Renal Cell Carcinoma:Nursing Considerations With the Use of Targeted Therapy Nancy Moldawer, RN, MSNClinical Research Operations ManagerDivision of Medical Oncology and Therapeutic ResearchCity of HopeDuarte, California

Renal Cell Carcinoma (RCC)Originates in the renal cortexMost common solid lesion occurring in the kidney (80-85% of all primary renal neoplasms)Diseased Kidney

RCC StatisticsUS estimates for 2007151,190 individuals diagnosed with cancer of the kidney and renal pelvis12,890 individuals died from cancer of the kidney and renal pelvis3rd most common genitourinary cancer after prostate cancer and bladder cancer2Median age at diagnosis: 65 years (2000-2004)1 Median age at death: 71 years (2000-2004)11. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008.2. Jemal A et al. CA Cancer J Clin. 2007;57:43.

RCC StatisticsAn estimated 240,266 US individuals with a history of kidney and renal pelvis cancer were alive in 200415-year survival has improved250.9% 1975197765.7% 19962003

1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008.2. Ries LAG, et al. SEER Cancer Statistics Review. 2007;1975-2004.

US Yearly Kidney and Renal Pelvis Cancer Incidence and MortalityRies LAG et al. SEER Cancer Statistics Review, 1975-2004;2007.

Etiology of RCCEnvironmental and clinical risk factorsSmoking1,2Obesity1,3,4Acquired cystic disease of the kidney (usually in association with dialysis)5,6Analgesic abuse nephropathy7,8Occupational exposure to toxic compounds9-11Genetic predisposition121. Setiawan VW et al. Am J Epidemiol. 2007;166:932. 2. Hunt JD et al. Int J Cancer. 2005;114:101. 3. Pischon T et al. J Natl Cancer Inst. 2006;98:920. 4.Chow WH et al. N Engl J Med. 2000;343:1305. 5. Brennan JF et al. Br J Urol. 1991;67:342. 6. Truong LD et al. Am J Kidney Dis. 1995;26:1. 7. Chow WH et al. Int J Cancer. 1994;59:467. 8. Lornoy W et al. Lancet. 1986;1:1271. 9. Mandel JS et al. Cancer. 1995;61:601. 10. McLaughlin JK, Blot WJ. Int Arch Occup Environ Health. 1997;70:222. 11. Brauch H et al. Toxicol Lett. 2004;151:301. 12. Zbar B et al. J Urol. 2007;177:461.

SymptomsMany patients with RCC are asymptomatic and have nonpalpable renal masses until late in natural disease course1,2

Common local symptomsHematuriaIpsilateral flank or abdominal painPalpable mass1. Lee CT et al. Urol Oncol. 2002;7:135. 2. Patard JJ et al. Eur Urol. 2003;44:226.

SymptomsCommon systemic symptomsParaneoplastic disordersHypertensionCachexiaWeight lossPyrexiaNeuromyopathyAmyloidosisElevated erythrocyte sedimentation rateAnemiaAbnormal liver functionHypercalcemiaPolycythemiaPain or mass related to metastatic disease

Physical ExaminationPlays a limited role in diagnosing RCCMay be valuable in situations where there isA palpable abdominal massA palpable cervical lymphadenopathyNon-reducing varicoceleBilateral lower extremity edema suggestive of venous involvementAny of the above findings warrants radiologic examination Ljungberg B et al. Eur Urol. 2007;51:1502.

Extent of Disease at DiagnosisMost renal cancers diagnosed when disease still localized to primary siteNational Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008.

Stages of RCCOregon Health & Science University. Kidney Cancer Program. Available at: http://www.ohsu.edu/health/page.cfm?id=13584 Stage I: Cancer is in the kidney only and size of the tumor is 7.0 cm in diameterStage II: Cancer is in the kidney only, but size of the tumor is >7.0 cm in diameterStage III: Tumor in the kidney may be any size, but extends beyond layer of tissue (Gerotas fascia) that encapsulates kidney and adrenal gland. Cancer may have spread to blood vessels that carry blood away from kidney.Stage IV: Tumor in the kidney extends beyond Gerotas fascia and/or cancer has spread to one or more lymph nodes near kidney. Cancer may have spread to other organs such as lungs, liver, brain, or bones.

RCC Subtypes1,21. Thoenes W et al. Path Res Pract. 1986;181:125. 2. Strkel S, van den Berg E. World J Urol. 1995;13:153.

