Methods and Biostatistics in Oncology Understanding Clinical Research as an Applied Tool Raphael L. C. Araújo Rachel P. Riechelmann Editors 123 Methods and Biostatistics in Oncology Raphael L. C. Araújo • Rachel P. Riechelmann Editors Methods and Biostatistics in Oncology Understanding Clinical Research as an Applied Tool Editors Raphael L. C. Araújo Rachel P. Riechelmann Hospital do Câncer de Barretos Department of Clinical Oncology Barretos, SP, Brazil AC Camargo Cancer Center São Paulo, SP, Brazil ISBN 978-3-319-71323-6 ISBN 978-3-319-71324-3 (eBook) https://doi.org/10.1007/978-3-319-71324-3 Library of Congress Control Number: 2018936135 © Springer International Publishing AG, part of Springer Nature 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recita- tion, broadcasting, reproduction on microfilms or in any other physical way, and transmission or infor- mation storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publica- tion does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Springer imprint is published by the registered company Springer International Publishing AG part of Springer Nature The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Foreword It is my pleasure to introduce this volume “Methods and Biostatistics in Oncology— Understanding Clinical Research as an Applied Tool.” It is a timely contribution to clinical research in oncology as we experience an unprecedented increase in the number of clinical scientists and clinical studies all around the world. Important advances in our understanding of several topics, such as genomics, immunology, targeted treatments, and biomarkers, capture headlines in the popular press. As translational efforts to use these advances in the clinic intensify, the need for appro- priate clinical research methodology has never been greater. It is for this reason that this volume will serve an important need. Dr. Araújo’s and Dr. Riechelmann’s editing skills are apparent in the team of authors they have recruited and the topics they have chosen. Each of the book’s 20 chapters has been written by one or more internationally recognized experts in the field. The chapters cover substantial ground, starting from a historical introduction and moving on to study design. Several important technical aspects, such as the interpretations of multivariate analysis and survival analysis, and descriptions of case-control and cohort studies, are aptly included. Clinical trial design receives the attention it deserves and emerging fields such as cost-effectiveness and patient- reported outcomes are also included. These chapters can be read sequentially like a textbook, which will be valuable for those who are in the early years of their clinical research training or careers. It would be a mistake, however, to think that seasoned investigators will not benefit from this volume. Since most clinical researchers lack comprehensive formal training in methodology, their knowledge of statistical meth- ods is limited. I would urge them to pick up this volume and read the chapters that interest them. They will find that the chapters are self-contained and not demanding. My primary advice to the reader is to come back to the chapters as they need to apply the material to their own work. This may, most commonly, be the research they are engaged in. If preclinical work has yielded a result ready for clinical test- ing, rereading the chapter “How to Design Phase I Trials in Oncology” will reveal the subtleties of the presentation and will, no doubt, increase retention of the knowl- edge. There are more opportunities to relate this material to work, however. If one is refereeing a paper and the survival analyses are puzzling, if one is mentoring a student who is struggling with a multivariate analysis, or if one is reading an article with a cost-effectiveness analysis there will be much to learn by visiting the relevant chapters. v vi Foreword This book also stands apart because it has a separate chapter for bias (my favorite topic). The word originates from Bias of Priene, one of the seven sages of ancient Greece who thought and wrote a great deal about justice and fairness. It is ironic that we use his name to refer to certain types of prejudice and, in the scientific con- text, a systematic dissonance between the findings and the truth. Bias is widely recognized as a threat to the validity of a study, to the point that several types of commonly encountered biases have earned their own names, such as selection bias, verification bias, recall bias, etc. Bias is possibly the single most important concept in research methods and yet it might be the most misunderstood one. Bias usually arises from systematic differences between the sample analyzed and the population for which conclusions are drawn. Bias can be due to deficiencies in design; inade- quacies in data collection; and legal, ethical, or other constraints. I am heartened to see bias receiving coverage in this volume, because it is even more important to consider bias in the age of big data, where automated data collection and the ability to merge disparate data sources leads to a huge amount of observational data and also makes it more difficult to understand what sorts of biases might have crept in. Some well-publicized failures such as Google Flu Trends and the Boston Pothole Experiment point to the importance and difficulty of detecting biases. Let me finally make the point that the understanding of research methodology and statistics remains challenging, requiring great intellect and creativity. There is a big gap between results obtained by pushing a button or executing a command in data analysis software, and gaining knowledge and insight from these results, and this gap can be closed only by having a good grasp of research methodology. That is why you should read this book and recommend it to others. New York, NY, USA Mithat Gönen Contents 1 Brief History of the Scientific Method and Its Application in Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Vinicius de Lima Vazquez and Raphael L. C. Araújo 2 Generating a Hypothesis for an Oncology Study . . . . . . . . . . . . . . . . . 