Publications by authors named "Jean-Yves Douillard"

135 Publications

BRAF V600E Mutation in First-line Metastatic Colorectal Cancer: an Analysis of Individual Patient Data from the ARCAD Database.

J Natl Cancer Inst 2021 Mar 18. Epub 2021 Mar 18.

Sorbonne University, department of medical oncology, Saint-Antoine hospital, AP-HP, F-75012 Paris, France.

Background: First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed at assessing the prognostic and predictive impact of BRAFmt for the efficacy of targeted therapies with first-line chemotherapy.

Methods: Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomized whenever possible.

Results: 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%) and 3759 double wild-type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] =1.46, 95% confidence interval [95%CI] = 1.30-1.64) and patients with double wild-type tumors (HRadj =2.14, 95%CI = 1.94-2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy ± anti-EGFR (HRadj =0.96, 95%CI = 0.71-1.30 and HRadj =0.85, 95%CI = 0.66-1.14, respectively).

Conclusion: Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.
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http://dx.doi.org/10.1093/jnci/djab042DOI Listing
March 2021

The global landscape of treatment standards for breast cancer.

J Natl Cancer Inst 2021 Jan 27. Epub 2021 Jan 27.

AI, Department of Noncommunicable Diseases, World Health Organization, Geneva, Switzerland.

Background: Breast cancer (BC) is a leading cause of morbidity, mortality, and disability for women, worldwide. There is substantial variation in treatment outcomes, which is function of multiple variables, including access to treatment. Treatment standards can promote quality and improve survival; thus, their development should be a priority for the cancer control planning.

Methods: We extracted the guidelines for the treatment of BC from a systematic review of the literature. We evaluated the development process, the methodology and the recommendations formulated, and surveyed the country resource stratification. Metrics of health system capacity were selected, to study the guidelines context- appropriateness.

Results: We analysed 49 distinct guidelines for BC, mostly in English language (n = 23), developed in upper-middle and high-income countries of the European and American Regions (n = 39). A resource-stratified approach was identified in a quarter of the guidelines (n = 11), mostly from resource- constrained settings. Only a half of the guidelines reached a gender balance of the authorship and 10.2% were based on a multidisciplinary steering committee. A number of efforts and solutions of resource adaptations were recognized, mostly in low- and middle-income countries. Overall, the national guidelines appeared not enough sensitive of the local health system capacity in formulating recommendations, with possible exception for the radiation therapy availability.

Conclusion: This global landscape of treatment standards for BC demonstrates that the majority are not context appropriate. Research on the formulation of cancer treatment standards is highly warranted, along with novel platforms for developing and disseminating resource-appropriate guidance.
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http://dx.doi.org/10.1093/jnci/djab011DOI Listing
January 2021

Efficacy and safety of panitumumab in a cohort of patients with metastatic colorectal cancer in France: PANI OUEST, a post-EMA-approval descriptive study with a geriatric oncology focus.

Turk J Gastroenterol 2020 10;31(10):695-705

Observatory of Cancer BPL, Angers, France;West Institut of Cancer (ICO), Paul Papin, Angers, France.

Background/aims: The Bretagne-Pays de la Loire cancer observatory, an oncology network created by the French Ministry of Health, is specifically dedicated to assess the use of new targeted anticancer therapies in routine practice. In line with the French National Cancer III program, our cancer network set up a real-life cohort, which is independent of the pharmaceutical industry, for patients with colorectal cancer to monitor patient safety and quality of care and promote pharmacovigilance.

Materials And Methods: Panitumumab monotherapy was assessed in 243 patients with wild-type Kirsten rat sarcoma who were treated for metastatic colorectal cancer (mCRC) between July 2008 and December 2010 after prior chemotherapy using oxaliplatine and irinotecan. This was a post-European medicine agency marketing (EMA-M) study Results: This study shed light on the best practices, strategic adaptations, clinical results (treatment objective responses, 13%; progression free survival, 2.99 months [2.73-3.15]; and overall survival, 6.8 months [5.49-8.38]) as well as expected or unexpected (grade 3 or 4: 11.5%) secondary effects in the phase IV panitumumab treatment of mCRC.

Conclusion: Our results are similar to those by Amado whose phase III study led to obtaining EMA-M for panitumumab and tend to confirm the antitumor activity of this antiepidermal growth factor receptor antibody in the treatment of mCRC. In addition, our results opened avenues to further assessment of panitumumab use as monotherapy as well as its benefit-risk ratio while taking into account the patients' general and clinical characteristics. In 2012, the French National Authority for Health appended these data to the panitumumab transparency committee report.
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http://dx.doi.org/10.5152/tjg.2020.19219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659902PMC
October 2020

Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1.

ESMO Open 2020 09;5(5):e000681

Medical Oncology, University Medical Centre Groningen, Groningen, Groningen, Netherlands. Electronic address:

Click here to listen to the Podcast BACKGROUND: Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments.

Methods: Adjuvant studies were identified in PubMed, Food and Drug Administration and European Medicines Agency registration sites, as well as ESMO and National Comprehensive Cancer Network guidelines. Studies meeting inclusion criteria were graded using form 1 of the ESMO-MCBS V.1.1 and field tested by ESMO Colorectal Cancer Faculty. Shortcomings of the scale were identified and evaluated.

