1. Renal cell carcinoma Juhász Balázs DEOEC Onkológiai Tanszék

2. 2 The global burden of renal cancer ~ 208,000 cases of renal cancer diagnosed worldwide each year 1 –2% of adult malignancies 1 –Annual mortality: ~102,000 1 –Overall lifetime risk (US alone): 1.38% (1 in 72) 2 Incidence and mortality increase with age –Median age at diagnosis (US): 65 years 2 More common in men than in women (~1.5:1.0) 1,2 Incidence highest in developed countries –51,190 new cases diagnosed in the US alone in 2007 3 Lower incidence in Asia and Africa ~ 90% of renal tumours are renal cell carcinomas (RCC) 4 1. Ferlay et al. GLOBOCAN 2002 version 2.0 Lyon: IARC Press 2004; 2. Ries et al. SEER Cancer Statistics Review, 1975–2005. Available at: http://seer.cancer.gov/csr/1975_2005/; 3. Jemal et al. CA Cancer J Clin 2007; 57:43–56; 4. ACS Detailed Guide: Kidney Cancer. Available at http://www.cancer.org.

3. 2001–2007-ben bejelentett új daganatos esetek a Nemzeti Rákregiszter adatai alapján; mindkét nem Kásler M. Magyar Oncol 2008.52.21-33 3 Lokalizáció Esetszám Év: 2001 2002 2003 2004 2005 2006 2007 1 Tüdő (C33–C34) 11 620 11079 10 571 10 042 10 161 10 48110431 2 Bőr egyéb* (C44) 9 555 9751 9593 9923 11 036 11 080 9840 3 Colorectalis (C18–C21) 8947 8712 8658 8841 9062 9022 8762 4 Emlő (C50) 7448 8551 8400 7744 7788 7585 6990 5 Ajak és szájüreg (C00–C14) 3894 3771 3628 3815 3890 3686 3539 6 Prosztata (C61) 2839 3102 4396 4031 4027 3774 3015 7 Nyirok- vérképzőr. (C81–C95) 3466 3036 3148 3271 3354 3511 3381 8 Húgyhólyag (C67) 2387 2515 2679 2502 2716 2772 2631 9 Gyomor (C16) 2604 2446 2362 2511 2354 2356 2258 10 Vese (C64–C66, C68) 2220 2209 2198 2246 2253 2223 2271 Összesen: 76321 76027 75801 75185 77438 7738975117 Összesen C44 nélkül: 66766 66276 66208 65262 66402 6630965277

4. 4 Risk factors for RCC Smoking 1–3 Occupational exposure 1,3 Petroleum products Asbestos Herbicides Solvents Obesity 1,3 von Hippel-Lindau (VHL) syndrome Tuberous sclerosis Hereditary papillary RCC 1. ACS Detailed Guide: Kidney Cancer. Available at: http://www.cancer.org; 2. NCI Renal Cell Cancer Treatment PDQ. Available at: http://www.cancer.gov; 3. McLaughlin and Liworth. Semin Oncol 2000; 27:115–123. Genetic factors 1–3

5. 5 RCC clinical presentation Classic presentation at diagnosis –Classic triad: Flank pain, hematuria, palpable abdominal mass 1,2 –Systemic symptoms: weight loss, fever, sweating, hypecalcaemia, hypertension In the majority of cases, RCC remains occult for most of its course 2 ~ 40% of patients present with advanced disease at diagnosis 3 –Prognosis is poorest in patients with metastatic disease 4 25%-50% of patients treated for localized disease experience recurrence 5 1. Cohen and McGovern. N Engl J Med. 2005;353:2477-2490; 2. Curti. JAMA. 2004;292:97-100; 3. Zisman et al. J Clin Oncol. 2002;20:4559-4566; 4. American Cancer Society. Cancer Facts & Figures 2008; 5. Janzen et al. Urol Clin North Am. 2003:30:843-852.

