Advanced Renal Cell Carcinoma: Role of the Radiologist in the Era of Precision Medicine.

For the past decade, advanced renal cell carcinoma (RCC) has been at the forefront of oncologic innovation. Our rapidly evolving understanding of the molecular and genetic basis of RCC has revolutionized the management of advanced RCC; 10 novel molecular targeted agents and immune checkpoint inhibitor have received U.S. Food and Drug Administration approval for treatment of advanced RCC in a little over a decade. Amid this progress, imaging has assumed a central role in metastatic surveillance and follow-up of advanced RCC. State-of-the-art knowledge of the molecular basis of RCC and its treatment and imaging will help ensure that the radiology community remains relevant and central in the care of patients with advanced RCC. This article will review developments in management of advanced RCC from a radiologist's perspective to highlight our clinical role. It will describe how the underlying molecular mechanisms of RCC provide specific targets for novel anticancer agents. The relationship between the mechanisms of action of these novel anticancer agents and the imaging appearance of tumor response will be discussed, along with the available tumor response criteria and their strengths and weaknesses, thus assisting radiologists in response assessment in the setting of clinical trials or routine practice. The class- and drug-specific toxicities and complications associated with the novel anticancer agents will be summarized, since these are frequently missed or misinterpreted and require the radiologist's input in prompt detection and management. The potential role of radiogenomics and texture analysis in the management of advanced RCC will also be discussed. © RSNA, 2017.

[1]  A. Shinagare,et al.  Impact of histologic subtype and sarcomatoid transformation on metastasis in renal cell carcinoma: a single institute experience in 149 patients , 2016, Abdominal Radiology.

[2]  P. D. Dal Cin,et al.  Adult Renal Cell Carcinoma: A Review of Established Entities from Morphology to Molecular Genetics. , 2015, Surgical pathology clinics.

[3]  T. Choueiri,et al.  Radiologic Heterogeneity in Responses to Anti–PD-1/PD-L1 Therapy in Metastatic Renal Cell Carcinoma , 2015, Cancer Immunology Research.

[4]  A. Ravaud,et al.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. , 2015, The New England journal of medicine.

[5]  G. Gibney,et al.  Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes , 2015, Clinical Cancer Research.

[6]  S. Signoretti,et al.  Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor‐risk metastatic renal cell carcinoma , 2015, Cancer.

[7]  J. Cheville,et al.  Oncologic Surveillance After Surgical Resection for Renal Cell Carcinoma: A Novel Risk-Based Approach. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  J. Hoffman,et al.  FDG and FLT-PET for Early measurement of response to 37.5 mg daily sunitinib therapy in metastatic renal cell carcinoma , 2015, Cancer Imaging.

[9]  Matthew A. Zapala,et al.  The Radiogenomic Risk Score: Construction of a Prognostic Quantitative, Noninvasive Image-based Molecular Assay for Renal Cell Carcinoma. , 2015, Radiology.

[10]  B. K. Park,et al.  Assessment of early therapeutic response to sorafenib in renal cell carcinoma xenografts by dynamic contrast-enhanced and diffusion-weighted MR imaging. , 2015, The British journal of radiology.

[11]  F. Hodi,et al.  Anti-PD-1-Related Pneumonitis during Cancer Immunotherapy. , 2015, The New England journal of medicine.

[12]  F. Hodi,et al.  Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab , 2015, Cancer Immunology Research.

[13]  W. Shabana,et al.  Diagnosis of Sarcomatoid Renal Cell Carcinoma With CT: Evaluation by Qualitative Imaging Features and Texture Analysis. , 2015, AJR. American journal of roentgenology.

[14]  A. Shinagare,et al.  Anti-VEGF molecular targeted therapies in common solid malignancies: comprehensive update for radiologists. , 2015, Radiographics : a review publication of the Radiological Society of North America, Inc.

[15]  Erich P Huang,et al.  Radiogenomics of clear cell renal cell carcinoma: preliminary findings of The Cancer Genome Atlas–Renal Cell Carcinoma (TCGA–RCC) Imaging Research Group , 2015, Abdominal Imaging.

