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 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)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

10 042

10 161

10 481

10431

•

1 Tüdő (C33–C34)

11 620

•

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)

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

2220

2209

2198

2246

2253

2223

2271

75801

75185

77438

77389

75117

66208

65262

66402

66309

65277

10 Vese (C64–C66, C68)

2839

11079 10 571

•

Összesen:

76321

76027

•

Összesen C44 nélkül:

66766

66276

3

Risk factors for RCC Smoking1–3

Herbicides

Asbestos

Solvents

Occupational exposure1,3 von Hippel-Lindau (VHL) syndrome

Risk factors for RCC

Genetic factors1–3

Hereditary papillary RCC

Petroleum products

Obesity1,3

Tuberous sclerosis

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 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; 5

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 PRIME ER TUMOR PRIM PRIMER T0 N incs primer tumorra utaló adat Nincs 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 T4A Gerota Gerota-fascián N YIROKCSOMÓ ÉRINTETTSÉG (regioná ális) (region is) NYIROKCSOMÓ (regionális) N0 Negatív Negatív nyirokcsomók N1 Egy, azonos oldali N2 >1 nyirokcsomó TÁVOLI METASTASIS M0 Nincs Nincs M1 Van

Capsula adiposa

Gerota fascia

Capsula fibrosa

Tumor, nyirokcsomó, metastasis (TNM) stádiumbeosztás vesesejtes carcinomában– 1997-es revízió Osztályozás

Definíció

Stádium

T1

Tumor < 7 cm és csak a vesére korlátozódik

1. stádium

T2

Tumor > 7 cm és csak a vesére korlátozódik

T3

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

T4

A tumor a Gerota-f. fascián túl terjed

N0

Nincs nyirokcsomó metastasis

N1

Egyetlen regionális nyirokcsomóban van metastasis

N2

Több regionális nyirokcsomóban van metastasis

M0 M1

Nincsen távoli metastasis Van távoli metastasis

2. stádium 3. stádium

4. stádium

TNM

T1 T2

NO NO

MO MO

T3 T1 T2 T4

NO N1 N1 N0

MO MO MO M0

Any T Any T

N2 Any N

M0 M1

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 recurrence2 • 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 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_guidelines.asp; 3. Janzen et al. Urol Clin North Am. 2003;30:843-852. 11

OEP

DEOEC Urológia Kinika

DEOEC Urológia Klinika

Histological classification of human renal epithelial neoplasms Proximalis nephron <=

Clear cell

Type

=> Distalis nephron

Non-clear cell

Clear cell

Papillary type 1

Papillary type 2

Chromophobe

Oncocytoma

Approximate incidence

75%

5%

10%

5%

5%

Associated mutations

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

6,000

5,000

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 )

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 RCC1

•

Inhibition of pathways downstream of VHL can interfere with angiogenesis3

VHL proteins cannot bind HIF-1α, which escapes proteolysis2,4

– VEGF antibodies – VEGFr-TKIs HIF-1α Ubiquitination and degradation

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

X

HIF-1β

X

Mutated pVHL

HIF-1α Increased transcription

Angiogenesis

pVHL: Normoxia-hypoxia

20

A vascularis endothel sejtek aktivációja

Házigazda sejt

Tumor sejt

⁭Proliferáció Invázió Migrácó

Vascularis Endothel Sejt VEC

Membrán degradáció Szignál Transzdukciós kaszkád Mitoticus orsó

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

EGFR

VEGFR

PDGFR

VEGFR

PDGFR

Tumor blood vessel

Tumor cell membrane

Pericyte P P

P

P

P

P P

P

P

P P

P

AKT

P

endothelial cell membrane

P

P P

P

Ras

PI3K

sorafenib/ sunitinib

P

P P

sorafenib

sorafenib/ sunitinib

Raf Mek

mTOR

Erk

Nucleus

Transcription Factors

Cell proliferation

Angiogenesis

Cell adhesion

Cell differentiation Apoptosis

Cell survival 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

Kd 1 nM 10 nM 100 nM 1 M 10 M

pazopanib

sunitinib

Kd: disszociációs konstans

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

sorafenib

Treatments for mRCC Cytokines: immunotherapy: IL-2 and IFN-α first to report activity1

