Renal Cancer

John A. Libertino • Jason R. GeeEditors

Renal Cancer

Contemporary Management

Second Edition

ISBN 978-3-030-24377-7 ISBN 978-3-030-24378-4 (eBook)https://doi.org/10.1007/978-3-030-24378-4

© Springer Nature Switzerland AG 2020This 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, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information 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 publication 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, expressed 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.

This Springer imprint is published by the registered company Springer Nature Switzerland AGThe registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

EditorsJohn A. LibertinoProfessor of Urology Tufts University School of Medicine Boston, MAUSA

Chairman Department of Urology MGH Cancer CenterEmerson Hospital Concord, MAUSA

Jason R. GeeAssociate Professor of Urology Tufts University School of Medicine Boston, MAUSA

Department of Urology MGH Cancer CenterEmerson Hospital Concord, MAUSA

Dedicated to

Dr. Harris Berman, M.D., Dean of Tufts University School of Medicine

A great Leader in medical education and healthcare delivery

vii

1 Epidemiology, Screening, and Clinical Staging . . . . . . . . . . . . . . 1Sana N. Siddiqui, Christopher R. Haas, and James M. McKiernanIntroduction to Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Incidence and Mortality Rates over Time . . . . . . . . . . . . . . . . . . . . 1Demographic Factors in Renal Cell Carcinoma . . . . . . . . . . . . . . . 3Risk Factors in the Development of RCC . . . . . . . . . . . . . . . . . . . . 3

Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Chronic Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Family History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Occupational Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Screening for RCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Screening of Targeted Populations . . . . . . . . . . . . . . . . . . . . . . . . . 7Clinical Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Renal Vein and IVC Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . 12T4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Nodal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Metastatic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Improving the TNM Staging System . . . . . . . . . . . . . . . . . . . . . . . 14References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2 Molecular Biology and Genetics of Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Sanaz Ghafouri, David C. Johnson, Kristen Kelly, Allan Pantuck, and Alexandra DrakakiIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Clear Cell Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Somatic Alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Whole Exome Sequencing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20DNA Methylation Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20RNA Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Integrative Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Prognostic Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Contents

viii

Loss of Chromosome 3/VHL Gene Mutations . . . . . . . . . . . . . . 21Carbonic Anhydrase IX (CAIX) . . . . . . . . . . . . . . . . . . . . . . . . . 22Chromatin-Remodeling Tumor Suppressor Genes . . . . . . . . . . . 22Tumor Suppressor Gene p53 (Chromosome 17) . . . . . . . . . . . . 23Somatic Copy Number Variations . . . . . . . . . . . . . . . . . . . . . . . . 24Loss of 9p . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Loss of 14q . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Gain of 8q . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Papillary Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Somatic Alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Whole Exome Sequencing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26RNA Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Integrative Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Prognostic Biomarkers in Papillary Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Chromophobe RCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Somatic Alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Whole Exome/Genome Sequencing . . . . . . . . . . . . . . . . . . . . . . 27Integrative Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28DNA Methylation Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28Mitochondrial DNA Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . 28Immune Signature Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29RNA Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

3 Familial and Hereditary Syndromes in Renal Cell Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35Mark Wayne Ball and Peter A. PintoIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35Clinical Features of Hereditary RCC and Genetic Testing . . . . . . . 35Description of Hereditary Syndromes . . . . . . . . . . . . . . . . . . . . . . 36

Von Hippel-Lindau . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Hereditary Papillary Renal Cell . . . . . . . . . . . . . . . . . . . . . . . . . 38Birt-Hogg-Dubé . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Hereditary Leiomyomatosis and Renal Cell . . . . . . . . . . . . . . . . 40Succinate Dehydrogenase-Deficient Kidney Cancer . . . . . . . . . 41BAP1-Associated RCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41MITF Family Translocation RCC . . . . . . . . . . . . . . . . . . . . . . . . 41Tuberous Sclerosis Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42Chromosome 3 Translocation Kidney Cancer . . . . . . . . . . . . . . 42