6. Diagnosis - CT

8. Capsula fibrosa Capsula adiposa Gerota fascia

10. 10 RCC clinical staging Stage at diagnosisIIIIIIVIV Patients diagnosed, % 1 49111624 5-year survival rates, % 2 96826423 1.Kane et al. Cancer. 2008;113:78-83; 2. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer, v.1.2008; http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. 25%-50% of patients treated for localized disease experience recurrence 2 The NCCN and EAU have established treatment algorithms for RCC

11. 11 Localized renal cell carcinoma current treatments Surgery ({open or laparoscopic} radical or partial nephrectomy) is used for localized RCC 1 –Potentially curative for patients with early-stage disease (e.g., stages I, II, III) Ongoing monitoring of these patients is critical, because ~ 25%-50% will relapse 2 –May be used for palliation or in combination with other treatments in advanced, metastatic disease Non-surgical techniques/approaches may be used for small tumors –Cryoablation, radiofrequency and high-intensity focused ultrasound ablation 3 1. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer,v.1.2008; 2. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp; 3. Janzen et al. Urol Clin North Am. 2003;30:843-852.

12. OEP

13. DEOEC Urológia Kinika

14. DEOEC Urológia Klinika

15. 15 Histological classification of human renal epithelial neoplasms VHL = von Hippel-Lindau FH = fumarate hydratase BHD = Birt-Hogg-Dube Modified from Linehan et al. J Urol. 2003;170:2163-2172. Clear cellNon-clear cell TypeClear cellPapillary type 1Papillary type 2ChromophobeOncocytoma Approximate incidence 75%5%10%5% Associated mutations VHLc-MetFHBHD Proximalis nephron <= => Distalis nephron

16. Follow-up 16 Every 6 months for 2 years, then annually for 5 years: - hematology, chemistry At 4-6 months, then as indicated: - abdominal / renal ultrasound and chest X-ray or - abdominal and chest CT NCCN guidelines. Kidney Cancer v.2.2011

17. Metastatic renal cell carcinoma (mRCC) TNM IV. stadium ~24% of patient Site of metastasis –lung: 75% –Soft tissue:36% –Bone:20% –Liver:18% –Skin: 9% –CNS: 9% 17

18. Adipose Adrenal Blood vessel Bone Bone marrow Breast Cervic CNS Colorectal Endometrium Oesophagus Gallbladder Head & neck Heart Kidney Liver Lung Lymphoid Muscle Myometrium Neuroendocrine Ovary Pancreas Pituitary Placenta Prostate Skin Small intestine Soft tissue Stomach Testis Thymus Thyroid Urinary WBC 6,000 5,000 4,000 3,000 2,000 1,000 0 Normal Diseased Invasive cancers Expression of VEGF in ~6,500 tissue specimens (GeneLogic/Affymetrix ® )

19. 19 VHL, HIF-1 and angiogenesis 1. Costa and Drabkin. Oncologist 2007; 12:1404–1415; 2. Patel et al. Clin Cancer Res 2006; 12:7215–7220; 3. Decker et al. Cancer Genet Cytogenet 1997; 93:74–83; 4. Kim and Kaelin. J Clin Oncol 2004; 22:4991–5004. The kidney is a highly vascularized organ –HIF-1/2 and HIF target genes (including VEGF) upregulated in ≥ 50% of clear cell RCC 1 Inhibition of pathways downstream of VHL can interfere with angiogenesis 3 –VEGF antibodies –VEGFr-TKIs Oxygen HIF-1α Ubiquitination and degradation HIF-1β VEGF-A PDGF EPO Mutated pVHL X Angiogenesis VHL proteins cannot bind HIF-1α, which escapes proteolysis 2,4 Increased transcription X

20. pVHL: Normoxia-hypoxia 20

21. A vascularis endothel sejtek aktivációja Tumor sejt Házigazda sejt Mitoticus orsó orsó Szignál Transz- dukciós kaszkád Proliferáció Invázió Migrácó Membrán degradáció Permeabilitás Kapillris fomáció VascularisEndothelSejtVEC

22. Endothelialis sejtek proliferációja, migrációja és differenciálódása

23. Az új erek stabilizációja/érése

24. Endothel proliferáció kapilláris képződés periciták endothel sejt tumor sejtek Permeábilitás  Proliferáció  Migráció  Adhézió  Túlélés  Permeábilitás  Proliferáció  Migráció  Adhézió  Túlélés 