[16]  J. Larkin,et al.  Revised Choi imaging criteria correlate with clinical outcomes in patients with metastatic renal cell carcinoma treated with sunitinib. , 2014, Radiology.

[17]  A. D. Van den Abbeele,et al.  10% Tumor diameter shrinkage on the first follow-up computed tomography predicts clinical outcome in patients with advanced renal cell carcinoma treated with angiogenesis inhibitors: a follow-up validation study. , 2014, The oncologist.

[18]  J. Wolchok,et al.  Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. , 2014, Endocrine-related cancer.

[19]  J. Manola,et al.  Comparison of performance of various tumour response criteria in assessment of regorafenib activity in advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib. , 2014, European journal of cancer.

[20]  M. Kuo,et al.  Behind the numbers: Decoding molecular phenotypes with radiogenomics--guiding principles and technical considerations. , 2014, Radiology.

[21]  D. Berney,et al.  Diffusion-weighted and multiphase contrast-enhanced MRI as surrogate markers of response to neoadjuvant sunitinib in metastatic renal cell carcinoma , 2013, British Journal of Cancer.

[22]  E. Jonasch,et al.  The Impact of Tyrosine Kinase Inhibitors on the Multimodality Treatment of Brain Metastases From Renal Cell Carcinoma , 2013, American journal of clinical oncology.

[23]  H. Hricak,et al.  Radiogenomics of clear cell renal cell carcinoma: associations between CT imaging features and mutations. , 2013, Radiology.

[24]  Blanca Paño Brufau,et al.  Metastatic renal cell carcinoma: radiologic findings and assessment of response to targeted antiangiogenic therapy by using multidetector CT. , 2013, Radiographics : a review publication of the Radiological Society of North America, Inc.

[25]  Lars Egevad,et al.  The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia , 2013, The American journal of surgical pathology.

[26]  M. P. Hayball,et al.  CT texture analysis using the filtration-histogram method: what do the measurements mean? , 2013, Cancer imaging : the official publication of the International Cancer Imaging Society.

[27]  A. Shinagare,et al.  Acute pancreatitis associated with molecular targeted therapies: a retrospective review of the clinico-radiological features, management and outcome. , 2013, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[28]  J. Reeves,et al.  Pazopanib versus sunitinib in metastatic renal-cell carcinoma. , 2013, The New England journal of medicine.

[29]  V. Goh,et al.  Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy , 2013, British Journal of Cancer.

[30]  A. Shinagare,et al.  Liver metastases in the era of molecular targeted therapy: new faces of treatment response. , 2013, AJR. American journal of roentgenology.

[31]  A. Giobbie-Hurder,et al.  Developing a Common Language for Tumor Response to Immunotherapy: Immune-Related Response Criteria Using Unidimensional Measurements , 2013, Clinical Cancer Research.

[32]  A. Shinagare,et al.  Ipilimumab-associated colitis: CT findings. , 2013, AJR. American journal of roentgenology.

[33]  K. Flaherty,et al.  MRI assessment of early tumor response in metastatic renal cell carcinoma patients treated with sorafenib. , 2013, AJR. American journal of roentgenology.

[34]  A. Shinagare,et al.  Pneumatosis intestinalis and bowel perforation associated with molecular targeted therapy: an emerging problem and the role of radiologists in its management. , 2012, AJR. American journal of roentgenology.

[35]  J. Jagannathan,et al.  Decade of molecular targeted therapy: abdominal manifestations of drug toxicities--what radiologists should know. , 2012, AJR. American journal of roentgenology.

[36]  W. Rathmell,et al.  Renal Cell Carcinoma , 2012, Springer US.

[37]  Christian Rothermundt,et al.  Choi response criteria for prediction of survival in patients with metastatic renal cell carcinoma treated with anti-angiogenic therapies , 2012, European Radiology.

[38]  A. Ravaud,et al.  Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[39]  Qian Wang,et al.  Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  C. Cuénod,et al.  Optimisation of the tumour response threshold in patients treated with everolimus for metastatic renal cell carcinoma: analysis of response and progression-free survival in the RECORD-1 study. , 2012, European journal of cancer.