Management of Hereditary Cancer Syndromes . . . . . . . . . . . . . . . 43Active Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Surgical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Enucleation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Wide Excision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Contents

ix

4 Pathology of Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . 49Franto Francis and Ming ZhouIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49Pathological Classification of RCC . . . . . . . . . . . . . . . . . . . . . . . . 50Pathologic and Molecular Characteristics of Subtypes of RCC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Renal Cell Carcinoma, Clear Cell Type (CCRCC) . . . . . . . . . . . 50Renal Cell Carcinoma, Papillary Type (Papillary RCC, PRCC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Renal Cell Carcinoma, Chromophobe Type (Chromophobe RCC, ChRCC) . . . . . . . . . . . . . . . . . . . . . . . . . . 54Other Uncommon Subtypes of Renal Cell Carcinoma . . . . . . . . 55Renal Cell Carcinoma, Unclassified Type . . . . . . . . . . . . . . . . . 55

Renal Cell Carcinomas in Inherited Cancer Syndromes . . . . . . . . . 55von Hippel-Lindau Disease (VHLD) . . . . . . . . . . . . . . . . . . . . . 55Hereditary Papillary Renal Cell Carcinoma (HPRCC) . . . . . . . . 59Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60Renal Cell Carcinomas in Hereditary Pheochromocytoma Paraganglioma Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61Renal Tumors in Tuberous Sclerosis Complex (TSC) . . . . . . . . 62Birt-Hogg-Dube Syndrome (BHD) . . . . . . . . . . . . . . . . . . . . . . . 62

Common Benign Renal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . 62Papillary Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62Renal Oncocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Angiomyolipoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Pathological Prognosis Parameters for Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64WHO/ISUP Nucleolar Grading . . . . . . . . . . . . . . . . . . . . . . . . . 65Sarcomatoid and Rhabdoid Differentiation . . . . . . . . . . . . . . . . 66Tumor Necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Microvascular Invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Histologic Subtyping in Localized and Metastatic RCC . . . . . . . . 67Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

5 Imaging of Renal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73Jalil Afnan, Jaclyn A. Therrien, and Christoph WaldRenal Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73Intravenous Pyelogram (IVP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74Ultrasound (US) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75Computed Tomography (CT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79Magnetic Resonance Imaging (MRI) . . . . . . . . . . . . . . . . . . . . . . . 87Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Contents

x

6 Molecular Imaging for Renal Cell Carcinoma . . . . . . . . . . . . . . . 99Jian Q. Yu and Yamin DouIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Primary Renal Cell Carcinoma Diagnosis . . . . . . . . . . . . . . . . . . . 100Locoregional Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102Distant Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104Liver Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105Lung Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105Bone Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107Prognostic Values of FDG PET for RCC . . . . . . . . . . . . . . . . . . . . 108Monitoring Therapeutic Response . . . . . . . . . . . . . . . . . . . . . . . . . 109Influence on Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111Novel Tracers and Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

124 I-cG250 for Clear Cell RCC . . . . . . . . . . . . . . . . . . . . . . . . . 112Other Novel Tracers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

7 Interventional Radiology and Angioinfarction: Embolization of Renal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . 119Sebastian Flacke and Shams IqbalIndications for Renal Artery Embolization . . . . . . . . . . . . . . . . . . . 119Technical Details . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119Central Occlusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119Combined Central and Peripheral Occlusion . . . . . . . . . . . . . . . . . 121Capillary Occlusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122Superselective Embolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125Clinical Value of Transcatheter Tumor Embolization . . . . . . . . . . . 126

Preoperative Embolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126Palliative Embolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

8 Natural History, Role of Biopsy, and Active Surveillance of Renal Masses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133Benjamin T. Ristau, Anthony Corcoran, Marc C. Smaldone, Robert G. Uzzo, and David Y. T. ChenIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133Natural History of Untreated Renal Masses . . . . . . . . . . . . . . . . . . 135

