Publications by authors named "Jan Bogaerts"

57 Publications

Controlling technical variation amongst 6693 patient microarrays of the randomized MINDACT trial.

Commun Biol 2020 Jul 27;3(1):397. Epub 2020 Jul 27.

Agendia NV/Agendia Inc, Amsterdam, The Netherlands.

Gene expression data obtained in large studies hold great promises for discovering disease signatures or subtypes through data analysis. It is also prone to technical variation, whose removal is essential to avoid spurious discoveries. Because this variation is not always known and can be confounded with biological signals, its removal is a challenging task. Here we provide a step-wise procedure and comprehensive analysis of the MINDACT microarray dataset. The MINDACT trial enrolled 6693 breast cancer patients and prospectively validated the gene expression signature MammaPrint for outcome prediction. The study also yielded a full-transcriptome microarray for each tumor. We show for the first time in such a large dataset how technical variation can be removed while retaining expected biological signals. Because of its unprecedented size, we hope the resulting adjusted dataset will be an invaluable tool to discover or test gene expression signatures and to advance our understanding of breast cancer.
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http://dx.doi.org/10.1038/s42003-020-1111-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385160PMC
July 2020

Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial.

J Clin Oncol 2020 04 21;38(11):1186-1197. Epub 2020 Feb 21.

Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal.

Purpose: MINDACT demonstrated that 46% of patients with early breast cancer at high clinical but low genomic risk on the basis of MammaPrint may safely avoid adjuvant chemotherapy. A second random assignment (R-C) compared docetaxel-capecitabine with an anthracycline-based regimen.

Patients And Methods: R-C randomly assigned patients 1:1 between standard anthracycline-based regimens, with or without taxanes (control) and experimental docetaxel 75 mg/m intravenously plus oral capecitabine 825 mg/m two times per day for 14 days (DC) every 3 weeks for 6 cycles. The primary end point was disease-free survival (DFS). Secondary end points included overall survival and safety.

Results: Of 2,832 patients, 1,301 (45%) were randomly assigned, and 97% complied with R-C assignment. In the control arm, 29.6% only received taxanes (0.5% of N0 patients). DFS events (n = 148) were much less than required (n = 422) as a result of a lower-than-expected accrual and event rate. At 5 years of median follow-up, DFS was not different between DC (n = 652) and control (n = 649; 90.7% [95% CI, 88% to 92.8%] 88.8% [95% CI, 85.9% to 91.1%]; hazard ratio [HR], 0.83 [95% CI, 0.60 to 1.15]; = .26). Overall survival (HR, 0.91 [95% CI, 0.54 to 1.53]) and DFS in the clinical high and genomic high-risk subgroup (86.1% 88.1%; HR, 0.83 [95% CI, 0.58 to 1.21]) were similar in both arms. DC led to more grade 1 neuropathy (27.1% 11.2%) and more grade 2 hand/foot syndrome (28.5% 3.3%) and diarrhea (13.7% 5.8%). Serious cardiac events occurred in 9 patients (control, n = 4; DC, n = 5). Fifty-three patients developed second cancers (control, n = 32; DC, n = 21; leukemia: 2 1). Five treatment-related deaths occurred (control, 2 [0.3%]; DC, 3 [0.5%]).

Conclusion: Although underpowered, this second randomization in MINDACT did not show any improvement in outcome or safety with the use of DC compared with anthracycline-based chemotherapy.
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http://dx.doi.org/10.1200/JCO.19.01371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840116PMC
April 2020

Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology.

Eur J Cancer 2019 06 3;114:128-136. Epub 2019 May 3.

Institut Gustave Roussy, Paris, France.

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit.
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http://dx.doi.org/10.1016/j.ejca.2019.03.025DOI Listing
June 2019

RECIST 1.1 for Response Evaluation Apply Not Only to Chemotherapy-Treated Patients But Also to Targeted Cancer Agents: A Pooled Database Analysis.

J Clin Oncol 2019 05 12;37(13):1102-1110. Epub 2019 Mar 12.

4 Queen's University, Kingston, Ontario, Canada.

Purpose: The mode of action of targeted cancer agents (TCAs) differs from classic chemotherapy, which leads to concerns about the role of RECIST in evaluating tumor response in trials with TCAs. We investigated the performance of RECIST using a pooled database from 50 clinical trials with at least one TCA.

Methods: We examined the impact of the number of target lesions (TLs) on within-patient variability of tumor response. The prognostic effect of TL response (at 12 weeks or on study on the basis of a maximum five TLs) on survival was studied through landmark and time-dependent Cox models adjusted for baseline tumor load, occurrence of new lesions, or unequivocal progression of nontarget disease.