SubtypePrevalenceTumor FeaturesMicroscopic FeaturesClear cell carcinoma7585%Multinodular; yellow cut surface with gray & white fociChromophilic (papillary) carcinomas1015%Ball-shaped outline, dotted pattern; beige, white, or greasy brownChromophobic carcinomas510%1 solid tumor nodule with slightly lobulated surface; orange cut surfaceOncocytomasUncommon (2%)Typically solitary, slightly lobulated; tan-brown cut surfaceCollecting duct tumors (a.k.a. Bellinis duct)Very rareLarge; cut surface firm, white, interspersed with necroses

Prognostic Clinical FactorsSeveral clinical factors associated with poor survival in patients with RCCPoor performance status1,2Presence of RCC symptoms and/or paraneoplastic syndrome1-6Anemia, hypercalcemia, hepatopathy, thrombocytosis, fever, weight lossObesity71. Zisman A et al. J Clin Oncol. 2001;19:1649. 2. Motzer RJ et al. J Clin Oncol. 1999;17:2530. 3. Suppiah R et al. Cancer. 2006;107:1793. 4. Bensalah K et al. J Urol 2006;175:859. 5. Fahn HJ et al. J Urol. 1991;145:248. 6. Patard JJ et al. J Urol. 2004;172:2167. 7. Calle EE et al. N Engl J Med. 2003;348:1625.

Recurrent/Metastatic RCC PrognosisPatients with recurrent or metastatic RCC have very poor prognosisFactors Associated With Survival Outcomes1-41. Motzer RJ et al. J Clin Oncol. 1999;17:2530. 2. Mekhail TM et al. J Clin Oncol. 2005;23:832. 3. Choueiri TK et al. Ann Oncol. 2007;18:249. 4. Han KR et al. Urology. 2003;61:314.

Longer SurvivalShorter SurvivalLong interval between nephrectomy & development of distant metastasesSingle site of metastatic diseaseAbsence of retroperitoneal adenopathyRight involved kidneyKarnofsky performance status 1.5 x ULNCorrected serum calcium >10 g/dLHemoglobin

Advanced RCCTreatment options other than surgeryRadiotherapyNot an effective optionChemotherapyNot an effective optionImmunotherapyLimited/some benefitTargeted therapyClinical benefit; active area of research and further refinement

1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008.2. Janzen N et al. Urol Clin North Am. 2003;30:843.

AngiogenesisAngiogenesis is a key determinant in pathophysiology of RCC1RCCs are most vascularized of all solid tumors2 1. Izawa JI, Dinney CP. CMAJ. 2001;164:662.2. Cristofanilli M et al. Nat Rev Drug Discov. 2002;1:415. Map of Blood Flow to a Metastatic RCC Lesion

Role of VEGF in AngiogenesisCristofanilli M et al. Nat Rev Drug Discov. 2002;1:415.

Growth FactorsVascular endothelial growth factor (VEGF) key growth factor involved in angiogenesis1,2VEGF mRNA expression correlates with vascularizationVEGF is overexpressed in most clear-cell RCCsPlatelet-derived growth factor (PDGF) and epidermal growth factor (EGF) play role in angiogenesis and oncogenesis1. Cristofanilli M et al. Nat Rev Drug Discov. 2002;1:415. 2. De Mulder PH. Ann Oncol. 2007;18:ix98.

Targeting the Molecular Pathways of RCC OncogenesisStadler WM. Cancer. 2005;104:2323.Angiogenesis/Cell proliferation/Cell survivalbevacizumabgefitinib, cetuximab, erlotinib, panitumumabGene expressionrapamycin, temsirolimus, everolimussorafenibEndothelial/ Tumor cellsUpregulation in response to HIF-1 transcriptionsorafenib, sunitinib

Clinically Available Targeted Agents for Advanced RCC4 targeted agents available for advanced RCC1. Escudier B et al. Lancet. 2007;370:2103. 2. Rini BI et al. 2008 ASCO Genitourinary Cancers Symposium. Abstract 350.3. Motzer RJ et al. N Engl J Med. 2007;356:115. 4. Escudier B et al. N Engl J Med. 2007;356:125. 5. Hudes G et al. N EngJ Med. 2007;356:2271. ORR=overall response rate; TTP=time to progression

AgentTargetEfficacy in Randomized Phase III TrialsComparisonNo. TreatedORRTTP (mos)BevacizumabVEGFBevacizumab + IFN- vs Placebo + IFN-1 64931% vs 13%10.2 vs 5.4;P=.0001Bevacizumab + IFN- vs IFN-273226% vs 13%8.5 vs 5.2;P

Integrating the Oncology Nurse Into the New Paradigm of Targeted TherapyThe new therapeutic paradigm of molecular-targeted therapy presents new challenges for oncology nursesInduces tumor stabilization vs complete responsesControls disease vs curing diseaseUnique side-effect profilesAs the landscape of RCC treatment continues to evolve, the nurse remains on the forefront of drug discovery, administration, and adverse event monitoringMoldawer N, Wood LS. Kidney Cancer J. 2006;4:25-32.