Benign Versus Malignant SRMs . . . . . . . . . . . . . . . . . . . . . . . . . 135Growth Characteristics of Untreated SRMs . . . . . . . . . . . . . . . . 135Radiographic Characteristics of SRMs . . . . . . . . . . . . . . . . . . . . 138

Role of Percutaneous Biopsy and Other Diagnostic Modalities . . . 139Traditional Role of Renal Mass Biopsy . . . . . . . . . . . . . . . . . . . 139Modern Biopsy Technique and Results . . . . . . . . . . . . . . . . . . . 140Complications of Biopsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Molecular Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Contents

xi

Predictive Models and Assessment of SRM Malignant Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

Active Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143The Rationale for AS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143Indications for AS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144Predictive Tools and Use in the Clinical Setting . . . . . . . . . . . . . 144AS Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Radiographic Predictors of Tumor Growth Rate and Malignant Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Small Renal Masses Exhibiting “Zero Net Growth” While Under Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Observed SRMs Progressing to Metastases . . . . . . . . . . . . . . . . 150

Cost-Effectiveness of AS Versus Active Treatment . . . . . . . . . . . . 151Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

9 Rationale for Partial Nephrectomy, Current Practice Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159Nicholas M. Donin and William C. HuangIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159Epidemiology of Renal Masses . . . . . . . . . . . . . . . . . . . . . . . . . . . 160Heterogeneity of Renal Cortical Tumors . . . . . . . . . . . . . . . . . . . . 162History of Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . 163Oncologic Outcomes in Partial Nephrectomy . . . . . . . . . . . . . . . . 164Renal Functional Outcomes in Partial Nephrectomy . . . . . . . . . . . 165Chronic Kidney Disease, Morbidity, and Mortality . . . . . . . . . . . . 168Renal Surgery, Morbidity, and Mortality . . . . . . . . . . . . . . . . . . . . 170Complications of Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . . . 176Utilization of Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . . . . . . 177Candidate Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178Small Renal Masses and Partial Nephrectomy in Clinical Practice Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

10 Objectifying Complexity of Kidney Cancers: Relationship of Tumor Anatomy and Outcomes . . . . . . . . . . . . . 185Serge Ginzburg, Alexander Kutikov, Robert G. Uzzo, and Stephen B. SchlossBasis of Anatomic Classification System Development . . . . . . . . . 186Tumor Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186Tumor Location . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186Tumor Depth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187Contemporary Classification Systems for Renal Masses . . . . . . . . 187Validation of Current Classification Systems . . . . . . . . . . . . . . . . . 191Application of Standardized Classifications . . . . . . . . . . . . . . . . . . 191Limitations of Current Classification Systems . . . . . . . . . . . . . . . . 192The Role of Nephrometry Score in Partial Nephrectomy: Lahey Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

Contents

xii

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

11 History of Renal Surgery for Cancer . . . . . . . . . . . . . . . . . . . . . . 197Brendan M. Browne and Karim Joseph HamawyThe Golden Era of Radical Nephrectomy . . . . . . . . . . . . . . . . . . . . 198History of Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199Rise of Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200Modern Renal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

12 The Surgical Approaches to Renal Masses and Their Impact on Postoperative Renal Function . . . . . . . . . . . . . . 205John A. Libertino and Robert HamburgerIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205Nephrectomy Versus Partial Nephrectomy: The Rationale for Partial Nephrectomy and Preservation of Renal Function . . . . 205Illustrative Case: Large Tumor in Solitary Kidney . . . . . . . . . . . . . 206Role of Preoperative CKD on Postoperative Renal Function Following Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . 207Role of Warm Ischemia on Postoperative Renal Function Following Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . 207Role of Volume on Postoperative Renal Function Following Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . 211Combined Role of Ischemia and Volume on Renal Function Following Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . 212Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213Surgical Approach to Multifocal or Bilateral Renal Tumors . . . . . 213Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

