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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. 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. 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). 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. 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.

In this randomized trial comparing cisplatin plus gemcitabine with gemcitabine alone for the treatment of biliary tract cancer, overall survival and progression-free survival were improved with the use of cisplatin plus gemcitabine. Adverse events were similar in the two groups. In this trial comparing cisplatin plus gemcitabine with gemcitabine alone for the treatment of biliary tract cancer, overall survival and progression-free survival were improved with the use of cisplatin plus gemcitabine. Biliary tract cancer is an uncommon cancer in developed countries. There are approximately 1200 new cases in the United Kingdom 1 and 9000 new cases in the United States per year, although the incidence is increasing, perhaps related to gallstone disease. 2 Most patients have advanced disease at presentation and relapse despite surgery. 3 Although advanced biliary tract cancer can have a response to chemotherapy, there is no recognized standard palliative regimen because no single randomized study has ever been sufficiently robust to define a schedule; fluoropyrimidines, 4 , 5 cisplatin, 6 and gemcitabine 7 , 8 have shown activity. Gemcitabine (Gemzar, Eli Lilly) treatment for biliary tract . . .

Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of oxaliplatin and fluorouracil chemotherapy. The addition of cetuximab to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype. We aimed to assess the benefit of addition of cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis. Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour (one or more of: ≥4 metastases, N2 disease, or poor differentiation of primary tumour), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 intravenously over 2 h and fluorouracil bolus 400 mg/m2 intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one) or oxaliplatin 130 mg/m2 intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given as an intravenous dose of 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint was progression-free survival. This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria. This trial is registered, ISRCTN22944367. 128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with cetuximab between Feb 26, 2007, and Nov 1, 2012. 117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis. The median follow-up was 21·1 months (95% CI 12·6–33·8) in the chemotherapy alone group and 19·8 months (12·2–28·7) in the chemotherapy plus cetuximab group. With an overall median follow-up of 20·7 months (95% CI 17·9–25·6) and 123 (58%) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus cetuximab group than in the chemotherapy alone group (14·1 months [95% CI 11·8–15·9] vs 20·5 months [95% CI 16·8–26·7], hazard ratio 1·48, 95% CI 1·04–2·12, p=0·030). The most common grade 3 or 4 adverse events were low neutrophil count (15 [11%] preoperatively in the chemotherapy alone group vs six [4%] in the chemotherapy plus cetuximab group; four [4%] vs eight [8%] postoperatively), embolic events (six [4%] vs eight [6%] preoperatively; two [2%] vs three [3%] postoperatively), peripheral neuropathy (six [4%] vs one [1%] preoperatively; two [2%] vs four [4%] postoperatively), nausea or vomiting (four [3%] vs six [4%] preoperatively; four [4%] vs two [2%] postoperatively), and skin rash (two [1%] vs 21 [15%] preoperatively; 0 vs eight [8%] postoperatively). There were three deaths in the chemotherapy plus cetuximab group (one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism) and one in the chemotherapy alone group (heart failure) that might have been treatment related. Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended. Cancer Research UK.

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 ( p interaction  = 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.

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.

Multiplex immunofluorescence (mIF) imaging can provide comprehensive quantitative and spatial information for multiple immune markers for tumour immunoprofiling. However, application at scale to clinical trial samples sourced from multiple institutions is challenging due to pre‐analytical heterogeneity. This study reports an analytical approach to the largest multi‐parameter immunoprofiling study of clinical trial samples to date. We analysed 12,592 tissue microarray (TMA) spots from 3,545 colorectal cancers sourced from more than 240 institutions in two clinical trials (QUASAR 2 and SCOT) stained for CD4, CD8, CD20, CD68, FoxP3, pan‐cytokeratin, and DAPI by mIF. TMA slides were multi‐spectrally imaged and analysed by cell‐based and pixel‐based marker analysis. We developed an adaptive thresholding method to account for inter‐ and intra‐slide intensity variation in TMA analysis. Applying this method effectively ameliorated inter‐ and intra‐slide intensity variation improving the image analysis results compared with methods using a single global threshold. Correlation of CD8 data derived by our mIF analysis approach with single‐plex chromogenic immunohistochemistry CD8 data derived from subsequent sections indicates the validity of our method (Spearman's rank correlation coefficients ρ between 0.63 and 0.66, p ≪ 0.01) as compared with the current gold standard analysis approach. Evaluation of correlation between cell‐based and pixel‐based analysis results confirms equivalency (ρ > 0.8, p ≪ 0.01, except for CD20 in the epithelial region) of both analytical approaches. These data suggest that our adaptive thresholding approach can enable analysis of mIF‐stained clinical trial TMA datasets by digital pathology at scale for precision immunoprofiling.

People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against breakthrough SARS-CoV-2 infections in patients with cancer at a population level. In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3–6 months after the second dose in the cancer cohort and control population. The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8–69·9) in the control population and 65·5% (65·1–65·9) in the cancer cohort. Vaccine effectiveness at 3–6 months was lower in the cancer cohort (47·0%, 46·3–47·6) than in the control population (61·4%, 61·4–61·5). COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer. University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.

