Renal Cell Carcinoma

1. Renal Cell Carcinoma AbdulrahimGari, MD Consultant of Internal Medicine Hematology and Oncology www.garimedical.com 02-2632099

2. Renal Cell Carcinoma (RCC) • RCC accounts for 2% to 3% of all adult malignant , 85% of all primary malignant renal tumors, is the most lethal of the urologic cancers • Renal cell carcinoma (RCC) affects 38,000 individuals in the U.S. yearly, and 11,900 patients die of this disease • RCC occurs most commonly in 5th~6th decade, male-female ratio 1.6:1

3. Etiology • Majority of RCC occurs sporadically • Tobacco smoking contributes to 24-30% of RCC cases • - Tobacco results in a 2-fold increased risk • Occupational exposure to cadmium, asbestos, petroleum • Obesity • Chronic phenacetin or aspirin use • Acquired polycystic kidney disease due to dialysis results in 30% increase risk

4. Etiology • 2-4% of RCC associated with inherited disorder * Von Hippel-Lindau disease - familial cancer syndrome of retinal angiomas, CNS hemangioblastomas, pheochromocytomas and clear cell RCC. * Hereditary papillary renal cancer - Multiple, bilateral papillary renal tumors , C-met oncogene on ch 7 * Birt-Hogg-Duke syndrome - Fibrofolliculomas, lung cysts, and RCC, Mutation in BHD gene ch 17p

5. Pathology • RCC originates from the proximal renal tubular epithelium. • Types: • Clear cell type • Granular cell type • Mixed cell type • RCC is most often a mixed adenocarcinoma.

6. Clinical Findings Symptoms & Signs Renal tumors are increasingly detected incidentally by CT or ultrasound A. Classical triad——gross hematuria, flank pain, palpable mass (only in 10~15% advanced cases) • Symptoms secondary to metastatic disease: dysnea & cough, seizure & headache, bone pain

7. Clinical Findings B. Paraneoplastic Syndromes • Erythrocytosis, hypercalcemia, hypertension C. Lab Findings • anemia, hematuria (60%), ESR↑

8. Clinical Findings B. Paraneoplastic Syndromes • Erythrocytosis, hypercalcemia, hypertension C. Lab Findings • anemia, hematuria (60%), ESR↑

9. Clinical Findings D. Imaging • Ultrasonography • Intravenous Urography (IVU): • CT scanning: more sensitive, mass+renal hilum, perinephric space and vena cava, adrenals, regional LN and adjacent organs • Renal Angiography • MRI: to evaluate collecting system and IVC involvement

10. Diagnosis • No screening for the general population • No bio-marker available • Radiographic evaluation

11. IVU of right RCC CT Scan of Left RCC

12. Right Cystic RCC RCC invading renal vein

13. CT scan with 3D reconstruction Neovascularity in Renal Angiographyassociated with RCC

14. A, Magnetic resonance scan of kidneys without administration of gadolinium suggests anterior right renal mass. B, After intravenous administration of gadolinium-labeled diethylenetriaminepentaacetic acid, MRI shows enhancement of this mass indicative of malignancy.

15. Tissue Diagnosis • Tissue diagnosis obtained from nephrectomy or biopsy Papillary (chromophilic) renal cell carcinoma extending into the collecting systemwith histological findings

16. Tumor Staging (Robson System)

17. Tumor Staging (International TNM Staging System)

18. Tumor Staging

19. Differential Diagnosis • Benign renal tumors -Angiomyolipoma • Renal Pelvis Cancer

20. Treatment A. Localized disease: • Surgical removal---only potentially curative therapy • Radical Nephrectomy (en bloc removal of the kidney and Gerota’s fascia including ipsilateral adrenal, proximal ureter, regional lymphadenectomy

21. Hand-Assisted Laparoscopic Radical Nephrectomy Laparoscopic Radical Nephrectomy

22. Treatment A. Localized disease: • Partial Nephrectomy(nephron-sparing surgery, NSS ) --polar tumor --tumor size<4cm --bilateral RCC --solitary kidney Laparoscopic NSS

23. Treatment A. Localized disease: • Percutaneous/Laparoscopic Radiofrequency Ablation or Cryoablation Laparoscopic Cryoablation

24. Prognosis • Stage 5-year survival rate • I 88~100% • II 60% • III 15~20% • IV 0~20%

25. Treatment B. Disseminated disease: • nephrectomy--- reducing tumor burden • radiation--- radioresistant tumor, metastases 2/3 effective • chemotherapy--- <10% effective • immunotherapy--- IL-2/interferon-alpha, 30% response rate • molecular therapy---eg. sorafenib

26. Interferons • They have antiviral, antiproliferative, and immunomodulatory properties. • They have a antiproliferative effect on renal tumor cells in vitro • They stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules. • Interferon alfa, which is derived from leukocytes, has an objective response rate of approximately 15% (range, 0-29%). • Preclinical studies have shown synergy between interferons and cytotoxic drugs. • However, in several prospective randomized trials, combinations do not appear to provide major advantages over single-agent therapy. • Many different types and preparations of interferons have been used without any difference in efficacy.