SunitinibAn orally administered tyrosine kinase inhibitorApproved for treatment of advanced RCC in January 2006Potent inhibitor of VEGFR, PDGFR, and FLT-31Has demonstrated efficacy in clear-cell RCC as second-line therapy after IL-23 and as first-line therapy compared with interferon2

1. Abrams TJ, et al. Mol Cancer Ther. 2003;2:471-478.2. Motzer RJ. JAMA. 2006;295:2516-2524.

Sunitinib: Dosing and AdministrationMay be taken with or without foodSunitinib and its active metabolite metabolized primarily by CYP3A4Requires dose adjustment when administered with CYP3A4 inhibitors or inducers2Important to assess any concomitant medications patient is taking

1.Faivre S, et al. J Clin Oncol. 2006;24:25-35. 2. Hiles JJ, Kolesar JM. Am J Health-Syst Pharm. 2008;65:123-131. 50 mg QD 4 weeks on 2 weeks off1

Sunitinib:Most Common Adverse Events (20%)Sutent (sunitinib) Full Prescribing Information. Pfizer Inc. October 2007.

Adverse EventAll Grades (%)

Fatigue58Diarrhea58Nausea49Altered taste44Mucositis/stomatitis43Anorexia38Hypertension30Bleeding 30Vomiting28Dyspepsia28Rash27Abdominal pain22Hand-foot syndrome21

SorafenibAn orally administered multikinase inhibitorApproved for treatment of advanced RCC in December 2005Inhibits VEGFR 1, 2, and 3, PDGFR, FLT-3, c-Kit, and RET kinases1,2Has demonstrated efficacy as second-line monotherapy in metastatic RCC3,41.Bhojani N, et al. Eur Urol. 2008;53:917-930. 2. Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109.3. Ratain MJ, et al. J Clin Oncol. 2006;24:2505-2512. 4. Escudier B et al. N Engl J Med. 2007;356:125.

Sorafenib: Dosing and AdministrationFormulated as a 200-mg tabletDaily dosing of 400 mg BIDIf dose reduction is required, dose may be reduced to:400 mg QD, and subsequently to 400 mg QODPrimarily metabolized by CYP3A4 and undergoes glucuronidation

Moldawer N, Wood LS. Kidney Cancer J. 2006;4:25-32.

Sorafenib:Most Common Adverse Events (20%)Nexavar (sorafenib) Full Prescribing Information. Bayer HealthCare. 2008.

Adverse EventAll Grades (%)

Diarrhea55Fatigue46Abdominal pain31Weight loss30Anorexia29Nausea24Hand-foot reaction21

Sunitinib and Sorafenib Adverse Events:Nursing Implications1,2DiarrheaTreat initially with diet modification (low residue) and loperamideIf loperamide insufficient, give diphenoxylate HCl with atropineAdditional options include tincture of opium, Culturelle (oral probiotic), and Dannon yogurt containing bifidobacteriumFatigueAdjust activities to allow for rest periods and maximize fluid and caloric intake

1. Wood LS. Oncology Nurs News. 2007;3:19-20. 2. Wood LS. Oncology Nurs News. 2007;4:37-38.

Sunitinib and Sorafenib Adverse Events:Nursing Implications1,2 (cont.)Functional or clinical mucositisDietary modificationsAvoidance of carbonated beverages and spicy foodsEating foods at room temperature

MedicationsTopical lidocaine or XylocaineBMX Solution (Benadryl/Mylanta, Xylocaine)Rincinol (OTC topical solution containing aloe vera)Nystatin suspension or clotrimazole troches for clinical mucositis

1. Wood LS. Oncology Nurs News. 2007;3:19-20. 2. Wood LS. Oncology Nurs News. 2007;4:37-38.

Sunitinib and Sorafenib Adverse Events:Nursing Implications1,2 (cont.)Taste changes and anorexiaMaximize caloric intakeEncourage 6 small meals per dayUse of flavorings and gravy to enhance food taste