9 Beatriz Teixeira Costa, Isadora Santos Ferreira, and Felipe Fregni 3 Types of Variables and Distributions . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Gregory R. Pond and Samantha-Jo Caetano 4 Testing Measures of Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Bruno S. Paolino, Raphael L. C. Araújo, and David Bristol 5 Sample Size Calculation in Oncology Studies . . . . . . . . . . . . . . . . . . . 51 Rachel P. Riechelmann, Raphael L. C. Araújo, and Benjamin Haaland 6 Interpretation of Results from Tables, Graphs, and Regressions in Cancer Research . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Raphael L. C. Araújo and Rachel P. Riechelmann 7 Survival Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Benjamin Haaland and Mina Georgieva 8 The Role of Cross-Sectional and Cohort Studies in Oncology . . . . . . 125 André Lopes Carvalho, Fabiana de Lima Vazquez, and Cleyton Zanardo de Oliveira 9 Design of Retrospective and Case- Control Studies in Oncology . . . . 147 Katherine S. Panageas, Debra A. Goldman, and T. Peter Kingham 10 How to Design Phase I Trials in Oncology . . . . . . . . . . . . . . . . . . . . . . 165 Louise Carter, Ciara O’Brien, Emma Dean, and Natalie Cook 11 The Many Different Designs of Phase II Trials in Oncology . . . . . . . 189 Rachel P. Riechelmann, Raphael L. C. Araújo, and Axel Hinke 12 Superiority and Non-inferiority Phase III Oncology Trials . . . . . . . . 203 Everardo D. Saad vii viii Contents 13 Phase IV Trials: Interventional and Non- interventional Studies . . . . 217 Deise Uema, Cheng Tzu Yen, Axel Hinke, and Gilberto de Castro Jr. 14 Identifying Bias in Clinical Cancer Research . . . . . . . . . . . . . . . . . . . 227 Francisco Emilio Vera-Badillo and Rachel P. Riechelmann 15 Ethics in Clinical Cancer Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Rodrigo Santa C. Guindalini, Rachel P. Riechelmann, and Roberto Jun Arai 16 Cost-Effectiveness Studies in Oncology . . . . . . . . . . . . . . . . . . . . . . . . 257 Pedro Aguiar Jr., Carmelia Maria Noia Barreto, Brittany L. Bychkovsky, and Gilberto de Lima Lopes Jr. 17 How to Undertake Outcomes Research in Oncology . . . . . . . . . . . . . . 267 Monika K. Krzyzanowska and Melanie Powis 18 Systematic Reviews and Meta-Analyses of Oncology Studies . . . . . . 287 Allan A. Lima Pereira and Andre Deeke Sasse 19 Meta-Research in Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 Everardo D. Saad and Rachel P. Riechelmann 20 Analysis of Health-Related Quality of Life and Patient-Reported Outcomes in Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Bellinda L. King-Kallimanis, Roxanne E. Jensen, Laura C. Pinheiro, and Diane L. Fairclough Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 Contributors Pedro Aguiar Jr., M.D. Faculdade de Medicina do ABC, Santo André, SP, Brazil Roberto Jun Arai, M.Sc., Ph.D. Clinical Research Unit, State of São Paulo Cancer Institute, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil Raphael L. C. Araújo, M.D., Ph.D. Department of Upper Gastrointestinal and Hepato-Pancreato-Biliary Surgery, Barretos Cancer Hospital, Barretos, SP, Brazil Carmelia Maria Noia Barreto, M.D. Clinical Oncology Sector, Sociedade Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil David Bristol, Ph.D. Independent Consultant, Wiston-Salem, NC, USA Brittany L. Bychkovsky, M.D., M.Sc. Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA Samantha-Jo Caetano, M.Sc. McMaster University, Hamilton, ON, Canada Louise Carter, M.A., M.B.B.S., Ph.D., M.R.C.P. The Christie NHS Foundation Trust, Manchester, UK Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester, University of Manchester, Manchester, UK André Lopes Carvalho, M.D., Ph.D., M.P.H. Teaching and Research Institute, Barretos Cancer Hospital, Barretos, SP, Brazil Gilberto de Castro Jr., M.D., Ph.D. ICESP—Medicine School of University of São Paulo, São Paulo, SP, Brazil Sirio Libanês Hospital, São Paulo, SP, Brazil Natalie Cook, M.B.Ch.B., M.R.C.P., Ph.D. The Christie NHS Foundation Trust, Manchester, UK Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK ix x Contributors Beatriz  Teixeira  Costa Laboratory of Neuromodulation, Center of Clinical Research Learning, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA Emma Dean, B.MedSci.,B.M.B.S.,PhD.,F.R.C.P. The Christie NHS Foundation Trust, Manchester, UK Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK Early Clinical Development, Oncology Translational Medicine Unit, Astra Zeneca, Melbourn, Hertfordshire, UK Diane  L.  Fairclough, Dr.P.H. Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, USA Isadora Santos Ferreira Laboratory of Neuromodulation, Center of Clinical Research Learning, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA Felipe  Fregni, M.D., Ph.D., M.P.H. Department of Physical Medicine and Rehabilitation, Laboratory of Neuromodulation, Center of Clinical Research Learning, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA Mina Georgieva, M.S. Georgia Institute of Technology, Atlanta, GA, USA Debra A. Goldman, M.S. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA Rodrigo Santa C. Guindalini, M.D., Ph.D. CLION, CAM Group, Salvador, BA, Brazil Department of Radiology and Oncology, State of São Paulo Cancer Institute, Faculty of Medicine of the University of São Paulo, São Paulo, SP, Brazil Benjamin Haaland, Ph.D. University of Utah, Salt Lake City, UT, USA Axel Hinke, Ph.D. CCRC, Düsseldorf, Germany WiSP Research Institute, Langenfeld, Germany Roxanne E. Jensen, Ph.D. Department of Oncology, Georgetown University, Washington, DC, USA Bellinda L. King-Kallimanis, M.Sc., Ph.D. Pharmerit International, Boston, MA, USA T. Peter Kingham, M.D. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Monika K. Krzyzanowska, M.D., M.P.H., F.R.C.P.C. Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada