• Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study

      Primrose, J; Fox, R; Palmer, D; Malik, H; Prasad, R; Mirza, D; Anthony, A; Corrie, P; Falk, S; Finch-Jones, M; et al. (2019)
      BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51�1 months (95% CI 34�6-59�1) in the capecitabine group compared with 36�4 months (29�7-44�5) in the observation group (adjusted hazard ratio [HR] 0�81, 95% CI 0�63-1�04; p=0�097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0�71 (95% CI 0�55-0�92; p=0�010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0�75, 95% CI 0�58-0�97; p=0�028). In the intention-to-treat analysis, median recurrence-free survival was 24�4 months (95% CI 18�6-35�9) in the capecitabine group and 17�5 months (12�0-23�8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25�9 months (95% CI 19�8-46�3) in the capecitabine group and 17�4 months (12�0-23�7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting.
    • Statins - No more cream for cancer

      Gillessen, Silke; Horvath, L; Division of Cancer Sciences, University of Manchester and The Christie, Manchester, United Kingdom (2019)
      In this issue of the European Journal of Cancer, Shao et al. and Van Rompay et al. [1,2] report that statins and, in the latter manuscript, also non-statin lipid-lowering medications appear to improve prostate cancer outcomes, both by retrospective analyses. This adds to the large body of epidemiological studies suggesting a favourable role for statins on the clinical outcomes of men with prostate cancer, but the precise nature of the anticancer effect of these drugs remains controversial. Retrospective studies have an inherent bias because all these men received the statin (or any other lipid-lowering drug) for a medical condition that may influence their prognosis or receiving a statin could be a surrogate for being under more ‘intensive’ medical care.
    • When RON MET TAM in mesothelioma: all druggable for one, and one drug for all?

      Baird, A; Easty, D; Jarzabek, M; Shiels, L; Soltermann, A; Klebe, S; Raeppel, S; MacDonagh, L; Wu, C; Griggs, K; et al. (2019)
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone.
    • Prophylactic irradiation of tracts in patients with malignant pleural mesothelioma: an open-label, multicenter, phase III randomized trial

      Bayman, Neil A; Appel, W; Ashcroft, Linda; Baldwin, D; Bates, A; Darlison, L; Edwards, J; Ezhil, V; Gilligan, D; Hatton, M; et al. (2019)
      PURPOSE: Prophylactic irradiation to the chest wall after diagnostic or therapeutic procedures in patients with malignant pleural mesothelioma (MPM) has been a widespread practice across Europe, although the efficacy of this treatment is uncertain. In this study, we aimed to determine the efficacy of prophylactic radiotherapy in reducing the incidence of chest wall metastases (CWM) after a procedure in MPM. METHODS: After undergoing a chest wall procedure, patients with MPM were randomly assigned to receive prophylactic radiotherapy (within 42 days of the procedure) or no radiotherapy. Open thoracotomies, needle biopsies, and indwelling pleural catheters were excluded. Prophylactic radiotherapy was delivered at a dose of 21 Gy in three fractions over three consecutive working days, using a single electron field adapted to maximize coverage of the tract from skin surface to pleura. The primary outcome was the incidence of CWM within 6 months from random assignment, assessed in the intention-to-treat population. Stratification factors included epithelioid histology and intention to give chemotherapy. RESULTS: Between July 30, 2012, and December 12, 2015, 375 patients were recruited from 54 centers and randomly assigned to receive prophylactic radiotherapy (n = 186) or no prophylactic radiotherapy (n = 189). Participants were well matched at baseline. No significant difference was seen in the incidence of CWM at 6 months between the prophylactic radiotherapy and no radiotherapy groups (no. [%]: 6 [3.2] v 10 [5.3], respectively; odds ratio, 0.60; 95% CI, 0.17 to 1.86; P = .44). Skin toxicity was the most common radiotherapy-related adverse event in the prophylactic radiotherapy group, with 96 patients (51.6%) receiving grade 1; 19 (10.2%), grade 2; and 1 (0.5%) grade 3 radiation dermatitis (Common Terminology Criteria for Adverse Events, version 4.0). CONCLUSION: There is no role for the routine use of prophylactic irradiation to chest wall procedure sites in patients with MPM.
    • Utilization of volumetric magnetic resonance imaging for baseline and surveillance imaging in neuro-oncology

      Mills, S; Radon, M; Radon, M; Baird, R; Hanemann, C; Keatley, D; Lewis, J; Pollock, J; Sanghera, P; Thomas, S; et al. (2019)
      The acquisition of volumetric post-contrast MRI has clear advantages in the interpretation of neuro-oncology studies but has yet to find its way into routine clinical practice beyond planning scans for surgery and radiotherapy. This commentary briefly highlights the benefits of these techniques whilst dispelling some of the perceived disadvantages.
    • Airflow relieves chronic breathlessness in people with advanced disease: an exploratory systematic review and meta-analyses

      Swan, F; Newey, A; Bland, M; Allgar, V; Booth, S; Bausewein, C; Yorke, Janelle; Johnson, M; Wolfson Palliative Care Research Centre, Institute for Clinical and Applied Health Research, Hull (2019)
    • Adjuvant chemotherapy and outcomes in patients with nodal and resection margin-negative pancreatic ductal adenocarcinoma: a systematic review and meta-analysis

      Flaum, Nicola; Hubner, Richard A; Valle, Juan W; Amir, E; McNamara, Mairead G; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK (2019)
      Adjuvant chemotherapy (AC) following pancreatic carcinoma (PC) resection improves overall survival (OS). A systematic review identified 10 phase-2/3 studies investigating AC in 3644 patients looking at the influence of nodal and resection status. AC significantly improved disease free survival, OS and 5-year odds of death risk. There was greater survival benefit in patients PS 0 and with body/tail tumors. There was a nonsignificant effect in N - ?/N? + patients on OS and no difference between R0/R1 patients.
    • Prophylactic cranial irradiation in stage IV small cell lung cancer: selection of patients amongst European IASLC and ESTRO experts

      Putora, P; Glatzer, M; Belderbos, J; Besse, B; Blackhall, Fiona H; Califano, Raffaele; Cappuzzo, F; de Marinis, F; Dziadziuszko, R; Felip, E; et al. (2019)
      BACKGROUND: Due to conflicting results between major trials the role of prophylactic cranial irradiation (PCI) in stage IV small cell lung cancer (SCLC) is controversial. METHODS: We obtained a list of 13 European experts from both the European Society for Therapeutic Radiation Oncology (ESTRO) and the International Association for the Study of Lung Cancer (IASLC). The strategies in decision making for PCI in stage IV SCLC were collected. Decision trees were created representing these strategies. Analysis of consensus was performed with the objective consensus methodology. RESULTS: The factors associated with the recommendation for the use of PCI included the fitness of the patient, young age and good response to chemotherapy. PCI was recommended by the majority of experts for non-elderly fit patients who had at least a partial response (PR) to chemotherapy (for complete remission (CR) 85% of radiation oncologists and 69% of medical oncologists, for PR: 85% of radiation oncologists and 54% of medical oncologists). For patients with stable disease after chemotherapy, PCI was recommended by 6 out of 13 (46%) radiation oncologists and only 3 out of 13 medical oncologists (23%). For elderly fit patients with CR, a majority recommended PCI (62%) and no consensus was reached for patients with PR. CONCLUSION: European radiation and medical oncologists specializing in lung cancer recommend PCI in selected patients and restrict its use primarily to fit, non-elderly patients who responded to chemotherapy.
    • Stability of radiomics features in apparent diffusion coefficient maps from a multi-centre test-retest trial

      Peerlings, J; Woodruff, H; Winfield, J; Ibrahim, A; Van Beers, B; Heerschap, A; Jackson, Andrew; Wildberger, J; Mottaghy, F; DeSouza, N; et al. (2019)
      Quantitative radiomics features, extracted from medical images, characterize tumour-phenotypes and have been shown to provide prognostic value in predicting clinical outcomes. Stability of radiomics features extracted from apparent diffusion coefficient (ADC)-maps is essential for reliable correlation with the underlying pathology and its clinical applications. Within a multicentre, multi-vendor trial we established a method to analyse radiomics features from ADC-maps of ovarian (n?=?12), lung (n?=?19), and colorectal liver metastasis (n?=?30) cancer patients who underwent repeated (<7 days) diffusion-weighted imaging at 1.5?T and 3?T. From these ADC-maps, 1322 features describing tumour shape, texture and intensity were retrospectively extracted and stable features were selected using the concordance correlation coefficient (CCC?>?0.85). Although some features were tissue- and/or respiratory motion-specific, 122 features were stable for all tumour-entities. A large proportion of features were stable across different vendors and field strengths. By extracting stable phenotypic features, fitting-dimensionality is reduced and reliable prognostic models can be created, paving the way for clinical implementation of ADC-based radiomics.
    • Women's perceptions of personalized risk-based breast cancer screening and prevention: an international focus group study

