Multidisciplinary approach for renal cell carcinoma Axel Bex, MD, PhD The Netherlands Cancer Institute

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1 Multidisciplinary approach for renal cell carcinoma Axel Bex, MD, PhD The Netherlands Cancer Institute 20 April, Antalya, Turkey

2 RCC European Union new diagnoses/year Cancer related deaths 30 % primary metastatic (with tumour in situ) 30 % develop metachronic metastasis patients total with metastasis with non-clear cell histology less than 25 % are estimated to be candidates for metastasectomy Ferlay et al., 2006, Eggener et al., 2006 und Alt et al. 2011

3 Why is there a need for a multidisciplinary approach? There is an increase in small renal masses with diverging treatment options including urologists, radiologists, physicians A substantial number of patients develops metachronous metastases: Who follows the patient? When to start systemic treatment? Local treatment of metastases or metastasectomy? In locally advanced or metastatic disease: Targeted therapies have effectivity on primary tumours and metastases: When to use them in combination with surgery? When and in whom to perform cytoreductive nephrectomy in synchronous metastatic disease? There is an increasing number of trials and eligibility needs to be discussed DFS = disease-free survival.

4 Organisation of Follow Up and Multidisciplinary Uro-oncology Panel Patient Urologist Follow- Up Medical Oncologist Neurosurgeon Follow-Up Radiologist Full Panel members Urologist Medical Oncologist Radiologist Radiotherapist Additional: Neurosurgeon General Surgeon Thoracic Surgeon Radiotherapist

5 Nomogram evaluating 5-year competing risks of death in patients with localized renal cell carcinoma. Kutikov A et al. JCO 2010;28: by American Society of Clinical Oncology

6 Kaplan-Meier survival analysis of 3119 patients based on University of California Los Angeles Integrated Staging with localized RCC LR, low risk; IR, intermediate risk; HR, high risk. Chin et al., Rev Urol Winter; 8(1): 1 7.

7 Surveillance protocol following nephrectomy for localized RCC using the University of California Los Angeles Integrated Staging System. Chin et al., Rev Urol Winter; 8(1): 1 7.

8 Why is there no consensus on follow up? Many suggestions not validated No prospective study data available No evidence that timely detection of metastatic disease improves outcome Targeted therapy does not cure how important is a delay in diagnosis of progression? Probably only of value for a very small minority with local recurrence or oligometastatic disease still open for local treatment with curative intent with or without combination of targeted therapy DFS = disease-free survival.

9 Current issues of combining targeted therapy and surgery Is there an adjuvant treatment following nephrectomy to improve DFS and outcome in high-risk disease? What about neoadjuvant therapy to improve outcome? Neoadjuvant/presurgical therapy to downsize and facilitate surgery? Caval thrombus: Primary resection or neoadjuvant therapy? Selection of candidates for cytoreductive nephrectomy? DFS = disease-free survival.

10 Ongoing Phase III Adjuvant Studies for RCC Trial N Patient Characteristics Treatment Arms Treatment Duration Primary End Point S-TRAC: Sunitinib Trial in Adjuvant Renal Cancer Treatment 600 High-risk patients according to UISS Sunitinib Placebo 1 yr DFS ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavorable RCC 1,923 Non-metastatic RCC; disease stage II IV Sunitinib Sorafenib Placebo 1 yr (9 treatment cycles) DFS SORCE: Sorafenib in Patients with Resected Primary RCC at High/Intermediate Risk of Relapse 1,656 Patients with high- and intermediate-risk resected RCC Sorafenib Sorafenib/ Placebo Placebo 3 yrs DFS EVEREST: Everolimus for Renal Cancer Ensuing Surgical Therapy 1,218 Pathological stage intermediate or very high-risk patients with full or partial nephrectomy Everolimus Placebo 9 treatment cycles RFS PROTECT: Pazopanib as an Adjuvant Treatment for Localized RCC 1,500 Patients with moderately high or high risk of relapse with nephrectomy of localized or locally advanced RCC Pazopanib Placebo 1 yr DFS ATLAS: Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients 592 High-risk, non-metastatic RCC with nephrectomy Axitinib Placebo 3 yrs DFS UISS = UCLA integrated staging system. US NIH, 2009, 2010a, 2010b, 2011a, 2011b.