Results: Data were obtained from 23,259 patients with cancer (36% lung, 28% colorectal, 11% breast, and 25% other); 15,620 received TCAs, predominantly transduction or angiogenesis inhibitors, as a single agent (37%), combined with other TCAs (7%), or as chemotherapy (56%); 28% received chemotherapy only; and 5% received best supportive care or placebo. A total of 17,222 patients contributed to the analyses. Within-patient variability decreased with increasing number of TLs, similarly for TCAs (with/without chemotherapy) and chemotherapy only. Mixed responses occurred proportionally in all treatment classes. Landmark analyses showed an ordinal relationship between percentage change from baseline to 12 weeks and overall survival, and demonstrated a clear distinction between tumor shrinkage and progressive disease according to RECIST. Time-dependent analysis showed no marked improvement in the ability to predict survival on the basis of TL tumor growth compared with nontarget progression or new lesion occurrence, regardless of treatment. Similar results were seen for major tumor types and different classes of TCAs.

Conclusion: This work reinforces that RECIST version 1.1 perform well for response assessment of TCAs.
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http://dx.doi.org/10.1200/JCO.18.01100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494357PMC
May 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

Late translational research: putting forward a new model for developing new anti-cancer treatments that addresses the needs of patients and society.

Mol Oncol 2019 03 19;13(3):558-566. Epub 2019 Jan 19.

EORTC Headquarters, Brussels, Belgium.

Bringing therapeutic innovation and the latest science to routine patient care, while safeguarding principles of affordability and equality, is a challenging mission in the current complex multi-stakeholder environment. Precision oncology and new approaches to clinical trials (methods and clinical setting) have dramatically changed clinical research and the clinical development of new treatments. Improved understanding of molecular biology and immunology paves the way for innovative pharmacological approaches. However, we argue that the evidence generated during the clinical development of these new products for the purpose of obtaining marketing authorisations often does not address fundamental questions concerning the impact of these new interventions on the most relevant clinical outcomes: namely, quality of life and patient survival. Similarly, patient populations (for example defined by biomarkers), treatment duration, and sequence and combination of treatments within current treatment pathways are often poorly defined by clinical developments for regulatory purposes. Finally, the lack of integrated translational research within the pathway of development is a major limiting factor to delivering cost-effective and affordable, evidence-based care to clinical practice. This leaves many gaps in the knowledge on the efficacy and therapeutic use of medicines, which can impose a significant financial burden on healthcare systems, possibly to the detriment of more cost-effective interventions. We argue that policy changes are required to integrate clinical research and healthcare to inform clinical practice. New routes toward optimising the integration of drug development and care are being proposed to achieve this ultimate goal.
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http://dx.doi.org/10.1002/1878-0261.12431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396352PMC
March 2019

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

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

'Mind the gap' between the development of therapeutic innovations and the clinical practice in oncology: A proposal of the European Organisation for Research and Treatment of Cancer (EORTC) to optimise cancer clinical research.

Eur J Cancer 2017 11 4;86:143-149. Epub 2017 Oct 4.

The European Organisation for Research and Treatment of Cancer (EORTC), Avenue E. Mounier 83, 1200 Brussels, Belgium. Electronic address:

In Europe, most of the cancer clinical research dedicated to therapeutic innovations aims primarily at regulatory approval. Once an anticancer drug enters the common market, each member state determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an innovation-centred clinical research landscape might neglect patient-relevant issues in real-world setting, such as comparative effectiveness of distinct treatment options or long-term safety monitoring. The European Organisation for Research and Treatment of Cancer (EORTC) advocates reforming the current 'innovation-centred' system to a truly 'patient-centred' paradigm with systematically coordinated applied clinical research in conjunction with drug development, featuring the following strategy.
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http://dx.doi.org/10.1016/j.ejca.2017.08.028DOI Listing
November 2017

A population-based approach to compare patient-reported outcomes of long-term Hodgkin's lymphoma survivors according to trial participation: a joint study from the Patient-Reported Outcomes Following Initial Treatment and Long-term Evaluation of Survivorship registry and European Organisation for Research and Treatment of Cancer.

Eur J Cancer Prev 2017 09;26 Joining forces for better cancer registration in Europe:S223-S228

aDepartment of Medical Psychology, Academic Medical Hospital, Amsterdam Public Health Research Institute, University of Amsterdam bDivision of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam cNetherlands Comprehensive Cancer Organisation (IKNL), Utrecht dDivision of Medical and Clinical Psychology, Tilburg University, Tilburg, The Netherlands eDepartment of Statistics fDepartment of Quality of Life, European Organisation for the Research and Treatment of Cancer (EORTC), Brussels, Belgium gEU Commission Joint Research Center, Ispra, Italy.