Hand-foot reactionLiberal use of emollientsAvoid activities that cause pressure, abrasion, or irritation to hands and feetApplication of Udderly Smooth lotion BIDOther options include:Bag BalmAveeno Skin Relief Moisturizing CreamAveeno Intense Relief Foot CreamKerasal ointmentKeralec creamZims Crack CrmeBiafine Topical Emulsion

1. Wood LS. Oncology Nurs News. 2007;3:19-20. 2. Wood LS. Oncology Nurs News. 2007;4:37-38.

BevacizumabMonoclonal antibody to VEGF active in multiple tumor typesFirst biological antiangiogenic agent approved by US FDAApproved for use in colorectal, non-small cell lung, and metastatic breast cancers1Phase 3 studies are evaluating bevacizumab in a variety of solid tumor types21. Avastin (bevacizumab) Full Prescribing Information. Genentech, Inc. March 2008.2. National Cancer Institute website. http://www.cancer.gov/clinicaltrials/search.

Bevacizumab: Dosing and AdministrationUsual dosage of bevacizumab for treatment of colorectal cancer is 5 mg/kg IV every 2 weeksDosage in investigational trials of RCC has generally been 10 mg/kg IV every 2 weeks1,2Can be associated with hypersensitivity reactions

1. Hainsworth JD, et al. J Clin Oncol. 2005;23:7889-7996.2. Bukowski RM, et al. J Clin Oncol. 2007;25:4536-4541.

Bevacizumab: Serious Adverse Events (10%) Yang CH, et al. N Engl J Med. 2003;349:427-434. aPercent of patients with grade 3 toxic effectsb1+ or 150 mg/24 hrsGrade 3 hypertension was defined as hypertension not completely controlled by one standard medicationGrade 3 proteinuria was defined as urinary excretion of >3.5 g of protein per 24 hrs

Adverse EventBevacizumab 10 mg/kg (N=39)%Bevacizumab 3 mg/kg (N=37)%Epistaxis2114Hypertension36 (21)a3Fever without infection103Malaise3316Hematuria133Hyponatremia811Proteinuriab64 (8)a41 (5)aElevated ALT105Chest pain5 (5)a0

Bevacizumab Adverse Events:Nursing ImplicationsBleedingObtain patient history of unusual bleeding or clotting, GI perforation, and use of anticoagulantsAvoid anticoagulant therapy if possible, especially concomitant use of bevacizumab with warfarin and 5-FUEducate patient about signs of bleeding (ie, epistaxis, bleeding gums during tooth brushing, red or black, tarry stools, vomiting blood)ThrombosisEducate patient about signs of thrombosis that includeSudden chest painDifficulty breathingIgnoffo RJ. Am J Health-Syst Pharm. 2004;61(Suppl 5):21-26.

Bevacizumab Adverse Events:Nursing Implications (cont.)HypertensionEstablish baseline blood pressure (BP) and monitor weekly during therapyEnsure that patient has a BP monitor at homeContinue antiphypertensive therapy in patients already taking it when bevacizumab is initiatedConsult MD to initiate mild antihypertensive if patient develops hypertension during bevacizumab therapyConsider using ACE inhibitor and avoid antihypertensive agents that inhibit CYP3A4 (eg, verapamil, diltiazem)ProteinuriaMonthly monitoring of renal function and serum protein concentrationIgnoffo RJ. Am J Health-Syst Pharm. 2004;61(Suppl 5):21-26.

TemsirolimusAn inhibitor of mammalian target of rapamycin (mTOR) kinase, a component of intracellular signaling pathways1Binds to an abundant intracellular protein FKBP-12, forming a complex that inhibits mTOR2,3First mTOR inhibitor approved for treatment of advanced RCC Approved by FDA on May 30, 2007

1. Schmelzle T, Hall MN. Cell. 2000;103:253-262.2. Skotnicki JS, et al. Clin Cancer Res. 2001;7(Suppl):3749-3750.3. Harding MW. Clin Cancer Res. 2003;9:2882-2886.

Temsirolimus: Dosing and AdministrationApproved dose for advanced RCC is 25 mg IV weekly over a 30- to 60-minute period Patients should receive prophylactic diphenhydramine 2550 mg IV prior to the start of each doseIf patient develops a hypersensitivity reaction during infusion:Stop infusion Observe patient at least 3060 minutesNotify MDTreatment may be resumed at discretion of MD with administration of an H1-receptor antagonist (eg, diphenhydramine), if not previously administered, and/or an H2-receptor antagonist (eg, famotidine 20 mg IV or ranitidine 50 mg IV) 30 minutes before restarting temsirolimusExtend infusion time to 60 minutes

Torisel (temsirolimus) Full Prescribing Information. Wyeth Pharmaceuticals. May 2007.