13 Open Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221Marianne M. Casilla-Lennon, Patrick A. Kenney, Matthew Wszolek, and John A. LibertinoIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221Epidemiology of Small Renal Masses . . . . . . . . . . . . . . . . . . . . . . 222Oncologic Efficacy of Partial Nephrectomy . . . . . . . . . . . . . . . . . . 223T1a Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224T1b Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225>T1 Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Preserving Renal Function: The Rationale Behind PN . . . . . . . . . . 226Underutilization of PN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Adoption of Minimally Invasive Techniques . . . . . . . . . . . . . . . . . 228Objective Analysis of Tumor Complexity . . . . . . . . . . . . . . . . . . . . 229Preoperative Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Cardiopulmonary Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . 232Renal Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

Contents

xiii

Surgical Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Vascular Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Kidney Mobilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Vascular Clamping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Excision of the Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Renorrhaphy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236Addressing the Adverse Impact of Ischemia. . . . . . . . . . . . . . . . 236

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

14 Minimally Invasive Partial Nephrectomy and Ablative Procedures for Small Renal Masses . . . . . . . . . . . . . . . . . . . . . . . 243Shanta T. Shepherd, Egor Parkhomenko, and David S. WangIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243Laparoscopic Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . . . . . . 243

Patient Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243Patient Positioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245Hilar Clamping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Tumor Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247Reconstruction of the Collecting System . . . . . . . . . . . . . . . . . . 248Hemostasis of the Tumor Bed . . . . . . . . . . . . . . . . . . . . . . . . . . . 248Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

Robotic-Assisted Laparoscopic Partial Nephrectomy (RALPN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

Patient Positioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

Ablative Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250Postoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251Complications of Minimally Invasive Partial Nephrectomy . . . . . . 252Intraoperative Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

Vascular Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Injury to Intra-abdominal Organs . . . . . . . . . . . . . . . . . . . . . . . . 252

Postoperative Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Urine Leak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

15 Surgery for Renal Cell Carcinoma with Thrombus Extension into the Vena Cava . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259John A. Libertino, Chad Wotkowicz, and Jason R. GeeIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Preoperative Renal Embolization . . . . . . . . . . . . . . . . . . . . . . . . . . 260Renal Vein Tumor Thrombus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261Infrahepatic Tumor Thrombus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262

Contents

xiv

Retrohepatic, Supradiaphragmatic, and Atrial Tumor Thrombus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267Venovenous Bypass (Caval-Atrial Shunt) . . . . . . . . . . . . . . . . . . . . 267Liver Mobilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268Traditional Cardiopulmonary Bypass (Median Sternotomy) . . . . . 268Cardiopulmonary Bypass (Minimally Access Approach) . . . . . . . . 270Comparative Effectiveness of Median Sternotomy Versus Minimal Access Cardiopulmonary Bypass and Circulatory Arrest for Resection of Renal Cell Carcinoma with Inferior Vena Caval Extension . . . . . . . . . . . . . . . . . . . . . . . . 271Occluded Vasculature Management . . . . . . . . . . . . . . . . . . . . . . . . 274Caval Wall Resection and Caval Interruption . . . . . . . . . . . . . . . . . 274Minimally Invasive Techniques and Tumor Thrombectomy . . . . . 275A Novel Approach: Combination of Interventional Radiologic Tumor Extraction and Surgery . . . . . . . . . . . . . . . . . . . 275Partial Nephrectomy and Tumor Thrombus . . . . . . . . . . . . . . . . . . 275Neoadjuvant Chemotherapy and Tumor Thrombus . . . . . . . . . . . . 276Tumor Thrombectomy and Metastectomy . . . . . . . . . . . . . . . . . . . 276Personal Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277International Renal Cell Carcinoma: Venous Thrombus Consortium (IRCC-VTC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

16 Role of Lymphadenectomy in Renal Cell Cancer . . . . . . . . . . . . 281Mattias Willem van Hattem, Eduard Roussel, Hendrik Van Poppel, and Maarten AlbersenIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281Anatomy of Regional Lymph Nodes . . . . . . . . . . . . . . . . . . . . . . . 281Extent of LND for RCC and Templates . . . . . . . . . . . . . . . . . . . . . 283Morbidity of LND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284False-Positive and False-Negative CT Findings . . . . . . . . . . . . . . . 285Prevalence of Lymph Node metastases . . . . . . . . . . . . . . . . . . . . . . 285Predicting Lymph Node Involvement . . . . . . . . . . . . . . . . . . . . . . . 286