Survival discrepancy between patients treated in a clinical trial and routine practice is well recognized. No study has assessed the health-related quality of life (HRQL) of long-term Hodgkin's lymphoma survivors (HLS) according to trial participation. We applied a population-based approach to examine the differences in HRQL, healthcare utilization, and satisfaction with healthcare among long-term HLS who had participated in a trial (tHLS) and those treated in routine care (rHLS). All HLS diagnosed during the period 1989-1998 and living in southern Netherlands were selected from the Netherlands Cancer Registry in 2004 to participate in the Patient Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship registry study. Data linkage with the European Organisation for Research and Treatment of Cancer was performed in 2015 to identify trial participation. The 65 tHLS and 67 rHLS had comparable demographic and clinical characteristics. Unadjusted and adjusted models indicated no association between trial participation and HRQL. There was no evidence of differences in healthcare satisfaction. Trial participation was associated with 48% more visits to specialists in the past year (adjusted 95% confidence interval: 10-99). No association of trial participation with cancer-related contacts was observed. tHLS and rHLS had comparable long-term HRQL. Although trial participation was associated with more specialist visits, there was no evidence of an association with healthcare satisfaction and the number of cancer-related visits. Identification of trial participation in population-based cancer registry through data linkage with clinical trials enables a population-based approach to examine patient-reported outcomes differences between tHLS and rHLS.
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http://dx.doi.org/10.1097/CEJ.0000000000000381DOI Listing
September 2017

Surrogate marker analysis in cancer clinical trials through time-to-event mediation techniques.

Stat Methods Med Res 2018 11 20;27(11):3367-3385. Epub 2017 Apr 20.

1 Department of Applied Mathematics, Computer Sciences and Statistics, Ghent University, Belgium.

The meta-analytic approach is the gold standard for validation of surrogate markers, but has the drawback of requiring data from several trials. We refine modern mediation analysis techniques for time-to-event endpoints and apply them to investigate whether pathological complete response can be used as a surrogate marker for disease-free survival in the EORTC 10994/BIG 1-00 randomised phase 3 trial in which locally advanced breast cancer patients were randomised to either taxane or anthracycline based neoadjuvant chemotherapy. In the mediation analysis, the treatment effect is decomposed into an indirect effect via pathological complete response and the remaining direct effect. It shows that only 4.2% of the treatment effect on disease-free survival after five years is mediated by the treatment effect on pathological complete response. There is thus no evidence from our analysis that pathological complete response is a valuable surrogate marker to evaluate the effect of taxane versus anthracycline based chemotherapies on progression free survival of locally advanced breast cancer patients. The proposed analysis strategy is broadly applicable to mediation analyses of time-to-event endpoints, is easy to apply and outperforms existing strategies in terms of precision as well as robustness against model misspecification.
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http://dx.doi.org/10.1177/0962280217702179DOI Listing
November 2018

iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.

Lancet Oncol 2017 03 2;18(3):e143-e152. Epub 2017 Mar 2.

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

Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies.
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http://dx.doi.org/10.1016/S1470-2045(17)30074-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648544PMC
March 2017

RECIST - learning from the past to build the future.

Nat Rev Clin Oncol 2017 03 20;14(3):187-192. Epub 2016 Dec 20.

EORTC Headquarters, Avenue E Mounier 83/11, 1200 Brussels, Belgium.

Response Evaluation Criteria In Solid Tumours (RECIST) remain an integral part of the assessment of tumour burden in many clinical trials in oncology; these criteria are used to evaluate the activity and efficacy of new cancer therapeutics in solid tumours. We aim to define the purpose of RECIST, and reflect on the level of documentation needed to enable changes for these criteria to develop a new RECIST. Maintaining the applicability of RECIST as a standard evaluation approach is associated with many challenges, in particular with maintaining a balance between the specificity and generalizability, continued validation and innovation, and use of RECIST in early phase versus late-phase drug development, as well as its relevance in clinical trials versus clinical practice. Key questions relate to different modes of actions of new classes of treatments and new imaging modalities; thus, the RECIST Working Group remains committed to maintain RECIST as a standard for the oncology community.
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http://dx.doi.org/10.1038/nrclinonc.2016.195DOI Listing
March 2017

ESMO / ASCO Recommendations for a Global Curriculum in Medical Oncology Edition 2016.

