Jianqing Lin, MD
Wm. Kevin Kelly, DO
BASICS
DESCRIPTION
• Advanced stage of renal cell carcinoma (RCC)
– N1: Metastasis in regional lymph node(s)
– M1: Distant metastasis
– Nodal involvement is now simplified to N0 vs. N1
• Other changes for staging from the AJCC Cancer Staging Manual (7th edition):
– Ipsilateral adrenal involvement is reclassified as T4 if contiguous invasion and M1 if not contiguous
– Renal vein involvement is reclassified as T3a
EPIDEMIOLOGY
Incidence
• Renal cancer increased by 2% per year for the past 65 yr. Increased by 3.1% per year from 2005–2009 primarily due to an increase in early-stage disease. Renal cancer accounts for 2–3% of all malignancies. Median age of diagnosis is 65 yr, median age of death is 70 yr.
– 1/3 of patients with RCC present M+/N+
• 40–50% will develop metastatic disease after initial diagnosis. Male > Female (ratio is 3:2).
• Death rates for kidney cancer decreased by 0.5% per year from 2005–2009
Prevalence
N/A
RISK FACTORS
• Smoking
• Obesity
• Hypertension and chronic renal failure
Chemicals or radiation exposure slightly increases risk.
• Rare hereditary conditions
– Von Hippel–Lindau (VHL) disease
– Hereditary papillary RCC
Genetics
• Majority of cases are sporadic
• VHL tumor suppressor gene (on 3p25–26) associated with clear cell RCC
• Chromosome 7q31 is associated with papillary RCC, type 1 associated with mutations in c-MET
• Fumarate hydratase (FH) associated with papillary RCC type 2
• Birt–Hogg–Dubé (BHD) syndrome associated with chromophobic RCC
• Xp11.2 translocation: Patients under 45 yr
• BRCA1-associated protein-1 (BAP1) loss associated with high tumor grade
PATHOPHYSIOLOGY
• RCCs derived from renal tubular epithelium
• Mode of spread is via direct extension, propagation into renal vein, or hematogenous
• Rare reports of spontaneous regressions, usually pulmonary, following nephrectomy
ASSOCIATED CONDITIONS
• VHL syndrome
• Chronic renal failure
• Lymphoma
GENERAL PREVENTION
Smoking cessation helps prevent primary tumor
DIAGNOSIS
HISTORY
• Usually no symptoms in early stage but incidental diagnosis of kidney mass. Metastasis may or may not cause symptoms.
• Gross hematuria
• Flank or abdominal pain
• Symptoms related to involved organ(s)
• Constitutional symptoms:
– Fatigue, weight loss, fever, or lower-extremity edema
PHYSICAL EXAM
• With attention to abdominal mass, adenopathy, lower-extremity edema
• Varicocele (classically on left)
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• CBC: Anemia of chronic disease in up to 30%
• Urinalysis: Hematuria
• Complete metabolic panel
• Paraneoplastic syndromes (found in 20% of patients):
– Hypercalcemia
– Hypertension
– Erythrocytosis
– Elevated erythrocyte sedimentation rate (ESR)
– Nonmetastatic hepatic dysfunction (Stauffer syndrome)
• Urine cytology: R/O urothelial carcinoma
Imaging
• MRI or CT of abdomen and pelvis (∼85% of enhancing renal masses are RCC)
– Most enlarged lymph nodes by imaging are inflammatory rather than neoplastic
• CNS imaging: In patients with symptoms or radiographic evidence of advanced disease
• Positron emission tomography (PET) has poor sensitivity and not commonly used
Diagnostic Procedures/Surgery
• Needle biopsy to the metastatic site or metastasectomy usually required to establish diagnosis
• Needle biopsy is generally safe and warranted if any uncertainty for M1 disease
Pathologic Findings
• Histologic subtypes:
– Clear cell: 70–80%
– Papillary: 10–15%
– Chromophobe: 3–5%
– Collecting duct/medullary cancer <1%
– Translocation Xp11.2: Clear and/or eosinophilic, voluminous cytoplasm
• Sarcomatoid variants all histologic subtypes:
– Represent poorly differentiated regions
– Portends a much more aggressive biology with recurrence/resistance to therapy
DIFFERENTIAL DIAGNOSIS
• Renal masses:
– Angiomyolipoma (fat-poor)
– Collecting-duct tumors
– Cystic nephromas
– Cysts (hemorrhagic, infected)
– Focal pyelonephritis
– Hemangioma
– Inflammatory masses (xanthogranulomatous pyelonephritis, abscess)
– Leiomyoma
– Metanephric adenoma
– Metastasis from other primary tumor
– Oncocytoma
– Pseudotumors (column of Bertin, others)
– RCC
– Renal lymphoma
– Renal medullary carcinoma
– Sarcomas
– Reninoma (Juxtaglomerular tumors)
– Urothelial carcinoma
– Wilms tumor (nephroblastoma)
• Lymphadenopathy:
– Inflammatory related to RCC
– RCC
– Infectious/inflammatory:
Granulomatous: TB, sarcoidosis, histoplasmosis, lymphogranuloma venereum, Castleman disease, etc.