Protocols and Nomograms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286Intra-Operative Lymph Node Assessment . . . . . . . . . . . . . . . . . 287Sentinel Lymph Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287Future Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

When to Perform a LND? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288Localized Disease (cT1abN0M0) . . . . . . . . . . . . . . . . . . . . . . . . 288Localized Disease: Larger Tumours (cT2abN0M0) . . . . . . . . . . 288Locally Advanced Disease (cT3-T4N0M0) . . . . . . . . . . . . . . . . 288Clinical Node-Positive (cT1-4, N+M0) RCC . . . . . . . . . . . . . . . 289

Regional Lymph Node Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . 289Distant Metastasis and Cytoreduction (cTanyNanyM1) . . . . . . . . . 290Conclusion and Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . 291References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Contents

xv

17 Role of Surgery in Locally Recurrent and Metastatic Renal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Andrew G. McIntosh, Eric C. Umbreit, and Christopher G. WoodKidney Cancer and Recurrence. . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Recurrence After RN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Recurrence After PN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

Local Recurrence Following Primary Ablative Therapy . . . . . . . . 299Renal Cell Carcinoma Metastasectomy . . . . . . . . . . . . . . . . . . . . . 300Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

18 Management of Non-Clear Cell Renal Cell Carcinoma . . . . . . . 307Jeremy A. Ross, Pavlos Msaouel, and Nizar M. TannirIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307Papillary Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 308Chromophobe Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . 311Translocation Renal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312Renal Medullary Carcinoma/Collecting Duct Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313Miscellaneous Renal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315The Role of Surgery in Metastatic Non-Clear Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

19 Surgical Management for Transitional Cell Carcinoma of the Upper Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325Jason R. GeeEpidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327Diagnosis and Clinicopathologic Risk Factors . . . . . . . . . . . . . . . . 328

Diagnostic Ureteroscopy: Biopsy When Feasible . . . . . . . . . . . 329Clinicopathologic Prognostic Factors . . . . . . . . . . . . . . . . . . . . . 329

Endoscopic Approaches to Treatment . . . . . . . . . . . . . . . . . . . . . . . 330Treatment with Topical Agents . . . . . . . . . . . . . . . . . . . . . . . . . . 332

Nephroureterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333Bladder Cuff Removal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

Segmental ureteral Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Autotransplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Role of Lymphadenectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Role of Neoadjuvant Versus Adjuvant Chemotherapy . . . . . . . . . . 337References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

20 Outcomes: Prognostic Factors, Models, and Algorithms . . . . . . 345Kristian D. Stensland and Michael W. KattanIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345Staging Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

Contents

xvi

Grading System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347Notes on Staging Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347Other Prognostic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348A Word About Prediction Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . 349Preoperative Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350Postoperative Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352Metastatic RCC Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356

21 Postoperative Surveillance Protocols for Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361Megan M. Merrill and Jose A. KaramIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361Natural History of RCC and Recurrence Patterns . . . . . . . . . . . . . 361Distant Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362

Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362Lymph Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

Local Recurrence After Radical Nephrectomy . . . . . . . . . . . . . . . . 363Recurrence After Partial Nephrectomy . . . . . . . . . . . . . . . . . . . . . . 363Surveillance Following Radical or Partial Nephrectomy . . . . . . . . 364

Rationale for Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364Components of Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365Prognostic Factors Influencing Recurrence . . . . . . . . . . . . . . . . 366

Surveillance Following Radical or Partial Nephrectomy in Patients with Sporadic RCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367Current NCCN and AUA Guidelines . . . . . . . . . . . . . . . . . . . . . . . 376Surveillance for Hereditary RCC . . . . . . . . . . . . . . . . . . . . . . . . . . 377Surveillance Following Ablative Therapies for RCC . . . . . . . . . . . 377

