Histological phenotypic subtypes predict recurrence risk and response to adjuvant chemotherapy in patients with stage III colorectal cancer

Histological ‘phenotypic subtypes’ that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I–III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I–III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease‐free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II–III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893‐patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p < 0.001) in these patients. In a 146‐patient external cohort, phenotypic subtype independently stratified patients by DFS (p = 0.028), validating their prognostic value. In 1343 SCOT trial patients, the effect of treatment type significantly depended on phenotypic subtype (pinteraction = 0.011). Phenotypic subtype independently associated with DFS in stage III patients receiving FOLFOX (p = 0.028). Furthermore, the immune subtype significantly associated with better response to FOLFOX compared to CAPOX adjuvant chemotherapy in stage III patients (p = 0.013). In conclusion, histological phenotypic subtypes are an effective prognostic classification in patients with stage III CRC that associates with risk of recurrence and response to FOLFOX adjuvant chemotherapy

More-than-human politics in the new arctic landscape of youth : Atmospheric shifts at the shopping mall

Peer reviewe

Three versus six months of adjuvant doublet chemotherapy for patients with colorectal cancer: a multi-country cost-effectiveness and budget impact analysis

Introduction: The Short Course Oncology Treatment (SCOT) trial demonstrated non-inferiority, less toxicity and cost-effectiveness from a UK perspective of 3 versus 6 months of oxaliplatin-based chemotherapy for patients with colorectal cancer. This study assessed the cost-effectiveness of shorter treatment, and the budget impact of implementing trial findings from the perspective of all countries that recruited to SCOT: Australia, Denmark, New Zealand, Spain, Sweden and the UK. Methods: Individual cost-utility analyses (CUAs) were performed from the perspective of each country. Resource, quality of life and survival estimates from the SCOT trial (n=6,065) were used. Probabilistic sensitivity analysis and sub-group analyses were undertaken. Using undiscounted costs from these CUAs, the impact on the country specific healthcare budgets of implementing the SCOT trial findings was calculated over a 5-year period. United States dollars were the currency used, with 2019 as base year. One-way and scenario sensitivity analysis addressed uncertainty within the budget impact analysis. Results: Three months of treatment was cost-saving and cost-effective compared to 6 months from the perspective of all countries. The incremental net monetary benefit per patient ranged from $8,972 (Spain) to$13,884 (Denmark). The healthcare budget impact over 5 years for the base case scenario ranged from $3.6 million (New Zealand) to$61.4 million (UK) and totalled over $150 million across all countries. Discussion: This study has widened the transferability of results from the SCOT trial, showing shorter treatment is cost-effective from a multi-country perspective. The vast savings from implementation could fully justify the investment in conducting the SCOT trial

COVID-19: Third dose booster vaccine effectiveness against breakthrough coronavirus infection, hospitalisations and death in patients with cancer: A population-based study

Purpose: People living with cancer and haematological malignancies are at increased risk of hospitalisation and death following infection with acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus third dose vaccine boosters are proposed to boost waning immune responses in immunocompromised individuals and increase coronavirus protection; however, their effectiveness has not yet been systematically evaluated. Methods: This study is a population-scale real-world evaluation of the United Kingdom’s third dose vaccine booster programme for cancer patients from 8th December 2020 to 7th December 2021. The cancer cohort comprises individuals from Public Health England’s national cancer dataset, excluding individuals less than 18 years. A test-negative case-control design was used to assess third dose booster vaccine effectiveness. Multivariable logistic regression models were fitted to compare risk in the cancer cohort relative to the general population. Results: The cancer cohort comprised of 2,258,553 tests from 361,098 individuals. Third dose boosters were evaluated by reference to 87,039,743 polymerase chain reaction (PCR) coronavirus tests. Vaccine effectiveness against breakthrough infections, symptomatic infections, coronavirus hospitalisation and death in cancer patients were 59.1%, 62.8%, 80.5% and 94.5% respectively. Lower vaccine effectiveness was associated with a cancer diagnosis within 12 months, lymphoma, recent systemic anti-cancer therapy (SACT) or radiotherapy. Lymphoma patients had low levels of protection from symptomatic disease. In spite of third dose boosters, following multivariable adjustment, individuals with cancer remain at increased risk of coronavirus hospitalisation and death compared to the population control (OR 3.38, 3.01 respectively. p<0.001 for both). Conclusions: Third dose boosters are effective for most individuals with cancer, increasing protection from coronavirus. However, their effectiveness is heterogenous, and lower than the general population. Many patients with cancer will remain at increased risk of coronavirus infections, even after 3 doses. In the case of patients with lymphoma, there is a particularly strong disparity of vaccine effectiveness against breakthrough infection and severe disease. Breakthrough infections will disrupt cancer care and treatment with potentially adverse consequences on survival outcomes. The data support the role of vaccine boosters in preventing severe disease, and further pharmacological intervention to prevent transmission and aid viral clearance to limit disruption of cancer care as the delivery of care continues to evolve during the coronavirus pandemic

