Clinico-pathological predictors of clinical complete response in rectal cancer.

PURPOSE: Prediction of clinical complete response in rectal cancer before neoadjuvant chemo-radiotherapy treatment enables treatment selection. Patients predicted to have complete response could have chemo-radiotherapy, and others could have additional doublet chemotherapy at this stage of their treatment to improve their overall outcome. This work investigates the role of clinical variables in predicting clinical complete response. METHOD: Using the UK-based OnCoRe database (2008 to 2019), we performed a propensity-score matched study of 322 patients who received neoadjuvant chemoradiotherapy. We collected pre-treatment clinic-pathological, inflammatory and radiotherapy-related characteristics. We determined the odds for the occurrence of cCR using conditional logistic regression models. We derived the post-model Area under the Curve (AUC) as an indicator of discrimination performance and stated a priori that an AUC of 0.75 or greater was required for potential clinical utility. RESULTS: Pre-treatment tumour diameter, mrT-stage, haemoglobin, alkaline phosphate and total radiotherapy depths were associated with cCR on univariable and multivariable analysis. Additionally, neutrophil to lymphocyte ratio (NLR), neutrophil-monocyte to lymphocyte ratio (NMLR), lymphocyte count and albumin were all significantly associated with cCR on multivariable analysis. A nomogram using the above parameters was developed with a resulting ROC AUC of 0.75. CONCLUSION: We identified routine clinic-pathological, inflammatory and radiotherapy-related variables which are independently associated with cCR. A nomogram was developed to predict cCR. The performance characteristics from this model were on the prior clinical utility threshold. Additional research is required to develop more associated variables to better select patients with rectal cancer undergoing chemoradiotherapy who may benefit from pursuing a W&W strategy.

Indications and outcomes for repeat cytoreductive surgery and heated intra-peritoneal chemotherapy in peritoneal surface malignancy.

INTRODUCTION: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is offered in specialist centres as a treatment for peritoneal surface tumours. Despite its demonstrated efficacy, intra-abdominal recurrence occurs in 31-57% of patients. The aim of this study is to review the early and long-term outcomes in patients who undergo repeat CRS/HIPEC. MATERIALS AND METHODS: A retrospective review of a prospectively maintained database of patients who had undergone repeat CRS/HIPEC for appendiceal neoplasms and colorectal peritoneal metastases (CRPM) from 2003 to 2019 was performed at a single specialist centre. Data pertaining to both short term outcomes and survival were evaluated. RESULTS: Of 1259 patients who had undergone CRS/HIPEC, 84(6.7%) underwent repeat surgery: 45(53.6%) had pseudomyxoma peritonei (PMP) secondary to low grade appendiceal mucinous neoplasms (LAMN), 21(25.0%) had appendix carcinoma and 18(21.4%) had CRPM. Demographics, intra-operative findings and short-term outcomes were comparable across tumour types and between procedures. Median (95% CI) interval between procedures was 22.7(18.9-26.6) months and was comparable between tumour types. Median (95%CI) overall survival was not reached for the cohort overall or for those with PMP, but was 61.0(32.6-89.4) months for those with appendix cancer and 76.9(47.4-106.4) months for CRPM (p=<0.001). Survival was favourable in the PMP group (HR [95%CI] 0.044 [0.008-0.262]; p = 0.000) and unfavourable in the CC2-3 at index CRS procedure group (HR [95%CI] 25.612 [2.703-242.703]; p = 0.005). CONCLUSION: Our findings demonstrate that repeat cytoredutive surgery with HIPEC can result in favourable survival, especially for patients with PMP when complete cytoreduction is achieved at index operation. We recommend that detailed patient assessment is performed through an expert multidisciplinary team meeting (MDT).

Obesity and Cancer Treatment Outcomes: Interpreting the Complex Evidence.

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.

Novel phase I trial design to evaluate the addition of cediranib or selumetinib to preoperative chemoradiotherapy for locally advanced rectal cancer: the DREAMtherapy trial.

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.

Referral and treatment pathways for pseudomyxoma peritonei of appendiceal origin within a national treatment programme.

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 intraperitoneal chemotherapy. 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) localized to the peri-appendiceal tissue. RESULTS: In all, 817 patients with confirmed PMP were referred increasing from 11 in 2002 to 103 in 2015. Disease burden was high with a 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 localized LAMN increased over time reaching 25% each year since 2010 (Ptrend  < 0.0001). Two-thirds of localized LAMN now undergo laparoscopically assisted risk-reducing CRS. 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 minimally invasive techniques for localized disease.