Radiofrequency Ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377Cryoablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378Recommendations for Surveillance Following Radiofrequency Ablation or Cryoablation . . . . . . . . . . . . . . . . . 379

The Future of Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380The Incorporation of Molecular Markers into Surveillance Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380Use of F-18 Fluorodeoxyglucose Positron Emission Tomography in Surveillance and Reducing the Risk of Radiation Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

Cost of Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382

22 Role of Radiation Therapy in Renal Cancer . . . . . . . . . . . . . . . . 387Andrea McKee, Arul Mahadevan, and Timothy WalshIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

Contents

xvii

Preoperative Neoadjuvant Radiation . . . . . . . . . . . . . . . . . . . . . . . . 387Postoperative Adjuvant Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . 388Intraoperative Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390Stereotactic Body Radiotherapy (SBRT) as Definitive Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391Palliative Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392Stereotactic Radiosurgery and Stereotactic Body Radiotherapy for Oligometastatic Disease . . . . . . . . . . . . . . . . . . . 393Immunoradiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

23 Systemic Therapies for the Treatment of Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401Eddy J. ChenIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401Drug Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402

Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402VEGF-Receptor Inhibitor Therapies . . . . . . . . . . . . . . . . . . . . . . 403mTOR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404

Contemporary Treatment Approaches . . . . . . . . . . . . . . . . . . . . . . 404Neoadjuvant Systemic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 404Adjuvant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405Advanced Disease Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . 405

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

24 Unified Approaches to Surgery and Systemic Therapy for Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411Alejandro Abello and Patrick A. KenneyIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411Adjuvant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

Contemporary Approach to Quantifying the Risk of Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411Models Incorporating Clinical and Pathologic Data . . . . . . . . . . 412Using Molecular Markers to Improve Prognostication . . . . . . . . 412Adjuvant Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412Thalidomide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417Targeted Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417Ongoing or Unreported Adjuvant Trials . . . . . . . . . . . . . . . . . . . 418Adjuvant Therapy: Current Status . . . . . . . . . . . . . . . . . . . . . . . 418

Neoadjuvant Therapy for Locally Advanced RCC . . . . . . . . . . . . . 421Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421Targeted Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421Targeted Therapy Is Active Against the Primary Tumor . . . . . . . 421Permitting Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423Enabling Nephron-Sparing Surgery . . . . . . . . . . . . . . . . . . . . . . 423Downsizing Caval Tumor Thrombus . . . . . . . . . . . . . . . . . . . . . 424

Contents

xviii

Neoadjuvant Therapy: Current Status . . . . . . . . . . . . . . . . . . . . . 425Integrated Therapy for Metastatic Disease . . . . . . . . . . . . . . . . . . . 425

Cytoreductive Nephrectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426The Importance of Proper Patient Selection . . . . . . . . . . . . . . . . 426Targeted Therapy and Cytoreductive Nephrectomy . . . . . . . . . . 427Treatment Chronology: Upfront Nephrectomy Versus Presurgical Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 428

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430

25 Defining an Individualized Treatment Strategy for Metastatic Renal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437Mamta Parikh, Jerad Harris, Sigfred Ian Alpajaro, Primo N. Lara Jr., and Christopher P. EvansRelevant Biologic Pathways in RCC . . . . . . . . . . . . . . . . . . . . . . . 437Prognostication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439Overview of Treatments of mRCC . . . . . . . . . . . . . . . . . . . . . . . . . 440

Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440Systemic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441

Molecular Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443Immune Checkpoint Inhibitor Therapy . . . . . . . . . . . . . . . . . . . . 443mTOR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444

Treatment Paradigm Based on Individualized Factors . . . . . . . . . . 444Patient Selection for Cytoreductive Nephrectomy . . . . . . . . . . . 444Timing of Cytoreductive Nephrectomy . . . . . . . . . . . . . . . . . . . 447Patient Selection for Metastasectomy . . . . . . . . . . . . . . . . . . . . . 447Patient Selection for Systemic Therapy . . . . . . . . . . . . . . . . . . . 447Patient Selection for Second-Line Therapy and Beyond . . . . . . 448Systemic Treatment Considerations Based on Histology . . . . . . 448

