Cytoreductive nephrectomy in the targeted therapy era

1. Cytoreductive nephrectomy in the targeted therapy era קבוצה 6

2. At presentation 25% will have locally advanced or mts 20-30% of local disease will progress to advanced disease despite surgical excision Poor Survival Natural history of RCC

3. Treatment of metastatic RCC Resistant to conventional chemotherapy and radiotherapy Immunotherapy – IFN-alfa , IL-2: - low response rate - few complete responses Targeted therapy

4. Multi modal therapy ?? CN in targeted therapy era?? Before/ after therapy???

5. Historical evidences in favor CN Retrospective studies improved survival with acceptable M&M

6. CN & immunotherapy vs. immunotherapy alone 2 randomized controlled studies in 2001: SWOG (nejm) – 2 arms of 123 Pts. Median survival - 11.1m Vs 8.1 m Response rate of 31% Vs 6% EORTC (Lancet) 2 arms 42/43 Median survival 17m Vs 7m Response rate 32% Vs 4.7%

7. CN & immunotherapy - 2001 combined Morbidity – 5.2% Mortality – 1.4% Time to IFN – 19 days 5.6 Vs 1.8% did not receive immunotherapy 1st line treatment and standard of care

8. Mechanism for survival benefit in CN Immune dysfunction in RCC “Immunologic sink” for antibodies & lymphocyte Tumor burden Proangiogenic agents (GF, vegf, pdgf, fgf) secreted by the tumor

9. Patients selection Prognostic factors In mts RCC (Motzer): ps , Hgb, plt LDH, Ca, albumin

10. Contraindications for CN Absolute – serious co morbid, unresectable poor ps

11. Targeted therapy era Sunitinib Vs INF alpfa in mts RCC Motzer nejm 2007

12. Targeted therapy era Sorafenib Vs placebo in clear cell RCC (Escudier nejm 2007)

13. Is CN necessary? CN is often selected with systemic therapy as 1st line of treatment. in all the phase 3 studies , the majority of patients have had CN Motzer – 90% Escudier – “most of patients” No level one evidence in favour of CN in targeted therapy

14. Ongoing trials - Carmena

15. Ongoing trials - EORTC

16. Pre surgical therapy ?? Small reports, small studies. unresectable tumors & metastatic burden poor and intermediate risk May delay surgery, Wound healing Selection - If responsive to therapy – surgery Best response is early response in the first 90 days If no early response is observed there is no point in continuining treatment (asco-Gu 2010)

17. Local recurrence (campbell) 2% to 4% after radical nephrectomy Risk factors include increasing T stage and locally advanced or node-positive disease . Only about 40% of local recurrences are isolated (in recent studies lower) should be considered for surgical resection, which can provide long-term cancer-free status for about 30% to 40% of patients

18. reports Few reports Wood (J urol 2009) 54 Ptsisolated local recurrence, 69% received systemic therapy (1.8% of cohort). Median cancer specific survival 61 m Factors – histology (sarcomatoid), size (5cm) , margins status. Mortality 2/54, grade 3 morbidity 8/54

20. conclusion CN in the targeted therapy era in currently being investigated. Current data is based on Pts treated by immunotherapy in suggestive of improved survival in pts treated by CN. Currently patient selection include patients with good preformance status, low metastatic burden good and intermediate risk pts.