Optimal Treatment of ct1b Renal Mass in Patient with Normal GFR: a Role for Radical Nephrectomy? Steven C. Campbell, MD, PhD Program Director, Vice Chairman Department of Urology Center for Urologic Oncology Glickman Urological and Kidney Institute Cleveland Clinic
Does Rad Nx make sense in this patient? 57-yr-old female L renal mass: 6 cm, down to hilum R kidney normal and no proteinuria SCr 0.79, egfr 82 RFS: L 42%, R 58% Rad Nx would yield GFR 55 Metastatic evaluation negative Otherwise healthy
Management Options Radical Nephrectomy (Rad Nx) versus Partial Nephrectomy (PNx) Campbell SC, Derweesh IH, Lane BR, Messing EM: The management of a ct1b renal tumor in the presence of a normal contralateral kidney. J Urol, 289:1198-202, 2013. Tomaszewski JJ, Smaldone MC, Uzzo RG, Kutikov A: Is RN a legitimate therapeutic option for patients with renal masses amenable to NSS. BJU International, 2014.
Weighing the Value of PNx Survival Advantage? Renal Oncologic PNx Function Morbidity Rad Nx
Tumor Size: Oncologic Potential Malignant Clear cell High Grade 0-4 cm 76.7% 50.5% 12.5% 4-7 cm 90.5% 73.2% 29.8% > 7 cm 93.7% 83.0% 62.1% Frank, et al.: J Urology, 170:2217, 2003
Local Recurrence Free Survival for PNx Mayo Clinic Tumor Size (cm) N 5 yr LR free survival 10 yr LR free survival 0-1 13 100 100 1-2 142 97.4 96.0 2-3 200 98.9 97.4 3-4 138 95.3 95.3 4-5 80 88.6 77.5 Crispen et al, J Urol, 180:1912, 2008
Complications after PN MSKCC Stephenson et al, J Urol, 171:130, 2004 Procedure Related: 9.0% PNx vs 3.0% Rad Nx, p = 0.0001 Reintervention: 2.5% PNx vs 0.6% Rad Nx, p = 0.02 Pathologic size/stage predictive of complications EORTC also showed increased complications with PNx in randomized setting Multiple studies show correlation between complications and tumor size and RENAL score: Simhan et al, Euro Urol, 60:724, 2011
The Function Issue: Does it Impact Survival? Meta-analysis of PNx vs. Rad Nx Kim SK, Thompson RH, Boorjian SA, et al., J Urol, 188:51-57, 2012 N = 36 studies, > 40,000 patients analyzed All but one retrospective, almost all subject to selection bias Advantages of PNx based on pooled estimates: 61% risk reduction for severe CKD, p<0.0001 19% risk reduction all cause mortality, p<0.0001 29% risk reduction in cancer specific mortality, p=0.0002 Shuch et al, CANCER, 119:2981-9, 2013, also supports strong selection bias in this literature
Selection Bias in Observational Studies Propensity Analyses? It is likely that no degree of sophisticated ex post facto statistical manipulation can eliminate the unmeasured or unqauntified biases inherent to observational study designs Tomaszewski JJ, Smaldone MC, Uzzo RG, Kutikov A: Is RN a legitimate therapeutic option for patients with renal masses amenable to NSS. BJU International, 2014.
Prospective Randomized Trial Elective PNx vs. Rad Nx EORTC 30904: 268 PNx vs. 273 Rad Nx Solitary tumor, 5.0 cm, normal contralateral kidney: ideal population for PNx Advantage for Rad Nx related to lower morbidity Severe postop bleed: 3.1% for PNx vs 1.2% for Rad Nx Urinary Fistulae: 4.4% for PNx vs 0.0% for Rad Nx Reoperation: 4.4% for PNx vs 2.4% for Rad Nx Advantage for PNx with respect to better renal function Mean SCr: 1.2 for PNx vs 1.4 for Rad Nx What about overall survival? Van Poppel et al.: European Urology, 59:543-552, 2011
EORTC 30904 10 yr overall survival (median f/up 9.3 years): 81% for Rad Nx vs 76% for PNx (p = 0.03) No survival advantage for PNx! - Multicenter study, perhaps quality of PN was variable??? - Study closed due to poor accrual - Renal function was not analyzed in comprehensive manner - Crossover: some patients switched groups after randomization (about 10%) - Only 9.3 years of follow-up Impact: despite limitations, this was a randomized study: very provocative data No matter how you want to interpret this, you have to concede: Suggests functional advantage related to PNx may not be as great as previously thought
MP44-04 Milan Italy GFR >60 prior to surgery CONCLUSIONS: When considering long-term survival and functional outcomes in patients with a clinical T1a-T1b mass and normal renal function before surgery, PNx protects from CKD but does not impact on OCM relative to Rad Nx.
