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