Temsirolimus:Most Common Adverse Events (30%)Torisel (temsirolimus) Full Prescribing Information. Wyeth Pharmaceuticals. May 2007.

Adverse EventAll Grades (%)

Asthenia51Rash47Mucositis41Nausea37Edema35Anorexia32

Temsirolimus Adverse Events:Nursing ImplicationsRashObserve for acne-like rashConsider antihistamines for itchingCounsel patient to use skin emollients, avoid agents that cause skin drying effects, and avoid sun exposureAnemiaMonitor hemoglobin and hematocrit regularly during therapyAnorexiaMaximize caloric intake

Temsirolimus Adverse Events:Nursing Implications (cont.)HyperlipidemiaMonitor serum cholesterol and triglycerides prior to and during therapyHyperglycemiaMonitor serum glucose prior to and periodically during therapyInfectionMonitor for sore throat, appearance of sputum, urine, and stoolMonitor vital signs regularlyEducate patient about recognizing signs of infection

Temsirolimus Adverse Events:Nursing Implications (cont.)

Interaction with CYP3A4 inhibitorsAvoid concomitant use of temsirolimus with:Grapefruit juiceKetoconazoleItraconazoleClarithromycinAtazanavirIndinavirNefazodoneNelfinavirRitonavirSaquinavirTelithromycinVorizonazoleTorisel (temsirolimus) Full Prescribing Information. Wyeth Pharmaceuticals. May 2007.

Temsirolimus Adverse Events:Nursing Implications (cont.)Interaction with CYP3A4 inducersAvoid concomitant use of temsirolimus with:DexamethasonePhenytoinCarbamazepinePhenobarbitalRifampinRifabutinTorisel (temsirolimus) Full Prescribing Information. Wyeth Pharmaceuticals. May 2007.

NCCN Guidelines:Explanation of Categories of EvidenceCategory 1Recommendation based on high-level evidence (ie, high-powered randomized clinical trials or meta-analyses) NCCN Guidelines Panel has reached uniform consensus that the recommendation is indicated

Category 2ARecommendation based on lower-level evidenceLower-level evidence is interpreted broadly and may range from phase 2 to large cohort studies to case studiesIn many instances, retrospective studies derived from clinical experience of treating large numbers of patients and Guidelines Panel members have first-hand knowledge of dataNational Comprehensive Cancer Network. Available at: http://www.nccn.org.

NCCN Guidelines:Explanation of Categories of EvidenceCategory 2BRecommendation based on lower-level evidence There is nonuniform consensus that the recommendation should be madeIn these instances, institutions take different approaches to the management of a particular clinical scenario

Category 3Including the recommendation has engendered a major disagreement among NCCN Guidelines Panel membersLevel of evidence not pertinent in this category because experts can disagree about the significance of high-level trialsNational Comprehensive Cancer Network. Available at: http://www.nccn.org.

NCCN Practice Guidelines in Oncology: Kidney CancerRelapse or Stage IV and medically or surgically unresectable Predominant clear cell histologyClinical trial orSunitinib (category 1)or Temsirolimus for poor-prognosis patientsa (category 1)orBevacizumab + IFNor High-dose IL-2 for selected patientsor Sorafenib for selected patientsandBest supportive carebFIRST-LINE THERAPYaTemsirolimus indicated for poor-prognosis patients, defined as thosewith 3 predictors of short survivalbBest supportive care can include palliative RT, metastasectomy or biphosphonates for bony metastasisNCCN Clinical Practice Guidelines in Oncology. 2007;v. 1. 2008.

NCCN Practice Guidelines in Oncology: Kidney CancerRelapse or Stage IV and medically or surgically unresectable Clinical trial (preferred)orTemsirolimusa (category 1 for poor-prognosis, category 2A for other risk groups)orSorafenib or Sunitinibor Chemotherapy (category 3):Gemcitabine or capecitabine or floxuridine or 5-FU or doxorubicin (in sarcomatoid only)and Best supportive carebFIRST-LINE THERAPY (cont.)Non clear cell histologyaTemsirolimus indicated for poor-prognosis patients, defined as those with 3 predictors of short survivalbBest supportive care can include palliative RT, metastasectomy or biphosphonates for bony metastasisNCCN Clinical Practice Guidelines in Oncology. 2007;v. 1. 2008.