25. 25 Tumor blood vessel endothelial cell membrane Modified from Rini and Small. J Clin Oncol 2005;23:1028-1043. Tumor cell membrane VEGFR PI3K AKT Raf Mek Ras VEGFR P P P P Erk Anti-angiogenics mechanism of action Nucleus Transcription Factors Cell adhesion Cell survival Cell proliferation Apoptosis Cell differentiation Angiogenesis P P P PDGFR P P P P P EGFR PDGFR P P P P P P P P sorafenib/ sunitinib Pericyte sorafenib sorafenib/ sunitinib bevacizumab mTOR

26. A különböző kináz célpontok elleni aktivitások különböző hatékonyságot és toxicitási profilt eredményeznek pazopanibsorafenibsunitinib 10  M 1  M 100 nM 10 nM 1 nM KdKd 1. Kumar et al. Br J Cancer 2009;101:1717–23. Figure adapted from Karaman et al. Nat Biotechnol 2008;26:127–32. K d : disszociációs konstans

27. 27 Treatments for mRCC 1980s1990s2000s 828384858687888990919293949596979899000102030405060708 Cytokines: immunotherapy: IL-2 and IFN-α first to report activity 1 High-dose IL-2: FDA-approval based on Phase II data VHL tumour suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors 2 Sorafenib and sunitinib: EMEA approval Temsirolimus: EMEA-approval Bevacizumab + IFN-  : EMEA-approval 1. Snow et al. Urology 1982; 20:177–181; 2. Latif et al. Science 1993; 260:1317–1320; 3. Yang et al. N Engl J Med 2003 July 31; 349(5): 427-434. Bevacizumab: Data established activity of anti- angiogenic agents in RCC 3 FDA approvals 2006: sorafenib, sunitinib and temsirolimus 2009: everolimus 09 Everolimus: FDA approval

28. Kane et al. Clin Cancer Res. 2006;12:7271, Gore et al. ASCO 2008, Nexavar PI, Figlin et al. ASCO 2008, Escudier ASCO 2008; Escudier et al. Lancet 2007;370:2103 Median OS IFN Figlin ASCO 2008 IFN Kane 2006 Nexavar Torisel Bevacizumab + IFN 2004- Nowadays Time (months) Best supportive care Temsirolimus SUTENT INF-α+ IL-2+5-FU 26,4* 21,8 23,3 NS 21,3 18,7 18,5 10,9 (MSKCC>3) 7,3 7-9 INF-α INF-α+ bevacizumab INF-α Overall survival in mRCC first line treatment (MSKCC>3) (MSKCC: 0-2)

29. Median PFS Kane et al. Clin Cancer Res. 2006;12:7271, Gore et al. ASCO 2008, Naxavar PI, Figlin et al. ASCO 2008, Escudier ASCO 2008 Progression free survival in mRCC first line treatment Escudier ASCO 2008 Figlin ASCO 2008 Multiple studies Torisel PI Gore ASCO 2008 Kane 2006 Time(Months) Nexavar PI CALGB 90206 Best supportive care INF-α+ IL-2+5-FU Temsirolimus Sunitinib Bevacizumab + INF-α Sorafenib Bevacizumab + INF-α INF-α 2004-Nowadays 11,0 10,2 8,5 5,7 (no indication in first line) 5,5 (MSKCC>3) 5,3 3-5 2-3 11,1 Pazopanib

30. 30 Cytokines 1980s1990s2000s 828384858687888990919293949596979899000102030405060708 Cytokines: immunotherapy: IL-2 and IFN-α first to report activity 1 High-dose IL-2: FDA-approval based on Phase II data VHL tumour suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors2 Sorafenib and sunitinib: EMEA approval Temsirolimus: EMEA-approval Bevacizumab + IFN-  : EMEA-approval 1. Snow et al. Urology 1982; 20:177–181; 2. Latif et al. Science 1993; 260:1317–1320; 3. Yang et al. N Engl J Med 2003 July 31; 349(5): 427-434. Bevacizumab: Data established activity of anti- angiogenic agents in RCC3 FDA approvals 2006: sorafenib, sunitinib and temsirolimus 2009: everolimus 09 Everolimus: FDA approval

31. 31 Cytokines in advanced RCC: IFN-  IFN-α produced a modest but significant OS prolongation vs medroxyprogesterone acetate (P = 0.017) 1 Mainly effective in patients with good PS, prior nephrectomy and metastasis confined to the lung 2 Used broadly in clinical practice 1. Medical research Council Renal Cancer collaborators. Lancet 1999 353:14–17; 2. Motzer and Russo J Urol 2000; 163:408–417. Efficacy vs comparator n Median PFS, months Median OS, months n* CR at 6 months, % PR at 6 months, % IFN-α16748.581211 Medroxyprogesterone acetate 168365607 *Patients for whom data were available.

