Pocket Oncology (Pocket Notebook Series), 1st Ed.

RENAL CELL CARCINOMA

Jarett L. Feldman and Robert J. Motzer

Epidemiology

• ∼64000 new case of kidney CA in the US in 2012

(5% of male adult malignancies & 3% of female adult malignancies), ∼13500 death from kidney CA in the US in 2012 (CA Cancer J Clin 2012;62:10–29)

• Most cases occur between ages 50–70 yo, M:F ratio is 1.6:1

• RFs: Cigarette smoking, obesity, & other environmental factors. Familial forms comprise of <5% of cases (shown below)

Histology and Molecular Biology

• Clear cell (80–90% of all kidney CA), Papillary (10–15%), Chromophobe (5%), Collecting duct/Medullary (<1%)

• Sarcomatoid is a variant seen w/any cell type reflecting an aggressive phenotype

Genetic Abnormalities Associated with Familial RCC

Clinical Presentation

• Mostly asx (minority will p/w pain, hematuria, a flank mass, pyrexia, cachexia, fatigue & wt loss)

• At presentation: 45% localized disease, 25% locally advanced renal carcinoma, 30% met disease (Urology 1986;27:291)

Staging: TNM Classification

• Tumor: T1: Tumor <7 cm, T2: Tumor >7 cm (both T1 & T2 are confined to the kidney parenchyma),T3: Tumor extends into the renal vein or perinephric tissues, T4: Tumor extends beyond the Gerota fascia to adjacent organs

• Node: (N0 vs. N1) Presence or absence of regional LN involvement

• Met: (M0 vs. M1) Presence or absence of distant met 5 y OS prior to targeted Rx from the National Cancer Data base classified by AJCC classification: stage I, II, III & IV is 81%, 74%, 53% & 8% (AJCC cancer staging manual. 7th ed. New York: Springer. 2010)

Prognosis (JCO 1999;17(8):2530)

• MSKCC RFs for met disease

LDH level >1.5× ULN

Hb < lower limit of nl

Corrected serum calcium level > ULNl

Interval of less than a y from original dx to the start of Rx

KPS ≤ 70%

• Median OS based on number of RFs

Good, 0 RFs

Intermediate, 1–2 RFs

Poor, >3 RFs

Treatment Principles

• Localized: Surgery alone (partial vs. radical nephrectomy) vs. active surveillance (in selective pts)

• Locally advanced: Surgery followed by systemic Rx when residual or recurrent disease becomes detectable

• Met: Cytoreductive nephrectomy—improved outcomes among pts w/met RCC who underwent cytoreductive nephrectomy + IFNα vs. IFNα alone (N Engl J Med 2001;345:1655; Lancet 2001;358:966.), cytoreductive Rx not yet been studied w/targeted therapies. Metastasectomy (surgical resection of a solitary met mass)

Targeted Therapy

Algorithm Based on Risk Category for Clear Cell RCC

Agents w/Anti-VEGF Activity

• Sorafenib (N Engl J Med 2007; 357:203.)

Efficacy (vs. placebo): Endpoint PFS: 5.5 mos vs. 2.8 mos (HR: 0.44, P: <0.01)

MOA: Activity against: VEGFR-1, -2, -3, PDGFR-β, FLT-3, ckit, RET

SE: hand-foot syndrome, rash, fatigue, diarrhea, nausea, & HTN

• Sunitinib (N Eng J Med 2007;356:115)

Efficacy (vs. IFNα): Endpoint PFS 11 mos vs. 5 mos (HR: 0.42, P <0.001). Other endpoints ORR 31% vs. 6% (P<0.001), OS 26.4 mos vs. 21.81 mos (p = 0.051)

MOA: Activity against: VEGFR-1,-2,-3, PDGFR-α, -β, FLT-3, CSF-1R, RET

SE: Neutropenia, thrombocytopenia, fatigue, diarrhea, nausea, stomatitis, hand-foot syndrome, HTN, LV dysfunction, thyroid abnormalities

• Bev + IFNα-2a (Lancet 2007;370:2103)

Efficacy (vs. IFNα): Endpoint PFS 10.2 mos vs. 5.4 mos (HR: 0.63, p <0.0001). Other endpoints: ORR: 70% vs. 39%, OS 23.3 mos vs. 21.3 mos not statistically significant.

MOA: Monoclonal Ab against VEGF-A

SE: Fatigue, anorexia, HTN, proteinuria

• Pazopanib (J Clin Oncol 2010;28:1061)

Efficacy (vs. placebo): Endpoint PFS: 9.2 mos vs. 4.2 mos (HR: 0.46, P <0.0001)

Other endpoint: ORR: 30% vs. 3% (P<0.0001)

MOA: Activity against VEGFR-1, -2, -3, PDGFR-α,-β, & c-kit

S/e: Diarrhea, HTN, nausea, vomiting, anorexia, elevated AST/ALT, hair color changes, fatigue

• Axitinib (Lancet 2011;378:1931)

Efficacy (vs. sorafenib): Endpoint PFS: 6.7 mos vs. 4.7 mos (HR: 0.665, P <0.0001)

ORR: 19% vs. 9% (P = 0.0001)

MOA: Activity against VEGFR-1, -2, -3

SE: Hand-foot syndrome, fatigue, HTN, dyspnea, diarrhea

mTOR Inhibitors

• Temsirolimus (N Eng J Med. 2007;356:2271.)

Efficacy (vs. IFNα): Endpoint OS: 10.9 mos vs. 7.3 mos (HR: 0.73, P = 0.008), Other endpoints: ORR: 8.6% vs. 4.8%, PFS: 5.5 mos vs. 3.1 mos

MOA: mTOR inhibitor

SE: Stomatitis, rash, edema, hyperglycemia, hyperlipidemia, neutropenia, & thrombocytopenia

• Everolimus (Lancet 2008; 372:449)

Efficacy (vs. placebo): Endpoint PFS: 4 mos vs. 1.9 mos (HR: 0.30, P <0.0001)

MOA: mTOR inhibitor

SE: Stomatitis, rash, fatigue, pneumonitis

Other Therapies

• Chemotherapy: Low RRs w/single agents

• Immunotherapy: IL-2 achieves small number of durable responses but a/w tox & require specialty center, PD-1 highly promising