Results: Eighteen of 57 trials and 7 out of 14 meta-analyses identified met criteria for ESMO-MCBS V.1.1 grading. In stage III colon cancer, randomised clinical trials and meta-analyses of modulated 5-fluorouracil (5-FU) based chemotherapy versus surgery scored ESMO-MCBS grade A and randomised controlled trials (RCTs) and meta-analyses comprising oxaliplatin added to this 5-FU backbone showed a more modest additional overall survival benefit (grade A and B). For stage II colon cancer, the findings are less consistent. The fluoropyrimidine trials in stage II were graded 'no evaluable benefit' but the most recent meta-analysis demonstrated a 5.4% survival advantage after 8 years follow-up (grade A). RCTs and a meta-analysis adding oxaliplatin demonstrated no added benefit. Exploratory toxicity evaluation and annotation was problematic given inconsistent toxicity reporting and limited results of late toxicity. Field testers (n=37) reviewed the scores, 25 confirmed their reasonableness, 12 found them mostly reasonable. Moreover, they identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming.

Conclusion: Form 1 of the ESMO-MCBS V.1.1 provided very reasonable grading for adjuvant colon cancer studies.
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http://dx.doi.org/10.1136/esmoopen-2020-000681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476457PMC
September 2020

ESMO management and treatment adapted recommendations in the COVID-19 era: colorectal cancer.

ESMO Open 2020 05;5(Suppl 3)

Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Diseses, Leipzig University Medical Center, Leipzig, Germany

COVID-19 pandemic challenges health system capacities in many countries. National healthcare services have to manage unexpected shortage of healthcare resources that have to be reallocated according to the principles of fair and ethical prioritisation, in order to maintain the highest levels of care to all patients, ensure the safety of patients and healthcare workers and save as many lives as possible. Beyond that, cancer care services have to pursue restructuring, following the same evidence-based dispositions. In this article, we propose guidance to the management of colorectal cancer during the pandemic, prioritised according to a three-tiered framework, based on expert clinical judgement and magnitude of benefit expected from specific interventions. Since the availability of resources for diagnostic procedures, surgery and postoperative care, systemic therapy and radiotherapy may differ, authors did separate prioritisation analyses. The impact of postponing or abrogating cancer interventions on outcomes according to a high, medium or low priority scale, is outlined and discussed. The implementation of healthcare services using telemedicine is explored: it reveals itself as functional and effective for limiting patients' need to travel to centres and thereby has the potential to reduce diffusion of severe acute respiratory syndrome coronavirus 2. Colorectal cancer demands a considerable amount of medical resources. Therefore, the redefinition of its diagnostic and therapeutic algorithms with a rigorous method is crucial in order to ensure the highest quality of continuum of care in the broader context of the pandemic and the challenged healthcare systems.
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http://dx.doi.org/10.1136/esmoopen-2020-000826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276236PMC
May 2020

ESMO Management and treatment adapted recommendations in the COVID-19 era: Pancreatic Cancer.

ESMO Open 2020 05;5(Suppl 3)

Department of Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases, University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany

The COVID-19 pandemic is challenging the capacities of health systems in many countries. National healthcare services have to manage unexpected shortages of healthcare resources that have to be re-allocated according to the principles of fair and ethical prioritisation, in order to maintain the highest levels of care to all patients, ensure the safety of patients and healthcare workers, and save as many lives as possible. Also, cancer care services have to pursue restructuring, following the same evidence-based dispositions. In this article, we propose a guidance to the management of pancreatic cancer during the pandemic, prioritised according to a three-tiered framework, and based on expert clinical judgement and magnitude of benefit expected from specific interventions. Since the availability of resources for diagnostic procedures, surgery and postoperative care, systemic therapy and radiotherapy may differ, the authors have separated the prioritisation analyses. The impact of postponing or abrogating cancer interventions on outcomes according to a high, medium or low priority scale is outlined and discussed. The implementation of healthcare services using telemedicine is explored; it reveals itself as functional and effective for limiting patients' need to travel to centres and thereby has the potential to reduce diffusion of SARS-CoV-2. Pancreatic cancer demands a considerable amount of medical resources. Therefore, the redefinition of its diagnostic and therapeutic algorithms with a rigorous method is crucial in order to ensure the highest quality of continuum of care in the broader context of the pandemic and the challenged healthcare systems.
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http://dx.doi.org/10.1136/esmoopen-2020-000804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239531PMC
May 2020

ESMO Clinical Research Observatory (ECRO): improving the efficiency of clinical research through rationalisation of bureaucracy.

ESMO Open 2020 05;5(3):e000662

Scientific and Medical Division, European Society for Medical Oncology (ESMO), Lugano, Switzerland.

