Ahmed Zeeneldin

Associate professor of Medical Oncology/HematologyNCI

2010

CT e Contrast: NB: Contrast nephropathy and the use of N-acetylcysteine

Typical renal cell carcinoma. CT scan obtained before contrast enhancement

NON-ENHANCED ENHANCED

¡ Contrast-enhanced MRI (renal cell carcinoma)

¡ 2-3 % of all malignancies¡ 58 000 case & 13 000 deaths¡ 5-y OS : 70%¡ 90% of renal tumors are RCC, and ¡ 85% of RCC are clear cell tumors.¡ Risk factors: § Smoking§ Obesity§ Von Hippel-Lindau disease (VHL):

▪ Mutations of VHL gene predisposed to clear RCC

¡ Tumor grade¡ Stage: § Tumor§ LN§ Mets

¡ Risk stratification: MSKCC1. LDH > 1.5 ULN2. HB < LLN3. Corrected serum calcium level > 10 mg/dl (2.5 mmol/liter)4. Interval of less than a year from original diagnosis to the start

of systemic therapy5. Karnofsky performance score <= 706. >= 2 sites of organ metastasis

¡ Mass (clinically in the flank, incidental by US)¡ Hematuria¡ Flank pain

¡ H&P¡ Lab: § CBC§ KFT & urine§ LFT§ Others: calcium, LDH, coagulation profile

¡ Imaging:§ CT with contrast: CAP§ MRI if we cannot use CT e contrast : CAP§ Others if indicated: MRI/CT brain, Bone scan§ PET??

¡ T1: limited to kidney <= 7cm§ T1a: <=4cm§ T1b: >4-7 cm

¡ T2: limited to kidney > 7cm¡ T3:§ T3a: adrenals§ T3b RV or infradiaph IVC§ T3c: perinephric fat, limited to

Gerota’s fascia¡ T4: beyond Gerota’s fascia

¡ N1: one LN¡ N2: >one LN

¡ M1: mets

Tis/0 T1 T2 T3 T4 M1=IV

N0 0 I96%

II82%

III IV

N1 III 64% 23%

N2 IV

¡ Modalities:§ Surgery§ Systemic therapy:

▪ Cytokines▪ Targeted therapy▪ Not including Chemox

§ RT: limited role¡ Treatment by stage:§ Stage I-III:

▪ Surgery: RN, NSS▪ No adjuvant Tx: no RT no systemic Tx

§ Stage: IV▪ Surgery if possible for 1ry and 2ry (metastatectomy)▪ Systemic therapy▪ RT limited role

¡ Only curative Tx¡ Localized (I-III; T1-3, N0-1)¡ Types: § radical nephrectomy and § nephron-sparing surgery

¡ Removes: § Tumor + SM +/- kidney§ Peri-renal fat§ Fascia§ Regional LN (prognostic)§ Ipsilateral adrenal (upper pole tunors)

¡ Feasibility¡ Very early tumors (T1)¡ If RN renders patient anephric:§ Tumor in a solitary kidney

§ Poor contralateral kidney functions

§ Bilateral tumors (VHL)

NO ROLEObservation:Low risk for Recurrence: High risk: LN+ large tumors, +ve Margin

¡ RCT of § INF and IL-2 vs. observation

§ Completely resected tumors

¡ No DFS advantage¡ No OS advantage

¡ RT for LN+ and SM+:§ No benefit

¡ Elderly¡ Poor general condition¡ Actions:§ Surveillance

§ Ablation▪ Radiofrequancy

▪ cryo

¡ Synchronous or metachronous mets¡ Surgery if possible§ for 1ry: complete or incomplete (cytoreduction)

§ 2ry (lung, bone, brain metastatectomy)

§ Simultaneously or sequentially ¡ RT can be used for irresectable or post

resection in bone or brain¡ Systemic therapy: INF, IL-2, targeted therapy

¡ Resectable Stage IV RCC

¡ RR of death decreased by 30%¡ Independent of § patient performance status,

§ the site of metastases and

§ the presence of measurable disease.

INF alone INF + SurgeryMOS (P<0.002) 7.8 m 13.6 m

¡ Memorial Sloan-Kettering Cancer Center (MSKCC) and ¡ Cleveland Clinic Foundation (CCF)

¡ Indicated in: § Metastatic§ Irresectable§ recurrent

¡ Agents:§ Cytokines:

▪ IL-2: high-dose produce high RR▪ INF

§ Targeted therapy:▪ Sunitinib▪ Sorafenib▪ Temsirolimus▪ Bevacizumab▪ Everolimus

¡ 1st line:§ Single agents:

▪ Sunitinb: good and intermediate risk▪ Temsirolimus: poor risk▪ Sorafenib: selected patients

