Renal Cell Carcinoma

Kidney Neoplasms• Primary or Secondary (metastatic) • Renal cell carcinoma (RCC) represents 80-85% of

primary renal neoplasms• Transitional cell carcinoma 8% • Rare tumors include: - Oncocytomas- Collecting duct tumors- Renal sarcomas - Nephroblastoma (Wilms’ tumor in children)- Renal medullar carcinoma (Sickle cell disease)

Incidence

• RCC represents 2% of overall cancer incidence and mortality

• 50,000 cases diagnosed and 13,000 deaths annually in the US

• 126% 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

Increasing Incidence

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

Epidemiology

• 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• Highest incidence in Scandinavia and North

America, lowest in Africa • No racial differences in the US

Risk Factors

• 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, HTN• Chronic phenacetin or aspirin use • Acquired polycystic kidney disease due to dialysis

results in 30% increase risk

Genetic Factors • 2-4% of RCC associated with inherited disorder• 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

Clinical Presentation

• Variety of symptoms, most asymptomatic • Hematuria present 40% of patients• 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

Paraneoplastic syndromes

• Anemia- anemia of chronic disease 29-88%• Hepatic dysfunction in the absence of mets

21%• Hypercalcemia 15%• Cachexia and Fever 20%• Erythrocytosis: 1-5% produce erythropoietin• Secondary AA amyloidosis 3-5%

Diagnosis

• No screening for the general population• Radiographic evaluation - Ultrasound: solid vs. cystic lesions- Contrast CT: test of choice to evaluate tumor

size, location, lymph node involvement- MRI: to evaluate collecting system and IVC

involvement

Tissue Diagnosis

• 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

Histology

• Clear cell: 75-85% of RCC

• Chromophilic papillary: 10-15%

• Chromophobic: 5-10%

Staging

• TNM staging system - Stage I-III: Localized

disease - Stage IV: Advanced,

metastatic disease

Staging and Prognosis

Cohen HT, McGovern FJ. NEJM. 2005;353:2477.

Prognosis

• 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

1992–1999, followed through 2000.

Drucker BJ. Cancer Treat Rev. 2005;31:536.

Localized RCC Treatment

• Surgery is the only curative therapy for stage I-III • Radical nephrectomy is gold standard• Partial nephrectomy in selected patients • No role for adjuvant therapy except under

investigational protocol • 20-30% of patients relapse within 2-3 years- Metastases to the lung most common 50%- Local recurrence is rare 2-3%

Advanced RCC Treatment

• 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

Targeted Therapy

• 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

VEGF Pathway Inhibition

• Tyrosine kinase (TK) inhibitors block the intracellular domain of the VGEF receptor

- Sunitinib (Sutent)- Sorafenib (Nexavar)• Monoclonal antibody that binds circulating

VEGF preventing the activation of the VEGF receptor

- Bevacizumab (Avastin)

Sunitinib

• 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

Sunitinib• 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

Sorafenib

• 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

Bevacizumab

• 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

mTOR Pathway Inhibition

• Temsirolimus (TMSR) is a rapamycin analog that inhibits mTOR kinase

• Phase III trial 626 untreated poor-prognosis 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

Immunotherapy

• 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

Chemotherapy • 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

Radiation Therapy

• RCC relatively radioresistant

• XRT has limited use in metastatic disease- Painful bone or recurrent abdominal

metastases- Brain metastases

Summary

• 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 • Stage IV disease holds poor prognosis despite

advancements in molecular understanding• IL-2, Sorafenib, Sunitinib, and Temsirolimus are

FDA approved treatments for advanced RCC

References• 1. Pantuck AJ, et al. The changing natural history of renal cell carcinoma. J Urology 2001;

166:1612. • 2. Cohen HT, McGovern FJ. Renal-cell carcinoma. NEJM. 2005;353:2477. • 3. Clinical Practice Guidelines in Oncology: Kidney Cancer, version 2.2006. National

Comprehensive Cancer Network. www.ncc.org• 4. Motzer RJ, et al. Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma.

NEJM;356:115. • 5. Drucker BJ. Renal cell carcinoma: current status and future prospects. Cancer Treat Rev.

2005;31:536.• 6. Lam JS et al. Renal cell carcinoma 2005: new frontiers in staging, prognostication and

targeted molecular therapy. J Urol. 2005; 173:1853. • 7. Twardowski PW et al. Emerging targeted therapies for renal cell carcinoma. 2006.

www.cancerpublications.com• 8. Escudier B, Eisen T, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. NEJM.

2007;365(2):125. • 9. Hudes G. et al. Temsirolimus, Interferon alfa, or both for advanced renal-cell carcinoma.

NEJM. 2007;356:2271. • 10. Atkins MB. Renal cell carcinoma. 2007. www.uptodate.com