NCCN Practice Guidelines in Oncology:Kidney CancerClinical trial (preferred)orSorafenib (category 1 following cytokine therapy and category 2A following TKI)or Sunitinib (category 1 following cytokine therapy and category 2A following TKI)or Temsirolimus (category 2A following cytokine therapy and category 2B following TKI)or IFN (category 2B)orHigh dose IL-2 (category 2B)orLow dose IL-2 + IFN (category 2B)or BevacizumabandBest supportive careaSUBSEQUENT THERAPYaBest supportive care can include palliative RT, metastasectomy or biphosphonates for bony metastasisNCCN Clinical Practice Guidelines in Oncology. 2007;v. 1. 2008.Progression

Targeted Therapies:Patient Education and ManagementAssess patient at initiation of therapyEstablish treatment schedule and regularly scheduled visits with healthcare providerEnsure that patient sees an MD or RN at the beginning of each treatment cycleProvide both written and verbal instructions about RCC treatment and side effect managementPatient should be instructed to contact healthcare provider immediately when experiencing any side effectsDocument therapy and response to treatment on appropriate medication flow sheets and nursing notesMoore SH. Online educational activity 2006.

Summary3 targeted therapies are currently FDA-approved for treatment of advanced RCCTargeted therapies have manageable side effects with appropriate nursing interventionsPatients have prolonged survival with control of their cancerIdentified prognostic factors correlate with prognosis and treatment decisions (NCCN guidelines)

Future ConsiderationsDo these targeted therapies have a role in the adjuvant setting?Do combinations of these targeted therapies offer better clinical results or cause increased toxicity?Patient preference: oral or IV therapy?

**RCC originates in the renal cortex and is the most common solid lesion that occurs in the kidney (80%-85% of all primary neoplasms).

First image obtained at : http://medicalimages.allrefer.com/large/kidney-anatomy.jpgSecond image obtained at: http://www.ecureme.com/emyhealth/data/Renal_Cell_Carcinoma.asp*US estimates for 2007 indicate that 51,190 individuals were diagnosed with cancer of the kidney and renal pelvis, and 12,890 individuals died from the disease.1 Kidney and renal pelvis cancer is the 3rd most common genitourinary cancer after prostate cancer and bladder cancer.2 The median age of individuals at diagnosis was 65 years; the median age of individuals at death was 71 years.1 Estimates predict that approximately 240,266 Americans with a history of cancer of the kidney and renal pelvis were alive as of January 1, 2004.1 5-year disease survival has improved from a rate of 50.9% in 1975-1977 to 65.7% in 1996-2003.3

National Cancer Institute. SEER cancer statistics fact sheet: Cancer of the kidney and renal pelvis. Available at http://seer.cancer.gov/statfacts/html/kidrp.html?statfacts_page=kidrp.html&x=22&y=16. Accessed February 8, 2008.Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43-66. Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004. Bethesda, MD: National Cancer Institute; 2007. Available at: http://seer.cancer.gov/csr/1975_2004/.*The incidence rate of RCC has steadily increased over time, from 7.1 per 100,000 individuals in 1975 to 13.1 per 100,000 individuals in 2004.1 The increasing incidence may be partially explained by the greater numbers of asymptomatic tumors that are being detected with noninvasive imaging modalities (ie, computed tomography, magnetic resonance imaging). The mortality rate of RCC has remained relatively stable over time, at 3.6 per 100,000 individuals in 1975 and 4.1 per 100,000 individuals in 2004.

Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004. Bethesda, MD: National Cancer Institute; 2007. Available at: http://seer.cancer.gov/csr/1975_2004/.

*Several environmental and clinical risk factors have been implicated in the etiology of RCC, as listed above.1-12

