Comprehensive overview of Kidney Cancer: staging, diagnosis and treatment

1. Ahmed Zeeneldin
Associate professor of Medical Oncology/Hematology
NCI
2010

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

8. Typical renal cell carcinoma.
CT scan obtained before
contrast enhancement

9. NON-ENHANCED ENHANCED

11. ¡ Contrast-enhanced MRI
(renal cell carcinoma)

13. ¡ 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

15. ¡ 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

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

19. ¡ 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??

20. ¡ 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

21. Tis/0 T1 T2 T3 T4 M1=IV
N0 0 I II III IV
96% 82%
N1 III 64% 23%
N2 IV

22. ¡ 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

23. ¡ 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)

24. ¡ Feasibility
¡ Very early tumors (T1)
¡ If RN renders patient anephric:
§ Tumor in a solitary kidney
§ Poor contralateral kidney functions
§ Bilateral tumors (VHL)

25. NO ROLE
Observation:
Low risk for Recurrence:
High risk: LN+ large tumors, +ve Margin

26. ¡ RCT of
§ INF and IL-2 vs. observation
§ Completely resected tumors
¡ No DFS advantage
¡ No OS advantage
¡ RT for LN+ and SM+:
§ No benefit

27. ¡ Elderly
¡ Poor general condition
¡ Actions:
§ Surveillance
§ Ablation
▪ Radiofrequancy
▪ cryo

28. ¡ 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

29. ¡ 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.

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

32. ¡ Indicated in:
§ Metastatic
§ Irresectable
§ recurrent
¡ Agents:
§ Cytokines:
▪ IL-2: high-dose produce high RR
▪ INF
§ Targeted therapy:
▪ Sunitinib
▪ Sorafenib
▪ Temsirolimus
▪ Bevacizumab
▪ Everolimus

33. ¡ 1st line:
§ Single agents:
▪ Sunitinb: good and intermediate risk
▪ Temsirolimus: poor risk
▪ Sorafenib: selected patients
§ Combination:
▪ Bevacizumab+ INF
▪ Sorafenib+INF
¡ 2nd line
▪ Everolimus
▪ Others

35. ¡ 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

36. Regimen Setting Therapy Options
1st line MSKCC risk: Sunitinib High-dose IL-2
Good or intermediate bevacizumab + IFN-α
MSKCC risk: Poor Temsirolimus Sunitinib
2nd line Cytokine-refractory Sorafenib Sunitinib
bevacizumab
Refractory to VEGF/VEGFR Sequential TKIs or
Everolimus
or mTOR inhibitors VEGF inhibitor

37. 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.

40. ¡ 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.

41. ¡ Oral multi-tyrosine kinase
inhibitor
§ 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

42. ¡ + 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

48. ¡ 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

51. ¡ The most common grade 3 or 4 AE include:
§ rash,
§ stomatitis,
§ pain,
§ infection,
§ peripheral edema,
§ Thrombocytopenia and neutropenia
§ hyperlipidemia, hypercholesteremia, and hyperglycemia

52. ¡ Oral multikinase
inhibitor
§ PDGFR
§ VEGFR
¡ Inhibits tumor
cell proliferation
and angiogenesis
Ahmed Zeeneldin 52

53. • 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

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

55. ¡ 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%).

57. ¡ 10 mg tablets
¡ 2nd line after failure of sunitinib or sorafenib

61. ¡ Best: Temsirolimus
¡ Next: Sunitinib, Sorafenib
¡ Third: chemotherapy with mild activity
§ Capecitabine
§ Gem+/- 5-FU
§ Doxorubicin-based