¡ 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: MSKCC 1. LDH > 1.5 ULN 2. HB < LLN 3. 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 therapy 5. Karnofsky performance score <= 70 6. >= 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??
Tis/0 T1 T2 T3 T4 M1=IVN0 0 I II III IV 96% 82%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
¡ 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 INF alone INF + Surgery MOS (P<0.002) 7.8 m 13.6 m¡ RR of death decreased by 30%¡ Independent of § patient performance status, § the site of metastases and § the presence of measurable disease.
¡ Memorial Sloan-Kettering Cancer Center (MSKCC) and¡ Cleveland Clinic Foundation (CCF)
¡ 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.
¡ + 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
¡ Oral multikinase inhibitor § PDGFR § VEGFR¡ Inhibits tumor cell proliferation and angiogenesis Ahmed Zeeneldin 52
• 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 53