Authors:
Christian Dittrich Michael Kosty Svetlana Jezdic Doug Pyle Rossana Berardi Jonas Bergh Nagi El-Saghir Jean-Pierre Lotz Pia Österlund Nicholas Pavlidis Gunta Purkalne Ahmad Awada Susana Banerjee Smita Bhatia Jan Bogaerts Jan Buckner Fatima Cardoso Paolo Casali Edward Chu Julia Lee Close Bertrand Coiffier Roisin Connolly Sarah Coupland Luigi De Petris Maria De Santis Elisabeth G E de Vries Don S Dizon Jennifer Duff Linda R Duska Alexandru Eniu Marc Ernstoff Enriqueta Felip Martin F Fey Jill Gilbert Nicolas Girard Andor W J M Glaudemans Priya K Gopalan Axel Grothey Stephen M Hahn Diana Hanna Christian Herold Jørn Herrstedt Krisztian Homicsko Dennie V Jones Lorenz Jost Ulrich Keilholz Saad Khan Alexander Kiss Claus-Henning Köhne Rainer Kunstfeld Heinz-Josef Lenz Stuart Lichtman Lisa Licitra Thomas Lion Saskia Litière Lifang Liu Patrick J Loehrer Merry Jennifer Markham Ben Markman Marius Mayerhoefer Johannes G Meran Olivier Michielin Elizabeth Charlotte Moser Giannis Mountzios Timothy Moynihan Torsten Nielsen Yuichiro Ohe Kjell Öberg Antonio Palumbo Fedro Alessandro Peccatori Michael Pfeilstöcker Chandrajit Raut Scot C Remick Mark Robson Piotr Rutkowski Roberto Salgado Lidia Schapira Eva Schernhammer Martin Schlumberger Hans-Joachim Schmoll Lowell Schnipper Cristiana Sessa Charles L Shapiro Julie Steele Cora N Sternberg Friedrich Stiefel Florian Strasser Roger Stupp Richard Sullivan Josep Tabernero Luzia Travado Marcel Verheij Emile Voest Everett Vokes Jamie Von Roenn Jeffrey S Weber Hans Wildiers Yosef Yarden

ESMO Open 2016 29;1(5):e000097. Epub 2016 Sep 29.

Department of General Medical Oncology , University Hospitals Leuven , Leuven , Belgium.

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.
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http://dx.doi.org/10.1136/esmoopen-2016-000097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070299PMC
September 2016

Survival differences between patients with Hodgkin lymphoma treated inside and outside clinical trials. A study based on the EORTC-Netherlands Cancer Registry linked data with 20 years of follow-up.

Br J Haematol 2017 Jan 21;176(1):65-75. Epub 2016 Oct 21.

Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands.

The survival of patients diagnosed with Hodgkin lymphoma (HL) has improved from 70% to 90% in clinical trials. However, population-based data has shown lower survival. In this study, clinical trial data were linked with cancer registry to identify trial and non-trial participants and differences in overall survival and associated factors were assessed. In 1986-2004, 27% of HL patients aged 15-70 years participated in clinical trials. Compared to non-trial participants, trial participants were younger (median age, 31 vs. 34 years), had staging registered more accurately and had an 8% higher 20-year survival rate (73% vs. 65%). After adjusting for baseline differences, no differences in survival (hazard ratio = 0·96, 95% confidence interval 0·82-1·12), or in subgroup analysis according to stage, remained. Over time, increased administration of chemotherapy in combination with radiotherapy, together with the decreased use of radiotherapy alone was observed among the trial population. This trend was later followed in non-trial participants, coinciding with a similar 'take-up' in survival. The observed superior survival among patients with HL treated in clinical trials can be largely explained by the differences in baseline characteristics, particularly younger age. High trial participation rate and centralized expertise facilitates the implementation of trial findings to real-world practice.
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http://dx.doi.org/10.1111/bjh.14379DOI Listing
January 2017

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.

N Engl J Med 2016 Aug;375(8):717-29

From Champalimaud Clinical Center-Champalimaud Foundation, Lisbon, Portugal (F.C.); Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (L.J.V.); European Organization for Research and Treatment of Cancer Headquarters (J.B., L. Slaets, V.G., B.M., K.T.), Breast International Group Headquarters (T.G., C. Straehle), and Institut Jules Bordet, Université Libre de Bruxelles (C. Sotiriou, M.P.), Brussels, and Centre Hospitalier Universitaire Université Catholique de Louvain, Namur (P.V.) - both in Belgium; University of Milan and Istituto Europeo di Oncologia (G.V.) and Europa Donna-European Breast Cancer Coalition (S.K.), Milan, and Azienda Istituti Ospitalieri di Cremona, Cremona (R.P.) - both in Italy; Gustave Roussy, Villejuif (S.D., M.S.), Institut Curie Paris Sciences et Lettres, Université Paris Descartes, Sorbonne Paris Cité, Paris (J.-Y.P.). Institut Curie-Hôpital Rene Huguenin, Saint-Cloud (E.B.), and Centre Georges-Francois-Leclerc, Dijon (S.C.) - all in France; Swiss Institute of Bioinformatics and University of Lausanne, Lausanne, Switzerland (M.D.); Agendia (A.M.G., L. Stork) and the Netherlands Cancer Institute (R.B., E.R.), Amsterdam, Alrijne Ziekenhuis, Rijnland Leiderdorp (P.A.N.), Jeroen Bosch Hospital, 's-Hertogenbosch (T.J.S.), and Medisch Centrum Alkmaar, Alkmaar (J.M.H.) - all in the Netherlands; Institute of Oncology, Ljubljana, Slovenia (E.M.); Evangelisches Krankenhaus Bethesda, Duisburg, Germany (U.N.); University of Texas Health Sciences Center, San Antonio (P.R.); Hospital Universitario Vall d'Hebron, Barcelona (I.T.R.); Imperial College London, London (G.T.); and University of Texas M.D. Anderson Cancer Center, Houston (A.M.T.).