11 What should neoadjuvant targeted therapy for localized RCC achieve? Downsizing - locally confined renal masses for nephron sparing surgery that would otherwise be candidates for nephrectomy - locally advanced renal tumours to allow complete surgical resection Downstaging - reduce extent of locoregional disease and micrometastasis before surgical resection Improve outcome parameters - prolong disease-free and overall survival in renal tumours with highrisk of recurrence

12 Importance of biopsy prior to initiating medical therapy for advanced or irresectible RCC Case of a 56 year old woman with B-cell lymphoma diagnosed as classical RCC on imaging RCC = renal cell carcinoma.

13 Primary Tumor Response to Targeted Agents in 168 Patients With mrcc Prior to sunitinib After 2 cycles of sunitinib Primary tumor maximum overall response to treatment with targeted agents Primary tumor response to a targeted agent according to the amount of response mrcc = metastatic RCC. Abel et al, 2011.

14 SLTS = surgery-limiting tumor site. Bex et al, Largest Decrease of Primary Tumor If Any Occurs in the First 2 4 Mos

15 Case October 2011: After 3 years FUP

16 Case December 2011: 40 % reduction after two cycles of sunitinib: Complete surgical resection with reconstruction of part of the diaphragm Patient currently NED

17 Metastatic Disease presurgical therapy Advantages in primary metastatic disease There is a need for systemic therapy Presurgical therapy may help to identify those who may not benefit from cytoreductive nephrectomy Metastases What is the role of metastasectomy after targeted therapy?

18 5-Year survival rates following complete resection of solitary or oligometastasis Bex et al, in P.N. Lara Jr. and E. Jonasch (eds.), Kidney Cancer, DOI / _8, Springer-Verlag Berlin Heidelberg 2012

19 Case: Male patient, 67 years March 2008: Left transabdominal nephrectomy owing to pt2cn0m0 Fuhrman grade II clear cell RCC Follow-Up Urologist

20 Case June 2010: After more than 2 years FUP by Urologist with CT scan every 6 months:

21 Case Decision at MUP: Advanced retroperitoneal lymphadenopathy Treat as systemic disease with first-line sunitinib 50 mg/day 4/2 Follow-Up Medical Oncologist

22 Case October 2010: After four cycles sunitinib and FUP by Medical Oncologist with CT scan after every two cycles:

23 Case Reason for MUP: Patient had adverse events and Medical Oncologist saw an opportunity to discuss RPLND and keep patient out of toxicity if complete resection would be feasible Decision MUP: Complete RPLND technically feasible Perform surgery

24 Complete remission with TKI in RCC only reported in those with previous nephrectomy n=64 with previous nephrectomy in all cases 61 % in CR after median FUP of 255d 48 % in CR after median FUP of 322d Albiges et al., JCO 2012

25 Case October 2010: RPLND Vital clear cell metastasis, completely resected Follow-Up Medical Oncologist September 2011: Almost 1 year later without any therapy and CT scans at 3-monthly intervals

26 Case Radiologist performed percutaneous RFA Since then, FUP by Medical Oncologist with NED

27 RAND Appropriateness Panel on cytoreductive nephrectomy Symptomatic Primary Good Risk Yes No Poor Risk Yes No CN: IMT Planned CN: Targeted Therapy Metastatic Burden Metastatic Burden Limited Extensive Limited Extensive Appropriate Appropriate Uncertain Uncertain Uncertain Inappropriate RAND = Research and Development; IMT = immunotherapy. Halbert et al, 2006.

28 Potential Reasons Against Nephrectomy Surgical morbidity/mortality may be significant Benefit of nephrectomy only proven in combination with IFN-α Short life expectancy spent mainly recovering from surgery Significant PD during post-operative recovery period may preclude systemic therapy Delays initiation of systemic therapy to treat metastatic disease IFN-α = interferon-alfa; PD = progressive disease. Van der Veldt et al, 2008.

