• 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial.

      Iveson, T; Kerr, R; Saunders, Mark P; Cassidy, J; Hollander, N; Tabernero, J; Haydon, A; Glimelius, B; Harkin, A; Allan, K; et al. (2018-04)
      6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.
    • 3-month versus 6-month adjuvant chemotherapy for patients with high-risk stage II and III colorectal cancer: 3-year follow-up of the SCOT non-inferiority RCT

      Iveson, T; Boyd, KA; Kerr, RS; Robles-Zurita, J; Saunders, Mark P; Briggs, AH; Cassidy, J; Hollander, NH; Tabernero, J; Haydon, A; et al. (2019)
      BACKGROUND: Oxaliplatin and fluoropyrimidine chemotherapy administered over 6 months is the standard adjuvant regimen for patients with high-risk stage II or III colorectal cancer. However, the regimen is associated with cumulative toxicity, characterised by chronic and often irreversible neuropathy. OBJECTIVES: To assess the efficacy of 3-month versus 6-month adjuvant chemotherapy for colorectal cancer and to compare the toxicity, health-related quality of life and cost-effectiveness of the durations. DESIGN: An international, randomised, open-label, non-inferiority, Phase III, parallel-group trial. SETTING: A total of 244 oncology clinics from six countries: UK (England, Scotland, Wales and Northern Ireland), Denmark, Spain, Sweden, Australia and New Zealand. PARTICIPANTS: Adults aged ³?18 years who had undergone curative resection for high-risk stage II or III adenocarcinoma of the colon or rectum. INTERVENTIONS: The adjuvant treatment regimen was either oxaliplatin and 5-fluorouracil or oxaliplatin and capecitabine, randomised to be administered over 3 or 6 months. MAIN OUTCOME MEASURES: The primary outcome was disease-free survival. Overall survival, adverse events, neuropathy and health-related quality of life were also assessed. The main cost categories were chemotherapy treatment and hospitalisation. Cost-effectiveness was assessed through incremental cost comparisons and quality-adjusted life-year gains between the options and was reported as net monetary benefit using a willingness-to-pay threshold of £30,000 per quality-adjusted life-year per patient. RESULTS: Recruitment is closed. In total, 6088 patients were randomised (3044 per group) between 27 March 2008 and 29 November 2013, with 6065 included in the intention-to-treat analyses (3-month analysis, n?=?3035; 6-month analysis, n?=?3030). Follow-up for the primary analysis is complete. The 3-year disease-free survival rate in the 3-month treatment group was 76.7% (standard error 0.8%) and in the 6-month treatment group was 77.1% (standard error 0.8%), equating to a hazard ratio of 1.006 (95% confidence interval 0.909 to 1.114; p-value for non-inferiority?=?0.012), confirming non-inferiority for 3-month adjuvant chemotherapy. Frequent adverse events (alopecia, anaemia, anorexia, diarrhoea, fatigue, hand-foot syndrome, mucositis, sensory neuropathy, neutropenia, pain, rash, altered taste, thrombocytopenia and watery eye) showed a significant increase in grade with 6-month duration; the greatest difference was for sensory neuropathy (grade ³?3 was 4% for 3-month vs.16% for 6-month duration), for which a higher rate of neuropathy was seen for the 6-month treatment group from month 4 to ³?5 years (p?<?0.001). Quality-of-life scores were better in the 3-month treatment group over months 4-6. A cost-effectiveness analysis showed 3-month treatment to cost £4881 less over the 8-year analysis period, with an incremental net monetary benefit of £7246 per patient. CONCLUSIONS: The study achieved its primary end point, showing that 3-month oxaliplatin-containing adjuvant chemotherapy is non-inferior to 6 months of the same regimen; 3-month treatment showed a better safety profile and cost less. For future work, further follow-up will refine long-term estimates of the duration effect on disease-free survival and overall survival. The health economic analysis will be updated to include long-term extrapolation for subgroups. We expect these analyses to be available in 2019-20. The Short Course Oncology Therapy (SCOT) study translational samples may allow the identification of patients who would benefit from longer treatment based on the molecular characteristics of their disease. TRIAL REGISTRATION: Current Controlled Trials ISRCTN59757862 and EudraCT 2007-003957-10. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 64. See the NIHR Journals Library website for further project information. This research was supported by the Medical Research Council (transferred to NIHR Evaluation, Trials and Studies Coordinating Centre - Efficacy and Mechanism Evaluation; grant reference G0601705), the Swedish Cancer Society and Cancer Research UK Core Clinical Trials Unit Funding (funding reference C6716/A9894). PLAIN-LANGUAGE-SUMMARY: Patients diagnosed with bowel cancer are likely to have surgery to remove the tumour. Patients diagnosed with a more advanced stage of the disease are then likely to be offered what is known as adjuvant chemotherapy Ð chemotherapy to kill any cancer cells that have already spread but cannot be seen. Adjuvant chemotherapy is usually given over 6 months using two medicines known as oxaliplatin and fluoropyrimidine. This chemotherapy has side effects of diarrhoea, nausea and vomiting, and it reduces the numbers of cells in the blood. It can also damage nerves, which causes discomfort, numbness and tingling; in some cases, this can go on for years. These side effects are more likely to develop with longer treatment. This study looked at whether or not shortening the time over which patients were given oxaliplatin and fluoropyrimidine chemotherapy reduced its effectiveness. In this large study of over 6000 patients, half of the patients were allocated by chance to be treated for 3 months and the other half to be treated for 6 months. Reducing the time that patients had chemotherapy from 6 months to 3 months did not make the treatment less effective. When patients treated with chemotherapy over 3 months were compared with those treated over 6 months, 77% of patients in both groups were well with no detectable disease 3 years after surgery. Patients were less likely to get side effects with 3-month chemotherapy. In particular, the chance of persistent long-term nerve damage was lower, resulting in patients with 3-month chemotherapy having better health-related quality of life. Overall, the study showed that 3-month adjuvant chemotherapy for patients with bowel cancer is as effective as 6-month adjuvant chemotherapy and causes fewer side effects.
    • Analysis of symptoms and functional HRQoL scales in TAGS, a phase III trial of trifluridine/tipiracil (FTD/TPI) in metastatic gastric cancer (mGC)

