RCC represents 3% of overall cancer incidence and mortality 50,000 cases diagnosed and 13,000 deaths annually in US 2-4%

4% per year increase in incidence and 35% increase in annual mortality over the last 50 years All stages increased, but greatest increase in localized disease 5-year survival rate has doubled since 1954

Pantuck, AJ, et al. J Urology 2001; 166:1612

Male predominance (1.6:1.0 M:F) Highest incidence between age 60-80 -Median age of diagnosis is 66 years -Median age of death 70 years

Majority of RCC occurs sporadically Tobacco smoking contributes to 24% female& 30% male of RCC cases - Tobacco results in a 2-fold increased risk Occupational exposure to cadmium, asbestos, petroleum Obesity, HTN Chronic phenacetin or aspirin use 35% - 47% pt on long term dialysis develop Acquired polycystic kidney disease, out of which 5.8% develops Renal cancer.

Von Hippel-Lindau disease - AD familial cancer syndrome of retinal angiomas, CNS hemangioblastomas, pheochromocytomas and clear cell RCC. - Inherited mutation in one VHL allele - Malignancy arises from inactivation of the remaining VHL allele VHL gene mutation associated with 60% sporadic RCC

Von Hippel-Lindau protein, product of VHL gene, is a tumor suppressor VHL inhibits hypoxia-inducible genes involved in angiogenesis such as VEGF, TGF-a, GLUT-1 VHL destabilizes and promotes ubiquination of HIF-a (hypoxia-inducible factor) Loss of VHL results in tumor angiogenesis, tumor-cell proliferation epithelial cell proliferation

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 Reed syndrome - Cutaneous and uterine leiomyomas and RCC

Variety of symptoms, most asymptomatic Hematuria present 40% of patients, flank pain38%, abd mass36%, wt loss27%, fever11% Classic triad: flank pain, hematuria, palpable abdominal mass occur in 9% of patients 45% present with localized disease, 25% with locally advanced disease, 30% with metastatic disease

75% with lung metstasis, 36% to soft tissues, 20% to bone, 18% to liver, 8% each to cutaneous tissue& CNS

Anemia of chronic disease 29-88% Hepatic dysfunction in the absence of mets 21%(Stauffers syndrome) Hypercalcemia 15% Cachexia and Fever 20% Erythrocytosis: 1-5% ( erythropoietin) Secondary amyloidosis 3-5%

No screening for the general population Radiographic evaluation Ultrasonography - Contrast CT: test of choice to evaluate tumor size, location, lymph node involvement - MRI: to evaluate collecting system and IVC involvement

the imaging procedure of choice for diagnosis and staging of renal cell cancer . In most cases, CT imaging can differentiate cystic masses from solid masses and supplies information about lymph node, renal vein, and inferior vena cava involvement.

USG: can be useful in evaluating questionable cystic renal lesions if computed tomography imaging is inconclusive MRI: When inferior vena cava involvement is suspected magnetic resonance angiography (MRA) is used. Knowledge of inferior vena cava involvement is important in planning the vascular aspect of the operative procedure BONE SCAN: A bone scan is recommended for patients with bone pain or an elevated alkaline phosphatase level

Tissue diagnosis obtained from nephrectomy or biopsy of metastatic lesion Surgery indicated for solid renal masses >1.5cm Tumors <1.5cm require periodic follow-up

Cell Type Clear cell Chromophilic Chromophobic Oncocytic

Features Most common Bilateral and multifocal Indolent course Rarely metastasize

Growth Pattern Acinar or sarcomatoid Papillary or sarcomatoid

Cell of Origin Proximal tubule Proximal tubule

Cytogenetic 3p+7, +17, -Y

Solid, tubular, or Cortical sarcomatoid collecting duct Tumor nests Cortical collecting duct Medullary collecting duct

Hypodiploid

Undetermine

Collecting duct Very aggressive Papillary or sarcomatoid

Undetermine

T - primary tumour
TX T0 T1 Primary tumour cannot be assessed No evidence of primary tumour Tumour confined to kidney, <7cm

T1a
T1b T2 T3 T3a T3b T3c T4

4cm, confined to kidney

>4cm but <7cm, confined to kidney Tumour >7cm, confined to kidney Tumour extends into major veins,r perinephric tissue but not beyond Gerotas fascia,not to adrenal Tumor renal vein or its segmental branches , perirenal &renal sinus but not beyond Gerotas fascia Gross extension to IVC below diaphragm Extends into IVC above diaphragm or wall of IVC Invasion beyond Gerotas fascia

N - regional lymph nodes

NX N0 N1 N2 Nodes cannot be assessed Regional lymph nodes not involved Metastasis in a single regional lymph node Metastases in >1 regional lymph node

M - distant metastases
MX M0 M1 Metastases cannot be assessed No distant metastases Distant metastases 22

TNM staging system - Stage I-III: Localized disease - Stage IV: Advanced, metastatic disease

Prognosis depends upon stage Other poor prognostic indications include poor performance status, anemia, hypercalcemia, and elevated LDH

Five-year relative survival rates by tumor stage at diagnosis based on cases diagnosed during 19921999, followed through 2000.
Drucker BJ. Cancer Treat Rev. 2005;31:536.

