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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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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