Renal cell carcinoma

Juhász Balázs

DEOEC Onkológiai Tanszék

2

The global burden of renal cancer• ~ 208,000 cases of renal cancer diagnosed worldwide each

year1

– 2% of adult malignancies1

– Annual mortality: ~102,0001

– Overall lifetime risk (US alone): 1.38% (1 in 72)2

• Incidence and mortality increase with age

– Median age at diagnosis (US): 65 years2

• 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 20073

• Lower incidence in Asia and Africa

• ~ 90% of renal tumours are renal cell carcinomas (RCC)41. 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.

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 10 481 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 7738975117

• Összesen C44 nélkül: 66766 66276 66208 65262 66402 66309 65277

4

Risk factors for RCC

Risk factorsfor RCC

Smoking1

–3

Occupational

exposure1,3

Petroleumproducts

AsbestosHerbicides

Solvents

Obesity1,3

von Hippel-Lindau (VHL)syndrome

Tuberoussclerosis

Hereditarypapillary 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 factors1–3

5

RCC clinical presentation• Classic presentation at diagnosis

– Classic triad: Flank pain, hematuria, palpable abdominal mass1,2

– Systemic symptoms: weight loss, fever, sweating, hypecalcaemia, hypertension

• In the majority of cases, RCC remains occult for most of its course2

• ~ 40% of patients present with advanced disease at diagnosis3

– Prognosis is poorest in patients with metastatic disease4

• 25%-50% of patients treated for localized disease experience recurrence5 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.

Diagnosis - CT

A vesesejtes carcinoma 1997-es TNM osztályozása

PRIMER 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)

N0 Negatív nyirokcsomók

N1 Egy, azonos oldali

N2 >1 nyirokcsomó

TÁVOLI METASTASIS

M0 Nincs

M1 Van

PRIMPRIMEER TUMORR TUMOR

T0T0 NNincsincs primer tumorra utaló adatprimer tumorra utaló adat

T1T1 Tumor <7 cmTumor <7 cm

T2T2 Tumor >7 cmTumor >7 cm

T3aT3a Vese környezetének Vese környezetének invázójainvázója

T3bT3b VenaVena cavacava inferiorinferior vagy vagy

vesevéna a rekesz alattvesevéna a rekesz alatt

T3cT3c VenaVena cavacava inferirorinferiror a rekesz a rekesz

felettfelett

T4T4A A GerotaGerota--fasciánfascián túli terjedéstúli terjedés

NNYIROKCSOMÓ ÉRINTETTSÉGYIROKCSOMÓ ÉRINTETTSÉG (region(regionáállisis))

N0 N0 NegatNegatív nyirokcsomókív nyirokcsomók

N1 N1 Egy, azonos oldaliEgy, azonos oldali

N2N2 >1 >1 nyirokcsomónyirokcsomó

TÁVOLI TÁVOLI METASTASISMETASTASIS

M0 NM0 Nincsincs

M1 M1 VanVan

Capsula fibrosa

Capsula adiposa

Gerota fascia

Tumor, nyirokcsomó, metastasis (TNM) stádiumbeosztás vesesejtes carcinomában– 1997-esrevízió

Van távoli metastasisM1 Nincsen távoli metastasisM0

Több regionális nyirokcsomóban van metastasis

N2

Egyetlen regionális nyirokcsomóban van metastasis

N1

Nincs nyirokcsomó metastasisN0

A tumor a Gerota-f. fasciántúl terjed

T4

A tumor beterjed a fő vénákba v. infiltrálja a mellékvesét v. a vesekörüli szöveteket, de nem haladja meg a Gerota-f. fasciát

T3

Tumor > 7 cm és csak a vesére korlátozódik

T2

Tumor < 7 cm és csak a vesére korlátozódik

T1

DefinícióOsztályozás

M1Any NAny T

M0N2Any T

M0N0T44. stádium

MON1T2

MON1T1MONOT33. stádium

MONOT22. stádium

MONOT11. stádium

TNMStádium

10

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

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 recurrence2

• The NCCN and EAU have established treatment algorithms for RCC

11

Localized renal cell carcinomacurrent treatments

• Surgery ({open or laparoscopic} radical or partial nephrectomy) is used for localized RCC1

– 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 relapse2

– 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 ablation3

1. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer,v.1.2008;

2. http://www.nccn.org/professionals/physician_gls/f_guideline

s.asp;3. Janzen et al. Urol Clin North Am. 2003;30:843-852.