Systematic review of outcome measures following chemoradiotherapy for the treatment of anal cancer (CORMAC).

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.

Measuring the biological effect of presurgical metformin treatment in endometrial cancer.

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.

Techniques and Outcome of Surgery for Locally Advanced and Local Recurrent Rectal Cancer.

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.

Digital histology quantification of intra-hepatic fat in patients undergoing liver resection.

BACKGROUND: High intra-hepatic fat (IHF) content is associated with insulin resistance, visceral adiposity, and increased morbidity and mortality following liver resection. However, in clinical practice, IHF is assessed indirectly by pre-operative imaging [for example, chemical-shift magnetic resonance (CS-MR)]. We used the opportunity in patients undergoing liver resection to quantify IHF by digital histology (D-IHF) and relate this to CT-derived anthropometrics, insulin-related serum biomarkers, and IHF estimated by CS-MR. METHODS: A reproducible method for quantification of D-IHF using 7 histology slides (inter- and intra-rater concordance: 0.97 and 0.98) was developed. In 35 patients undergoing resection for colorectal cancer metastases, we measured: CT-derived subcutaneous and visceral adipose tissue volumes, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), fasting serum adiponectin, leptin and fetuin-A. We estimated relative IHF using CS-MR and developed prediction models for IHF using a factor-clustered approach. RESULTS: The multivariate linear regression models showed that D-IHF was best predicted by HOMA-IR (Beta coefficient(per doubling): 2.410, 95% CI: 1.093, 5.313) and adiponectin (ß(per doubling): 0.197, 95% CI: 0.058, 0.667), but not by anthropometrics. MR-derived IHF correlated with D-IHF (rho: 0.626; p = 0.0001), but levels of agreement deviated in upper range values (CS-MR over-estimated IHF: regression versus zero, p = 0.009); this could be adjusted for by a correction factor (CF: 0.7816). CONCLUSIONS: Our findings show IHF is associated with measures of insulin resistance, but not measures of visceral adiposity. CS-MR over-estimated IHF in the upper range. Larger studies are indicated to test whether a correction of imaging-derived IHF estimates is valid.

Excess adiposity and gastrointestinal cancer.

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.

Equivalent survival in patients with and without steatosis undergoing resection for colorectal liver metastases following pre-operative chemotherapy.

BACKGROUND: We previously reported that the presence of steatosis did not adversely influence survival in patients undergoing resection for colorectal liver metastases (CLM) without pre-operative chemotherapy. Here, this hypothesis is tested in patients undergoing resection for CLM following pre-operative chemotherapy. METHODS: We assessed the effects of background liver pathology, categorized as 'normal', 'steatosis' and 'other', on perioperative mortality, overall survival (OS) and cancer-specific survival (CSS) in LiverMetSurvey patients. Survival analyses included log-rank tests and multivariate Cox models, incorporating well-established prognosticators. In secondary analyses, re-populating the model with non-chemotherapy patients, the effect modification of chemotherapy on the impact of steatosis on survival was tested. RESULTS: Of 4329 patients undergoing first-time liver resection following pre-operative chemotherapy, histologies were normal in 1913 (44%), steatosis in 1675 (39%), and other abnormal pathologies in 741 (17%). For normal, steatosis and other, 90-day mortalities were 2.1%, 2.3%, and 3.5% (P = 0.103). For the three histo-pathological groups, 5-year OS rates were 39%, 42%, and 36% (Plogrank = 0.363); 5-year CSS rates were 43%, 45% and 41% (Plogrank = 0.496), respectively. The associations of steatosis with OS and CSS were materially unchanged in the multivariate models. Chemotherapy did not interact with the effect of steatosis on survival. CONCLUSION: The findings of equivalent survivals challenge the common perception that steatosis in CLM patients after pre-operative chemotherapy is associated with increased peri-operative mortality and poorer long-term survival.

Slowing down of adult body mass index trend increases in England: a latent class analysis of cross-sectional surveys (1992-2010).

BACKGROUND: 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. OBJECTIVE: We address the hypothesis that the slowing down of BMI trend increases in England reflects a majority sub-population resistant to further BMI elevation. DESIGN: 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. SUBJECTS: BMI was available for 164 155 adults (men: 76 382; women: 87 773). RESULTS: 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). CONCLUSION: 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.