Future of Individualized Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 449Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453

Contents

xix

Alejandro Abello, MD Department of Urology/Yale School of Medicine, Yale New Haven Hospital, New Haven, CT, USA

Jalil  Afnan, MD, MRCS Department of Radiology, Lahey Hospital & Medical Center, Burlington, MA, USA

Maarten  Albersen, MD Department of Urology, UZ Leuven, Leuven, Belgium

Sigfred  Ian  Alpajaro, MD Department of Surgery, Section of Urology, University of Santo Tomas Hospital, Manila, Philippines

Mark Wayne Ball, MD Center for Cancer Research, NCI, NIH, Urologic Oncology Branch, Bethesda, MD, USA

Brendan M. Browne, MD, MS Department of Urology, Lahey Hospital and Medical Center, Burlington, MA, USA

Marianne  M.  Casilla-Lennon, MD Department of Urology, Yale New Haven Health, New Haven, CT, USA

David Y. T. Chen, MD, FACS Department of Surgical Oncology, Division of Urology, Fox Chase Cancer Center – Temple University Health System, Philadelphia, PA, USA

Eddy  J.  Chen, MD Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

MGH Cancer Center, Emerson Hospital, Concord Mass, USA

Anthony  Corcoran, MS, MD Department of Urology, NYU Winthrop Hospital, Garden City, NY, USA

Nicholas  M.  Donin, MD Department of Urology, Division of Urologic Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Yamin  Dou, MD Department of Radiology, Tufts School of Medicine, Lahey Hospital and Medical Center, Burlington, MA, USA

Alexandra Drakaki, MD, PhD David Geffen School of Medicine of UCLA, Institute for Urologic Oncology, Los Angeles, CA, USA

Christopher  P.  Evans, MD Department of Urologic Surgery, UC Davis, Sacramento, CA, USA

Contributors

xx

Sebastian Flacke, MD, PhD Department of Radiology, Lahey Hospital and Medical Center, Burlington, MA, USA

Franto Francis, MD, PhD Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Jason R. Gee, MD Tufts University School of Medicine, Boston, MA, USA

Department of Urology, MGH Cancer Center, Emerson Hospital, Concord, MA, USA

Sanaz  Ghafouri, MD Department of Internal Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA

Serge  Ginzburg, MD Urology Institute of Southeastern Pennsylvania, Einstein Hospital System, Philadelphia, PA, USA

Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA

Christopher R. Haas, MD Department of Urology, New York-Presbyterian, Columbia University Irving Medical Center, Herbert Irving Pavilion, New York, NY, USA

Karim Joseph Hamawy, MD Department of Urology, Lahey Hospital and Medical Center, Burlington, MA, USA

Robert  Hamburger, MD Department of Medicine, Boston University School of Medicine, Boston VA Health Care System, Boston, MA, USA

Jerad Harris, BS Department of Urologic Surgery, UC Davis, Sacramento, CA, USA

Mattias  Willem  van Hattem, MD Department of Urology, UZ Leuven, Leuven, Belgium

William  C.  Huang, MD Department of Urology, Division of Urologic Oncology, NYU Langone Medical Center, New York, NY, USA

Shams Iqbal, MD Department of Radiology, Lahey Hospital and Medical Center, Burlington, MA, USA

David  C.  Johnson, MD, MPH Department of Veterans Affairs/UCLA National Clinician Scholars Program, West Los Angeles Veterans Affairs Hospital, Los Angeles, CA, USA

Jose A. Karam, MD, FACS Urology and Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA

Michael  W.  Kattan, PhD Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

Kristen Kelly, MD Department of Internal Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA

Patrick A. Kenney, MD Department of Urology/Yale School of Medicine, Yale New Haven Hospital, New Haven, CT, USA