OEP

DEOEC Urológia Kinika

DEOEC Urológia Klinika

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 cell Non-clear cell

Type Clear cell Papillary type 1 Papillary type 2 Chromophobe Oncocytoma

Approximateincidence

75% 5% 10% 5% 5%

Associatedmutations

VHL c-Met FH BHD BHD

Proximalis nephron <= => Distalis nephron

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

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

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Normal

Diseased

Invasive cancers

Expression of VEGF in ~6,500 tissue specimens (GeneLogic/Affymetrix

®)

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 RCC1

• Inhibition of pathways downstreamof VHL can interfere withangiogenesis3

– VEGF antibodies

– VEGFr-TKIs

Oxygen

HIF-1α

HIF-1α

Ubiquitination and

degradation

HIF-1β

VEGF-A PDGFEPO

MutatedpVHLX

Angiogenesis

VHL proteins cannot bindHIF-1α, which escapes proteolysis2,4

Increased transcription

X

pVHL: Normoxia-hypoxia

20

A vascularis endothel sejtek aktivációjaA vascularis endothel sejtek aktivációja

Tumorsejt

Házigazda sejt

MitoticusMitoticus orsóorsó

SzignálSzignálTransz-Transz-dukciósdukcióskaszkádkaszkád

Proliferáció

Invázió

Migrácó

Membrán degradáció

Permeabilitás

Kapillris fomáció

VascularisVascularisEndothel Endothel

SejtSejtVECVEC

Endothelialis sejtek proliferációja, Endothelialis sejtek proliferációja, migrációja és differenciálódásamigrációja és differenciálódása

Az új erek stabilizációja/éréseAz új erek stabilizációja/érése

Endothel proliferáció kapilláris képződésEndothel proliferáció kapilláris képződés

periciták endothel sejt

tumor sejtek

Permeábilitás Proliferáció

Migráció

Adhézió Túlélés

Permeábilitás Proliferáció

Migráció

Adhézió Túlélés

25

Tumor blood vessel

endothelial cell membrane

Modified from Rini and Small. J Clin Oncol 2005;23:1028-1043.

Tumor cell membrane

VEGFR

PI3K

AKTRaf

Mek

Ras

VEGFR

P P P P

Erk

Anti-angiogenics mechanism of action

Nucleus Transcription Factors

Cell adhesionCell survival

Cell proliferation

ApoptosisCell differentiation

Angiogenesis

P P P

PDGFR

PP PP P

EGFR PDGFR

P P P PPP P P

sorafenib/sunitinib

Pericyte

sorafenib sorafenib/sunitinib

bevacizumab

mTOR

A különböző kináz célpontok elleni aktivitások különböző hatékonyságot és toxicitási profilt eredményeznek

pazopanib sorafenibsunitinib

10 M

1 M

100 nM

10 nM

1 nM

Kd

1. Kumar et al. Br J Cancer 2009;101:1717–23.Figure adapted from Karaman et al. Nat Biotechnol 2008;26:127–32.

Kd: disszociációs konstans

27

Treatments for mRCC

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

Cytokines: immunotherapy: IL-2 and IFN-αfirst 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 proportionof 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 approvals2006: sorafenib, sunitinib and temsirolimus2009: everolimus

09

Everolimus: FDA approval

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

20

04

- Now

ad

ays

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+ bevacizumabINF-α

INF-α

INF-α

Overall survival in mRCC first line Overall survival in mRCC first line treatmenttreatment

(MSKCC>3)

(MSKCC: 0-2)

(MSKCC: 0-2)

(MSKCC: 0-2)

(MSKCC: 0-2)

(MSKCC: 0-2)

(MSKCC: 0-2)

30

Cytokines

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

Cytokines: immunotherapy: IL-2 and IFN-αfirst 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 approvals2006: sorafenib, sunitinib and temsirolimus2009: everolimus

09

Everolimus: FDA approval

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 andmetastasis confined to the lung2

• 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

nMedian

PFS, months

Median OS

, monthsn*

CR at6 months,

%

PR at6 months,

%

IFN-α 167 4 8.5 81 2 11

Medroxyprogesterone acetate

168 3 6 56 0 7

*Patients for whom data were available.