      Alsina, M; Tabernero, J; Shitara, K; Doi, T; Dvorkin, M; Mansoor, Was; Arkenau, HT; Prokharau, A; Ghidini, M; Faustino, C; et al. (2019)
    • BEACON: A randomised, phase 3 study of encorafenib and cetuximab plus /- binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E-mutant metastatic colorectal cancer patients

      Wasan, H; Arkenau, T; Braun, Michael S; Samuel, L; Graham, J; Kopetz, S; Grothey, A; Van Cutsem, E; Yaeger, R; Yoshino, T; et al. (2019)
    • Career opportunities and benefits for young oncologists in the European Society for Medical Oncology (ESMO).

      Morgan, G; Lambertini, M; Kourie, Hampig R; Amaral, T; Argiles, G; Banerjee, S; Cardone, C; Corral, J; De Mattos-Arruda, L; Öztürk, A; et al. (2016)
      The European Society for Medical Oncology (ESMO) is one of the leading societies of oncology professionals in the world. Approximately 30% of the 13 000 ESMO members are below the age of 40 and thus meet the society's definition of young oncologists (YOs). ESMO has identified the training and development of YOs as a priority and has therefore established a comprehensive career development programme. This includes a leadership development programme to help identify and develop the future leaders in oncology. Well-trained and highly motivated future generations of multidisciplinary oncologists are essential to ensure the optimal evolution of the field of oncology with the ultimate goal of providing the best possible care to patients with cancer. ESMO's career development portfolio is managed and continuously optimised by several dedicated committees composed of ESMO officers and is directly supervised by the ESMO Executive Board and the ESMO President. It offers unique resources for YOs at all stages of training and includes a broad variety of fellowship opportunities, educational courses, scientific meetings, publications and resources. In this article, we provide an overview of the activities and career development opportunities provided by ESMO to the next generation of oncologists.
    • Efficacy and safety of trifluridine/tipiracil (FTD/TPI) in European patients with heavily pretreated metastatic gastric cancer (mGC): An analysis of the TAGS study

      Alsina, M; Tabernero, J; Arkenau, HT; Squadroni, M; Doi, T; Faustino, C; Ghidini, M; Mansoor, Was; Shitara, K; Van Cutsem, E; et al. (2019)
    • Efficacy and safety of trifluridine/tipiracil treatment in patients with metastatic gastric cancer who had undergone gastrectomy: subgroup analyses of a randomized clinical trial