§ Combination:▪ Bevacizumab+ INF▪ Sorafenib+INF

¡ 2nd line▪ Everolimus▪ Others

¡ VHL = von Hippel–Lindau protein; ¡ HIF = hypoxia-inducible factor, ¡ TGF-α = transforming growth factor α; ¡ VEGF = vascular endothelial growth factor A; ¡ PDGFβ = platelet-derived growth factor β; ¡ EGFR = epidermal growth factor receptor, ¡ VEGFR2 = VEGF receptor 2; ¡ PDGFRβ = PDGF receptor β; ¡ PTEN = phosphatase and tensin homologue; ¡ TSC1 and TSC2 = tuberous sclerosis complex 1 and 2; ¡ FKBP12 = FK506-binding protein 12 kD; ¡ mTOR = mammalian target of rapamycin complex 1 kinase; ¡ eIF4E = eukaryotic translation initiation factor 4E; ¡ S6K = S6 kinase

Regimen Setting Therapy Options

1st line MSKCC risk: Good or intermediate

Sunitinibbevacizumab + IFN-α

High-dose IL-2

MSKCC risk: Poor Temsirolimus Sunitinib

2nd line Cytokine-refractory Sorafenib Sunitinibbevacizumab

Refractory to VEGF/VEGFR or mTOR inhibitors

EverolimusSequential TKIs or VEGF inhibitor

Fig. 1 Biologic agents and their targets in metastatic renal cell cancer.VHL = von Hippel-Lindau; HIF = hypoxia-inducible factor; mTOR = mammalian target of rapamycin; VEGF = vascular endothelial growth factor; PDGF = platelet-derived growth factor; TGF-α = tumour growth factor-alfa; VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor; EGFR = epidermal growth factor; HGF = hepatocyte growth factor.

¡ Consequences of mutation or inactivation of the von Hippel Lindau(VHL) gene.

¡ VHL normally encodes a protein (p-VHL) that targets hypoxia-inducible factor (HIF) for proteolysis.

¡ As a result of VHL inactivation, a defective p-VHL is produced and HIF is up-regulated, translocates to the nucleus, and results in the transcription of several genes involved in angiogenesis and tumor growth. These genes include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor (TGF)-α, basic fibroblast growth factor (bFGF), carbonic anhydrase IX (CA IX) or G250, erythropoietin (EPO), and others.

¡ OH indicates hydroxyl group; ¡ Ub, ubiquitin; ¡ Glut-1, glucose transporter 1; ¡ PAI-1, plasminogen activator inhibitor 1.

¡ Oral multi-tyrosine kinaseinhibitor§ PDGF§ VEGF-R§ Stem cell factor receptor (c-KIT)§ FMS-like tyrosine kinase (Flt3), § colony stimulating factor (CSF-1R), § The neurotrophic factor receptor (RET)

¡ Inhibits angiogenesis and cell proliferation.

¡ Indication: advanced RCC§ 1st line § Met/Rec or irresectable

¡ + PFS by 6 m § (from 5m to 11 m)

¡ + OS by 4 m § (from 22 m to 26m)

¡ AE: § HTN, HFS, diarrhea, +AST/ALT,

- plt, -ANC

¡ Dose: 50 mg daily x 6 weeks and 2 weeks rest

¡ Cost : 10500$/Month

¡ 25 mg IV weekly over 30-60 min

¡ Premedication with antihistamine

¡ 1st line in RCC with >=3 poor prognostic criteria

¡ till progression or unacceptable toxicity

¡ inhibit mammalian Target of Rapamycin (mTOR) protein

¡ Cost: 7500$/month

¡ The most common grade 3 or 4 AE include:§ rash,

§ stomatitis,

§ pain,

§ infection,

§ peripheral edema,

§ Thrombocytopenia and neutropenia§ hyperlipidemia, hypercholesteremia, and hyperglycemia

Ahmed Zeeneldin 52

¡ Oral multikinaseinhibitor § PDGFR§ VEGFR

¡ Inhibits tumor cell proliferation and angiogenesis

• Oral • 400 mg BID continuously• Can be increased to 600 mg

BID• Cost: 5000 $/Month

• PFS:• Sorafenib vs INF:

• 5.7 m vs 5.6m

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¡ Anti-VEFG-A MAB¡ IV 10 mg q 2weeks¡ Costs: 7500$/month

¡ PFS: 8.5 m vs 5.2 m¡ OS: 18m vs 17m¡ RR: 25% vs 13%¡ Grade 3 AE: § hypertension(9% v 0%),

§ anorexia(17% v 8%),

§ fatigue(35% v 28%),

§ proteinuria(13% v 0%).

¡ 10 mg tablets¡ 2nd line after failure of sunitinib or sorafenib

¡ Best: Temsirolimus¡ Next: Sunitinib, Sorafenib¡ Third: chemotherapy with mild activity§ Capecitabine

§ Gem+/- 5-FU

§ Doxorubicin-based