Setiawan VW, Stram DO, Nomura AM, Kolonel LN, Henderson BE. Risk factors for renal cell cancer: the multiethnic cohort. Am J Epidemiol. 2007;166:932-940. Hunt JD, van der Hel OL, McMillan GP, Boffetta P, Brennan P. Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies. Int J Cancer. 2005;114:101-108. Pischon T, Lahmann PH, Boeing H, et al. Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst. 2006;98:920-931. Chow WH, Gridley G, Fraumeni JF Jr, Jrvholm B. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med. 2000;343:1305-1311. Brennan JF, Stilmant MM, Babayan RK, Siroky MB. Acquired renal cystic disease: implications for the urologist. Br J Urol. 1991;67:342-348. Truong LD, Krishnan B, Cao JT, Barrios R, Suki WN. Renal neoplasm in acquired cystic kidney disease. Am J Kidney Dis. 1995;26:1-12. Chow WH, McLaughlin JK, Linet MS, Niwa S, Mandel JS. Use of analgesics and risk of renal cell cancer. Int J Cancer. 1994;59:467-470. Lornoy W, Becaus S, de Vleeschouwer M, et al. Renal cell carcinoma, a new complication of analgesic nephropathy. Lancet. 1986;1:1271-1272. Mandel JS, McLaughlin JK, Schlehofer B, et al. International renal-cell cancer study. IV. Occupation. Int J Cancer. 1995;61:601-605. McLaughlin JK, Blot WJ. A critical review of epidemiology studies of trichloroethylene and perchloroethylene and risk of renal-cell cancer. Int Arch Occup Environ Health. 1997;70:222-231. Brauch H, Weirich G, Klein B, Rabstein S, Bolt HM, Brning T. VHL mutations in renal cell cancer: does occupational exposure to trichloroethylene make a difference? Toxicol Lett. 2004;151:301-310. Zbar B, Glenn G, Merino M, et al. Familial renal carcinoma: clinical evaluation, clinical subtypes and risk of renal carcinoma development. J Urol. 2007;177:461-465.

*Many patients with RCC remain asymptomatic and have nonpalpable renal masses until late in the natural course of the disease.1,2 When present, common local symptoms include hematuria, ipsilateral flank or abdominal pain, and a palpable mass. Lee CT, Katz J, Fearn PA, Russo P. Mode of presentation of renal cell carcinoma provides prognostic information. Urol Oncol. 2002;7:135-140. Patard JJ, Leray E, Rodriguez A, Rioux-Leclercq N, Guill F, Lobel B. Correlation between symptom graduation, tumor characteristics and survival in renal cell carcinoma. Eur Urol. 2003;44:226-232.

*Common systemic symptoms include paraneoplastic disorders and/or pain or a mass related to metastatic disease.

*A physical examination has a limited role in RCC diagnosis, but it may be valuable in select situations.1 Radiologic examination is warranted if any of the above findings are identified during a physical exam.

1. Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol. 2007;51:1502-1510.

*Most kidney and renal pelvis cancers are diagnosed when the disease is still localized to the primary site (55%).1

1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Available at http://seer.cancer.gov/statfacts/html/kidrp.html?statfacts_page=kidrp.html&x=22&y=16. Accessed February 8, 2008.*RCC is divided into 4 stages:

Stage I: Cancer is in the kidney only and the size of the tumor is less than or equal to 7.0 cm in diameter. Stage II: Cancer is in the kidney only but the size of the tumor is greater than 7.0 cm in diameter. Stage III: The tumor in the kidney may be any size, but it extends beyond the layer of tissue (Gerota's fascia) that encapsulates the kidney and adrenal gland. Additionally, cancer may have spread to blood vessels that carry blood away from the kidney, or to the adjacent adrenal gland. Stage IV: Tumor in the kidney extends beyond Gerota's fascia and/or cancer has spread to one or more lymph node near the kidney. In addition, there may be evidence that cancer has spread to other organs in the body, such as the lungs, liver, brain, or bones.

ReferenceOregon Health & Science University. Kidney Cancer Program. Available at: http://www.ohsu.edu/health/page.cfm?id=13584.

*There are 5 distinct subtypes of RCC that reflect differences in morphology, growth pattern, cellular origin, histochemical features, and molecular features in renal adenocarcinomas.

Thoenes W, Strkel S, Rumpelt HJ. Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics. Pathol Res Pract. 1986;181:125-143. Strkel S, van den Berg E. Morphological classification of renal cancer. World J Urol. 1995;13:153-158.

*Several clinical factors have been associated with poor survival in patients with RCC, including poor performance status, the presence of disease symptoms and/or paraneoplastic syndrome, and obesity.1-7

Zisman A, Pantuck AJ, Dorey F, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001;19:1649-1657. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17:2530-2540. Suppiah R, Shaheen PE, Elson P, et al. Thrombocytosis as a prognostic factor for survival in patients with metastatic renal cell carcinoma. Cancer. 2006;107:1793-1800. Bensalah K, Leray E, Fergelot P, et al. Prognostic value of thrombocytosis in renal cell carcinoma. J Urol. 2006;175:859-863. Fahn HJ, Lee YH, Chen MT, Huang JK, Chen KK, Chang LS. The incidence and prognostic significance of humoral hypercalcemia in renal cell carcinoma. J Urol. 1991;145:248-250. Patard JJ, Dorey FJ, Cindolo L, et al. Symptoms as well as tumor size provide prognostic information on patients with localized renal tumors. J Urol. 2004;172:2167-2171.Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625-1638.