      Ilson, DH; Tabernero, J; Prokharau, A; Arkenau, HT; Ghidini, M; Fujitani, K; Van, CE; Thuss-Patience, P; Beretta, GD; Mansoor, Was; et al. (2019)
    • Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer

      Kopetz, S; Grothey, A; Yaeger, R; Van, CE; Desai, J; Yoshino, T; Wasan, H; Ciardiello, F; Loupakis, F; Hong, YS; et al. (2019)
    • Epigenetic EGFR gene repression confers sensitivity to therapeutic BRAFV600E blockade in colon neuroendocrine carcinomas

      Capdevila, J; Arques, O; Mora, JRH; Matito, J; Caratu, G; Mancuso, FM; Landolfi, S; Barriuso, Jorge; Jimenez-Fonseca, P; Lopez, CL; et al. (2020)
      PURPOSE: The limited knowledge of the molecular alterations that characterize poorly differentiated neuroendocrine carcinomas has limited the clinical development of targeted agents directed to driver mutations. Here we aim to identify new molecular targets in colon neuroendocrine carcinomas (co-NEC) and proof the efficacy of matching drugs. EXPERIMENTAL DESIGN: We performed a multi-omic analysis of co-NEC to identify genetic or epigenetic alterations that could be exploited as effective drug targets. We compared co-NEC samples with colorectal carcinomas (CRC) to identify neuroendocrine-specific traits. Patients with co-NEC and patient-derived xenografts were treated with a BRAFV600E-blocking drug to demonstrate sensitivity. RESULTS: co-NEC and CRC are similar in their mutational repertoire, although co-NECs are particularly enriched in BRAFV600E mutations. We report for the first time that V600EBRAF-mutant co-NECs may benefit from BRAF inhibition in monotherapy and how EGFR status is essential to predict innate sensitivity and acquired resistance by a differential methylation of its gene regulatory regions. CONCLUSIONS: The identification of V600E BRAF mutations in high-grade co-NECs has allowed the description of radiological responses to combination therapy of BRAF and MEK inhibitors in basket clinical trials. However, the molecular rationale for this treatment combination was based on the presence of the BRAF mutation and the efficacy observed in other cancer types such as melanoma. Future drug development in this setting should test BRAF inhibitors upfront and the addition of anti-EGFR antibodies instead of MEK inhibitors for an efficient blockade of acquired resistance.
    • Health-related quality of life associated with trifluridine/tipiracil in heavily pretreated metastatic gastric cancer: results from TAGS

      Tabernero, J; Alsina, M; Shitara, K; Doi, T; Dvorkin, M; Mansoor, Was; Arkenau, HT; Prokharau, A; Ghidini, M; Faustino, C; et al. (2020)
      BACKGROUND: In TAGS, an international, double-blind, phase 3 trial, trifluridine/tipiracil significantly improved overall survival and progression-free survival compared with placebo in heavily pretreated metastatic gastric cancer patients. This paper reports pre-specified quality of life (QoL) outcomes for TAGS. METHODS: Patients were randomized 2:1 to trifluridine/tipiracil (35 mg/m2 twice daily on days 1-5 and 8-12 of each 28-day cycle) plus best supportive care (BSC) or placebo plus BSC. QoL was evaluated at baseline and at each treatment cycle, using the EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires; results were considered valid for analysis only if ≥ 10% of patients completed the questionnaires. Key QoL outcomes were mean changes from baseline and time to deterioration in QoL. A post hoc analysis assessed the association between QoL and time to deterioration of Eastern Cooperative Oncology Group performance score (ECOG PS) to ≥ 2. RESULTS: Of 507 randomized patients, 496 had baseline QoL data available. The analysis cut-off was 6 cycles for trifluridine/tipiracil and 3 cycles for placebo. In both treatment groups, there were no clinically significant deteriorations in the mean QLQ-C30 Global Health Status (GHS) score, or in most subscale scores. In a sensitivity analysis including death and disease progression as events, there was a trend towards trifluridine/tipiracil reducing the risk of deterioration of QoL scores compared with placebo. Deterioration in the GHS score was associated with deterioration in ECOG PS. CONCLUSION: QoL was maintained in TAGS, and there was a trend towards trifluridine/tipiracil reducing the risk of QoL deterioration compared with placebo. Trial registration ClinicalTrials.gov number: NCT02500043.
    • Nintedanib plus best supportive care (BSC) versus placebo plus BSC for the treatment of patients (pts) with colorectal cancer (CRC) refractory to standard therapies: results of the phase III LUME-colon 1 study.