      Rainey, L; Jervaeus, A; Donnelly, L; Evans, D Gareth; Hammarstrom, M; Hall, P; Wengstrom, Y; Broeders, M; van der Waal, D; Radboud Institute for Health Sciences, Radboud university Medical Center, Nijmegen (2019)
      OBJECTIVE: Increased knowledge of breast cancer risk factors enables a shift from one-size-fits-all breast cancer screening to a risk-based approach, tailoring screening policy to a woman's individual risk. New opportunities for prevention will arise. However, before this novel screening and prevention program is introduced, its acceptability from a woman's perspective needs to be explored. METHODS: Women eligible for breast cancer screening in the Netherlands, United Kingdom, and Sweden were invited to take part in focus groups. A total of 143 women participated. Data were transcribed verbatim and analyzed using thematic analysis. RESULTS: Analysis identified five themes across the three countries. The first theme "impact of knowledge" describes women's concern of not being able to unlearn their risk, perceiving it as either a motivator for change or a burden which may lead to stigma. The second theme "belief in science" explains women's need to trust the science behind the risk assessment and subsequent care pathways. Theme three "emotional impact" explores, eg, women's perceived anxiety and (false) reassurance, which may result from knowing their risk. Theme four "decision making" highlights cultural differences in shared versus individual decision making. Theme five "attitude to medication" explores the controversial topic of offering preventative medication for breast cancer risk reduction. CONCLUSIONS: Acceptability of risk-based screening and prevention is mixed. Women's perceptions are informed by a lack of knowledge, cultural norms, and common emotional concerns, which highlights the importance of tailored educational materials and risk counselling to aid either shared or individual informed decision making.
    • Evaluation of apoptosis imaging biomarkers in a genetic model of cell death

      Vassileva, V; Stribbling, M; Barnes, C; Carroll, L; Braga, M; Abrahams, J; Heinzmann, K; Haegeman, C; MacFarlane, M; Simpson, Kathryn L; et al. (2019)
      PURPOSE: We have previously developed the caspase-based radiotracer, 18F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18F-ICMT-11 specificity in a murine melanoma death-switch tumour model with conditional activation of caspase-3 induced by doxycycline. METHODS: Caspase-3/7 activity and cellular uptake of 18F-ICMT-11, 18F-ML-10 and 18F-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction. Death-switch induction was confirmed in vivo in xenograft tumours, and 18F-ICMT-11 and 18F-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with 18F-ICMT-11, 18F-ML-10 and 18F-FDG. Caspase-3 activation was confirmed by immunohistochemistry. RESULTS: Significantly increased caspase-3/7 activity was observed only in B16ovaRevC3 cells after death-switch induction, accompanied by significantly increased 18F-ICMT-11 (p?<?0.001) and 18F-ML-10 (p?<?0.05) and decreased 18F-FDG (p?<?0.001) uptake compared with controls. B16ova and B16ovaRevC3 tumours had similar growth in vivo; however, B16ovaRevC3 growth was significantly reduced with death-switch induction (p?<?0.01). Biodistribution studies showed significantly increased 18F-ICMT-11 tumour uptake following death-switch induction (p?<?0.01), but not for 18F-ML-10. Tumour uptake of 18F-ICMT-11 was higher than that of 18F-ML-10 after death-switch induction. PET imaging studies showed that 18F-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. 18F-FDG signal decreased in tumours after death-switch induction. CONCLUSIONS: We demonstrate that 18F-ICMT-11 can be used to detect caspase-3 activation in a death-switch tumour model, independent of the confounding effects of cancer therapeutics, thus confirming its specificity and supporting the development of this radiotracer for clinical use to monitor tumour apoptosis and therapy response.
    • Medical treatment for cholangiocarcinoma