[41]  I. Pedrosa,et al.  Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome. , 2012, European journal of cancer.

[42]  U. Tateishi,et al.  Early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma treated with tyrosine kinase inhibitors is predictive of disease course , 2012, BMC Cancer.

[43]  K. Flaherty,et al.  From genes to drugs: targeted strategies for melanoma , 2012, Nature Reviews Cancer.

[44]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[45]  A. Ravaud,et al.  Targeted Therapies in Metastatic Renal Cell Carcinoma: Overview of the Past Year , 2012, Current Urology Reports.

[46]  R. Motzer,et al.  Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial , 2011, The Lancet.

[47]  J. Vauthey,et al.  CT findings of response and recurrence, independent of change in tumor size, in colorectal liver metastasis treated with bevacizumab. , 2011, AJR. American journal of roentgenology.

[48]  A. D. Van den Abbeele,et al.  Hereditary cancer syndromes: a radiologist's perspective. , 2011, AJR. American journal of roentgenology.

[49]  V. Goh,et al.  Assessment of response to tyrosine kinase inhibitors in metastatic renal cell cancer: CT texture as a predictive biomarker. , 2011, Radiology.

[50]  W. Kaelin,et al.  New insights into the biology of renal cell carcinoma. , 2011, Hematology/oncology clinics of North America.

[51]  F. Hodi,et al.  Radiologic aspects of immune-related tumor response criteria and patterns of immune-related adverse events in patients undergoing ipilimumab therapy. , 2011, AJR. American journal of roentgenology.

[52]  R. Motzer,et al.  mTOR inhibitors in advanced renal cell carcinoma. , 2011, Hematology/oncology clinics of North America.

[53]  Peter N. Burns,et al.  Dynamic microbubble contrast-enhanced US to measure tumor response to targeted therapy: a proposed clinical protocol with results from renal cell carcinoma patients receiving antiangiogenic therapy. , 2011, Radiology.

[54]  T. Choueiri,et al.  Systemic therapy for metastatic non-clear-cell renal cell carcinoma: recent progress and future directions. , 2011, Hematology/oncology clinics of North America.

[55]  T. Powles,et al.  Sequential FDG-PET/CT as a Biomarker of Response to Sunitinib in Metastatic Clear Cell Renal Cancer , 2011, Clinical Cancer Research.

[56]  T. Choueiri,et al.  Everolimus- and temsirolimus-associated enteritis: report of three cases. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  E. Van Cutsem,et al.  Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  Ivan Pedrosa,et al.  Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0, tumor shrinkage, computed tomography tumor density, Choi criteria) in assessing outcome to vascular endothelial growth factor-targeted therapy in patients with advanced renal cell carcinoma. , 2011, European Urology.

[59]  J. Maroto,et al.  Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  J. Zucman‐Rossi,et al.  Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[61]  Shenhong Wu,et al.  Increased Risk of Serious Hemorrhage with Bevacizumab in Cancer Patients: A Meta-Analysis , 2010, Oncology.

[62]  Gilles Chatellier,et al.  Metastatic renal carcinoma: evaluation of antiangiogenic therapy with dynamic contrast-enhanced CT. , 2010, Radiology.

[63]  Shetal N Shah,et al.  Morphology, Attenuation, Size, and Structure (MASS) criteria: assessing response and predicting clinical outcome in metastatic renal cell carcinoma on antiangiogenic targeted therapy. , 2010, AJR. American journal of roentgenology.

[64]  T. Choueiri,et al.  Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  L. Trinquart,et al.  Optimizing the size variation threshold for the CT evaluation of response in metastatic renal cell carcinoma treated with sunitinib. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[66]  S. Koscielny,et al.  Metastatic Renal Cell Carcinoma Treated with Sunitinib: Early Evaluation of Treatment Response Using Dynamic Contrast-Enhanced Ultrasonography , 2010, Clinical Cancer Research.

[67]  Vicky Goh,et al.  CT response assessment combining reduction in both size and arterial phase density correlates with time to progression in metastatic renal cancer patients treated with targeted therapies , 2010, Cancer biology & therapy.

