Renal Cell Carcinoma

Table 1.  Hereditary and Non-Hereditary Rick Factors

	Hereditary	Non-Hereditary
Risk Factors	Tuberous sclerosis, von Hippel-Lindau gene, hereditary papillary renal cell carcinoma, hereditary leiomyoma – renal cell carcinoma, Birt-Hogg-Dube syndrome, hereditary renal oncocytoma	Tobacco, obesity, male, African American, hypertension, phenacetin, acquired cystic disease, workplace exposures (such as asbestos, benzene, trichloroethylene)

Source: American Cancer Society, 2011.

Table 2.  Genetics of Renal Cell Carcinoma

Type	Incidence	Origin	Cromosomal Abnormality	Gene
Clear cell	65%	Proximal tubule	Loss of 3p	VHL, PBRM1, TCS1, and TSC2
Papillary cell	15%	Proximal tubule	Trisomy 7, 16, 17	MET, FLCN, TFE3
Chromophobe cell	10%	Intercalated cell of cortical collecting duct	Hypodiploid loss of chromosomes 1,2,6,10,13,17,21
Collecting duct carcinoma	1%	Closely related to principal cells of the medullary collecting duct and collecting duct of distal nephron	None	No consistent genetic abnormality noted
Unclassified type	5%	Varied origin	None	FH – leiomyomatosis renal cell carcinoma SDH

Notes: VHL = vonHipppel-Lindau, MET = met proto-oncogene (hepatocyte growth factor receptor), FLCN = folliculin, TFE3 = transcription factor E3, TCS1 = Treacher Collins syndrome 1, TCS2 = Treacher Collins syndrome 2, PBRM1 = Protein polybromo-1 (PB1) also known as BRG1-associated factor 180 (BAF180).
Source: Kennedy et al., 1990.

Source: Fuhrman et al., 1982.

Source: Edge et al., 2010.

Table 5.  Anatomic Staging System/Prognostic Group

Anatomic Stage	Prognostic Group
Stage 1	T1 N0 M0
Stage 2	T2 N0 M0
Stage 3	T1 or T2, N1 M0	T3 N0 or N1, M0
Stage 4	T4 any N M0	Any T, any N, M1

Source: Edge et al., 2010.