During the last years, there has been a dramatic increase in the administrative and bureaucratic burden associated with clinical research, which has clearly had an impact on its overall efficiency and on the activity of clinical investigators and research teams. Indeed, the supervision of the adherence of clinical research to Good Clinical Practice (GCP) guidelines and legal regulations is of the utmost importance. Yet, while such regulations have remained largely unchanged during recent years, the number of administrative tasks and their complexity have grown markedly, as supported by the results of a survey performed among 940 clinical investigators that we report in this manuscript. Therefore, many investigators believe that it has become necessary to undertake a rigorous analysis of the causes and consequences of this issue, and to create a conduit to channel the advice from experienced investigators regarding clinical research procedures, in order to improve them. Based on these premises, ESMO has launched the ESMO Clinical Research Observatory (ECRO), a task force that will analyse different aspects of clinical research. ECRO will aim to provide the views of ESMO on clinical research procedures based on the feedback from clinical investigators, under complete adherence to the Declaration of Helsinki, the GCP guidelines and any other applicable legal regulations, while at the same time showing profound respect for all the stakeholders involved in clinical research. This manuscript provides the background and rationale for the creation of ECRO, its planned activity and an analysis of the current administrative burden in clinical research with recommendations to rationalise it. Indeed, we expect that this effort shall lead to a relevant improvement in the care of patients and in the development of clinical research.
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http://dx.doi.org/10.1136/esmoopen-2019-000662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223268PMC
May 2020

Threshold Change in CEA as a Predictor of Non-Progression to First-Line Systemic Therapy in Metastatic Colorectal Cancer Patients With Elevated CEA.

J Natl Cancer Inst 2020 11;112(11):1127-1136

Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Carcinoembryonic antigen (CEA) levels are used in conjunction with imaging to monitor response to systemic therapy in metastatic colorectal cancer (mCRC). We sought to identify a threshold for CEA change from baseline to predict progressive disease (PD) in mCRC patients receiving first-line therapy.

Methods: Patients from trials collected in the ARCAD database were included if baseline CEA was at least 10 ng/mL and repeat CEA was available within 14 days of first restaging scan. Optimal cutoffs for CEA change were identified by receiver operating characteristic analysis. Prediction performance of cutoffs was evaluated by sensitivity, specificity, and negative predictive value. Analyses were conducted by treatment class: chemotherapy alone, chemotherapy with anti-VEGF antibody, and chemotherapy with anti-EGFR antibody.

Results: A total of 2643 mCRC patients treated with systemic therapy were included. Median percent change of CEA from baseline to first restaging for patients with complete response, partial response, or stable disease (non-PD) and PD was -53.1% and +23.6% for chemotherapy alone (n = 957) and -71.7% and -45.3% for chemotherapy with anti-VEGF antibody (n = 1355). The optimal area under the curve cutoff for differentiating PD from non-PD on first restaging was -7.5% for chemotherapy alone and -62.0% for chemotherapy with anti-VEGF antibody; chemotherapy alone, adjusted odds ratio = 6.51 (95% CI = 3.31 to 12.83, P < .001), chemotherapy with anti-VEGF antibody, adjusted odds ratio = 3.45 (95% CI = 1.93 to 6.18, P < .001). A 99% negative predictive value clinical cutoff for prediction of non-PD would avoid CT scan at first restaging in 21.0% of chemotherapy alone and 16.2% of chemotherapy with anti-VEGF antibody-treated patients. Among patients with stable disease on first restaging, those with decreased CEA from baseline had statistically significantly improved progression-free and overall survival.

Conclusions: Change in CEA from baseline to first restaging can accurately predict non-progression and correlates with long-term outcomes in patients receiving systemic chemotherapy.
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http://dx.doi.org/10.1093/jnci/djaa020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669230PMC
November 2020

Concurrent losses of skeletal muscle mass, adipose tissue and bone mineral density during bevacizumab / cytotoxic chemotherapy treatment for metastatic colorectal cancer.

Clin Nutr 2020 11 22;39(11):3319-3330. Epub 2020 Feb 22.

Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton, Canada. Electronic address:

Background: Changes in skeletal muscle mass (SMM), total adipose tissue mass (TAT) or bone mineral density (BMD) have been described in patients with cancer undergoing various treatments; simultaneous variations of all 3 tissues has not been reported.

Methods: Data were prospectively collected in a clinical study (NCT00489697) including patients with liver metastases of colorectal cancer who received 4 cycles of bevacizumab in combination with cytotoxic chemotherapy. Computerized tomography (CT) at baseline and after chemotherapy was used to quantify skeletal muscle and adipose tissue cross-sectional areas, and mean lumbar spine BMD using validated approaches.

Results: After exclusion of patients lacking adequate CT images or missing data, 72 subjects were included. Patients were 63% male, aged 63.2 ± 10.3 years, 100% had liver metastases and 54%, 24% and 22% respectively has 0, 1 and ≥2 extrahepatic metastases. 100% tolerated 4 cycles of treatment and none showed progressive disease at the end of treatment. The scan interval was 70 days (95% CI, 62.3 to 80.5). Thresholds for loss of tissue were defined as loss ≥ measurement error. 10% of patients showed no loss of any tissue and a further 43% lost one tissue (SMM, TAT or BMD); 47% of patients lost 2 tissues (16.5% lost SMM + TAT, 8% lost SMM + BMD, 10% lost TAT + BMD) or all 3 tissues (12.5%). Catabolic behavior (2 or 3 tissue loss vs 0 or 1 tissue loss) associated with disease burden, including unresectable primary tumor (p = 0.010), presence of extrahepatic (EH) metastases (p = 0.039) and number of EH metastases (p = 0.004). No association was found between the number of tissues lost and treatment response, which was uniformly high, or treatment toxicity, which was uniformly low.

Conclusion: Multiple tissues can be measured in routine CT images and these show considerable inter-individual variation. Substantial losses in some individuals appear to associate with disease burden.
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http://dx.doi.org/10.1016/j.clnu.2020.02.017DOI Listing
November 2020

Design and Conduct of Early Clinical Studies of Immunotherapy: Recommendations from the Task Force on Methodology for the Development of Innovative Cancer Therapies 2019 (MDICT).