Background: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy.

Methods: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher.

Results: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease.

Conclusions: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).
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http://dx.doi.org/10.1056/NEJMoa1602253DOI Listing
August 2016

RECIST 1.1 - Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group.

Eur J Cancer 2016 07 26;62:138-45. Epub 2016 May 26.

Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.

Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta-analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation.
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http://dx.doi.org/10.1016/j.ejca.2016.03.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737786PMC
July 2016

RECIST 1.1-Update and clarification: From the RECIST committee.

Eur J Cancer 2016 07 14;62:132-7. Epub 2016 May 14.

Canadian Cancer Trials Group, Queen's University, Kingston, Canada.

The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication.
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http://dx.doi.org/10.1016/j.ejca.2016.03.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737828PMC
July 2016

Discordant assessment of tumor biomarkers by histopathological and molecular assays in the EORTC randomized controlled 10041/BIG 03-04 MINDACT trial breast cancer : Intratumoral heterogeneity and DCIS or normal tissue components are unlikely to be the cause of discordance.

Breast Cancer Res Treat 2016 Feb 28;155(3):463-9. Epub 2016 Jan 28.

Breast Unit, Champalimaud Cancer Center, Lisbon, Portugal.

Accurate identification of breast cancer patients most likely to benefit from adjuvant systemic therapies is crucial. Better understanding of differences between methods can lead to an improved ER, PgR, and HER-2 assessment. The purpose of this preplanned translational research is to investigate the correlation of central IHC/FISH assessments with microarray mRNA readouts of ER, PgR, and HER-2 status in the MINDACT trial and to determine if any discordance could be attributed to intratumoral heterogeneity or the DCIS and normal tissue components in the specimens. MINDACT is an international, prospective, randomized, phase III trial investigating the clinical utility of MammaPrint in selecting patients with early breast cancer for adjuvant chemotherapy (n = 6694 patients). Gene-expression data were obtained by TargetPrint; IHC and/or FISH were assessed centrally (n = 5788; 86 %). Macroscopic and microscopic evaluation of centrally submitted FFPE blocks identified 1427 cases for which the very same sample was submitted for gene-expression analysis. TargetPrint ER had a positive agreement of 98 %, and a negative agreement of 95 % with central pathology. Corresponding figures for PgR were 85 and 94 % and for HER-2 72 and 99 %. Agreement of mRNA versus central protein was not different when the same or a different portion of the tumor tissue was analyzed or when DCIS and/or normal tissue was included in the sample subjected to mRNA assays. This is the first large analysis to assess the discordance rate between protein and mRNA analysis of breast cancer markers, and to look into intratumoral heterogeneity, DCIS, or normal tissue components as a potential cause of discordance. The observed difference between mRNA and protein assessment for PgR and HER-2 needs further research; the present analysis does not support intratumoral heterogeneity or the DCIS and normal tissue components being likely causes of the discordance.
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http://dx.doi.org/10.1007/s10549-016-3690-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764628PMC
February 2016

A European Organisation for Research and Treatment of Cancer randomized, double-blind, placebo-controlled, multicentre phase II trial of anastrozole in combination with gefitinib or placebo in hormone receptor-positive advanced breast cancer (NCT00066378).

Eur J Cancer 2016 Jan 24;53:144-54. Epub 2015 Dec 24.

NHS-Lothian, University of Edinburgh, Edinburgh, United Kingdom. Electronic address:

Background: Preclinical data suggest that epidermal growth factor receptor (EGFR) inhibitors (e.g. gefitinib) can delay endocrine resistance in breast cancer. A double-blind, placebo-controlled, phase II trial investigated whether adding gefitinib (G) to anastrozole (A) would improve outcome in advanced breast cancer (ABC).

Methods: Postmenopausal pre-treated hormone receptor-positive ABC patients (locally recurrent or metastatic) were 1:1 randomized to A (1 mg/d) plus G 250 mg/d or plus placebo (P). Patients who had prior treatment with an aromatase inhibitor in metastatic setting or with trastuzumab, anti-EGFR or anti-VEGF agents were excluded. Treatment was given until disease progression, unacceptable toxicity or patient withdrawal. Progression-free survival (PFS) rate at 1 year was assessed according to Response Evaluation Criteria in Solid Tumours, version 1.0.