      Adeva, J; Sangro, B; Salati, M; Edeline, J; La, C; Bittoni, A; Berardi, R; Bruix, J; Valle, Juan W; Department of Medical Oncology, Hospital Universitario, 12 de Octubre, Madrid, Spain (2019)
      Most of patients with cholangiocarcinoma (CCA) present with advanced (inoperable or metastatic) disease, and relapse rates are high in those undergoing potentially-curative resection. Previous treatment nihilism of patients with advanced disease has been replaced by active clinical research with the advent of randomized clinical trials (RCTs) and a much greater effort at understanding molecular mechanisms underpinning CCA. Three RCTs have recently been reported evaluating adjuvant chemotherapy following curative resection; only one of these has the potential to change practice. The BILCAP study failed to meet its primary endpoint by intention-to-treat (ITT) analysis; however, a survival benefit was seen in a pre-planned sensitivity analysis (predominantly adjusting for lymph nodes status). This, along with the numerical difference in median overall survival has led to uptake of adjuvant capecitabine by many clinicians. In patients with advanced disease, the only level 1 data available supports the use of cisplatin and gemcitabine for the first-line treatment of patients with advanced disease; there is no established second-line chemotherapy. Previous forays into targeted therapy have proven unfruitful (namely targeting the epithelial growth factor receptor [EGFR] and vascular endothelial growth factor [VEGF] pathways). An increasing number of genomic subtypes are being defined; for some of these on-target therapeutic options are under active investigation. The most developed are studies targeting IDH-1 (isocitrate dehydrogenase) mutations and FGFR-2 (fibroblast growth factor receptor) fusions, with promising early results. Several other pathways are under evaluation, along with early studies targeting the immune environment; these are too premature to change practice to date. These emerging treatments are discussed.
    • Differentiated thyroid cancer in children: a UK multicentre review and review of the literature

      Lee, K; Sharabiani, M; Tumino, D; Wadsley, J; Gill, V; Gerrard, G; Sindhu, Retnabai; Gaze, M; Moss, L; Newbold, K; et al. (2019)
      AIMS: To obtain an overview of the management and outcomes of children aged 18 years or younger diagnosed with differentiated thyroid carcinoma of follicular cell origin across the UK, by collecting and analysing data from the limited number of centres treating these patients. This multicentre data might provide a more realistic perspective than single-institution series. MATERIALS AND METHODS: Six centres submitted data extracted from historical records on patients aged 18 years or younger, diagnosed between 1964 and 2017. The univariate and multivariable Cox proportional hazard model was used to identify potential predictors of progression-free survival, using national data as a control. RESULTS: Data on 166 patients were available for analysis. Females (74%) were predominant, and the age ranged from 3 to 19 years at diagnosis, mean 14.1 years. Nodal metastases were present in 51%; 12% had distant metastases. After surgery, 95% received radioactive iodine (39% on more than one occasion) and 4% received external beam radiotherapy. With a median follow-up duration of 5 years, 69% are alive with no evidence of disease; 20% are alive with a raised thyroglobulin level as the only evidence of residual disease; 6% have residual structural disease detectable on imaging; 2% have died, from cerebral metastases. CONCLUSION: Despite most patients having advanced disease at presentation, outcomes are very good. A national prospective registry should allow systematic collection of good-quality data and may facilitate research to further improve outcomes
    • Correction: Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium

      Goranova, T; Ennis, D; Piskorz, A; Macintyre, G; Lewsley, L; Stobo, J; Wilson, C; Kay, D; Glasspool, R; Lockley, M; et al. (2019)
      This article was originally published under a CC BY NC SA License, but has now been made available under a CC BY 4.0 License. Erratum for: Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium. [Br J Cancer. 2017]
    • BEECH: a dose-finding run-in followed by a randomised phase 2 study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with oestrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population

      Turner, N; Alarcon, E; Armstrong, Anne C; Philco, M; Lopez, Chuken Y; Sablin, M; Tamura, K; Gomez, V; Perez-Fidalgo, J; Cheung, S; et al. (2019)
      BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with first-line weekly paclitaxel for advanced or metastatic oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase 1b safety run-in (Part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase 2 expansion (Part B) in 110 women with ER+/HER2- metastatic breast cancer. In Part A, patients received paclitaxel 90?mg/m2 (Days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (BID) at two intermittent ascending dosing schedules. In Part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary endpoint for Part A was safety to recommend a dose and schedule for Part B; primary endpoints for Part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400?mg BID 4 days on/3 days off treatment schedule selected in Part A. In Part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo (hazard ratio [HR] 0.80; P = 0.308). In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). The most common Grade ?3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.
    • Oxygen-enhanced MRI is feasible, repeatable, and detects radiotherapy-induced change in hypoxia in xenograft models and in patients with non-small cell lung cancer