Clin Cancer Res 2020 06 21;26(11):2461-2465. Epub 2020 Feb 21.

Medical and Scientific Affairs Division, ESMO, Lugano, Switzerland.

Purpose: To review key aspects of the design and conduct of early clinical trials (ECT) of immunotherapy agents.

Experimental Design: The Methodology for the Development of Innovative Cancer Therapies Task Force 2019 included experts from academia, nonprofit organizations, industry, and regulatory agencies. The review focus was on methodology for ECTs testing immune-oncology therapies (IO) used in combination with other IO or chemotherapy.

Results: Although early successes have been seen, the landscape continues to be very dynamic, and there are ongoing concerns regarding the capacity to test all new drugs and combinations in clinical trials.

Conclusions: Optimization of drug development methodology is required, taking into account early, late, and lower grade intolerable toxicities, novel response patterns, as well as pharmacodynamic data.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3136DOI Listing
June 2020

EHA evaluation of the ESMO-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for haematological malignancies.

ESMO Open 2020 01;5(1)

Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Zuid-Holland, The Netherlands.

Objective: Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS).

Methods: Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies.

Results: In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described.

Conclusions: Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials.
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http://dx.doi.org/10.1136/esmoopen-2019-000611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003483PMC
January 2020

Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer.

JAMA Netw Open 2019 09 4;2(9):e1911750. Epub 2019 Sep 4.

Hasselt University, Diepenbeek, Belgium.

Importance: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS).

Objective: To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer.

Design, Setting, And Participants: Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer.

Main Outcomes And Measures: Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS.

Results: For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti-epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78).

Conclusions And Relevance: In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.11750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755539PMC
September 2019

Cancer medicines in Asia and Asia-Pacific: What is available, and is it effective enough?

ESMO Open 2019 17;4(4):e000483. Epub 2019 Jul 17.

Department of Haematology and Oncology, University of Milano, Milan, Italy.

This review article is an overview of the session at the European Society for Medical Oncology (ESMO) Asia 2018 Congress entitled: 'Cancer medicines in Asia and Asia-Pacific: What is available, and is it effective enough?'. The article provides an overview of the session speakers' views on the impact that the lack of accessibility and availability of medicines has on patient outcomes in the treatment of breast cancer, colorectal cancer and lung cancer, responsible for more than one-third of cancer deaths in the Asian region. It also lists the various global policy initiatives that ESMO supports to promote the best cancer care in the Asian and Asia-Pacific region. The review presents extrapolated data from the 'ESMO International Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in countries outside of Europe', which reveals several disparities among Asian countries, across the different income levels. In low- and middle-income countries, some barriers to the accessibility of anticancer medicines include the lack of government reimbursement, budget allocation for healthcare and quality-assured generic and biosimilar medicines, as well as shortages and patent rights. Throughout the article, the session presenters provide their views on strategies that can be considered to overcome these barriers.
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http://dx.doi.org/10.1136/esmoopen-2018-000483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677966PMC
July 2019

Educational needs in gastrointestinal cancer: a consensus position paper from the ESMO Gastrointestinal Cancer Faculty.

ESMO Open 2019 5;4(3):e000533. Epub 2019 Jul 5.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.

Gastrointestinal (GI) cancers are common in all parts of the world. Effective prevention and early detection of GI cancers are not universally implemented. Therefore, it must be anticipated that the incidence and the mortality of GI cancers will remain high within the next decades. The European Society for Medical Oncology (ESMO) Gastrointestinal Cancer Faculty aims to increase the skills of medical oncologists and other disciplines involved in treating GI malignancies. We aimed to increase the survival chances for patients with GI cancers, augment their quality of life and enable successful return to normal social and professional life during the period of survivorship. ESMO also aims to decrease the economic burden of GI cancer in our societies and national healthcare systems. Therefore, the ESMO Gastrointestinal Cancer Faculty initiated a consensus process based on the Delphi method to identify the most important educational needs of physicians who are concerned with GI malignancies. This paper summarises the process and its results and outlines the mission of ESMO in education.
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http://dx.doi.org/10.1136/esmoopen-2019-000533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615870PMC
July 2019

Care of adolescents and young adults with cancer in Asia: results of an ESMO/SIOPE/SIOP Asia survey.

ESMO Open 2019 6;4(3):e000467. Epub 2019 Jun 6.

2nd Department of Oncology, Henry Dunant Hospital Center, Athens, Greece.

Background: Adolescents and young adults (AYAs) with cancer require dedicated management encompassing both adult and paediatric cancer services. Following a European survey, the European Society for Medical Oncology, the European Society for Paediatric Oncology and the Asian continental branch of International Society of Paediatric Oncology undertook a similar survey to assess AYA cancer care across Asia.

Methods: A link to the online survey was sent to healthcare professionals (HCPs) in Asia interested in AYA cancer care. Questions covered the demographics and training of HCPs, their understanding of AYA definition, availability and access to specialised AYA services, the support and advice offered during and after treatment, and factors of treatment non-compliance.