Results: Of 108 planned patients, 71 were recruited (36 in A/G and 35 in A/P). The trial closed prematurely due to slow recruitment; 31 patients had prior chemotherapy and 53 prior endocrine therapy (all except one received tamoxifen); 60% in adjuvant and 16% in metastatic setting received tamoxifen; 59 patients had visceral disease. Median follow-up was 18 months. PFS rate at 1 year was 35% for A/G and 32% for A/P arm. Objective responses were six (22%) in the A/G and nine (28%) in the A/P arm. Median duration of response was 13.8 and 18.6 months in the A/G and A/P arms, respectively. Fatigue (35%), diarrhoea (31%), rash (32%), dry skin (27%), and arthralgia/myalgia (27%) were the commonest adverse events in the A/G arm.

Conclusions: This phase II study, although prematurely closed, did not show a signal that adding G to A improves PFS at 1 year and its use is not supported. Gastrointestinal and skin toxicities were more pronounced with G resulting in premature therapy interruption in almost 1 in 3 patients (ClinicalTrials.gov number, NCT00066378).
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http://dx.doi.org/10.1016/j.ejca.2015.10.012DOI Listing
January 2016

Clinical Utility of Metrics Based on Tumor Measurements in Phase II Trials to Predict Overall Survival Outcomes in Phase III Trials by Using Resampling Methods.

J Clin Oncol 2015 Dec 26;33(34):4048-57. Epub 2015 Oct 26.

Ming-Wen An, Vassar College, Poughkeepsie, NY; Yu Han, Novartis Pharmaceuticals, East Hanover NJ; Jeffrey Meyers, Daniel J. Sargent, and Sumithra J. Mandrekar, Mayo Clinic, Rochester, MN; and Jan Bogaerts, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.

Purpose: Phase II clinical trials inform go/no-go decisions for proceeding to phase III trials, and appropriate end points in phase II trials are critical for facilitating this decision. Phase II solid tumor trials have traditionally used end points such as tumor response defined by Response Evaluation Criteria for Solid Tumors (RECIST). We previously reported that absolute and relative changes in tumor measurements demonstrated potential, but not convincing, improvement over RECIST to predict overall survival (OS). We have evaluated the metrics by using additional measures of clinical utility and data from phase III trials.

Methods: Resampling methods were used to assess the clinical utility of metrics to predict phase III outcomes from simulated phase II trials. In all, 2,000 phase II trials were simulated from four actual phase III trials (two positive for OS and two negative for OS). Cox models for three metrics landmarked at 12 weeks and adjusted for baseline tumor burden were fit for each phase II trial: absolute changes, relative changes, and RECIST. Clinical utility was assessed by positive predictive value and negative predictive value, that is, the probability of a positive or negative phase II trial predicting an effective or ineffective phase III conclusion, by prediction error, and by concordance index (c-index).

Results: Absolute and relative change metrics had higher positive predictive value and negative predictive value than RECIST in five of six treatment comparisons and lower prediction error curves in all six. However, differences were negligible. No statistically significant difference in c-index across metrics was found.

Conclusion: The absolute and relative change metrics are not meaningfully better than RECIST in predicting OS.
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http://dx.doi.org/10.1200/JCO.2015.60.8778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669590PMC
December 2015

Evaluating Continuous Tumor Measurement-Based Metrics as Phase II Endpoints for Predicting Overall Survival.

J Natl Cancer Inst 2015 Nov 21;107(11). Epub 2015 Aug 21.

Department of Mathematics, Vassar College, Poughkeepsie, NY (MWA); Department of Biostatistics, Analytical Science, Takeda Pharmaceuticals, Deerfield, IL (XD); Department of Health Sciences Research, Mayo Clinic, Rochester, MN (JM, DJS, SJM); Biometrics and Data Management Department, Novartis Pharmaceuticals Corporation, East Hanover, NJ (YH); Department of Oncology, Mayo Clinic, Rochester, MN (AG); European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium (JB).

Background: We sought to develop and validate clinically relevant, early assessment continuous tumor measurement-based metrics for predicting overall survival (OS) using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 data warehouse.

Methods: Data from 13 trials representing 2096 patients with breast cancer, non-small cell lung cancer (NSCLC), or colorectal cancer were used in a complete case analysis. Tumor measurements from weeks 0-6-12 assessments were used to evaluate the ability of slope (absolute change in tumor size from 0-6 and 6-12 weeks) and percent change (relative change in tumor size from 0-6 and 6-12 weeks) metrics to predict OS using Cox models, adjusted for average baseline tumor size. Metrics were evaluated by discrimination (via concordance or c-index), calibration (goodness-of-fit type statistics), association (hazard ratios), and likelihood (Bayesian Information Criteria), with primary focus on the c-index. All statistical tests were two-sided.