      Salem, Ahmed; Little, R; Latif, A; Featherstone, A; Babur, M; Peset, Isabel; Cheung, S; Watson, Y; Tessyman, V; Mistry, Hitesh; et al. (2019)
      Purpose: Hypoxia is associated with poor prognosis and is predictive of poor response to cancer treatments, including radiotherapy. Developing noninvasive biomarkers that both detect hypoxia prior to treatment and track change in tumor hypoxia following treatment is required urgently.Experimental Design: We evaluated the ability of oxygen-enhanced MRI (OE-MRI) to map and quantify therapy-induced changes in tumor hypoxia by measuring oxygen-refractory signals in perfused tissue (perfused Oxy-R). Clinical first-in-human study in patients with non-small cell lung cancer (NSCLC) was performed alongside preclinical experiments in two xenograft tumors (Calu6 NSCLC model and U87 glioma model).Results: MRI perfused Oxy-R tumor fraction measurement of hypoxia was validated with ex vivo tissue pathology in both xenograft models. Calu6 and U87 experiments showed that MRI perfused Oxy-R tumor volume was reduced relative to control following single fraction 10-Gy radiation and fractionated chemoradiotherapy (P < 0.001) due to both improved perfusion and reduced oxygen consumption rate. Next, evaluation of 23 patients with NSCLC showed that OE-MRI was clinically feasible and that tumor perfused Oxy-R volume is repeatable [interclass correlation coefficient: 0.961 (95% CI, 0.858-0.990); coefficient of variation: 25.880%]. Group-wise perfused Oxy-R volume was reduced at 14 days following start of radiotherapy (P = 0.015). OE-MRI detected between-subject variation in hypoxia modification in both xenograft and patient tumors.Conclusions: These findings support applying OE-MRI biomarkers to monitor hypoxia modification, to stratify patients in clinical trials of hypoxia-modifying therapies, to identify patients with hypoxic tumors that may fail treatment with immunotherapy, and to guide adaptive radiotherapy by mapping regional hypoxia.
    • Patient-reported outcome results from the open-label, randomized phase III myeloma X trial evaluating salvage autologous stem-cell transplantation in relapsed multiple myeloma

      Ahmedzai, SH; Snowden, JA; Ashcroft, AJ; Cairns, DA; Williams, C; Hockaday, A; Cavenagh, JD; Ademokun, D; Tholouli, E; Allotey, D; et al. (2019)
      PURPOSE: Salvage autologous stem-cell transplantation (sASCT) in patients with multiple myeloma (MM) relapsing after a prior autologous stem-cell transplantation leads to increased remission duration and overall survival. We report a comprehensive study on patient-reported outcomes, including quality of life (QoL) and pain in sASCT. METHODS: Patients were randomly assigned to either sASCT or nontransplantation consolidation (NTC). Pain and QoL were assessed as secondary outcomes using validated QoL instruments (European Organisation for Research and Treatment of Cancer QLQ-C30 and myeloma-specific module, QLQ-MY20; the Brief Pain Inventory [Short Form]; and the Leeds Assessment of Neuropathic Symptoms and Signs [Self-Assessment] scale). RESULTS: A total of 288 patients (> 96%) consented to the QoL substudy. The median follow-up was 52 months. The European Organisation for Research and Treatment of Cancer QLQ-C30 Global health status scores were higher (better) in the NTC group at 100 days after random assignment ( P = .0496), but not at later time points. Pain interference was higher (worse) in the sASCT group than in the NTC group at 6 months after random assignment ( P = .0267), with patients with sASCT reporting higher scores for Pain interference with daily living for up to 2 years after random assignment. Patients reporting lower concerns about adverse effects of treatment after sASCT had a time to progression advantage. CONCLUSION: Patients with sASCT with relapsed MM demonstrated a comparative reduction in QoL and greater impact of treatment adverse effects lasting for 6 months and up to 2 years for pain, after which patients who had received sASCT reported better outcomes. Patients who experienced lower adverse effects after sASCT had longer time to progression and overall survival, showing the need to improve symptom management peritransplantation. To our knowledge, this study provides the most comprehensive picture of QoL before and after sASCT in patients with relapsed MM.
    • Early demise from high grade serous ovarian cancer is predictable and likely related to tumour biology

      Hawarden, A; Russell, B; Gee, M; Skayali, F; Edmondson, M; Clamp, Andrew R; Jayson, Gordon C; Crosbie, E; Edmondson, R; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary’s Hospital,Manchester, UK (2019)
    • The case for screening all endometrial cancer patients for lynch syndrome

      Ryan, N; Glaire, M; Ramchander, N; Davison, N; Walker, T; Donnelly, L; McMahon, R; Tobi, S; Wallace, A; Payne, K; et al. (2019)
    • REQUITE: a prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer

      Seibold, P; Webb, A; Aguado-Barrera, ME; Azria, D; Bourgier, C; Brengues, M; Briers, E; Bultijnck, R; Calvo-Crespo, P; Carballo, A; et al. (2019)
      PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n?=?4409) and PAXgene tubes (n?=?3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ³2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity.