalated CRT in locally advanced T3/4 and N+ stage disease. Results The PLATO (personalizing radiotherapy dose in anal cancer) umbrella trial comprising of the ACT3, 4 and 5 trials is funded by Cancer Research UK and is due to commence recruitment in Q3 2016.The ACT 3 trial (n = 90) is a non-randomized phase II study that will evaluate a strategy of local excision for T1N0 anal margin tumors with selective postoperative involved field CRT using 41.4 Gy in 23 fractions (F) and concurrent capecitabine reserved for patients with margins

There is a common perception that excess adiposity, commonly approximated by body mass index (BMI), is associated with reduced cancer survival. A number of studies have emerged challenging this by demonstrating that overweight and early obese states are associated with improved survival. This finding is termed the "obesity paradox" and is well recognized in the cardio-metabolic literature but less so in oncology. Here, we summarize the epidemiological findings related to the obesity paradox in cancer. Our review highlights that many observations of the obesity paradox in cancer reflect methodological mechanisms including the crudeness of BMI as an obesity measure, confounding, detection bias, reverse causality, and a specific form of the selection bias, known as collider bias. It is imperative for the oncologist to interpret the observation of the obesity paradox against the above methodological framework and avoid the misinterpretation that being obese might be "good" or "protective" for cancer patients.

background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to optimise their use. methods: Blood samples were collected during and following treatment and, where appropriate, upon progression from ovarian cancer patients in ICON7, a randomised phase III trial of carboplatin and paclitaxel with or without bevacizumab. Plasma concentrations of 15 circulating angio-biomarkers were measured using a validated multiplex ELISA, analysed through a novel network analysis and their relevance to the PFS then determined. results: Samples (n=650) were analysed from 92 patients. Bevacizumab induced correlative relationships between Ang1 and Tie2 plasma concentrations, which reduced after initiation of treatment and remained decreased until progressive disease occurred. A 50% increase from the nadir in the concentration of circulating Tie2 (or the product of circulating Ang1 and Tie2) predicted tumour progression. Combining Tie2 with GCIG-defined Ca125 data yielded a significant improvement in the prediction of progressive disease in patients receiving bevacizumab in comparison with Ca125 alone (74.1% vs 47.3%, P

Background: Circulating total cytokeratin 18 (tCK18) and/or caspase cleaved cytokeratin 18 (cCK18) (measured by M65 and M30 enzyme-linked immunosorbent assays (ELISAs), respectively) are used as pharmacodynamic (PD) biomarkers of epithelial cell death in clinical trials. Having validated these ELISAs, we assessed their utility in colorectal cancer (CRC). Methods: We applied the assays in several settings: 53 controls; 97 patients undergoing surgery and 74 patients with metastatic CRC undergoing chemotherapy (55 first line; 56 patients with repeated sampling through chemotherapy). Prognostic significance was evaluated using Kaplan–Meier life tables and Cox models; PD utility was assessed by analysis of repeated measures. Results: Median cCK18 and tCK18 levels were elevated in patients with cancer (both P=0.0001), and among cancer patients, there were increasing trends from early to advanced stages (both Ptrends=0.0001). Increasing tCK18 predicted for reduced survival after surgery with curative intent (adjusted hazard ratio (HR) for doubling in concentration 1.77, 95% CI: 1.04, 3.01) and after first-line chemotherapy in metastatic disease (adjusted HR per doubling in concentration=1.78, 95% CI: 1.37, 2.30). In patients with progressive disease during chemotherapy, repeated sampling revealed profiles with high baselines and progressive upwardly increases after cycle 1. Conclusion: This study provides evidence for cytokeratin 18 (CK18) as a prognostic and PD biomarker in patients with CRC and supports continued deployment of circulating CK18 in biomarker-enhanced trials.

