Surgery Before Systemic Therapy in metastatic RCC Viraj Master MD, - PDF document

Winship Cancer Institute of Emory University Surgery Before Systemic Therapy in metastatic RCC Viraj Master MD, PhD, FACS Department of Urology Emory University Disclosures • Nothing relevant to report. 1

Cytoreductive Nephrectomy – Trial Results • EORTC • NTX +IFN vs IFN • SWOG • Time to progression: • NTX +IFN vs IFN 5 vs 3 months, p=.04 • Difference in • Median survival: comparison groups 17 vs 7 months, p=.03 • Median survival: 11 vs. 8 months, p=.05 Pooled Analysis 331 patients 13.8 months NTX + IFN vs 7.8 months IFN alone, p=.0002 Overall survival advantage ~6 months for the entire group Flanigan RC, J Urol 2004 NTX=nephrectomy Selection of Patients for Cytoreductive Nephrectomy (CN) • MD Anderson • 1991 ‐ 2007 • 566 patients underwent CN • 110 received medical tx alone • Multivariate analysis conducted Culp SH Cancer 2010 2

Selection of Patients for Cytoreductive Nephrectomy (CN) • Albumin < normal • LDH > normal • cT3/T4 • Symptomatic from mets • Liver metastases • Retroperitoneal Adenopathy • Supradiaphragmatic adenopathy Culp SH Cancer 2010 Selection of Patients for Cytoreductive Nephrectomy (CN) • Albumin < normal • LDH > normal • cT3/T4 • Symptomatic from mets • Liver metastases • Retroperitoneal Adenopathy • Supradiaphragmatic adenopathy Culp SH Cancer 2010 3

Metastasectomy ‐ Rationale • Old view – Locally confined cancers curable with local therapy – Distant metastatic disease managed with systemic therapy, no role for local therapy Metastasectomy ‐ Rationale • ‘New’ view – Integrating therapies, local, regional and systemic may provide for better survival – Prototype disease: Testis Cancer – Old view – Locally confined cancers curable with local therapy – Distant metastatic disease managed with systemic therapy, no role for local therapy 4

Advanced RCC 2002 6 th ed AJCC RCC Staging – Stage IV 5

2002 6 th ed AJCC Staging • Capitanio examined 310 patients with clinical T4N0 ‐ 2 RCC surgery (246) or no surgery (64). • + surgery med. survival 48mo • ‐ surgery med surv. 6 mo (HR 2.2) • The effect of surgery for those patients (125) who had T4N0 disease even stronger, with a hazard ratio of 3.7, with a cancer specific mortality of approximately 40% at 10 years Capitanio BJUI 2010 2010 7 th ed AJCC RCC staging – Stage IV 6

Which is better for prognosis? ‘Old’ 2002 TNM staging ‘New’ 2010 TNM staging Johnson, Master unpublished 7

Increasing Incidence of RCC (localized), BUT no change in regional or distant disease Rise in poorly differentiated cancers 8

C-reactive protein 9

• 24 studies, 4100 patients • Elevated CRP level independently associated – higher stage RR 2.90 , 95% CI 2.52–3.32, P<0.00001 – higher grade RR 4.31 , 95% CI 3.35–5.56, P<0.00001 • Overall survival HR 1.5 , 95% CI 1.09–1.93, P< 0.00001 • cancer-specific survival HR 3.91 , 95% CI 2.18–5.64, P<0.00001) • localized RCC, elevated CRP level was associated with – Decreased CSS (HR 3.49, 95% CI 2.93–4.05, P<0.00001 – progression-free survival (HR 3.29, 95% CI 2.91–3.67, P<0.00001 • metastatic RCC, elevated CRP level was associated with – Decreased overall survival (HR 2.37, 95% CI 2.14–2.60, P<0.00001 – Decreased CSS (HR 3.70, 95% CI 3.19–4.22, P<0.00001 • ccRCC histology only, elevated CRP level associated with – higher stage RR 2.92, 95% CI 2.25–3.80, P<0.00001 – CSS HR 2.60, 95% CI 2.32–2.88, P<0.00001 – progression-free survival HR 1.21, 95% CI 0.94–1.47, P<0.00001 10