32. Motzer féle kockázati faktorok mRCC-ben Kockázati faktorok az mRCC elsővonalbeli kezelésekor –LDH > 1.5 X a normal érték felett –Hemoglobin < a normal érték alatt –Korrigált calcium > 10 mg/dl –Diagnózistól az első kezelésig eltelt idő < 1 év –ECOG performance status 1 (  Karnofsky score < 80) Kockázati faktorokra alapozott prognosztikai csoportok Jó: 0 kockázati faktor Átmeneti vagy közepes: 1 vagy 2 kockázati faktor Rossz: 3 vagy több kockázati faktor (MSKCC /Memorial Sloan-Kettering Cancer Center/ rizikó csoport) Az Egészségügyi Minisztérium szakmai protokollja a vese daganatok ellátásáról Készítette: Az Urológiai, Sugárterápiás és Onkológia, Radiológia és Nucleáris Medicina Szakmai Kollégium

33. 33 MSKCC risk criteria for mRCC in patients treated initially with IFN-α MSKCC parameterAt-risk group 1 Karnofsky performance status< 80% Serum lactate dehydrogenase> 1.5 x ULN Hemoglobin< LLN ‘Corrected’ serum calcium> 10 mg/dL (2.6 mmol/L) Time from initial diagnosis to IFN- α< 1 year MSKCC risk group 1 No. of factors, n No. patients, % Median survival, months (95%CI) 1yr, % 3yr, % Favourable01829.6 (20.9-37.8)8345 Intermediate1-26213.8 (12.4-15.9)5817 Poor3+204.9 (4.3-6.3)202 ULN = upper limit of normal LLN = lower limit of normal 1. Motzer et al. J Clin Onc 2002: 20; 289-96.

34. 34 Anti-angiogenic agents 1980s1990s2000s 828384858687888990919293949596979899000102030405060708 Cytokines: immunotherapy: IL-2 and IFN-α first to report activity1 High-dose IL-2: FDA-approval based on Phase II data VHL tumour suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors 2 Sorafenib and sunitinib: EMEA approval Temsirolimus: EMEA-approval Bevacizumab + IFN-  : EMEA-approval 1. Snow et al. Urology 1982; 20:177–181; 2. Latif et al. Science 1993; 260:1317–1320; 3. Yang et al. N Engl J Med 2003 July 31; 349(5): 427-434. Bevacizumab: Data established activity of anti- angiogenic agents in RCC 3 FDA approvals 2006: sorafenib, sunitinib and temsirolimus 2009: everolimus 09 Everolimus: FDA approval

35. Tirozine kinase inhibitor (TKI) 35

36. 36 Event Sorafenib, %Placebo, % All gradesGrade 3 or 4All gradesGrade 3 or 4 Fatigue375284 Diarrhea432131 Nausea23<1191 Vomiting161121 Rash or desquamation40116<1 Hand-Foot syndrome 30670 Alopecia27<130 Escudier et al. N Engl J Med 2007;356:125-134. Sorafenib in mRCC: treatment-related adverse events

37. 37 Escudier et al. Paper presented at: The European Cancer Conference; October 30-November 3, 2005; Paris, France. hand-foot syndrome - HFS

38. 38 Sunitinib vs IFN-α best tumor response Independent central review Investigator assessment Sunitinib (n = 335) IFN-  (n = 327) Sunitinib (n = 374) IFN-  (n = 373) Response (RECIST) No. of patients, n (%) Objective response 103 (31)20 (6)137 (37)33 (9) Complete response 001 (<1)0 Partial response 103 (31)20 (6)136 (36)33 (9) Stable disease 160 (48)160 (49)176 (47)213 (57) PD or not evaluable 72 (21)147 (45)61 (16)127 (34) Motzer et al. N Engl J Med 2007;356:115-124.