*The prognosis for patients with recurrent or metastatic RCC is very poor. Within this subgroup of patients, several factors have been identified that predict for either longer or shorter survival.1-4

LLN: lower limit of normal; ULN: lower limit of normal.

Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17:2530-2540. Mekhail TM, Abou-Jawde RM, Boumerhi G, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005;23:832-841. Choueiri TK, Rini B, Garcia JA, et al. Prognostic factors associated with long-term survival in previously untreated metastatic renal cell carcinoma. Ann Oncol. 2007;18:249-255. Han KR, Pantuck AJ, Bui MH, et al. Number of metastatic sites rather than location dictates overall survival of patients with node-negative metastatic renal cell carcinoma. Urology. 2003;61:314-319.

*Unfortunately, because RCC is clinically silent for much of its natural history, many individuals present with unresectable disease, metastatic disease, or locally advanced RCC prone to recurrence.1,2 Surgery is not an option for cure in these individuals. Several other treatment options exist, but not all are effective. In particular, advanced RCC is extremely resistant to radiotherapy and chemotherapy.

National Cancer Institute. SEER cancer statistics fact sheet: Cancer of the kidney and renal pelvis. Available at http://seer.cancer.gov/statfacts/html/kidrp.html?statfacts_page=kidrp.html&x=22&y=16. Accessed February 8, 2008. Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am. 2003;30:843-852.*Angiogenesis has been defined as a key determinant in the pathophysiology of RCC.1 RCC tumors are among the most vascularized of all solid tumors.2

Izawa JI, Dinney CP. The role of angiogenesis in prostate and other urologic cancers: a review. CMAJ. 2001;164:662-670.Cristofanilli M, Charnsangavej C, Hortobagyi GN. Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov. 2002;1:415-426.

*The above figure depicts a simplified overview of some key steps in tumor angiogenesis.1 First, tumor cells secrete proangiogenic factors (e.g., VEGF) that bind to receptors on endothelial cells of pre-existing blood vessels. These interactions lead to the release of proteolytic enzymes (e.g., matrix metalloproteinases) that digest through the basement membrane and extracellular matrix. These breaches enable growth factors to reach and activate endothelial cells that migrate toward the tumor. Integrin molecules also help to pull newly formed blood vessels toward the tumor. The endothelial cells lay down a new basement membrane and release additional growth factors (e.g., PDGF) to recruit supporting cells for vessel stabilization.

PDGFR: PDGF receptor; VEGFR: VEGF receptor.

Cristofanilli M, Charnsangavej C, Hortobagyi GN. Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov. 2002;1:415-426.*Vascular endothelial growth factor (VEGF) is a key growth factor involved in angiogenesis.1,2 VEGF mRNA expression correlates with vascularization, and VEGF is overexpressed in the majority of patients with clear-cell RCC. Other growth factors that contribute to angiogenesis and oncogenesis include platelet-derived growth factor (PDGF) and epithelial growth factor (EGF), among others.

Cristofanilli M, Charnsangavej C, Hortobagyi GN. Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov. 2002;1:415-426.De Mulder PH. Targeted therapy in metastatic renal cell carcinoma. Ann Oncol. 2007;18:ix98-102.

*Knowledge of biologic basis of renal oncogenesis has facilitated the transition from a nonspecific immune approach using cytokines (ie, IL-2, IFN-) to a molecular approach that targets the specific pathways involved in RCC pathology. Some of these agents have been FDA approved for the treatment of advanced RCC, whereas others are still considered investigational for this indication.1

1. Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer. 2005;104:2323-2333. *There are 4 targeted agents available for the treatment of advanced RCC. These agents are the first new drugs to be approved for RCC in almost 2 decades. Three of these agents target the VEGF pathway, whereas 1 targets the mTOR pathway. All of these agents significantly prolong the time to disease progression in comparison with either placebo or IFN-a.1-5 As such, these agents represent the new standard of care for metastatic disease.

ORR: overall response rate; PBO: placebo; TTP: time to progression.

Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-2111. 2. Rini BI, Halabi S, Rosenberg JE, et al. CALGB 90206: a phase III trial of bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in metastatic renal cell carcinoma. Program and abstracts of the 2008 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 14-16, 2008; San Francisco, CA. Abstract 350.3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124. 4. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134.5. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281.

**********************NCCN Clinical Practice Guidelines in Oncology 2007;v.1.2008.

*NCCN Clinical Practice Guidelines in Oncology 2007;v.1.2008.