Results: Comparison of c-indices suggests slight improvement in predictive ability for the continuous tumor measurement-based metrics vs categorical RECIST response metrics, with slope metrics performing better than percent change metrics for breast cancer and NSCLC. However, these differences were not statistically significant. The goodness-of-fit statistics for the RECIST metrics were as good as or better than those for the continuous metrics. In general, all the metrics performed poorly in breast cancer, compared with NSCLC and colorectal cancer.

Conclusion: Absolute and relative change in tumor measurements do not demonstrate convincingly improved overall survival predictive ability over the RECIST model. Continued work is necessary to address issues of missing tumor measurements and model selection in identifying improved tumor measurement-based metrics.
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http://dx.doi.org/10.1093/jnci/djv239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643633PMC
November 2015

Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative.

Eur J Cancer 2015 Feb 24;51(3):271-81. Epub 2014 Dec 24.

National Institute for Health Research Clinical Research Network/Cancer, United Kingdom.

Background: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.

Settings: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.

Results: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.

Interpretation: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.
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http://dx.doi.org/10.1016/j.ejca.2014.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639696PMC
February 2015

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.

Lancet Oncol 2014 Nov 15;15(12):1303-10. Epub 2014 Oct 15.

Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands. Electronic address:

Background: If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects.

Methods: Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612.

Findings: Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years.

Interpretation: Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity.

Funding: EORTC Charitable Trust.
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http://dx.doi.org/10.1016/S1470-2045(14)70460-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291166PMC
November 2014

The dream and reality of histology agnostic cancer clinical trials.

Mol Oncol 2014 Sep;8(6):1057-63

Emerging technologies and progress in data processing allowed for new insights on gene expression, genomics and epigenomics, and mechanisms of cancer genesis and progression. The development of new therapeutic strategies should therefore be triggered by the understanding of the underlying biology through sophisticated clinical trials. Therefore, the methodology and the design of cancer clinical trials as well as the methods of their implementation are under profound changes. Targeting specific pathways has open the hope of a more focused and personalized medicine which has the potential to bring more efficient and tailored treatments to patients. It has been questioned therefore whether clinical trials traditionally designed for specific tumor types could not re-visited towards trials gathering patients based on molecular features rather than pure pathology criteria. The complexity of the cancer biology being the result of so many different interactive mechanisms whether driving or not the process of cancer cells is an additional level of complexity to approach more inclusive clinical trial access. Nevertheless, a number of innovative solutions to address biological challenges across histologies have been initiated and the question of whether histology agnostic trials could be conceived is a logical next question. This paper questions the advantages and the limits of clinical trials performed across tumor types bearing similar selected molecular features and looks further into the feasibility of such histology agnostic trials.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528617PMC
http://dx.doi.org/10.1016/j.molonc.2014.06.002DOI Listing
September 2014

A phase I pharmacokinetics study of lapatinib and tamoxifen in metastatic breast cancer (EORTC 10053 Lapatam study).

Breast 2014 Oct 24;23(5):663-9. Epub 2014 Jul 24.

Institut Jules Bordet, Boulevard de Waterloo 121, 1000 Brussels, Belgium; Institut Jules Bordet (currently at Champalimaud Cancer Center), Av. de Brasília, s/n, 1400-038 Lisbon, Portugal. Electronic address:

Objective: This phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC).

Methods: Patients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug-drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day.

Results: Twenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3-4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months.

Conclusions: The combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index.
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http://dx.doi.org/10.1016/j.breast.2014.07.003DOI Listing
October 2014

Cavitation: a blessing in disguise? New method to establish vulnerability curves and assess hydraulic capacitance of woody tissues.

Tree Physiol 2015 Apr 15;35(4):400-9. Epub 2014 Jul 15.

Laboratory of Plant Ecology, Department of Applied Ecology and Environmental Biology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium.

The hydraulic performance of woody species during drought is currently of high interest in the context of climate change. It is known that woody species have the capacity to mitigate water shortage by using internally stored water. Elastic shrinkage of living cells and also water release during cavitation contribute to the so-called 'hydraulic capacitance' (C) of the plant, which adds water to the transpiration stream and buffers fluctuations in water potential. Although sap-conducting conduits may ultimately serve as a water pool, cavitation will hamper the conduction of sap. Both hydraulic conductivity and C are thus inextricably linked and the interaction between both should be studied to better understand hydraulic functioning of woody species during drought. However, measurements of C are scarce and no distinction is usually made between C from elastic storage and C supplied by cavitation. In this paper, we propose a new method to assess both the decrease in hydraulic conductivity and the change in C during bench dehydration of a whole-branch segment using continuous measurements of acoustic emissions, radial diameter shrinkage and gravimetrical water loss. With this method we could establish proper vulnerability curves for grapevine (Vitis vinifera L. 'Johanniter') and quantify C during dehydration. Our results showed that loss in hydraulic conductivity during the cavitation phase was accompanied by 22-92% gain in hydraulic capacitance; therefore, a certain degree of cavitation may be tolerated in grapevine during periods of drought stress.
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http://dx.doi.org/10.1093/treephys/tpu056DOI Listing
April 2015

The components of progression as explanatory variables for overall survival in the Response Evaluation Criteria in Solid Tumours 1.1 database.