Bevacizumab Everolimus: FDA + IFN-: approval EMEA-approval

VHL tumour suppressor gene isolated: first gene identified to cause a proportion of hereditary RCC and other tumors2

1980s 82

83

84

85

86

Temsirolimus: EMEA-approval

1990s 87

88

89

90

91

92

93

94

95

2000s 96

97

98

99

00

01

Bevacizumab: Data established activity of antiangiogenic agents in RCC3

High-dose IL-2: FDA-approval based on Phase II data

02

03

04

05

06

07

08 09

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 INF-α

2004- Nowadays

Temsirolimus INF-α

Kane 2006

7-9

IFN Torisel

7,3

(MSKCC>3) 10,9

(MSKCC>3)

Nexavar

18,5 18,7

INF-α+ IL-2+5-FU INF-α INF-α+ bevacizumab

INF-α SUTENT

(MSKCC: 0-2) (MSKCC: 0-2)

21,3

(MSKCC: 0-2)

23,3 NS

Bevacizumab + IFN IFN

21,8

Figlin ASCO 2008

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

(MSKCC: 0-2)

(MSKCC: 0-2) 26,4* (MSKCC: 0-2)

Progression free survival in mRCC first line treatment Median PFS Best supportive care INF-α

2004-Nowadays

INF-α+ IL-2+5-FU Temsirolimus Sorafenib

Kane 2006

2-3

Multiple studies Gore ASCO 2008 Torisel PI

5,3 5,5 (MSKCC>3) 5,7 (no indication in first line)

Nexavar PI

Bevacizumab + INF-α

CALGB 90206

Bevacizumab + INF-α

Escudier ASCO 2008

Sunitinib

3-5

8,5

10,2 11,0

Figlin ASCO 2008

Pazopanib

11,1

Time(Months) 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 activity1



1980s 82

83

84

85

86


1990s 87

88

89

90

91

92

93

94

95

2000s 96

97

98

99

00

01



02

03

04

05

06

07

08 09




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 Median OS , months , 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 lung2

•

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:

0 kockázati faktor

Átmeneti vagy közepes:

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 At-risk group1

MSKCC parameter 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

MSKCC risk group1

< 1 year

No. of No. patients, factors, n %

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 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 tumors2 Temsirolimus: EMEA-approval 1980s 82

83

84

85

86

1990s 87

88

89

90

91

92

93

94

95

2000s 96

97

98

99

00

01



02

03

04

05

06

07

08 09




Tirozine kinase inhibitor (TKI)

36

Sorafenib in mRCC: treatment-related adverse events Sorafenib, %

Event

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 (n = 335)

Sunitinib (n = 374)

IFN- (n = 373)

No. of patients, n (%)

Response (RECIST) Objective response

IFN- (n = 327)

Investigator assessment

103 (31)

20 (6)

137 (37)

33 (9)

0

0

1 (<1)

0

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)

Complete response Partial response

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:

375

235

90

32

2

IFN-α:

375

152

42

18

0

40


Sunitinib in mRCC: treatment-related adverse events Sunitinib, %

Event

All grades

IFN-α, %

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


Sunitinib in mRCC: haematological toxicities 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

Event

42


New front line alternatives: mTOR inhibitor for poor risk patients Cytokines: immunotherapy: IL-2 and IFN-α first to report activity1



1980s 82

83

84

85

86


1990s 87

88

89

90

91

92

93

94

95

2000s 96

97

98

99

00

01


High-dose IL-2 FDA-approval: based on Phase II data

02

03

04

05

06

07

08 09




Axitinib (Inlyta), 2012,

VEGFR,

Second line 44

PFS

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

50

Renal cell carcinoma. Juhász Balázs. DEOEC Onkológiai Tanszék

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