Table 6.  Biological Response Modifiers

	Temsirolimus (Torisel®)	Sunitinib (Sutent®)	Everolimus (Afinitor®)	Sorafenib (Nexavar®)	Pazopanib (Votrient®)
Mechanism of Action	Mammalian target of rapamycin (mTOR) inhibitor. Torisel binds to an intracellular protein FKB12, and the protein drug complex inhibits the activity of mTOR that controls cell division. Inhibitor of mTOR prevents transcription of mRNAs and translational proteins required for cell cycle progression from G1 to S phase.	A kinase inhibitor.	A kinase inhibitor; indicated for patients with advanced RCC after failure of Rx with sunitinib or sorafenib.	A tyrosine protein kinase inhibitor; targets the Raf/Mek/Erk pathway (MAP kinase pathway).	A selective multitargeted tyrosine kinase inhibitor (TK-1), it specifically targets growth factors associated with angiogenesis and tumor cell proliferation.
Dose	25 mg IV infusion over a 30-to 60-minute period once/week. Rx continues until disease progression or significant toxicity. Prophylaxis with IV diphenhydramine 25 to 50 mg approximately 30 minutes before each dose of Torisel.	Starting dose is 50 mg qd for a schedule of 4 weeks of treatment followed by 2 weeks off treatment. Can be taken with or without food. Dose interruption and/or dose modifications in 12.5 mg increments or decrements based on individual safety and tolerability.	10 mg po qd with or without food. Treatment interruption and/or decrease dose to 5 mg may be needed to manage AEs.	400 mg (two 200 mg tabs) po BID. May change to 400 mg qd or qod if significant AEs.	800 mg (4x200 mg tablets) qd. Monitor serum liver tests before start of treatment and once every 4 weeks for at least first 4 months of Rx.
Efficacy	49% increase in median overall survival with Torisel (10.9 months; range: 8.6 to 12.7 months) compared with interferon alpha (7.3 months; range – 6.1 to 8.8 months).	In 2 trials, evaluation efficacy in patients with cytokine refractory mRCC, objective response rates in 34% and 36% treated with Sutent.	Superior to PBO for progression-free survival 4.9 months (range – 4 to 5.5 months) for Afinitor compared with 1.9 months (range – 1.8 to 1.9 months) for PBO	In a study of patients with mRCC randomized to PBO or sorafenib, the progression-free rate was significantly higher with sorafenib (50%) compared with PBO (18%), and the progression-free survival significantly longer for sorafenib (163 days) than placebo (41 days).	In all patients, there was a 9.2 months overall median progression free survival with Votrient use for two months. In treatment naïve (non-prior systemic therapy) patients, it was 11 months.
Adverse Effects	Hyperglycemia, hyperlipidemia, iummnosuppression, interstitial lung disease, rash, asthenia, mucositis, nausea, edema, anorexia.	Fatigue, asthenia, diarrhea, nausea, mucositis, stomatitis, vomiting, dyspepsia, abdominal pain, constipation, headache, rash, hand-foot syndrome, skin discoloration, altered taste, anorexia, bleeding.	Stomatitis, infections, asthenia, fatigue, cough, diarrhea.	Diarrhea, rash/desquamation, fatigue, hand-foot syndrome, skin reaction, alopecia, NV.	Transaminase elevations, QT prolongation and Torsade de Pointes, hemorrhagic events, arterial thrombotic events, GI perforation and fistula, HTN, hypothyroidism, proteinuria, diarrhea, hair color changes, nausea, anorexia and vomiting
Warnings/Precautions/DDIs	Caution when using with potent CYP3A4 inducers and inhibitors.	CYP3A4 inhibitors may increase Sutent plasma concentration; therefore, dose reduction to a minimum of 37.5 mg. CYP3A4 inducers, such as rifampin, may decrease Sutent concentration; therefore, increase dose to a max of 87.5 mg recommended; LV ejection fraction decreases to below lower limits of normal.	For patients with children – Pugh class B hepatic impairment, decrease dose to 5 mg qd; if strong inducers of CYP3A4, increase dose in 5 mg increments to max of 20 mg qd; due to significant increase in exposure, co-administration with strong or moderate CYP3A4 inhibitor should be avoided.	When used concomitantly with Docetaxel, doxorubicin, or fluorouracil increases area under the curve of these agents; CYP3A4 inducers increase metabolism of sorafenib and decrease sorafenib concentrations. CYP2B6 and CYP2C8 substrates: caution; systemic exposure is expected to increase with co-administration of sorafenib.	Drug interactions – avoid use of strong CYP3A4 inhibitors, caution with CYP3A4 inducers. Caution with patients at higher risk of developing QT interval prolongation and in patients taking anti-arrythmics. Use with caution in patients with hepatic impairment.

Notes: AE = adverse events, CYP3A4 = cytochrome P4503A4, DDi = drug-drug interactions, LV = left ventricle, mRCC = metastatic renal cell carcinoma, PBO = placebo, Rx = treatment, qd = daily, BID = twice a day, QOD = every other day, NV = nausea/vomiting, GI = gastrointestional, HTN = hypertension.
Source: Adapted from Ellsworth, 2011.

Authors and Disclosures

Chintan Patel, MD
PGY-1 in Urology, The Lahey Clinic, Burlington, MA.

Asma Ahmed, CUNP
Certified Urology Nurse Practitioner, Division of Urology/Department Surgery, Providence Veterans Administration Hospital, Providence, RI.

Pamela Ellsworth, MD
Associate Professor, Urology, Warren Alpert School of Medicine, Brown University, Providence, RI.

Statement of Disclosure
The authors reported no actual or potential conflict of interest in relation to this continuing nursing education activity.