Surgery is the only curative therapy for stage I-III Radial nephrectomy is gold standard Partial nephrectomy in selected patients No role for adjuvant therapy 20-30% of patients relapse within 2-3 years - Metastases to the lung most common 50% - Local recurrence is rare 2-3%

is the primary treatment for localized RCC. Its goal is to achieve the removal of tumor and to take a wide margin of normal tissue. Radical nephrectomy (Robson, 1963) entails en bloc removal of the kidney and its enveloping fascia (Gerota's) including the ipsilateral adrenal, proximal one-half of the ureter, and lymph nodes up to the area of transection of the renal vessels Removal of the adrenal is unnecessary if the tumor is not in the upper pole

Nephron sparing surgery Tumor smaller than 4cm b/l tumor involvement Renal insufficiency, Solitary kidney VHL 5 yr survival90 & 70% for stage I &II

Primary treatments are systemic therapy with molecularly targeted therapy or immunotherapy Surgery is palliative therapy - Solitary metastatic site - Solitary recurrence following nephrectomy - Symptoms related to bulkiness of disease including pain, nausea, or GI obstruction

Based on advances in the understanding of the molecular biology of RCC - Highly vascularlized tumor with increased VEGF and EGFR expression - Tumor growth mediated via VEGF pathway and mammalian target of rapamycin (mTOR) pathway

Tyrosine kinase (TK) inhibitors block the intracellular domain of the VEGF receptor - Sunitinib - Sorafenib Monoclonal antibody that binds circulating VEGF preventing the activation of the VEGF receptor - Bevacizumab

Immunotherapy with IL-2 activates immune response against RCC resulting in tumor remission rates 10-20% with median duration of 19-91 months Severe toxicity including hypotension, capillary leak syndrome, MI, renal insufficiency, pulmonary edema, hepatic dysfunction, CNS dysfunction Treatment requires ICU monitoring Used for patients that can tolerate side effects

RCC is only minimally responsive to chemotherapy 83 clinic trials involving over 4000 pts, overall response rate is only 6% On-going clinical trials of combination chemotherapy including Gemcitabine and 5-FU Limited data reveals some response in non-clear cell RCC to Carboplatin, Cisplatin plus Gemcitabine

RCC relatively radioresistant RT has limited use in metastatic disease Painful bone or recurrent abdominal metastases Brain metastases

RCC is relatively rare but increasing incidence Associated with tobacco and inherited disorders Surgery is the only curative modality for Stage I, II, and III RCC is radio resistant, RTs role in paliation Stage IV disease holds poor prognosis despite advancements in molecular understanding IL-2, Sorafenib, Sunitinib, and Temsirolimus are FDA approved treatments for advanced RCC

38

Two phase II trials evaluating activity and safety in previously treated advanced RCC 25-36% of patients had an objective response Progression free survival (PFS) 8.3-8.7 months Median survival 16.4 months Side effects include fatigue, HTN, nausea, diarrhea, mucositis, and hypothyroidism

Phase III trial 750 pts with untreated stage IV RCC Sunitinib vs. INFa Sunitinib showed prolonged median PFS 11 vs. 5m and higher response rate of 31% vs. 6%

Motzer RJ, et al. NEJM. 2007;356:115-124

Phase II and phase III trials in advanced RCC Phase III TARGET study of 903 previously tx pts w/ stage IV RCC randomized to Sorafenib vs. placebo - Sorafenib improved median PFS 5.5 vs. 2.8m - No statistically significant survival benefit, median survival of 17.8 vs. 15.2 m Side effects include HTN, fatigue, rash, hand-foot syndrome, diarrhea, nausea

Phase II trial of 116 pts, Bevacizumab increased TTP 4.8 vs. 2.5m for placebo group. -No difference in median survival Phase III AVOREN trial of 648 untreated pts - INFa plus Avastin or placebo - Avastin group resulted in PFS of 10.2 vs. 5.4 m. - Unclear activity as single agent however Not FDA approved, but can be used as second-line therapy

Temsirolimus (TMSR) is a rapamycin analog that inhibits mTOR kinase Phase III trial 626 untreated poorprognosis pts with stage IV RCC tx w/ TMSR, TMSR +INFa, or INFa. - TMSR prolonged survival compared to INFa (10.9 vs. 7.3m) and prolonged PFS (3.8 vs. 1.9m) - Benefit greater in non-clear cell RCC