Contributors

xxi

Alexander  Kutikov, MD Division of Urology and Urologic Oncology, Department of Urology, Fox Chase Cancer Center, Temple University School of Medicine Center, Philadelphia, PA, USA

Primo  N.  Lara Jr., MD Hematology/Oncology, Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA

UC Davis School of Medicine, Sacramento, CA, USA

John A. Libertino, MD Tufts University School of Medicine, Boston, MA, USA

Department of Urology, MGH Cancer Center, Emerson Hospital, Concord, MA, USA

Arul Mahadevan, MD Department of Radiation Oncology, Sophia Gordon Cancer Center, Lahey Clinic Medical Center, Burlington, MA, USA

Andrew  G.  McIntosh, MD Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Andrea McKee, MD Department of Radiation Oncology, Sophia Gordon Cancer Center, Lahey Clinic Medical Center, Burlington, MA, USA

James M. McKiernan, MD Department of Urology, New York-Presbyterian, Columbia University Irving Medical Center, Herbert Irving Pavilion, New York, NY, USA

Megan M. Merrill, DO Department of Urology, Kaiser Permanente South Sacramento, Sacramento, CA, USA

Pavlos Msaouel, MD Department of Genitourinary Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

Allan  Pantuck, MD, MS Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Mamta  Parikh, MD, MS Hematology/Oncology, Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA

Egor  Parkhomenko, MD Department of Urology, Boston University School of Medicine, Boston, MA, USA

Peter  A.  Pinto, MD NIH Clinical Center, Urologic Oncology Branch, Bethesda, MD, USA

Hendrik  Van Poppel, MD, PhD Department of Urology, UZ Leuven, Leuven, Belgium

Benjamin  T.  Ristau, MD, MHA Department of Surgery/Division of Urology, UConn Health, Farmington, CT, USA

Jeremy  A.  Ross, MD Cancer Medicine, Fellowship Program, UT MD Anderson Cancer Center, Houston, TX, USA

Eduard Roussel, MD Department of Urology, UZ Leuven, Leuven, Belgium

Contributors

xxii

Stephen  B.  Schloss, MD Department of Urology, MGH Cancer Center, Emerson Hospital, Concord, MA, USA

Shanta  T.  Shepherd, MD Department of Urology, Boston University School of Medicine, Boston, MA, USA

Sana N. Siddiqui, DO, MS Department of Urology, New York-Presbyterian, Columbia University Irving Medical Center, Herbert Irving Pavilion, New York, NY, USA

Marc C. Smaldone, MD, MSHP, FACS Department of Surgery, Fox Chase Cancer Center – Temple University Health System, Philadelphia, PA, USA

Kristian D. Stensland, MD, MPH Division of Urology, Lahey Hospital and Medical Center, Burlington, MA, USA

Nizar  M.  Tannir, MD, FACP Genitourinary Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

Jaclyn  A.  Therrien, DO Section Head Body Imaging, Department of Radiology, Lahey Hospital & Medical Center, Burlington, MA, USA

Eric  C.  Umbreit, MD Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Robert  G.  Uzzo, MD Department of Surgical Oncology, Division of Urology, Fox Chase Cancer Center – Temple University Health System, Philadelphia, PA, USA

Christoph  Wald, MD, PhD, MBA Department of Radiology, Lahey Hospital & Medical Center, Burlington, MA, USA

Timothy Walsh, MD Department of Radiation Oncology, Tufts University School of Medicine, Boston, MA, USA

David S. Wang, MD Department of Urology, Boston University School of Medicine, Boston, MA, USA

Christopher G. Wood, MD, FACS Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Chad  Wotkowicz, MD Department of Urology, Lahey Clinic Medical Center, Burlington, MA, USA

Matthew  Wszolek, MD Department of Urology, Massachusetts General Hospital, Boston, MA, USA

Jian Q. Yu, MD, FRCPC Department of Diagnostic Imaging, Fox Chase Cancer Center, Philadelphia, PA, USA

Ming Zhou, MD Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA

Tufts Medical Center and Tufts School of Medicine, Boston, MA, USA

Contributors