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

Renal Cell Carcinoma

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Renal Cell Carcinoma. Abdulrahim Gari , MD Consultant of Internal Medicine Hematology and Oncology www.garimedical.com 02-2632099. Renal Cell Carcinoma (RCC). - PowerPoint PPT Presentation

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Page 1: Renal Cell Carcinoma

Renal Cell CarcinomaAbdulrahim Gari, MD

Consultant of Internal MedicineHematology and Oncology

www.garimedical.com02-2632099

Page 2: Renal Cell Carcinoma

• 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

Renal Cell Carcinoma (RCC)

Page 3: Renal Cell Carcinoma

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

Page 4: Renal Cell Carcinoma

• 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

Etiology

Page 5: Renal Cell Carcinoma

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.

Page 6: Renal Cell Carcinoma

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

Page 7: Renal Cell Carcinoma

Clinical Findings

B. Paraneoplastic Syndromes• Erythrocytosis, hypercalcemia, hypertensionC. Lab Findings• anemia, hematuria (60%), ESR↑

Page 8: Renal Cell Carcinoma

Clinical Findings

B. Paraneoplastic Syndromes• Erythrocytosis, hypercalcemia, hypertensionC. Lab Findings• anemia, hematuria (60%), ESR↑

Page 9: Renal Cell Carcinoma

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

Page 10: Renal Cell Carcinoma

Diagnosis

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

Page 11: Renal Cell Carcinoma

IVU of right RCC

CT Scan of Left RCC

Page 12: Renal Cell Carcinoma

RCC invading renal vein

Right Cystic RCC

Page 13: Renal Cell Carcinoma

CT scan with 3D reconstructionNeovascularity in Renal

Angiographyassociated with RCC

Page 14: Renal Cell Carcinoma

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.

Page 15: Renal Cell Carcinoma

Tissue Diagnosis

• Tissue diagnosis obtained from nephrectomy or biopsy

Papillary (chromophilic) renal cell carcinoma extending into the collecting

system with histological findings

Page 16: Renal Cell Carcinoma

Tumor Staging (Robson System)

Page 17: Renal Cell Carcinoma

Tumor Staging (International TNM Staging System)

Page 18: Renal Cell Carcinoma

Tumor Staging

Page 19: Renal Cell Carcinoma

Differential Diagnosis

• Benign renal tumors -Angiomyolipoma

• Renal Pelvis Cancer

Page 20: Renal Cell Carcinoma

TreatmentA. 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

Page 21: Renal Cell Carcinoma

Laparoscopic Radical NephrectomyHand-Assisted Laparoscopic

Radical Nephrectomy

Page 22: Renal Cell Carcinoma

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

Laparoscopic NSS

Page 23: Renal Cell Carcinoma

TreatmentA. Localized disease:• Percutaneous/

Laparoscopic Radiofrequency Ablation or Cryoablation

Laparoscopic Cryoablation

Page 24: Renal Cell Carcinoma

Prognosis

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

Page 25: Renal Cell Carcinoma

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

Page 26: Renal Cell Carcinoma

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.

Page 27: Renal Cell Carcinoma

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

Page 28: Renal Cell Carcinoma

IL2 +/- LAK in RCC

Law et al., Cancer 1995;76:824

Page 29: Renal Cell Carcinoma

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.

Page 30: Renal Cell Carcinoma

Bevacizumab + INF in RCC

PFS was shown in: Lancet 2007;370:2103

Escudier et al., JCO 2010;28:2144

Page 31: Renal Cell Carcinoma

Newer Targeted Therapy

Page 32: Renal Cell Carcinoma

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

Page 33: Renal Cell Carcinoma

Sorafenib in RCC

Escudier et al., JCO 2009;27:3312

Page 34: Renal Cell Carcinoma

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

Page 35: Renal Cell Carcinoma

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 po od, with or

without food, 4 weeks on & 2 weeks off

Page 36: Renal Cell Carcinoma

Sunitinib in RCC

Motzer et al., JCO 2009;27:3584

Page 37: Renal Cell Carcinoma

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)

Page 38: Renal Cell Carcinoma

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.

Page 39: Renal Cell Carcinoma

Temsirolimus in RCC, PFS

Hudes et al., NEJM 2007;356:2271

Page 40: Renal Cell Carcinoma

Temsirolimus in RCC, OS

Hudes et al., NEJM 2007;356:2271

Temsirolimus vs 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

Page 41: Renal Cell Carcinoma

2nd line Everolimus in RCC

• Everolimus mTOR (important in cell growth and division)

• Dose is 10 mg po od 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

Page 42: Renal Cell Carcinoma

2nd line Everolimus in RCC PFS by central radiology review

Motzer et al., Cancer 2010;116:4256

Page 43: Renal Cell Carcinoma

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.

Page 44: Renal Cell Carcinoma

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

Page 45: Renal Cell Carcinoma

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

Page 46: Renal Cell Carcinoma

Thank You

Page 47: Renal Cell Carcinoma

AE of Sorafenib

5% ischaemic /infarct in study group