•This ESMO Clinical Practice Guideline provides key recommendations for managing anal cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment, ...follow-up and survivorship.•Treatment algorithms for locoregional and advanced anal cancer are provided.•Opportunities for personalised medicine in anal cancer are discussed.•Recommendations were compiled by the authors based on available scientific data and the authors' collective expert opinions.
Substantial evidence suggests that people with type 2 diabetes have an increased risk of developing several types of cancers. These associations may be due to a number of direct and indirect ...mechanisms. Observational studies of these associations, including the potential role for glucose-lowering therapy, are being increasingly reported, but face a number of methodological challenges. This paper is the first of two review papers addressing methodological aspects underpinning the interpretations of links between diabetes and cancer, and suggests potential approaches to study designs to be considered in observational studies. This paper reviews factors related to cancer incidence in the diabetic population; the second paper relates to studies of cancer mortality.
Summary Background Excess bodyweight, expressed as increased body-mass index (BMI), is associated with the risk of some common adult cancers. We did a systematic review and meta-analysis to assess ...the strength of associations between BMI and different sites of cancer and to investigate differences in these associations between sex and ethnic groups. Methods We did electronic searches on Medline and Embase (1966 to November 2007), and searched reports to identify prospective studies of incident cases of 20 cancer types. We did random-effects meta-analyses and meta-regressions of study-specific incremental estimates to determine the risk of cancer associated with a 5 kg/m2 increase in BMI. Findings We analysed 221 datasets (141 articles), including 282 137 incident cases. In men, a 5 kg/m2 increase in BMI was strongly associated with oesophageal adenocarcinoma (RR 1·52, p<0·0001) and with thyroid (1·33, p=0·02), colon (1·24, p<0·0001), and renal (1·24, p <0·0001) cancers. In women, we recorded strong associations between a 5 kg/m2 increase in BMI and endometrial (1·59, p<0·0001), gallbladder (1·59, p=0.04), oesophageal adenocarcinoma (1·51, p<0·0001), and renal (1·34, p<0·0001) cancers. We noted weaker positive associations (RR <1·20) between increased BMI and rectal cancer and malignant melanoma in men; postmenopausal breast, pancreatic, thyroid, and colon cancers in women; and leukaemia, multiple myeloma, and non-Hodgkin lymphoma in both sexes. Associations were stronger in men than in women for colon (p<0·0001) cancer. Associations were generally similar in studies from North America, Europe and Australia, and the Asia–Pacific region, but we recorded stronger associations in Asia–Pacific populations between increased BMI and premenopausal (p=0·009) and postmenopausal (p=0·06) breast cancers. Interpretation Increased BMI is associated with increased risk of common and less common malignancies. For some cancer types, associations differ between sexes and populations of different ethnic origins. These epidemiological observations should inform the exploration of biological mechanisms that link obesity with cancer.
Abstract Locally advanced primary rectal cancer is variably defined, but generally refers to T3 and T4 tumours. Radical surgery is the mainstay of treatment for these tumours but there is a high-risk ...for local recurrence. National Institute for Health and Care Excellence (2011) guidelines recommend that patients with these tumours be considered for preoperative chemoradiotherapy and this is the starting point for any discussion, as it is standard care. However, there are many refinements of this pathway and these are the subject of this overview. In surgical terms, there are two broad settings: (i) patients with tumours contained within the mesorectal envelope, or in the lower rectum, limited to invading the sphincter muscles (namely some T2 and most T3 tumours); and (ii) patients with tumours directly invading or adherent to pelvic organs or structures, mainly T4 tumours – here referred to as primary rectal cancer beyond total mesorectal excision (PRC-bTME). Major surgical resection using the principles of TME is the mainstay of treatment for the former. Where anal sphincter sacrifice is indicated for low rectal cancers, variations of abdominoperineal resection – referred to as tailored excision – including the extralevator abdominoperineal excision (ELAPE), are required. There is debate whether or not plastic reconstruction or mesh repair is required after these surgical procedures. To achieve cure in PRC-bTME tumours, most patients require extended multivisceral exenterative surgery, carried out within specialist multidisciplinary centres. The surgical principles governing the treatment of recurrent rectal cancer (RRC) parallel those for PRC-bTME, but typically only half of these patients are suitable for this type of major surgery. Peri-operative morbidity and mortality are considerable after surgery for PRC-bTME and RRC, but unacceptable levels of variation in clinical practice and outcome exist globally. To address this, there are now major efforts to standardise terminology and classifications, to allow appropriate comparisons in future studies.
