renal cell carcinoma

Renal Cell CarcinomaAbdulrahim Gari, MD

Consultant of Internal MedicineHematology and Oncology

www.garimedical.com02-2632099

• 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)

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

• 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

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.

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

Clinical Findings

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

Clinical Findings

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

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

Diagnosis

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

IVU of right RCC

CT Scan of Left RCC

RCC invading renal vein

Right Cystic RCC

CT scan with 3D reconstructionNeovascularity in Renal

Angiographyassociated with RCC

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.

Tissue Diagnosis

• Tissue diagnosis obtained from nephrectomy or biopsy

Papillary (chromophilic) renal cell carcinoma extending into the collecting

system with histological findings

Tumor Staging (Robson System)

Tumor Staging (International TNM Staging System)

Tumor Staging

Differential Diagnosis

• Benign renal tumors -Angiomyolipoma

• Renal Pelvis Cancer

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

Laparoscopic Radical NephrectomyHand-Assisted Laparoscopic

Radical Nephrectomy

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

Laparoscopic NSS

TreatmentA. Localized disease:• Percutaneous/

Laparoscopic Radiofrequency Ablation or Cryoablation

Laparoscopic Cryoablation

Prognosis

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

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

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.

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

IL2 +/- LAK in RCC

Law et al., Cancer 1995;76:824

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.

Bevacizumab + INF in RCC

PFS was shown in: Lancet 2007;370:2103

Escudier et al., JCO 2010;28:2144

Newer Targeted Therapy

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

Sorafenib in RCC

Escudier et al., JCO 2009;27:3312

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

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

Sunitinib in RCC

Motzer et al., JCO 2009;27:3584

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)

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.

Temsirolimus in RCC, PFS

Hudes et al., NEJM 2007;356:2271

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

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

2nd line Everolimus in RCC PFS by central radiology review

Motzer et al., Cancer 2010;116:4256

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.

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

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

Thank You

AE of Sorafenib

5% ischaemic /infarct in study group