Rad Nx: Normal Contralateral Kidney YES Increased Risk of CKD??? Potential Increased Risk of CKD Sequelae, Mortality There may be a difference between: CDK from medical causes: the drivers (HTN, DM, etc) towards CKD are still operative CKD due to surgery: the driver (surgery) is no longer operative
Probability of all-cause mortality All-Cause Mortality: Median Follow-up 9.4 Years Lane BR, Demirjian S, Derweesh IH, Takagi T, Zhang Z, Velet L, Ercole CE, Fergany AF, Campbell SC, European Urology, 68:996-1003, 2015 1.0 0.8 CKD Medical/Surgical CKD-Surgical vs. No CKD P <.001 CKD Surgical CKD-Surgical vs. CKD-Medical/Surgical P <.001 No CKD No CKD vs. CKD-Medical/Surgical P <.001 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Years 1234 1027 883 725 458 224 89 8 CKD-Medical/Surgical 1112 997 929 828 551 301 105 2 CKD-Surgical 1947 1798 1731 1514 1061 599 233 18 No CKD
Probability of 50% drop in egfr or dialysis Progressive Decline of Renal Function 1.0 0.8 CKD Medical/Surgical CKD-Surgical vs. No CKD P <.69 CKD Surgical CKD-Surgical vs. CKD-Medical/Surgical P <.001 No CKD No CKD vs. CKD-Medical/Surgical P <.001 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 Years
5 Year probability for all cause mortality Five-Year Probability of All-Cause Mortality (Adjusted for Age, Gender, Race, Diabetes, Hypertension, and Heart Disease) 0.4 0.3 0.2 0.1 Medical/Surgical Surgical p <.001 10 20 30 40 50 60 New baseline GFR
Multivariable Analysis Stability of Renal Function and Survival 50% Decline GFR or Dialysis All Cause Mortality Non-Renal Cancer Mortality CKD-S vs. no CKD 1.10 (.82-1.49) 1.19 (1.02-1.40) 1.07 (.86-1.32) CKD-M/S vs. no CKD 2.33 (1.76-3.10) 2.01 (1.73-2.33) 1.97 (1.63-2.38) CKD-M/S vs. CKD-S 2.13 (1.59-2.86) 1.69 (1.45-1.96) 1.85 (1.53-2.22) Adjusted for age, gender, race, HTN, DM, and cardiac disease
Surgical Chronic Kidney Disease Appears to be a Distinct Subtype of Chronic Kidney Disease Based on Mortality Risks Following Renal Surgery Ronak Gor, Robert Uzzo, Mohammed Haseebudin, Nikhil Waingankar, Serge Ginzburg, Marc Smaldone, Alexander Kutikov (Fox Chase, PA) Surgically treated patients between 1994 and 2014 PD49-11 CONCLUSION: Developing CKD-S does not portend the same prognosis, as these patients have similar survival characteristics as patients with normal pre and postoperative renal function
Estimated Function at 5 Years after Renal Cancer Surgery Derived from 4,299 pts Rx d surgically for renal mass Incorporates age, gender, comorbidities, preop and postop function Presumes: PN will lose 10% global function, RN will lose 40% Preop Function Preop GFR Intervention GFR < 45 GFR <30 GFR <15 Normal 80 PNx 0.07 <0.01 <0.01 Normal 80 Rad Nx 0.25 0.05 <0.01 CKD 50 PNx 0.48 0.20 0.04 CKD 50 Rad Nx 1.00 0.39 0.12
Estimated 10-Year Non-Renal Cancer-Related Survival Derived from 4,299 pts Rx d surgically for renal mass Incorporates age, gender, comorbidities, preop and postop function Presumes: PN will lose 10% global function, RN will lose 40% Preop Function Preop GFR Age Intervention 10 year Survival Normal 80 54 PNx 0.10 Normal 54 Rad Nx 0.12 Normal 80 72 PNx 0.25 Normal 72 Rad Nx 0.27 CKD 50 54 PNx 0.17 CKD 54 Rad Nx 0.19 CKD 50 72 PNx 0.33 CKD 72 Rad Nx 0.35
Estimated 10-Year Non-Renal Cancer-Related Survival Derived from 4,299 pts Rx d surgically for renal mass Presumes: PN will lose 10% global function, RN will lose 40% Incorporates age, gender, comorbidities, preop and postop function Preop Function Preop GFR Age Intervention 10 year Survival Normal 80 54 PNx 0.10 Normal 54 Rad Nx 0.12 Normal 80 72 PNx 0.25 Normal 72 Rad Nx 0.27 CKD 50 54 PNx 0.17 CKD 54 Rad Nx 0.19 CKD 50 72 PNx 0.33 CKD 72 Rad Nx 0.35
Estimated 10-Year Non-Renal Cancer-Related Survival Derived from 4,299 pts Rx d surgically for renal mass Incorporates age, gender, comorbidities, preop and postop function Presumes: PN will lose 10% global function, RN will lose 40% Preop Function Preop GFR Age Intervention 10 year Survival Normal 80 54 PN 0.10 Normal 54 RN 0.12 Normal 80 72 PN 0.25 Normal 72 RN 0.27 CKD 50 54 PN 0.17 CKD 54 RN 0.19 CKD 50 72 PN 0.33 CKD 72 RN 0.35
Weighing the Value of PNx Survival Advantage??? Renal Oncologic PNx Function Morbidity Rad Nx
Individualize Management for T1b/T2 Renal Tumor Patient related: age, comorbidities, life expectancy Tumor related: size, location, imaging characteristics Function: global function, status of contralateral kidney Patient preference Some patients with ct1b/t2 may be better off with Rad Nx if no preexisting CKD, no proteinuria, and new baseline GFR will be > 40-45, particularly if tumor size/location are not favorable for PNx
2015 Where do we stand? Recent studies blunt the impetus towards PNx Normal Contralateral Kidney, No Proteinuria T1a T1b T2a T2b/T3?? PNx??? Rad Nx??? Will need a randomized trial to resolve this issue for T1b-T2 renal masses