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 19921999, 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