      Van Cutsem, E; Yoshino, T; Lenz, H; Lonardi, S; Falcone, A; Limon, M; Saunders, Mark P; Sobrero, A.; Maiello, E.; Park, Y.S.; et al. (2016-10-01)
    • Overall survival results from a phase III trial of trifluridine/tipiracil versus placebo in patients with metastatic gastric cancer refractory to standard therapies (TAGS).

      Tabernero, J; Shitara, K; Dvorkin, M; Mansoor, Was; Arkenau, H; Prokharau, A; Alsina, M; Ghidini, M; Faustino, C; Gorbunova, V; et al. (2018-06)
    • Pembrolizumab plus chemotherapy for advanced G/GEJ adenocarcinoma (GC): The phase III KEYNOTE-062 study

      Chung, HC; Bang, YJ; Tabernero, J; Van Cutsem, E; Fuchs, CS; Wyrwicz, L; Lee, KW; Kudaba, I; Garrido, M; Castro, H; et al. (2019)
    • A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer.

      Starling, N; Vázquez-Mazón, F; Cunningham, D; Chau, I; Tabernero, J; Ramos, F; Iveson, T; Saunders, Mark P; Aranda, E; Countouriotis, A; et al. (2012-01)
      This study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m2 given over 90 min i.v. and l-leucovorin 200 mg/m2 given over 120 min on day 1, followed by 5-FU 400 mg/m2 bolus and then 2400 mg/m2 infused over 46 h) in untreated metastatic colorectal cancer (mCRC).
    • Professional burnout in european young oncologists: results of The European Society for Medical Oncology (ESMO) young oncologists committee burnout survey.

      Banerjee, S; Califano, Raffaele; Corral, J; de Azambuja, E; De Mattos-Arruda, L; Guarneri, V; Hutka, M; Jordan, K; Martinelli, E; Mountzios, G; et al. (2017-04-25)
      Burnout in health care professionals could have serious negative consequences on quality of patient care, professional satisfaction and personal life. Our aim was to investigate the burnout prevalence, work and lifestyle factors potentially affecting burnout amongst European oncologists ≤40 (YOs).
    • Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial.

      Argilés, G; Saunders, Mark P; Rivera, F; Sobrero, A; Benson, A; Guillén Ponce, C; Cascinu, S; Van Cutsem, E; Macpherson, I; Strumberg, D; et al. (2015-03-24)
      The oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC.
    • SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant oxaliplatin combination chemotherapy for colorectal cancer.

      Robles-Zurita, J; Boyd, KA; Briggs, AH; Iveson, T; Kerr, RS; Saunders, Mark P; Cassidy, J; Hollander NH; Tabernero, J; Segelov, E; et al. (2018)
      BACKGROUND: The Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3?M) versus the usually given 6 months (6?M) of adjuvant chemotherapy in colorectal cancer. METHODS: In total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3-8 years. The within-trial cost-effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease-free survival after treatment (DFS) and overall survival (OS) data. Quality-adjusted partitioned survival analysis and Kaplan-Meier Sample Average Estimator estimated QALYs and costs. Probabilistic sensitivity and subgroup analysis was undertaken. RESULTS: The 3?M arm is less costly (-£4881; 95% CI: -£6269; -£3492) and entails (non-significant) QALY gains (0.08; 95% CI: -0.086; 0.230) due to a better significant quality of life. The net monetary benefit was significantly higher in 3?M under a wide range of monetary values of a QALY. The subgroup analysis found similar results for patients in the CAPOX regimen. However, for the FOLFOX regimen, 3?M had lower QALYs than 6?M (not statistically significant). CONCLUSIONS: Overall, 3?M dominates 6?M with no significant detrimental impact on QALYs. The results provide the economic case that a 3?M treatment strategy should be considered a new standard of care