Renal cell carcinoma. Juhász Balázs. DEOEC Onkológiai Tanszék

Renal cell carcinoma Juhász Balázs DEOEC Onkológiai Tanszék

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; 2 4. ACS Detailed Guide: Kidney Cancer. Available at http://www.cancer.org.

2001 2007-ben bejelentett új daganatos esetek a Nemzeti Rákregiszter adatai alapján; mindkét nem Kásler M. Magyar Oncol 2008.52.21-33 Lokalizáció Esetszám Év: 2001 2002 2003 2004 2005 2006 2007 1 Tüdő (C33 C34) 11 620 11079 10 571 10 042 10 161 10 481 10431 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 77389 75117 Összesen C44 nélkül: 66766 66276 66208 65262 66402 66309 65277 3

Risk factors for RCC Smoking 1 3 Herbicides Asbestos Solvents Occupational exposure 1,3 von Hippel-Lindau (VHL) syndrome Genetic factors 1 3 Risk factors for RCC Petroleum products Hereditary papillary RCC Tuberous sclerosis Obesity 1,3 4 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.

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; 5 4. American Cancer Society. Cancer Facts & Figures 2008; 5. Janzen et al. Urol Clin North Am. 2003:30:843-852.

Diagnosis - CT

A vesesejtes carcinoma 1997-es TNM osztályozása PRIMER R TUMOR T0 Nincs primer tumorra utaló adat T1 Tumor <7 cm T2 Tumor >7 cm T3a Vese környezetének invázója T3b Vena cava inferior vagy vesevéna a rekesz alatt T3c Vena cava inferiror a rekesz felett T4A Gerota-fascián túli terjedés NYIROKCSOMÓ ÉRINTETTSÉG (regionális) is) N0 Negatív nyirokcsomók N1 Egy, azonos oldali N2 >1 nyirokcsomó TÁVOLI METASTASIS M0 NincsN M1 Van

Capsula adiposa Gerota fascia Capsula fibrosa

Tumor, nyirokcsomó, metastasis (TNM) stádiumbeosztás vesesejtes carcinomában 1997-es revízió Osztályozás T1 T2 T3 T4 N0 Definíció Tumor < 7 cm és csak a vesére korlátozódik Tumor > 7 cm és csak a vesére korlátozódik A tumor beterjed a fő vénákba v. infiltrálja a mellékvesét v. a vesekörüli szöveteket, de nem haladja meg a Gerota-f. fasciát A tumor a Gerota-f. fascián túl terjed Nincs nyirokcsomó metastasis Stádium 1. stádium 2. stádium 3. stádium 4. stádium T1 T2 T3 T1 T2 T4 Any T Any T TNM NO NO NO N1 N1 N0 N2 Any N MO MO MO MO MO M0 M0 M1 N1 Egyetlen regionális nyirokcsomóban van metastasis N2 Több regionális nyirokcsomóban van metastasis M0 M1 Nincsen távoli metastasis Van távoli metastasis

RCC clinical staging Stage at diagnosis I II III IV Patients diagnosed, % 1 49 11 16 24 5-year survival rates, % 2 96 82 64 23 25%-50% of patients treated for localized disease experience recurrence 2 The NCCN and EAU have established treatment algorithms for RCC 10 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.

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 11 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.

OEP

DEOEC Urológia Kinika

DEOEC Urológia Klinika

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

Follow-up 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 16

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

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 Expression of VEGF in ~6,500 tissue specimens (GeneLogic/Affymetrix ) 6,000 5,000 Normal Diseased Invasive cancers 4,000 3,000 2,000 1,000 0

VHL, HIF-1 and angiogenesis 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 VHL proteins cannot bind HIF-1α, which escapes proteolysis 2,4 VEGF antibodies VEGFr-TKIs HIF-1α X HIF-1β X Mutated pvhl Ubiquitination and degradation HIF-1α Increased transcription 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. 19 Angiogenesis

pvhl: Normoxia-hypoxia 20

A vascularis endothel sejtek aktivációja Házigazda sejt Tumor sejt Proliferáció Invázió Vascularis Endothel Sejt VEC Mitoticus orsó Szignál Transzdukciós kaszkád Migrácó Membrán degradáció Permeabilitás Kapillris fomáció

Endothelialis sejtek proliferációja, migrációja és differenciálódása

Az új erek stabilizációja/érése

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

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

A különböző kináz célpontok elleni aktivitások különböző hatékonyságot és toxicitási profilt eredményeznek K d 1 nm 10 nm 100 nm 1 M 10 M pazopanib sunitinib sorafenib K d : disszociációs konstans 1. Kumar et al. Br J Cancer 2009;101:1717 23. igure adapted from Karaman et al. Nat Biotechnol 2008;26:127 32.

Treatments for mrcc Cytokines: immunotherapy: IL-2 and IFN-α first to report activity 1 VHL tumour suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors 2 Bevacizumab + IFN- : EMEA-approval Temsirolimus: EMEA-approval Everolimus: FDA approval 1980s 1990s 2000s 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 High-dose IL-2: FDA-approval based on Phase II data Bevacizumab: Data established activity of antiangiogenic agents in RCC 3 Sorafenib and sunitinib: EMEA approval FDA approvals 2006: sorafenib, sunitinib and temsirolimus 2009: everolimus 27 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.

7 új hatóanyag 2005 óta 28

Overall survival in mrcc first line treatment Median OS Best supportive care Kane 2006 7-9 INF-α IFN 7,3 (MSKCC>3) 2004- Nowadays Temsirolimus INF-α INF-α+ IL-2+5-FU INF-α INF-α+ bevacizumab Torisel Nexavar Bevacizumab + IFN 10,9 (MSKCC>3) 18,5 18,7 (MSKCC: 0-2) (MSKCC: 0-2) 21,3 23,3 NS (MSKCC: 0-2) (MSKCC: 0-2) INF-α SUTENT IFN Figlin ASCO 2008 21,8 (MSKCC: 0-2) 26,4* (MSKCC: 0-2) Time (months) 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

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

Cytokines Cytokines: immunotherapy: IL-2 and IFN-α first to report activity 1 VHL tumour suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors2 Bevacizumab + IFN- : EMEA-approval Temsirolimus: EMEA-approval Everolimus: FDA approval 1980s 1990s 2000s 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 High-dose IL-2: FDA-approval based on Phase II data Bevacizumab: Data established activity of antiangiogenic agents in RCC3 Sorafenib and sunitinib: EMEA approval FDA approvals 2006: sorafenib, sunitinib and temsirolimus 2009: everolimus 31 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.

Cytokines in advanced RCC: IFN- IFN-α produced a modest but significant OS prolongation vs medroxyprogesterone acetate (P = 0.017) 1 Efficacy vs comparator n Median PFS, months Median OS, months n* CR at 6 months, % PR at 6 months, % IFN-α 167 4 8.5 81 2 11 Medroxyprogesterone acetate 168 3 6 56 0 7 *Patients for whom data were available. Mainly effective in patients with good PS, prior nephrectomy and metastasis confined to the lung 2 Used broadly in clinical practice 32 1. Medical research Council Renal Cancer collaborators. Lancet 1999 353:14 17; 2. Motzer and Russo J Urol 2000; 163:408 417.

Motzer féle kockázati faktorok mrcc-ben (MSKCC /Memorial Sloan-Kettering Cancer Center/ rizikó csoport) 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: Átmeneti vagy közepes: 0 kockázati faktor 1 vagy 2 kockázati faktor Rossz: 3 vagy több kockázati faktor Az Egészségügyi Minisztérium szakmai protokollja a vese daganatok ellátásáról Készítette: Az Urológiai, Sugárterápiás és Onkológia, Radiológia és Nucleáris Medicina Szakmai Kollégium

MSKCC risk criteria for mrcc in patients treated initially with IFN-α MSKCC parameter At-risk group 1 Karnofsky performance status < 80% Serum lactate dehydrogenase Hemoglobin Corrected serum calcium Time from initial diagnosis to IFN- α > 1.5 x ULN < LLN > 10 mg/dl (2.6 mmol/l) < 1 year MSKCC risk group 1 No. of factors, n No. patients, % Median survival, months (95%CI) Favourable 0 18 29.6 (20.9-37.8) 83 45 Intermediate 1-2 62 13.8 (12.4-15.9) 58 17 Poor 3+ 20 4.9 (4.3-6.3) 20 2 1yr, % 3yr, % ULN = upper limit of normal LLN = lower limit of normal 34 1. Motzer et al. J Clin Onc 2002: 20; 289-96.

Anti-angiogenic agents Cytokines: immunotherapy: IL-2 and IFN-α first to report activity1 VHL tumour suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors 2 Bevacizumab Everolimus: FDA + IFN- : approval EMEA-approval Temsirolimus: EMEA-approval 1980s 1990s 2000s 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 High-dose IL-2: FDA-approval based on Phase II data Bevacizumab: Data established activity of antiangiogenic agents in RCC 3 Sorafenib and sunitinib: EMEA approval FDA approvals 2006: sorafenib, sunitinib and temsirolimus 2009: everolimus 35 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.

Tirozine kinase inhibitor (TKI) 36

Sorafenib in mrcc: treatment-related adverse events Event Sorafenib, % Placebo, % All grades Grade 3 or 4 All grades Grade 3 or 4 Fatigue 37 5 28 4 Diarrhea 43 2 13 1 Nausea 23 <1 19 1 Vomiting 16 1 12 1 Rash or desquamation 40 1 16 <1 Hand-Foot syndrome 30 6 7 0 Alopecia 27 <1 3 0 37 Escudier et al. N Engl J Med 2007;356:125-134.

hand-foot syndrome - HFS 38 Escudier et al. Paper presented at: The European Cancer Conference; October 30-November 3, 2005; Paris, France.

Sunitinib vs IFN-α best tumor response Independent central review Sunitinib IFN- Sunitinib (n = 335) (n = 327) (n = 374) Response (RECIST) No. of patients, n (%) Investigator assessment IFN- (n = 373) Objective response 103 (31) 20 (6) 137 (37) 33 (9) Complete response 0 0 1 (<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) 39 Motzer et al. N Engl J Med 2007;356:115-124.

Sunitinib: Kaplan-Meier estimates of PFS Independent review Median PFS Sunitinib = 11 months (95% CI, 10 to 11); IFN- = 5 months (95% CI, 4 to 6) No. at risk, n Sunitinib: IFN-α: 375 235 90 32 2 375 152 42 18 0 40 Motzer et al. N Engl J Med 2007;356:115-124.

Sunitinib in mrcc: treatment-related adverse events Event Sunitinib, % IFN-α, % All grades Grade 3 or 4 All grades Grade 3 or 4 Diarrhea 53 5 / 0 12 0 Fatigue 51 7 / 0 51 11 / 1 Nausea 44 3 / 0 33 1 / 0 Stomatitis 25 1 / 0 2 1 / 0 Nausea 44 3 / 0 33 1 / 0 Hypertension 24 8 / 0 1 1 / 0 Hand-Foot Syndrome 20 5 / 0 1 0 Mucosal inflammation 20 2 / 0 1 1 / 0 Rash 19 1 / 1 6 1 / 0 Asthenia 17 4 / 0 20 4 / 0 Dry Skin 16 1 / 0 5 0 Skin discoloration 16 0 0 0 Changes in hair color 14 0 0 0 Epistaxis 12 1 / 0 1 0 Pain in a limb 11 1 / 0 3 0 Headache 11 1 / 0 14 0 Dry Mouth 11 0 6 1 / 0 Decline in Ejection Fraction 10 2 / 0 3 1 / 0 Pyrexia 7 1 / 0 34 0 41 Motzer et al. N Engl J Med 2007;356:115-124.

Sunitinib in mrcc: haematological toxicities Sunitinib, % IFN-α, % Event All grades Grade 3 or 4 All grades Grade 3 or 4 Leukopenia 78 0 56 2 / 0 Neutropenia 72 11 / 1 46 7 / 0 Anemia 71 3 / 1 64 4 / 0 Lymphopenia 60 12 / 0 63 22 / 0 Thrombocytopenia 65 8 / 0 21 0 42 Motzer et al. N Engl J Med 2007;356:115-124.

New front line alternatives: mtor inhibitor for poor risk patients Cytokines: immunotherapy: IL-2 and IFN-α first to report activity1 VHL tumour suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors2 Bevacizumab + IFN- : EMEA-approval Temsirolimus: EMEA-approval Everolimus: FDA approval 1980s 1990s 2000s 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 High-dose IL-2 FDA-approval: based on Phase II data Bevacizumab: Data established activity of antiangiogenic agents in RCC3 Sorafenib and sunitinib: EMEA approval FDA approvals 2006: sorafenib, sunitinib and temsirolimus 2009: everolimus 43 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.

Axitinib (Inlyta), 2012, VEGFR, Second line PFS 44

Axitinib

NCCN ajánlás mrcc elsővonal (2010. v2.)

NCCN ajánlás mrcc másodvonal (2010. v2.)

48

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 49

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