Experience matters! • All-Canada study • 816 cases over 20 yrs • In hosp mortality 7% • 75% deaths occurred in the first 2 cases of surgeon experience • Overall complication profile 78% • Increasing surgeon volume, not hospital volume associated with lower mortality on MVA Toren, P: Urology 2013 82:572 Quality of Pathology Reporting – Implications for Nomograms • Evaluated 344 pathology reports in LA (2002- 2006) from community, teaching and cancer center hospitals • 10% -no data on histology • 20% -no data on Fuhrman grade • 30% (27.8%) T-stage absent • Only 60% met CAP criteria for tumor classification, margin, size and grade Shuch B, BJUI 2010 11

Quality of Pathology Reporting – Implications for Nomograms • Evaluated 344 pathology • CAP criteria satisfied reports in LA from – 54% community community, teaching and – 71% teaching cancer ctr hospitals – 75% cancer center • 10% -no data on histology • Implications for using • 20% -no data on Fuhrman prognositic nomograms grade – SSIGN 16% • 30% (27.8%) T-stage absent – Kattan 12% • Only 60% met CAP criteria for tumor classification, • UCLA-UISS 66% margin, size and grade Shuch B, BJUI 2010 A quote for Surgeons/ Interventionalists "From inability to let alone; from too much zeal for the new and contempt for what is old; from putting knowledge before wisdom, and science before art, and cleverness before common sense; from treating patients as cases; and from making cure of the disease more grievous than the endurance of the same, Good Lord, deliver us.” -Sir Robert Hutchinson Courtesy Niall Galloway FRCS BMJ 1953 1:671 12

C-Reactive Protein in patients with advanced mRCC: Usefulness in identifying patients most likely to benefit from initial nephrectomy • Retrospective • 181 patients – 52 immuno/TKI only – 129 cytoreductive NTX • CRP measured preop • ROC curves to identify 3 ranges (<18, 18-67, >67) Ito H, BMC Cancer 2013 12:337 Potential Influence of Surgery? (not randomized – selection bias) Surgery NO Surgery Median OS >4 yrs Median OS <1 yrs Ito H, BMC Cancer 2013 12:337 13

Cytoreductive Nephrectomy in metastatic RCC patients with non-clear cell histology • SEER, 4914 mRCC • 64% underwent patients diagnosed with cytoreductive NTX metastatic RCC between • non-clear cell histology pts 2000- 2009 with CN displayed lower • 591 non-clear mRCC RCC-specific and all-cause mortality than those who did • Median F/U 20 mos not (p<.001 in both cases) • CSS • Adjusted for year, race, gender, location, histology, CN decreased both – CSS (HR 0.62, 95% CI 0.48- 0.80, p<.001) – OS (HR 0.45, 95% CI 0.37- 0.55, p<.001) Aizer AA BJU Int 2014 Cytoreductive Nephrectomy in metastatic RCC patients with non-clear cell histology still relevant in era of TKI’s? • Results unchanged when looking at patients diagnosed CSS 2006-2009 (Targeted therapy era, Sutent/Nexavar Dec 2005) • Reductions of 38% and 55% respectively, when CN performed • CSS HR 0.50, 95% CI 0.34- 0.72, p<.001 • OS HR 0.43, 95% CI 0.31- 0.59, p<.001 • Reductions of 38% and 55% respectively, when CN performed • Most benefit for chromophobe, then papillary, collecting duct Aizer AA BJU Int 2014 14

Cytoreductive Nephrectomy in metastatic RCC patients with non-clear cell histology still relevant in era of TKI’s? • Results unchanged when looking at patients diagnosed 2006-2009 (Targeted therapy era, Sutent/Nexavar Dec OS 2005) • Reductions of 38% and 55% respectively, when CN performed • CSS HR 0.50, 95% CI 0.34- 0.72, p<.001 • OS HR 0.43, 95% CI 0.31- 0.59, p<.001 • Reductions of 38% and 55% respectively, when CN performed • Most benefit for chromophobe, then papillary, collecting duct Aizer AA BJU Int 2014 Conclusions ? 15