Results: We received 268 responses from 22 Asian countries. There was a striking variation in the definition of AYA (median lower age 15 years, median higher age 29 years). The majority of the respondents (78%) did not have access to specialised cancer services and 73% were not aware of any research initiatives for AYA. Over two-thirds (69%) had the option to refer their patients for psychological and/or nutritional support and most advised their patients on a healthy lifestyle. Even so, 46% did not ask about smokeless tobacco habits and only half referred smokers to a smoking cessation service. Furthermore, 29% did not promote human papillomavirus vaccination for girls and 17% did not promote hepatitis B virus vaccination for high-risk individuals. In terms of funding, 69% reported governmental insurance coverage, although 65% reported that patients self-paid, at least partially. Almost half (47%) reported treatment non-compliance or abandonment as an issue, attributed to financial and family problems (72%), loss of follow-up (74%) and seeking of alternative treatments (77%).

Conclusions: Lack of access to and suboptimal delivery of AYA-specialised cancer care services across Asia pose major challenges and require specific interventions.
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http://dx.doi.org/10.1136/esmoopen-2018-000467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555609PMC
June 2019

3,4-Dideoxy-3,3,4,4-tetrafluoro- and 4-OH epimeric 3-deoxy-3,3-difluoro-α-GalCer analogues: Synthesis and biological evaluation on human iNKT cells stimulation.

Eur J Med Chem 2019 Sep 29;178:195-213. Epub 2019 May 29.

Université de Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UMR CNRS 6230, Faculté des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France. Electronic address:

iNKT cells recognize CD1d/α-galactosylceramide (α-GalCer) complexes via their invariant TCR receptor and stimulate the immune response. Many α-GalCer analogues have been investigated to interrogate this interaction. Following our previous work related to the modification of the hydrogen bond network between α-GalCer and CD1d, we have now focused our attention on the synthesis of 3-deoxy-3,3-difluoro- and 3,4-dideoxy-3,3,4,4-tetrafluoro-α-GalCer analogues, and studied their ability to stimulate human iNKT cells. In each case, deoxygenation at the indicated positions was accompanied by difluoro introduction in order to evaluate the resulting electronic effect on the stability of the ternary CD1d/Galcer/TCR complex which has been rationalized by modeling study. With deoxy-difluorination at the 3-position, the two epimeric 4-OH analogues were investigated to establish their capacity to compensate for the lack of the hydrogen bond donating group at the 3-position. The 3,4-dideoxytetrafluoro analogue was of interest to highlight the amide NH-bond hydrogen bond properties.
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http://dx.doi.org/10.1016/j.ejmech.2019.05.069DOI Listing
September 2019

Comparative Assessment of Clinical Benefit Using the ESMO-Magnitude of Clinical Benefit Scale Version 1.1 and the ASCO Value Framework Net Health Benefit Score.

J Clin Oncol 2019 02 17;37(4):336-349. Epub 2018 Dec 17.

American Society of Clinical Oncology, Alexandria, VA.

Purpose: To better understand the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) and the ASCO Value Framework Net Health Benefit score version 2 (ASCO-NHB v2), ESMO and ASCO collaborated to evaluate the concordance between the frameworks when used to assess clinical benefit attributable to new therapies.

Methods: The 102 randomized controlled trials in the noncurative setting already evaluated in the field testing of ESMO-MCBS v1.1 were scored using ASCO-NHB v2 by its developers. Measures of agreement between the frameworks were calculated and receiver operating characteristic curves used to define thresholds for the ASCO-NHB v2 corresponding to ESMO-MCBS v1.1 categories. Studies with discordant scoring were identified and evaluated to understand the reasons for discordance.

Results: The correlation of the 102 pairs of scores for studies in the noncurative setting is estimated to be 0.68 (Spearman's rank correlation coefficient; overall survival, 0.71; progression-free survival, 0.67). Receiver operating characteristic curves identified thresholds for ASCO-NHB v2 for facilitating comparisons with ESMO-MCBS v1.1 categories. After applying pragmatic threshold scores of 40 or less (ASCO-NHB v2) and 2 or less (ESMO-MCBS v1.1) for low benefit and 45 or greater (ASCO-NHB v2) and 4 to 5 (ESMO-MCBS v1.1) for substantial benefit, 37 discordant studies were identified. Major factors that contributed to discordance were different approaches to evaluation of relative and absolute gain for overall survival and progression-free survival, crediting tail of the curve gains, and assessing toxicity.

Conclusion: The agreement between the frameworks was higher than observed in other studies that sought to compare them. The factors that contributed to discordant scores suggest potential approaches to improve convergence between the scales.
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http://dx.doi.org/10.1200/JCO.18.00729DOI Listing
February 2019

Panitumumab-based maintenance after oxaliplatin discontinuation in metastatic colorectal cancer: A retrospective analysis of two randomised trials.

Int J Cancer 2019 07 24;145(2):576-585. Epub 2019 Jan 24.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest (ICO) René Gauducheau, Nantes, France.