Body mass index (BMI) is a major risk factor for endometrial cancer incidence but its impact on post-treatment survival is unclear. We investigated the relationships of BMI (categorised using the WHO definitions) with clinico-pathological characteristics and outcome in women treated within the MRC ASTEC randomised trial, which provides data from patients who received standardised allocated treatments and therefore reduces biases. The impact of BMI on both recurrence-free survival (RFS) and overall survival (OS) was analysed using the Cox regression models. An apriori framework of evaluating potential biases was explored. From 1408 participants, there were 1070 women with determinable BMI (median=29.1 kg/m(2)). Histological types were endometrioid (type 1) in 893 and non-endometrioid (type 2) in 146 women; the proportion of the latter decreasing with increasing BMI (8% versus 19% for obese III WHO category versus normal weight, p(trend)=0.003). For type 1 carcinomas, increasing BMI was associated with less aggressive histopathological features (depth of invasion, p=0.006; tumour grade, p=0.015). With a median follow-up of 34.3 months, there was no influence of BMI on RFS - adjusted HRs per 5 kg/m(2) were 0.98 (95% CI 0.86, 1.13) and 0.95 (0.74, 1.24), for type 1 and 2 carcinomas; and no influence on OS - adjusted HRs per 5 kg/m(2) were 0.96 (0.81, 1.14) and 0.92 (0.70, 1.23), respectively. These findings demonstrate an important principle: that an established link between an exposure (here, obesity) and increased incident cancer risk, does not necessarily translate into an inferior outcome following treatment for that cancer.

Following curative treatment for colorectal cancer (CRC), 30% to 50% of patients will develop recurrent disease. For CRC there are several lines of evidence supporting the hypothesis that early detection of metachronous disease offers a second opportunity for cure. This paper revisits the potential role of serum carcinoembryonic antigen (CEA) in follow-up. A comprehensive review of the literature (1978-2008) demonstrates that the initial promise of serum CEA as an effective surveillance tool has been tarnished through perpetuation of poorly designed studies. Specific limitations included: testing CEA as only an 'add-on' diagnostic tool; lack of standardization of threshold values; use of static thresholds; too low measurement frequency. Major changes in localizing imaging techniques and treatment of metastatic CRC further cause a decrease of clinical applicability of past trial outcomes. In 1982, Staab hypothesized that the optimal benefit of serum CEA as a surveillance tool is through high-frequency triage using a dynamic threshold (HiDT). Evidence supporting this hypothesis was found in the biochemical characteristics of serum CEA and retrospective studies showing the superior predictive value of a dynamic threshold. A multi-centred randomized phase III study optimizing the usage of HiDT against resectability of recurrent disease is commencing recruitment in the Netherlands.

Background: Body mass index (BMI) is a risk factor for endometrial cancer. We quantified the risk and investigated whether the association differed by use of hormone replacement therapy (HRT), menopausal status, and histologic type. Methods: We searched MEDLINE and EMBASE (1966 to December 2009) to identify prospective studies of BMI and incident endometrial cancer. We did random-effects meta-analyses, meta-regressions, and generalized least square regressions for trend estimations assuming linear, and piecewise linear, relationships. Results: Twenty-four studies (17,710 cases) were analyzed; 9 studies contributed to analyses by HRT, menopausal status, or histologic type, all published since 2003. In the linear model, the overall risk ratio (RR) per 5 kg/m2 increase in BMI was 1.60 (95% CI, 1.52–1.68), P < 0.0001. In the piecewise model, RRs compared with a normal BMI were 1.22 (1.19–1.24), 2.09 (1.94–2.26), 4.36 (3.75–5.10), and 9.11 (7.26–11.51) for BMIs of 27, 32, 37, and 42 kg/m2, respectively. The association was stronger in never HRT users than in ever users: RRs were 1.90 (1.57–2.31) and 1.18 (95% CI, 1.06–1.31) with P for interaction = 0.003. In the piecewise model, the RR in never users was 20.70 (8.28–51.84) at BMI 42 kg/m2, compared with never users at normal BMI. The association was not affected by menopausal status (P = 0.34) or histologic type (P = 0.26). Conclusions: HRT use modifies the BMI-endometrial cancer risk association. Impact: These findings support the hypothesis that hyperestrogenia is an important mechanism underlying the BMI-endometrial cancer association, whilst the presence of residual risk in HRT users points to the role of additional systems. Cancer Epidemiol Biomarkers Prev; 19(12); 3119–30. ©2010 AACR.