Eur J Cancer 2014 Jul 10;50(10):1847-1853. Epub 2014 Apr 10.

European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.

Purpose: Progressive disease (PD) per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 is defined as growth of measurable target lesions, presence of new lesions or unequivocal progression of non-target disease. In this manuscript we explored whether a more refined categorisation of tumour response and/or these components of progression, varying over time, can improve prediction of overall survival (OS) in the RECIST database.

Methods: Data were randomly selected from 13 randomised clinical trials (3758 patients with breast, lung or colorectal cancer). A maximum of five target lesions contributed to the sum of longest diameters. At each measurement time we determined: best target response as best % improvement from baseline; tumour growth of target lesions as worst % change and worst rate of increase (mm/week) from nadir; presence of new lesions and occurrence of non-target PD. OS was analysed by tumour type using Cox regression, adjusting for baseline sum and including these parameters as time-dependent covariates.

Results: 36% of patients had new lesions, 28% non-target PD and 49% experienced target lesion growth (median strongest growth 1.5mm/week). Regardless of tumour type, presence of new lesions (hazard ratio (HR) ranging 1.5-2.3) and non-target PD (HR 1.5-2.0) were strongly associated with worse OS. The explanatory value of tumour growth for OS was low compared to the other components.

Conclusion: Modelling target lesion tumour growth did not show a marked improvement in OS prediction over and above the other components. These analyses enable a better understanding of the role of each component in PD evaluation. Work is ongoing to incorporate this information into an updated version of RECIST with enhanced prediction of subsequent survival.
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http://dx.doi.org/10.1016/j.ejca.2014.03.014DOI Listing
July 2014

Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.

Lancet 2014 Jul 14;384(9938):164-72. Epub 2014 Feb 14.

German Breast Group, Neu-Isenburg, Germany.

Background: Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS.

Methods: We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS.

Findings: We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70).

Interpretation: Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.

Funding: US Food and Drug Administration.
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http://dx.doi.org/10.1016/S0140-6736(13)62422-8DOI Listing
July 2014

Evaluation of alternate categorical tumor metrics and cut points for response categorization using the RECIST 1.1 data warehouse.

J Clin Oncol 2014 Mar 10;32(8):841-50. Epub 2014 Feb 10.

Sumithra J. Mandrekar, Jeffrey Meyers, Axel Grothey, and Daniel J. Sargent, Mayo Clinic, Rochester, MN; Ming-Wen An, Vassar College, Poughkeepsie, NY; and Jan Bogaerts, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.

Purpose: We sought to test and validate the predictive utility of trichotomous tumor response (TriTR; complete response [CR] or partial response [PR] v stable disease [SD] v progressive disease [PD]), disease control rate (DCR; CR/PR/SD v PD), and dichotomous tumor response (DiTR; CR/PR v others) metrics using alternate cut points for PR and PD. The data warehouse assembled to guide the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was used.

Methods: Data from 13 trials (5,480 patients with metastatic breast cancer, non-small-cell lung cancer, or colorectal cancer) were randomly split (60:40) into training and validation data sets. In all, 27 pairs of cut points for PR and PD were considered: PR (10% to 50% decrease by 5% increments) and PD (10% to 20% increase by 5% increments), for which 30% and 20% correspond to the RECIST categorization. Cox proportional hazards models with landmark analyses at 12 and 24 weeks stratified by study and number of lesions (fewer than three v three or more) and adjusted for average baseline tumor size were used to assess the impact of each metric on overall survival (OS). Model discrimination was assessed by using the concordance index (c-index).

Results: Standard RECIST cut points demonstrated predictive ability similar to the alternate PR and PD cut points. Regardless of tumor type, the TriTR, DiTR, and DCR metrics had similar predictive performance. The 24-week metrics (albeit with higher c-index point estimate) were not meaningfully better than the 12-week metrics. None of the metrics did particularly well for breast cancer.

Conclusion: Alternative cut points to RECIST standards provided no meaningful improvement in OS prediction. Metrics assessed at 12 weeks have good predictive performance.
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http://dx.doi.org/10.1200/JCO.2013.52.3019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940541PMC
March 2014