Panitumumab is approved for RAS wild-type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first-line randomised studies. This retrospective analysis of these trials investigated efficacy and toxicity of panitumumab-based maintenance after oxaliplatin discontinuation in RAS wild-type patients. First-line regimens were FOLFOX4 ± panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression-free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5-fluorouracil/leucovorin (5-FU/LV) maintenance was 21 (interquartile range: 11-41) weeks; that of 5-FU/LV ± bevacizumab maintenance was 16 (6-31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3-50.4) and 39.1 (34.2-63.0) months for panitumumab plus 5-FU/LV maintenance and 24.1 (17.7-33.0) and 28.9 (21.0-32.0) months for 5-FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3-23.6) and 15.4 (11.6-18.4) months for panitumumab plus 5-FU/LV maintenance and 12.6 (9.4-16.2) and 13.1 (9.5-16.6) months for 5-FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7-42.8) and 33.5 (24.5-54.9) months for panitumumab plus 5-FU/LV maintenance and 16.4 (12.4-24.1) and 23.3 (15.7-26.3) months for 5-FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8-19.2) and 9.7 (5.8-14.8) months and 7.1 (5.6-10.2) and 7.0 (3.9-10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5-FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first-line treatment. Prospective studies are warranted.
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http://dx.doi.org/10.1002/ijc.32110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590196PMC
July 2019

LACE-Bio: Validation of Predictive and/or Prognostic Immunohistochemistry/Histochemistry-based Biomarkers in Resected Non-small-cell Lung Cancer.

Clin Lung Cancer 2019 03 11;20(2):66-73.e6. Epub 2018 Oct 11.

Departments of Medical Oncology and Hematology (FAS) and Pathology (M-ST), University Health Network, Princess Margaret Cancer Centre, and the University of Toronto, Toronto, Ontario, Canada.

Background: Complete resection of non-small-cell lung cancer (NSCLC) offers the potential for cure after surgery and adjuvant chemotherapy. Patients may not benefit and may experience severe toxicity. There are no validated molecular tools to allow better patient selection.

Materials And Methods: The LACE-Bio (LACE [Lung Adjuvant Cisplatin Evaluation]) project includes 4 trials (International Adjuvant Lung Cancer Trial [IALT], Adjuvant Navelbine International Trialist Association [ANITA], JBR10, and Cancer and Leukemia Group B (CALGB)-9633). Immunohistochemistry biomarkers shown in one trial to have a prognostic/predictive effect on overall survival were tested.

Results: The majority of the promising biomarkers could not be validated; the prognostic effect of tumor infiltrating lymphocytes and β-tubulin was confirmed. Potential causes include tissue fixation, storage, the use of tissue microarrays, and varying reagent/antibody batches.

Conclusions: Immunohistochemistry assays from single trials may be misleading and require validation before being used for patient selection. LACE-Bio-2 is evaluating potential genomic biomarkers that may allow more precise selection of patients with NSCLC for adjuvant chemotherapy in NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2018.10.001DOI Listing
March 2019

Clinical validation of the next-generation sequencing-based Extended RAS Panel assay using metastatic colorectal cancer patient samples from the phase 3 PRIME study.

J Cancer Res Clin Oncol 2018 Oct 17;144(10):2001-2010. Epub 2018 Jul 17.

Department of Medical Oncology, ICO René Gauducheau, Nantes, France.

Purpose: To validate a next-generation sequencing (NGS)-based companion diagnostic using the MiSeqDx sequencing instrument to simultaneously detect 56 RAS mutations in DNA extracted from formalin-fixed paraffin-embedded metastatic colorectal cancer (mCRC) tumor samples from the PRIME study. The test's ability to identify patients with mCRC likely to benefit from panitumumab treatment was assessed.

Methods: Samples from PRIME, which compared first-line panitumumab + FOLFOX4 with FOLFOX4, were processed according to predefined criteria using a multiplex assay that included input DNA qualification, library preparation, sequencing, and the bioinformatics reporting pipeline. NGS mutational analysis of KRAS and NRAS exons 2, 3, and 4 was performed and compared with Sanger sequencing.

Results: In 441 samples, positive percent agreement of the Extended RAS Panel with Sanger sequencing was 98.7% and negative percent agreement was 97.6%. For clinical validation (n = 528), progression-free survival (PFS) and overall survival (OS) were compared between patients with RAS mutations (RAS Positive) and those without (RAS Negative). Panitumumab + FOLFOX4 improved PFS in RAS Negative patients (P = 0.02). Quantitative interaction testing indicated the treatment effect (measured by the hazard ratio of panitumumab + FOLFOX4 versus FOLFOX4) differed for RAS Negative versus RAS Positive for PFS (P = 0.0038) and OS (P = 0.0323).

Conclusions: NGS allows for broad, rapid, highly specific analyses of genomic regions. These results support use of the Extended RAS Panel as a companion diagnostic for selecting patients for panitumumab, and utilization is consistent with recent clinical guidelines regarding mCRC RAS testing. Overall, approximately 13% more patients were detected with the Extended RAS Panel versus KRAS exon 2 alone.

Clinical Trial Registry Identifier: NCT00364013 (ClinicalTrials.gov).
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http://dx.doi.org/10.1007/s00432-018-2688-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153611PMC
October 2018

Effect of Primary Tumor Location on Second- or Later-line Treatment Outcomes in Patients With RAS Wild-type Metastatic Colorectal Cancer and All Treatment Lines in Patients With RAS Mutations in Four Randomized Panitumumab Studies.

Clin Colorectal Cancer 2018 09 8;17(3):170-178.e3. Epub 2018 Mar 8.

Center for Oncological Research, University of Antwerp, Wilrijk, Belgium; Department of Oncology, Antwerp University Hospital, Edegem, Belgium. Electronic address:

Background: The primary tumor location has a prognostic impact in metastatic colorectal cancer (mCRC). We report the results from retrospective analyses assessing the effect of tumor location on prognosis and efficacy of second- and later-line panitumumab treatment in patients with RAS wild-type (WT) mCRC and on prognosis in all lines of treatment in patients with RAS mutant (MT) mCRC.