[68]  Axel Hoos,et al.  Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria , 2009, Clinical Cancer Research.

[69]  T. Choueiri,et al.  Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. , 2009, The Lancet. Oncology.

[70]  J. Blay,et al.  Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: the intergroup EORTC-ISG-AGITG phase III trial. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  W. Linehan,et al.  Targeting the Met signaling pathway in renal cancer , 2009, Expert review of anticancer therapy.

[72]  R. Vikram,et al.  Papillary renal cell carcinoma: radiologic-pathologic correlation and spectrum of disease. , 2009, Radiographics : a review publication of the Radiological Society of North America, Inc.

[73]  Shenhong Wu,et al.  Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. , 2008, JAMA.

[74]  Gregory Karczmar,et al.  Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[75]  Ivan Pedrosa,et al.  Magnetic Resonance Imaging–Measured Blood Flow Change after Antiangiogenic Therapy with PTK787/ZK 222584 Correlates with Clinical Outcome in Metastatic Renal Cell Carcinoma , 2008, Clinical Cancer Research.

[76]  R. Motzer,et al.  Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial , 2008, The Lancet.

[77]  W. Kaelin,et al.  Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. , 2008, Molecular cell.

[78]  K. Flaherty,et al.  Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma , 2008, Cancer biology & therapy.

[79]  D. Fisher,et al.  MiT Transcription Factor Associated Malignancies in Man , 2007, Cell cycle.

[80]  David McDermott,et al.  Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. , 2007, The New England journal of medicine.

[81]  Haesun Choi,et al.  Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  J. Cheville,et al.  PD-1 Is Expressed by Tumor-Infiltrating Immune Cells and Is Associated with Poor Outcome for Patients with Renal Cell Carcinoma , 2007, Clinical Cancer Research.

[83]  M. Ladanyi,et al.  TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. , 2007, Cancer research.

[84]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[85]  R. Motzer,et al.  Targeted therapy for metastatic renal cell carcinoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  Linda Chami,et al.  To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound. , 2006, European journal of cancer.

[87]  Robert E. Brown,et al.  Morphoproteomic and molecular concomitants of an overexpressed and activated mTOR pathway in renal cell carcinomas. , 2006, Annals of clinical and laboratory science.

[88]  R. Motzer,et al.  Sunitinib in patients with metastatic renal cell carcinoma. , 2006, JAMA.

[89]  J. Cheville,et al.  Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. , 2006, Cancer research.

[90]  W. Kaelin,et al.  Role of VHL gene mutation in human cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[91]  G. Jakse,et al.  Cytogenetic and morphologic typing of 58 papillary renal cell carcinomas: evidence for a cytogenetic evolution of type 2 from type 1 tumors. , 2003, Cancer research.

[92]  Seth M Steinberg,et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. , 2003, The New England journal of medicine.

[93]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[94]  W. Linehan,et al.  Novel mutations of the MET proto-oncogene in papillary renal carcinomas , 1999, Oncogene.

[95]  F. Mostofi,et al.  Renal Medullary Carcinoma The Seventh Sickle Cell Nephropathy , 1995, The American journal of surgical pathology.

[96]  Y Kubota,et al.  Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. , 1994, Cancer research.

[97]  E. van den Berg,et al.  Cytogenetic analysis of epithelial renal‐cell tumors: Relationship with a new histopathological classification , 1993, International journal of cancer.

[98]  D. Sargent,et al.  The role of response evaluation criteria in solid tumour in anticancer treatment evaluation: results of a survey in the oncology community. , 2014, European journal of cancer.

[99]  A. Rabinstein,et al.  Clinical features and outcomes of posterior reversible encephalopathy syndrome following bevacizumab treatment. , 2012, QJM : monthly journal of the Association of Physicians.

[100]  Shetal N Shah,et al.  Assessing tumor response and detecting recurrence in metastatic renal cell carcinoma on targeted therapy: importance of size and attenuation on contrast-enhanced CT. , 2010, AJR. American journal of roentgenology.

[101]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.

[102]  A. Ravaud,et al.  Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.