The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer

Background The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, and now requires validation and assessment of interactions with adjuvant therapy. Methods Two cohorts were utilised; 862 TNM I–III CRC validation cohort, and 2912 TNM II–III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction. Results GMS independently associated with DFS (p = 0.001) and RFS (p < 0.001). GMS significantly stratified RFS for both low risk (GMS 0 v GMS 2: HR 3.24 95% CI 1.85–5.68, p < 0.001) and high-risk disease (GMS 0 v GMS 2: HR 2.18 95% CI 1.39–3.41, p = 0.001). In TransSCOT, chemotherapy type (pinteraction = 0.013), but not duration (p = 0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX (HR 2.23 95% CI 1.19–4.16, p = 0.012). Conclusions This study validates the GMS as a prognostic tool for patients with stage I–III colorectal cancer, independent of TNM, with the ability to stratify both low- and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX

Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial

Background Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer. Methods The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30. Findings Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2–30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4–7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1–5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50–0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2–46·0) at 6 months and 11·4% (5·6–19·5) at 12 months, compared with 50·6% (39·3–60·9) at 6 months and 25·9% (17·0–35·8) at 12 months in the ASC plus FOLFOX group. Grade 3–5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3–5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients). Interpretation The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials. Funding Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research

Variable water input controls evolution of the Lesser Antilles volcanic arc

Oceanic lithosphere carries volatiles, notably water, into the mantle through subduction at convergent plate boundaries. This subducted water exercises control on the production of magma, earthquakes, formation of continental crust and mineral resources. Identifying different potential fluid sources (sediments, crust and mantle lithosphere) and tracing fluids from their release to the surface has proved challenging1. Atlantic subduction zones are a valuable endmember when studying this deep water cycle because hydration in Atlantic lithosphere, produced by slow spreading, is expected to be highly non-uniform2. Here, as part of a multi-disciplinary project in the Lesser Antilles volcanic arc3, we studied boron trace element and isotopic fingerprints of melt inclusions. These reveal that serpentine—that is, hydrated mantle rather than crust or sediments—is a dominant supplier of subducted water to the central arc. This serpentine is most likely to reside in a set of major fracture zones subducted beneath the central arc over approximately the past ten million years. The current dehydration of these fracture zones coincides with the current locations of the highest rates of earthquakes and prominent low shear velocities, whereas the preceding history of dehydration is consistent with the locations of higher volcanic productivity and thicker arc crust. These combined geochemical and geophysical data indicate that the structure and hydration of the subducted plate are directly connected to the evolution of the arc and its associated seismic and volcanic hazards

Longitudinal quality of life and quality adjusted survival in a randomised controlled trial comparing six months of bolus fluorouracil/leucovorin vs. twelve weeks of protracted venous infusion fluorouracil as adjuvant chemotherapy for colorectal cancer

Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n = 404) or 12 weeks of protracted venous infusion (PVI) 5-FU (n = 397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU (P &lt; 0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up (P &lt; 0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV. <br/

Add-aspirin trial: a phase III, double blind, placebo-controlled, randomized trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common nonmetastatic solid tumors

Background: Pre-clinical data demonstrate that aspirin inhibits tumour growth and prevents metastases. Meta-analyses of individual patient data from randomized trials evaluating cardiovascular (CV) effects of aspirin show reduced metastases and cancer deaths for those on aspirin. Toxicity concerns have limited aspirin use as a primary anti-cancer prevention agent. In the adjuvant setting, the risk:benefit ratio differs, with higher morbidity and mortality from recurrence potentially outweighing risks. Aspirin, an inexpensive drug with a potential therapeutic role in several common cancers, could have a large impact on the global cancer burden. The Add-Aspirin trial investigates if aspirin use after curative treatment for non-metastatic solid tumours prevents recurrence and prolongs survival. Methods: Add-Aspirin is a double blind, placebo-controlled, multicentre, international trial. Eligible participants (n=9,920) from the UK and India will have had potentially curative treatment for non-metastatic cancer. There are 4 separate tumour cohorts – breast (BC), colorectal (CRC), gastro-oesophageal (GOC) and prostate cancer (PC). Following an 8 week active run-in period of aspirin 100mg daily to assess adherence and tolerability, participants are randomised to aspirin 100mg, 300mg or placebo daily for &gt; 5 years. Each tumour specific cohort is individually powered and has a separate disease-specific primary outcome measure: BC (n = 3,100) invasive disease-free survival (DFS); CRC (n = 2,600) DFS; GOC (n = 2,100) overall survival (OS); and PC (n = 2,120) biochemical recurrence-free survival. Secondary outcome measures include adherence, toxicity and CV events. OS across the 4 cohorts is a co-primary outcome measure. Sub-studies include assessment of thromboxane B2 for compliance and methodological work to assess the utility of long-term passive follow up. Blood/tissue specimens collected at enrolment will allow tumour-specific mutations to be used as stratification factors. Funder CRUK; Sponsor University College UK. Clinical trial information: 2013-004398-28