Tumour-infiltrating CD8+ cytotoxic T cells confer favourable prognosis in colorectal cancer. The added prognostic value of other infiltrating immune cells is unclear and so we sought to investigate their prognostic value in two large clinical trial cohorts. We used multiplex immunofluorescent staining of tissue microarrays to assess the densities of CD8+, CD20+, FoxP3+, and CD68+ cells in the intraepithelial and intrastromal compartments from tumour samples of patients with stage II–III colorectal cancer from the SCOT trial (ISRCTN59757862), which examined 3 months versus 6 months of adjuvant oxaliplatin-based chemotherapy, and from the QUASAR 2 trial (ISRCTN45133151), which compared adjuvant capecitabine with or without bevacizumab. Both trials included patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–1. Immune marker predictors were analysed by multiple regression, and the prognostic and predictive values of markers for colorectal cancer recurrence-free interval by Cox regression were assessed using the SCOT cohort for discovery and QUASAR 2 cohort for validation. After exclusion of cases without tissue microarrays and with technical failures, and following quality control, we included 2340 cases from the SCOT trial and 1069 from the QUASAR 2 trial in our analysis. Univariable analysis of associations with recurrence-free interval in cases from the SCOT trial showed a strong prognostic value of intraepithelial CD8 (CD8IE) as a continuous variable (hazard ratio [HR] for 75th vs 25th percentile [75vs25] 0·73 [95% CI 0·68–0·79], p=2·5 × 10−16), and of intrastromal FoxP3 (FoxP3IS; 0·71 [0·64–0·78], p=1·5 × 10−13) but not as strongly in the epithelium (FoxP3IE; 0·89 [0·84–0·96], p=1·5 × 10−4). Associations of other markers with recurrence-free interval were moderate. CD8IE and FoxP3IS retained independent prognostic value in bivariable and multivariable analysis, and, compared with either marker alone, a composite marker including both markers (CD8IE-FoxP3IS) was superior when assessed as a continuous variable (adjusted [a]HR75 vs 25 0·70 [95% CI 0·63–0·78], p=5·1 × 10−11) and when categorised into low, intermediate, and high density groups using previously published cutpoints (aHR for intermediate vs high 1·68 [95% CI 1·29–2·20], p=1·3 × 10−4; low vs high 2·58 [1·91–3·49], p=7·9 × 10−10), with performance similar to the gold-standard Immunoscore. The prognostic value of CD8IE-FoxP3IS was confirmed in cases from the QUASAR 2 trial, both as a continuous variable (aHR75 vs 25 0·84 [95% CI 0·73–0·96], p=0·012) and as a categorical variable for low versus high density (aHR 1·80 [95% CI 1·17–2·75], p=0·0071) but not for intermediate versus high (1·30 [0·89–1·88], p=0·17). Combined evaluation of CD8IE and FoxP3IS could help to refine risk stratification in colorectal cancer. Investigation of FoxP3IS cells as an immunotherapy target in colorectal cancer might be merited. Medical Research Council, National Institute for Health Research, Cancer Research UK, Swedish Cancer Society, Roche, and Promedica Foundation.

We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m2, 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m2 orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2–4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4–12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1–8·8] vs 6·9 months [6·4–7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97–1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3–9·7], HR 1·05, 98·25% CI 0·85–1·29, p=0·64; overall log-rank of χ22df=4·3; p=0·11). The commonest grade 3–4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. Cancer Research UK and KAEL-GemVax.

Background: The ABC-02 (Advanced Biliary Tract Cancer) study established cisplatin and gemcitabine (CisGem) as the standard first-line chemotherapy for patients with locally advanced or metastatic biliary tract cancer (BTC). We examine quality of life (QoL), describe the long-term survivors and provide a long-term outcome. Methods: A total of 410 BTC patients were randomised to receive either CisGem or gemcitabine alone (Gem); 324 patients consented to complete EORTC QLQ-C30 and EORTC QLQ-PAN26 QoL questionnaires; 268 (83%) patients returned at least one QoL questionnaire (134 in each arm). Long-term survivors were defined as those surviving over 2 years and we performed a final analysis of the primary outcome; overall survival (OS). Results: Most QoL scales showed a trend favouring the combined CisGem arm, including functional and symptomatic scales, although the differences were not statistically significant. Forty-five (11%)) patients survived at least 2 years (34 received CisGem and 11 Gem) and 21 (5%) 3 years or more (14 received CisGem and 7 Gem). After a median follow-up of 9.2 months and 398 deaths, the median OS was 11.7 months for CisGem and 8.1 months for Gem (hazard ratio (HR)=0.65, 95% CI: 0.53–0.79, P <0.001). Conclusions: The survival advantage of CisGem compared to Gem was not associated with an improvement or deterioration of QoL. Long-term survivors were more likely to have received CisGem and the long-term OS is identical to that previously described.