39. 39 Motzer et al. N Engl J Med 2007;356:115-124. No. at risk, n Sunitinib: IFN-α: 37523590322 37515242180 Independent review Median PFS Sunitinib = 11 months (95% CI, 10 to 11); IFN-  = 5 months (95% CI, 4 to 6) Sunitinib: Kaplan-Meier estimates of PFS

40. 40 Sunitinib in mRCC: treatment-related adverse events Event Sunitinib, %IFN-α, % All gradesGrade 3 or 4All gradesGrade 3 or 4 Diarrhea535 / 0120 Fatigue517 / 05111 / 1 Nausea443 / 0331 / 0 Stomatitis251 / 02 Nausea 443 / 0331 / 0 Hypertension 248 / 011 / 0 Hand-Foot Syndrome 205 / 010 Mucosal inflammation202 / 011 / 0 Rash191 / 161 / 0 Asthenia174 / 0204 / 0 Dry Skin161 / 050 Skin discoloration16000 Changes in hair color14000 Epistaxis121 / 010 Pain in a limb111 / 030 Headache111 / 0140 Dry Mouth11061 / 0 Decline in Ejection Fraction102 / 031 / 0 Pyrexia71 / 0340 Motzer et al. N Engl J Med 2007;356:115-124.

41. 41 Sunitinib in mRCC: haematological toxicities Event Sunitinib, %IFN-α, % All gradesGrade 3 or 4All gradesGrade 3 or 4 Leukopenia780562 / 0 Neutropenia7211 / 1467 / 0 Anemia713 / 1644 / 0 Lymphopenia6012 / 06322 / 0 Thrombocytopenia658 / 0210 Motzer et al. N Engl J Med 2007;356:115-124.

42. 42 New front line alternatives: mTOR inhibitor for poor risk patients 1980s1990s2000s 828384858687888990919293949596979899000102030405060708 Cytokines: immunotherapy: IL-2 and IFN-α first to report activity1 High-dose IL-2 FDA-approval: based on Phase II data VHL tumour suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors2 Sorafenib and sunitinib: EMEA approval Temsirolimus: EMEA-approval Bevacizumab + IFN-  : EMEA-approval 1. Snow et al. Urology 1982; 20:177–181; 2. Latif et al. Science 1993; 260:1317–1320; 3. Yang et al. N Engl J Med 2003 July 31; 349(5): 427-434. Bevacizumab: Data established activity of anti- angiogenic agents in RCC3 FDA approvals 2006: sorafenib, sunitinib and temsirolimus 2009: everolimus 09 Everolimus: FDA approval

43. 43

44. 44 Treatment algorithm for advanced or metastatic RCC SettingFirst lineOptions (≥ Level 2) Treatment-naïve MSK: Good or intermediate risk* Sunitinib or Pazopanib HD IL-2 Bevacizumab + IFN-  MSK: Poor risk*TemsirolimusSunitinib Previously treated (≥ 2nd Line) Cytokine refractory Sorafenib, Pazopanib Sunitinib, Bevacizumab Refractory to VEGF/VEGFR Inhibitors mTOR inhibitors Sequential TKI’s or VEGF Inhibitor Refractory to mTOR inhibitors Investigational * Motzer et al. J Clin Onc, 1999: 2530; Adapted from Atkins; ASCO 2006; Bukowski ASCO 2007.

46. NCCN ajánlás – mRCC elsővonal (2010. v2.)

47. NCCN ajánlás – mRCC másodvonal (2010. v2.)

48. 48

49. 49 Summary RCC is now recognized as a malignancy in which the paradigm of targeted treatment is both rational and effective 25 years of clinical investigation have provided significant clinical impact –Cytokine therapy with high dose IL-2 may be appropriate for selected patient subsets –Therapy with TKIs and VEGF inhibitors produces tumor regressions, increased PFS and survival, but progression occurs –Treatment with the first mTOR inhibitor is clinically effective in poor risk patients Further refinement of the current treatment paradigm requires –Development of therapy for VEGFr-TKI and mTOR resistant patients. New target: FGF-FGFR –Integration of biomarker data into current clinical classification schemes to refine patient selection –Integration of new/novel agents in clinical trials into treatment paradigm

50. 50