27. Interleukin-2 immunotherapy • High-dose IL-2 for robust patients with excellent cardiopulmonary reserve • This remains the only treatment known to induce complete and durable remissions although in a minority of patients • Studies are under way to identify patients responding to IL-2

28. IL2 +/- LAK in RCC Law et al., Cancer 1995;76:824

29. AE of IL2 • Therapy requires inpatient monitoring, often in an intensive care unit. • The major toxic effect of high-dose IL-2 is a sepsislike syndrome with decrease in systemic vascular resistance and an associated decrease in intravascular volume due to capillary leak. • Other toxic effects are fever, chills, fatigue, infection, and hypotension. • Only to patients with no cardiac ischemia or significant impairment of renal or pulmonary functions.

30. Bevacizumab + INF in RCCPFS wasshown in: Lancet 2007;370:2103 Escudier et al., JCO 2010;28:2144

31. Newer Targeted Therapy

32. Sorafenib • Sorafenib, a small-molecule targets RAF, VEGF, PDGFR-beta, KIT, FLT-3 • Dose is 400 mg bid away from meals. • Interruptions or dose reductions because of AE

33. Sorafenib in RCC Escudier et al., JCO 2009;27:3312

34. AE of Sorafenib • reversible skin rashes in 40% • hand-foot skin reaction in 30% (grade 3 and 4 in 5%) • diarrhea was reported in 43% • treatment-emergent hypertension in 17% • sensory neuropathic changes in 13% • were also reported more commonly in the sorafenib arm. • treatment-emergent cardiac ischemia/infarction events 2.9% (placebo 0.4%) • asymptomatic hypophosphatemia in 45% • lipase elevations in 41% • Others: alopecia, oral mucositis, and hemorrhage, pancreatitis, hypothyroidism

35. Sunitinib • Sunitinib is multikinase inhibitor • High response rate (40% partial responses), TTP of 8.7 months, and OS of 16.4 months. • Sunitinib inhibits tyrosine kinases in VEGFR 1-3 and PDGFR-alpha and –beta pathways • Dose of sunitinib is 50 mg pood, with or without food, 4 weeks on & 2 weeks off

36. Sunitinib in RCC Motzer et al., JCO 2009;27:3584

37. AE of Sunitinib • fatigue (38%) • hypothyroidism (in as many as 30%) • diarrhea (24%) • nausea (19%) • dyspepsia (16%) • stomatitis (19%) • decline in cardiac ejection fraction (11%) • dermatitis in 8% • hypertension in 5% (but correlates with response, DFS and OS)

38. Temsirolimus in RCC • Temsirolimus inhibits mTOR (important in cell growth and division) • hypoxia-inducible factor (HIF) pathway are also upregulated by mTOR • This pathway is central in pathogenesis of kidney cancers. • Dose 25 mg IV weekly until progression. • Common toxicities: asthenia, rash, anemia, hypophosphatemia, hyperlipidemia.

39. Temsirolimus in RCC, PFS Hudes et al., NEJM 2007;356:2271

40. Temsirolimus in RCC, OS Temsirolimusvs INF: HR for death 0.73 (CI 0.58-0.92) P <0.008 Combination vs INF: HR 0.96 (CI 0.76-1.20) P <0.70 Hudes et al., NEJM 2007;356:2271

41. 2ndline Everolimus in RCC • EverolimusmTOR (important in cell growth and division) • Dose is 10 mg pood with or without food • Approved as 2nd line after sunitinib and/or sorafenib • Tablets should be swallowed whole, not be chewed or crushed, with a glass of water • Common toxicities: stomatitis, infections, asthenia, fatigue, cough, and diarrhea

42. 2ndline Everolimus in RCC PFS by central radiology review Motzer et al., Cancer 2010;116:4256

43. Axitinib in RCC • Multicenter randomised phase 3 study comparing axitinib with sorafenib as second-line therapy in metastatic RCC. • Patients randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). • PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; CI 0·544-0·812; p<0·0001) • Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. • AE of axitinib were diarrhoea, hypertension, and fatigue • AE of sorafenib were diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia • Conclusion: Axitinib had significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma.

44. 1st line Targeted Therapy of RCC • For naïve patients with CC-RCC of low or intermediate risk, sunitinib or bevacizumab and IFN-alfa. • For naïve patients with CC-RCC of high-risk temsirolimus • Pazopanib for relapsed or unresectable CC-RCC of high-risk • In separate trials following drugs are more effective than IFN-alpha as 1st line therapy for mRCC: sunitinib, bevacizumab plus IFN-alpha , and temsirolimus in terms of PFS or OS or both

45. 2nd line Targeted Therapy of RCC • 2nd line for CC-RCC sorafenib: standard dose, then increased dose • Everolimus is approved as 2nd line after sunitinib and/or sorafenib • For sunitinib naïve this drug can be used as 2nd line

46. Thank You

47. AE of Sorafenib 5% ischaemic /infarct in study group