Patients And Methods: RAS WT data (n = 483) from 2 randomized phase III panitumumab trials (ClinicalTrials.gov identifiers, NCT00339183 and NCT00113763) were analyzed for treatment outcomes stratified by tumor location. The second analysis assessed the effect of tumor location in RAS MT patients (n = 1205) from 4 panitumumab studies (ClinicalTrials.gov identifiers, NCT00364013, NCT00819780, NCT00339183, and NCT00113763). Primary tumors located in the cecum to transverse colon were coded as right-sided; those located from the splenic flexure to the rectum were coded as left-sided.

Results: Of all patients, the tumor location was ascertained for 83% to 88%; 71% to 77% of patients had left-sided tumors. RAS WT patients with right-sided tumors did worse for all efficacy parameters compared with those with left-sided tumors. The patients with left-sided tumors had better outcomes with panitumumab than with the comparator treatment. Because of the low patient numbers, no conclusions could be drawn for right-sided mCRC. The prognostic effect of tumor location on survival was unclear for RAS MT patients.

Conclusion: These retrospective analyses have confirmed that RAS WT right-sided mCRC is associated with a poor prognosis, regardless of the treatment. RAS WT patients with left-sided tumors benefitted from the addition of panitumumab in second or later treatment lines. Further research is warranted to determine the optimum management of right-sided mCRC and RAS MT tumors.
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http://dx.doi.org/10.1016/j.clcc.2018.03.005DOI Listing
September 2018

RE: Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration.

J Natl Cancer Inst 2018 10;110(10):1142-1143

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1093/jnci/djy029DOI Listing
October 2018

Global cancer control: responding to the growing burden, rising costs and inequalities in access.

ESMO Open 2018 2;3(2):e000285. Epub 2018 Feb 2.

Cancer Control, Management of Noncommunicable Diseases Unit Department for Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention (NVI), World Health Organization, Geneva, Switzerland.

The cancer burden is rising globally, exerting significant strain on populations and health systems at all income levels. In May 2017, world governments made a commitment to further invest in cancer control as a public health priority, passing the World Health Assembly Resolution 70.12 on cancer prevention and control within an integrated approach. In this manuscript, the 2016 European Society for Medical Oncology Leadership Generation Programme participants propose a strategic framework that is in line with the 2017 WHO Cancer Resolution and consistent with the principle of universal health coverage, which ensures access to optimal cancer care for all people because health is a basic human right. The time for action is now to reduce barriers and provide the highest possible quality cancer care to everyone regardless of circumstance, precondition or geographic location. The national actions and the policy recommendations in this paper set forth the vision of its authors for the future of global cancer control at the national level, where the WHO Cancer Resolution must be implemented if we are to reduce the cancer burden, avoid unnecessary suffering and save as many lives as possible.
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http://dx.doi.org/10.1136/esmoopen-2017-000285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812392PMC
February 2018

Personalizing Survival Predictions in Advanced Colorectal Cancer: The ARCAD Nomogram Project.

J Natl Cancer Inst 2018 06;110(6):638-648

Mayo Clinic, Rochester, MN.

Background: Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database.

Methods: Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257).

Results: In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted [>50% vs < 50% probability] and actual [yes/no] overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals.

Conclusions: The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient-physician communication and balance risk in colorectal cancer trials.
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http://dx.doi.org/10.1093/jnci/djx253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005015PMC
June 2018

Value of Contrast-Enhanced Ultrasound Quantification Criteria for Identifying Patients not Responding to Bevacizumab-Based Therapy for Colorectal Liver Metastases.

Ultraschall Med 2018 Oct 12;39(5):544-558. Epub 2017 Dec 12.

CNRS GICC UMR 9272, Universite Francois-Rabelais de Tours, France.

Purpose:  To evaluate changes in tumor vascularization parameters based on contrast-enhanced ultrasound (CEUS) quantification criteria of at least one visible liver metastasis as an early predictor of non-response to chemotherapy, including bevacizumab for colorectal cancer (CRC) liver metastases.

Materials And Methods:  This multicenter prospective study included patients who received first-line bevacizumab-based chemotherapy. Tumor enhancement measured using CEUS within one liver metastasis and in relation to the surrounding healthy liver was quantified within 8 days before the first infusion of bevacizumab (E0), 24 hours after the end of the first infusion of bevacizumab (E1), in the 24 hours before the 2nd and 3 rd infusion of bevacizumab on day 15 (E2) and day 30 (E3), respectively, and after 2 months of treatment (E4). Endpoints were tumor response using RECIST criteria at 2 months, progression-free survival (PFS) and overall survival (OS).

Results:  Among the 137 patients included in this study, 109 were analyzed. Only CEUS parameters calculated in relation to healthy liver were significant. High wash-in and wash-out rates at baseline were significantly associated with a better tumor response. Increases over time E2-E0 and E3-E0 for peak enhancement were significantly associated with shorter progression-free survival. Increases over time E2-E0 and E3-E0 for peak enhancement and wash-in area under the curve were significantly associated with a shorter overall survival.