In this paper we address methodological aspects of aetiological importance in the link between diabetes and mortality in patients with cancer. We identified nine key points on the cancer pathway at ...which confounding may arise—cancer screening use, stage at diagnosis, cancer treatment selection, cancer treatment complications and failures, peri-treatment mortality, competing risks for long-term mortality, effects of type 2 diabetes on anti-cancer therapies, effects of glucose-lowering treatments on cancer outcome and differences in tumour biology. Two types of mortality studies were identified: (1) inception cohort studies that evaluate the effect of baseline diabetes on cancer-related mortality in general populations, and (2) cohorts of patients with a cancer diagnosis and pre-existing type 2 diabetes. We demonstrate, with multiple examples from the literature, that pre-existing diabetes affects presentation, cancer treatment, and outcome of several common cancer types, often to varying extents. Diabetes is associated with increased all-cause mortality in cancer patients, but the evidence that it influences cancer-specific mortality is inconsistent. In the absence of data that address the potential biases and confounders outlined in the above framework, we caution against the reporting of cancer-related mortality as a main endpoint in analyses determining the impact of diabetes and glucose-lowering medications on risk of cancer.
Previous studies have shown that extracapsular dissection (ECD) is an alternative approach to superficial parotidectomy (SP) for pleomorphic adenoma parotid tumours, associated with low recurrence ...rates equal to those following SP, but with significantly reduced morbidity. However, if a malignant tumour masquerades as a clinically benign lump, this approach may be inappropriate. This study addressed this question by analysing the outcome of 821 consecutive patients with parotid tumours treated at one centre over 40 years and with a median 12 (range 5-30) years follow-up. Tumours were classified as 'simple' (discrete, mobile, < 4 cm: n=662) and 'complex' (deep, fixed, facial nerve palsy, > or =4 cm: n=159). Among the 'simple' or clinically benign tumours, 503 patients underwent ECD; 159 patients underwent SP. In all, 32 (5%) clinically benign cases were subsequently revealed as malignant histologies (ECD, 12; SP, 20). For each group, 5- and 10-year cancer-specific survival rates were 100 and 98%, respectively. There were no differences in recurrence rates when subanalysed by surgical groups, but ECD was associated with significantly reduced morbidity (P < 0.001). This study demonstrates that ECD is a viable alternative to superficial parotidectomy for the majority of parotid tumours, associated with reduced morbidity without oncological compromise.
The prevalence of excess body weight, commonly measured as body mass index (BMI)≥25 kg m(-2), has increased substantially in many populations worldwide over the past three decades, but the rate of ...increase has slowed down in some western populations.
We address the hypothesis that the slowing down of BMI trend increases in England reflects a majority sub-population resistant to further BMI elevation.
Pseudo-panel data derived from annual cross-sectional surveys, the Health Surveys for England (1992-2010). Trends in median BMI values were explored using regression models with splines, and gender-specific mixture model (latent class analysis) were fit to take an account of increasing BMI distribution variance with time and identify hidden subgroups within the population.
BMI was available for 164 155 adults (men: 76 382; women: 87 773).
Until 2001, the age-adjusted yearly increases in median BMI were 0.140 and 0.139 kg m(-2) for men and women, respectively, decreasing thereafter to 0.073 and 0.055 kg m(-2) (differences between time periods, both P-values<0.0001). The mixture model identified two components--a normal BMI and a high BMI sub-population--the proportions for the latter were 23.5% in men and 33.7% in women. The remaining normal BMI populations were 'resistant' with minimal increases in mean BMI values over time. By age, mean BMI values in the normal BMI sub-population increased greatest between 20 and 34 years for men; for women, the increases were similar throughout age groups (slope differences, P<0.0001).
In England, recent slowing down of adult BMI trend increases can be explained by two sub-populations--a high BMI sub-population getting 'fatter' and a majority 'resistant' normal BMI sub-population. These findings support a targeted, rather than a population-wide, policy to tackle the determinants of obesity.
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.
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.
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.
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.
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.
This brief review has shown that many human diseases may result when cells die that shouldn't or others live that should die. Modulation of apoptotic processes may thus offer valuable methods of ...treatment It is now known that many existing drugs (for example, non-steroidal anti-inflammatories) act by altering the levels of apoptosis. Virtually all cytotoxic drugs and radiotherapy programmes induce apoptosis in tumour cells, and resistance to apoptosis is associated with treatment failure.
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