Renal Cell Carcinoma

A Reappraisal

Chintan Patel, MD; Asma Ahmed, CUNP; Pamela Ellsworth, MD

Urol Nurs. 2012;32(4):182-190.

Treatment Options for Stage IV Disease

The value of nephrectomy in metastatic RCC has long been debated. For Stage IV disease, surgery may be considered in carefully selected patients. Cytoreductive nephrectomy can be considered for palliation of local symptoms before initiating systemic immunotherapy. Two welldesigned randomized-controlled trials comparing immuno therapy alone versus immuno therapy and radical nephrectomy showed increased survival in the combined group (Flanigan et al., 2001; Mickisch, Garin, von Poppel, de Prijck, & Sylvester, 2001). Reports have documented regression of metastatic RCC after removal of the primary tumor; however, this is extremely uncommon (Marcus et al., 1993).

Removal of a solitary metastasis is indicated in select patients with good overall performance status. A retrospective analysis from a single institution revealed improved cancer-specific survival advantage, even with removal of more than one metastatic lesion. The authors also reported increased risk of death due to RCC in patients who did not undergo surgical resection of metastasis (Alt et al., 2011). This area is still under great debate, and more studies are needed.

Paraneoplastic syndromes in RCC include hypercalcemia, polycythemia, galactorrhea, anemia, nonmetastatic hepatic dysfunction (Stauffer's syndrome), hypertension, Cushing's syndrome, altered glucose metabolism, amyloidosis, neuromyopathies, vasculopathies, nephropathies, and prostaglandin elevation (Palapattu, Kristo, & Rajfer, 2002). Palliative nephrectomy can be considered in patients with metastatic disease for alleviation of symptoms, such as pain, hemorrhage, malaise, hypercalcemia, erythrocytosis, or hypertension, but many clinicians believe most symptoms can be treated medically without surgical intervention.

Biological therapies include interferons, interleukins, colonystimulating factors, monoclonal antibodies, vaccine gene therapy, and non-specific immunomodulators. Interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. Interleukin-2 (IL-2) is a T-cell growth factor and activator of T cells, as well as a natural killer cell. IL-2 affects tumor growth by activating lymphoid cells in vivo without directly affecting tumor proliferation. Interferons and interleukins are cytokines with low response rates (5% to 20%); a median overall survival is approximately 12 months (Fisher, Rosenberg, & Fyfe, 2000; Janzen, Kim, Figlin, & Belldegrun, 2003; McDermott et al., 2005).

Immunomodulators, such as lenalidomide, a derivative of thalidomide, inhibits vascular endo thelial growth factor (VEGF), stimulates T and natural killer cells and inhibits inflammatory cytokines. Currently in phase 2 trials, this drug showed an antitumor effect in selective cases (Choueiri et al., 2006; Patel et al., 2008). Vaccine trials are still being developed, and autologous vaccine therapy is now being tried in combination with cytokine therapy. Rahma et al. (2010) carried out a pilot clinical trial testing mutant von Hippel-Lindau peptide as a novel immune therapy in metastatic RCC.

More recent developments have focused on targeted cancer therapies (see Table 6). Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression (everolimus, sorafenib tosylate, sunitinib maleate, temsirolimus). Pazopanib (Votrient®) is an oral medication that interferes with angiogenesis. It is a kinase inhibitor indicated for treatment of patients with advanced RCC (Kidney Cancer Assoication, 2012). Several targeted therapies have been approved for the treatment of metastatic RCC. One newer form of therapy under investigation is low intensity stem cell transplantation with multiple lymphocyte infusions to treat advanced RCC (NCI, 2012).

Although these therapies are more commonly administered by oncologists, an awareness of these agents by nursing staff and urologists is helpful. Patients with advanced disease are often followed by both urologists and oncologists, and an understanding of the indications and contraindications for use, as well as method of administration and potential adverse effects, may allow urologists and nurses to alleviate some anxieties of patients with metastatic and/or unresectable disease. Urologists and their nursing staff can also provide these patients with basic information that will better prepare the patient for his or her meeting with the oncologist. Finaly, since management of advanced RCC involves a multidisciplinary approach, questions pertinent to therapy may arise in the urologist's office, and thus, an awareness of these agents may allow the urologist and/or urology nurse to address some of the patient's questions.

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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.

Table 3. Fuhrman Grading System
Grade	Description
Grade 1	Nuclei of the tumor cells are small (< 10 μm), hyperchromatic, and round (resembling mature lymphocytes), with no visible nucleoli and little detail in the chromatin.
Grade 2	Nuclei of the tumor cells are slightly larger (15 μm) with finely granular "open" chromatin but small, inconspicuous nucleoli.
Grade 3	Nuclei of the tumor cells are larger (20 μm in size) and may be oval in shape, with coarsely granular chromatin. The nucleoli are easily recognizable.
Grade 4	The nuclei are pleomorphic with open chromatin or hyperchromatic and single or multiple macronucleoli.

Source: Fuhrman et al., 1982.

Table 4. Tumor Node Metastasis
Primary	Tumor (T) Description
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor 7 cm or less, limited to kidney
T1a	Tumor 4 cm or less in greatest dimension, limited to the kidney
T1b	Tumor more than 4 cm but not more than 7 cm in greatest dimen-sion, and limited to the kidney
T2	Tumor greater than 7 cm, limited to kidney
T2a	Tumor more than 7 cm but less than or equal to 10 cm in greatest dimension, limited to the kidney
T2b	Tumor more than 10 cm, limited to the kidney
T3	Tumor extends into major veins/adrenal/perinephric tissue; not beyond Gerota's fascia
T3a	Tumor invades perinephric tissue, renal sinus or renal vein
T3b	Tumor extends into renal vein(s) or vena cava below diaphragm
T3c	Tumor extends into vena cava above diaphragm or into wall of vane cava at any level
T4	Tumor invades beyond Gerota's fascia or directly into adrenal gland
N-	Regional lymph nodes
NX	Regional nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in a single regional lymph node
N2	Metastasis in more than one regional lymph node
M-	Distant metastasis
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis

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.

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