Conclusion:  This large study demonstrated that early dynamic changes in the vascularity of liver metastases evaluated by quantified CEUS are associated with outcome in patients receiving first-line bevacizumab-based treatment for metastatic CRC.
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http://dx.doi.org/10.1055/s-0043-122497DOI Listing
October 2018

Patterns of locoregional failure in locally advanced non-small cell lung cancer treated with definitive conformal radiotherapy: Results from the Gating 2006 trial.

Radiother Oncol 2018 02 1;126(2):291-299. Epub 2017 Dec 1.

Department of Radiation Oncology, Centre Léon Bérard, Lyon, France.

Purpose: To determine the patterns of locoregional failure (LRF) in patients with locally advanced non-small cell lung cancer treated with definitive radiotherapy (RT).

Patients And Methods: One hundred and fifty-four patients from the Gating 2006 prospective randomized trial were treated with conformal RT with or without respiratory motion management. For patients with a LRF as first event, treatment planning with simulation CT, pre-treatment FDG PET-CT and post-treatment images demonstrating recurrence were registered and analyzed. Measurable LRF was contoured (rGTV) and classified as in-field, marginal, or out-of-field.

Results: Median follow-up was 27.8 months. Forty-eight patients presented with LRF. One-year and 2-year locoregional disease-free survival rates were 77% (95% CI 70-83) and 72% (95% CI 64-79) respectively. 79% of the patients with LRF as first event relapsed within the RT field (55% isolated), 30% had marginal LRF component. Isolated out-of-field failure occurred in only 3% of all patients. The regions of highest FDG-uptake on pre-treatment PET-CT were located within the recurrence in 91% of patients with in-field LRF.

Conclusion: In-field failure was the most common pattern of failure. Escalated dose RT with high-dose fractions guided by PET parameters warrants further investigation.
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http://dx.doi.org/10.1016/j.radonc.2017.11.002DOI Listing
February 2018

Detailed statistical assessment of the characteristics of the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) threshold rules.

ESMO Open 2017 9;2(4):e000216. Epub 2017 Oct 9.

Department of Medical Oncology, Cancer Pain and Palliative Medicine Service, Shaare Zedek Medical Center, Jerusalem, Israel.

Background: The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), a tool to assess the magnitude of clinical benefit from new cancer therapies. Grading is guided by a dual rule comparing the relative benefit (RB) and the absolute benefit (AB) achieved by the therapy to prespecified threshold values. The ESMO-MCBS v1.0 dual rule evaluates the RB of an experimental treatment based on the lower limit of the 95%CI (LL95%CI) for the hazard ratio (HR) along with an AB threshold. This dual rule addresses two goals: inclusiveness: not unfairly penalising experimental treatments from trials designed with adequate power targeting clinically meaningful relative benefit; and discernment: penalising trials designed to detect a small inconsequential benefit.

Methods: Based on 50 000 simulations of plausible trial scenarios, the sensitivity and specificity of the LL95%CI rule and the ESMO-MCBS dual rule, the robustness of their characteristics for reasonable power and range of targeted and true HRs, are examined. The per cent acceptance of maximal preliminary grade is compared with other dual rules based on point estimate (PE) thresholds for RB.

Results: For particularly small or particularly large studies, the observed benefit needs to be relatively big for the ESMO-MCBS dual rule to be satisfied and the maximal grade awarded. Compared with approaches that evaluate RB using the PE thresholds, simulations demonstrate that the MCBS approach better exhibits the desired behaviour achieving the goals of both inclusiveness and discernment.

Conclusions: RB assessment using the LL95%CI for HR rather than a PE threshold has two advantages: it diminishes the probability of excluding big benefit positive studies from achieving due credit and, when combined with the AB assessment, it increases the probability of downgrading a trial with a statistically significant but clinically insignificant observed benefit.
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http://dx.doi.org/10.1136/esmoopen-2017-000216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640101PMC
October 2017

The care of adolescents and young adults with cancer: results of the ESMO/SIOPE survey.

ESMO Open 2017 8;2(4):e000252. Epub 2017 Sep 8.

Klinikum Stuttgart - Olgahospital, Stuttgart, Germany.

Introduction: Adolescents and young adults (AYA) with cancer require dedicated clinical management and care. Little is known about the training and practice of European healthcare providers in regard to AYA and the availability of specialised services.

Methods: A link to an online survey was sent to members of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE). The link was also sent to ESMO National Representatives and circulated to other European oncology groups. Questions covered the demographics and clinical training of respondents, their definition of AYA, education about AYA cancer, access to specialised clinical and supportive care, research and further education. Data from Europe were analysed by region.

Results: Three hundred tweenty two questionnaires were submitted and we focused on data from the 266 European healthcare professionals. Responses revealed considerable variation both within and between countries in the definition of AYA. Over two-thirds of respondents did not have access to specialised centres for AYA (67%), were not aware of research initiatives focusing on AYA with cancer (69%) and had no access to specialist services for managing the late effects of treatment (67%). The majority of the respondents were able to refer AYA patients to professional psychological support and specialised social workers. However, more than half had no access to an age-specialised nurse or specialised AYA education. Overall, 38% of respondents reported that their AYA patients did not have access to fertility specialists. This figure was 76% in Eastern Europe. Lack of specialised AYA care was particularly evident in Eastern and South-Eastern Europe.

Conclusion: There is important underprovision and inequity of AYA cancer care across Europe. Improving education and research focused on AYA cancer care should be a priority.
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http://dx.doi.org/10.1136/esmoopen-2017-000252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604713PMC
September 2017