29 Arguments in Favor of Nephrectomy Palliate local symptoms Primary tumor has not responded to systemic therapy and progresses Long interval between progression and death with potential progression of the primary tumor if left in situ Possibility of CR more likely in combination with nephrectomy Benefit of pivotal phase III trials of targeted agents largely demonstrated in nephrectomised patients Adequate histology can be obtained Removal of the source of metastases, growth factors, cytokines, etc CR = complete response. Touijer et al, 2010.

30 Multidisciplinary decision on cytoreductive nephrectomy Information required when planning cytoreductive nephrectomy as part of a multimodality treatment in patients with primary mrcc Age Comorbidity Performance Symptoms of the disease at diagnosis including weight loss Risk factor scores Ability to receive systemic therapy Metastatic burden and its relation to primary tumor volume Resectability of primary tumor and metastasis Likelihood to achieve complete surgical resection of all lesions Histological subtype

31 Evaluation of resectability

32 treated with VEGF-targeted therapy: a population-based study patients intermediate Heng risk months 12 months 2 years another 2 years 45 % on targeted therapy survive 2 years (n=346). Of those 346 another 45 % live another 2 years. % patients alive % patients dead Harshman et al., Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study. The Lancet Oncology Volume 13(9): , 2012

33 treated with VEGF-targeted therapy: a population-based study patients poor Heng risk months 12 months 2 years another 2 years 11 % survive 2 years (n=54). Of those % live another 2 years or 16 patients of 441 live 4 years % patients alive % patients dead Harshman et al., Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study. The Lancet Oncology Volume 13(9): , 2012

34 Predictors of survival in advanced RCC: Long-term results from SWOG Trial S8949 Multivariate proportional hazards model in 191patients, including earlyprogression Survival HR Variable Adjusted for Other Factors in Model (95% CI) p Value Performance status (1 vs 0) 1.70 (1.26, 2.31) Lung metastasis (yes vs no) 0.81 (0.59, 1.11) 0.19 Randomized to nephrectomy 0.79 (0.58, 1.06) 0.12 Alkaline phosphatase (above vs below median) 1.24 (0.92, 1.68) 0.26 Hemoglobin (above vs below median) 0.84 (0.62, 1.14) 0.26 Progression by 90 days (yes vs no) 2.10 (1.50, 2.92) < Survival was defined as starting 90 days after registration. Lara P et al., J Urol 181(2): , 2009 Progression within first 90 days: Yes vs. No HR 2.10 (1.50, 2.92) <0.0001

35 The Outcome of Patients Treated with Sunitinib Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer Patients with MSKCC intermediate risk and absence of progression at metastatic sites following pretreatment with sunitinib have the longest overall survival after cytoreductive nephrectomy Powles et al, European Urology 2011.

36 CARMENA Phase III Study of Sunitinib Only Vs. Nephrectomy Followed by Sunitinib Metastatic clear cell RCC N = 576 Nephrectomy Sunitinib 50 mg/day (schedule 4/2) N Primary objective: Is sunitinib alone non-inferior to nephrectomy plus sunitinib in terms of OS? R A N D O M I Z A T I O Sunitinib 50 mg/day (schedule 4/2) Biswas et al, 2009; US NIH, 2010c.

37 SURTIME, a EORTC-GU Phase III Study Investigating the Sequence of Nephrectomy and Sunitinib Patients with synchronous mrcc and primary tumor in situ N = 458 Primary end point: PFS R A N D O M I Z A T I O N Nephrectomy Sunitinib 50 mg/day (schedule 4/2) Secondary end points: OS, association with prognostic gene and protein expression profiles Sunitinib 50 mg/day (schedule 4/2) Nephrectomy Biswas et al, 2009; US NIH, 2010d.

38 Recommendations for a RCC multidisciplinary tumour board Presence of at least urologist, radiologist, medical oncologist, pathologist and radiotherapist Meet regularly and document decisions Make use of prognostic nomograms for locally confined and advanced disease to tailor follow up and therapy Decisions on integrating surgery with targeted therapy are complex. The team has to be aware of prognostic scores AND conditions affecting surgery Decisions should follow evidence whenever appropriate and available Agree on and document transfer of care between specialists if necessary or have physician assistants (nurse practitioners) keep track of the patient DFS = disease-free survival.