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)(MSKCC /Memorial Sloan-Kettering Cancer Center/ rizikó csoport)

Az Egészségügyi Minisztérium szakmai protokollja a vese daganatok ellátásárólKészítette: Az Urológiai, Sugárterápiás és Onkológia, Radiológia és Nucleáris Medicina Szakmai Kollégium

33

MSKCC risk criteria for mRCC in patients treated initially with IFN-α

MSKCC parameter At-risk group1

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 group1

No. of factors,

n

No. patients, %

Median survival, months (95%CI)

1yr, %

3yr, %

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

ULN = upper limit of normalLLN = lower limit of normal

1. Motzer et al. J Clin Onc 2002: 20; 289-96.

34

Anti-angiogenic agents

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

Cytokines: immunotherapy: IL-2 and IFN-αfirst 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 proportionof 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 approvals2006: sorafenib, sunitinib and temsirolimus2009: everolimus

09

Everolimus: FDA approval

Tirozine kinase inhibitor (TKI)

35

36

EventSorafenib, % Placebo, %

All grades Grade 3 or 4All

gradesGrade 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

Escudier et al. N Engl J Med 2007;356:125-134.

Sorafenib in mRCC: treatment-related adverse events

37Escudier et al. Paper presented at: The European Cancer

Conference; October 30-November 3, 2005; Paris, France.

hand-foot syndrome - HFS

38

Sunitinib vs IFN-α best tumor response

Independentcentral review

Investigatorassessment

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 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)

Motzer et al. N Engl J Med 2007;356:115-124.

39 Motzer et al. N Engl J Med 2007;356:115-124.

No. at risk, n

Sunitinib:

IFN-α:

375 235 90 32 2

375 152 42 18 0

Independent reviewMedian PFSSunitinib = 11 months (95% CI, 10 to 11); IFN- = 5 months (95% CI, 4 to 6)

Sunitinib: Kaplan-Meier estimates of PFS

40

Sunitinib in mRCC: treatment-related adverse events

EventSunitinib, % IFN-α, %

All grades Grade 3 or 4 All grades Grade 3 or 4Diarrhea 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 / 0Decline in Ejection Fraction 10 2 / 0 3 1 / 0

Pyrexia 7 1 / 0 34 0

Motzer et al. N Engl J Med 2007;356:115-124.

41

Sunitinib in mRCC: haematological toxicities

Event

Sunitinib, % IFN-α, %

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

Motzer et al. N Engl J Med 2007;356:115-124.

42

New front line alternatives: mTOR inhibitor for poor risk patients

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

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 approvals2006: sorafenib, sunitinib and temsirolimus2009: everolimus

09

Everolimus: FDA approval

43

44

Treatment algorithm for advanced or metastatic RCC

Setting First lineOptions (≥ Level

2)

Treatment-naïve

MSK: Good or intermediate risk*

Sunitinib or Pazopanib

HD IL-2Bevacizumab +

IFN-

MSK: Poor risk* Temsirolimus Sunitinib

Previously treated(≥ 2nd Line)

Cytokine refractorySorafenib, Pazopanib

Sunitinib,

Bevacizumab

Refractory to VEGF/VEGFR Inhibitors

mTOR inhibitorsSequential TKI’s or

VEGF Inhibitor

Refractory to mTOR inhibitors

Investigational Investigational

* Motzer et al. J Clin Onc, 1999: 2530; Adapted from Atkins; ASCO 2006;

Bukowski ASCO 2007.

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

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

48

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