Growth hormone (GH), insulin-like growth factor (IGF)-I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of concern for several decades. The evidence that GH, IGF-I and insulin can promote and contribute to cancer progression comes from various sources, including transgenic and knockout mouse models and animal and human cell lines derived from cancers. Assessments of the GH-IGF axis in healthy individuals followed up to assess cancer incidence provide direct evidence of this risk; raised IGF-I levels in blood are associated with a slightly increased risk of some cancers. Studies of human diseases characterized by excess growth factor secretion or treated with growth factors have produced reassuring data, with no notable increases in de novo cancers in children treated with GH. Although follow-up for the vast majority of these children does not yet extend beyond young adulthood, a slight increase in cancers in those with long-standing excess GH secretion (as seen in patients with acromegaly) and no overall increase in cancer with insulin treatment, have been observed. Nevertheless, long-term surveillance for cancer incidence in all populations exposed to increased levels of GH is vitally important.

Standard approaches to estimating population-attributable risk (PAR) include modelling estimates of exposure prevalence and relative risk. Here, we examine the associations between body mass index (BMI) and cancer risk and how effect modifications of these associations impact on PAR estimates. In 2008, sex- and population-specific risk estimates were determined for associations with BMI in a standardised meta-analysis for 20 cancer types. Since then, refinements of these estimates have emerged: (i) absence of menopausal hormonal therapy (MHT) is associated with elevated BMI associations in post-menopausal breast, endometrial and ovarian cancers; (ii) current smoking attenuates the BMI associations in oesophageal squamous cell carcinoma, lung and pancreatic cancers; (iii) prostate screening attenuates BMI associations when all prostate cancers are considered together; and (iv) BMI is differentially associated with different histological subtypes within the same cancer group. Using secondary analyses of the aforementioned meta-analysis, we show 2 3-fold shifts in PAR estimations for breast and endometrial cancers depending on the MHT usage in European countries. We also critically examine how to best handle exposures (in this example, BMI distributions) and relative risk estimates in PAR models, and argue in favour of a counterfactual approach based around BMI means. From these observations, we develop a research framework in which to optimally evaluate future trends in numbers of new cancers attributable to excess BMI. Overall, this framework gives conservative estimates for PAR nonetheless, the numbers of avoidable cancers across Europe through avoidance of excess weight are substantial. (C) 2010 Elsevier Ltd. All rights reserved.

Intentional weight loss may reduce breast cancer risk through lowering levels of circulating free IGF-I but few studies have measured this longitudinally. We determined the effect of weight loss (=5% body weight) over 12 months, using an energy restriction and exercise programme, on an expanded panel of IGF-related peptides amongst 23 weight losing and 46 weight stable or gaining pre-menopausal women at increased risk of breast cancer, BMI (mean ± SD) 29.2 ± 6.2 kg/m2. Fasting measures of total and free IGF-I (ultra-filtration), and IGFBP-1, -2 and -3, body weight, body fat (DXA), intra-abdominal fat (MRI) were assessed at 6 and 12 months. After 12 months, women who lost ≥ 5% of body weight had a significant increase in serum total IGF-I; mean (95% CI difference) 17 (2.3 to 34.0) μg/l, P < 0.05, and IGFBP-2; mean (95% CI ratio) 1.24 (1.06 to 1.46) P < 0.001, compared to weight stable/gaining women. Serum IGFBP-1 tended to increase in weight losers compared to the weight stable/gaining women; mean (95% CI ratio) 1.19 (0.97 to 1.45) P=0.09, whereas IGFBP-3 remained unchanged; mean (95% CI ratio) 1.02 (0.94 to 1.20] P=0.99. Weight loss did not significantly alter serum levels of free IGF-I; mean difference 0.1 (-0.1 to 3.4) μg/l, P=0.21. Increased serum total IGF-I levels, and maintenance of free IGF-I despite increased concentrations of serum IGFBP-1 and -2 with weight loss, does not suggest intentional weight loss with diet and exercise mediates reduced risk through the circulating IGF-axis.