Nongranulomatous: Viral, bacterial (if abscess in local areas), sinus histiocytosis
– Primary lymphatic malignancy: Lymphoma (non-Hodgkin and Hodgkin, others)
– Other metastatic malignancies:
Gastrointestinal (GI) (carcinoid, colorectal, lymphoma), urothelial, prostate, melanoma, penile, germ cell, cervical, ovarian, uterine
• Pulmonary nodules:
– Benign hamartoma/AVM, nonspecific granuloma, infectious granuloma (aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis, tuberculosis, atypical mycobacterial infections), septic emboli, abscesses
– Malignancy: Lung primary, metastasis (choriocarcinoma, RCC, melanoma, thyroid carcinoma, Kaposi’s sarcoma), non-Hodgkin lymphoma
TREATMENT
GENERAL MEASURES
• Stage IV disease may also benefit from cytoreductive surgery
• Minimal regional adenopathy does not preclude surgery
• Potential candidate for nephrectomy and/or surgical metastasectomy:
– Resectable primary RCC and a solitary resectable metastasis
– A solitary recurrence after prolonged disease-free interval from nephrectomy
• Tends to be resistant to both traditional chemotherapy and radiation therapy
• Antiangiogenesis via targeting vascular endothelial growth factor (VEGF) pathway is the mainstay of treatment; improve survival for M1
• Multityrosine kinase inhibitors (TKI) or mTOR inhibitors or monoclonal antibody
• Data for nonclear cell RCC therapy limited
• Sarcomatoid RCC: Gemcitabine- or capecitabine- or floxuridine- or 5-FU- or doxorubicin-based chemotherapy (category 3 and limited data)
• Other immunotherapy is under development
MEDICATION
First Line
• High-dose (bolus) interleukin-2 (IL-2) (Aldesleukin, Proleukin) (1)
– IL-2: Only agent shown to produce durable and complete responses (CR) in 6–8% of patients; Partial response 10–15%
– 1st line. Selected patients: Mostly clear cell, <65 yr old, good cardiac, pulmonary, liver and renal function, no brain mets
– Typical regimen 600,000–720,000 IU/kg IV Q8h for 5 days. One course as 2 cycles on days 1–5 and 15–19 of 28-day cycle. If no progression, repeat approximately every 3 mo to a max of 3 courses.
– Systemic inflammatory response syndrome (SIRS), “capillary leak syndrome” side effects
– “Treat as tolerated” significantly reduces treatment-related mortality
• Sunitinib: Targets VEGF receptor tyrosine kinase and other pathways (2)
– 1st line
– 50 mg/d PO for 4 wk of 6-wk cycle (4 wk on, 2 wk off)
• Pazopanib: Targets VEGF receptors and other pathways
– 1st line or postcytokine: 800 mg PO daily
• Bevacizumab: VEGF antibody
– 1st line with interferon-α 10 mg/kg IV Q2wk
• Interferon-α: Stimulates immune function
– 1st line, only combination with bevacizumab
– SubQ a start of 9 MU on 3 nonconsecutive days per week, with dose reduction to 6 MU and to 3 MU if toxicity
• Temsirolimus: mTOR inhibitor (3)
– 1st line for poor-risk patients or nonclear cell histology: 25 mg IV weekly
• Sorafenib: Targets VEGF receptor and other pathways: 1st or 2nd line: 400 mg PO BID (4)
Second Line
• Agents as noted above after failure of 1st targeted therapy
• Axitinib: Potent, selective, 2nd-generation inhibitor of VEGFR 1, 2, and 3 (5):
– 2nd line: 5 mg PO BID,10 mg PO BID max
• Everolimus: mTOR inhibitor
– 2nd line: 10 mg PO daily
SURGERY/OTHER PROCEDURES
• Cytoreductive nephrectomy in patients with metastatic disease is generally considered standard of care (6):
– SWOG 8949: Improved overall survival for debulking nephrectomy in interferon-treated patients with advanced RCC. However, no similar data is available in TKI era.
• Strongly consider metastasectomy for amendable and isolated solitary metastasis (synchronous or metachronous)
– Lymphadenectomy should be performed in radiographically suspicious cases; however, ultimate role and benefit is yet to be defined.
ADDITIONAL TREATMENT
Radiation Therapy
Palliative role for osseous or CNS metastasis or pain control
Additional Therapies
• Many other agents under study and reported:
– Nonmyeloablative allogeneic hematopoietic cell transplantation
– Interferon-γ, vaccines, other interleukins alone and in combination
• Multiple studies under way addressing sequencing and combination of targeted therapies along with immunotherapy
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• 5-yr survival: Improving (7)
– Stage III: 15–35%
– Stage IV: 0–10%
– Enhanced survival with the following characteristics: Long interval between nephrectomy and the appearance of distant metastases, a single metastatic site, and the absence of retroperitoneal adenopathy
COMPLICATIONS
• Related to treatment
– High-dose IL-2: Vascular leak syndrome
– TKIs: Fatigue, HTN, hand and foot syndrome, GI toxicity, hypothyroidism
– mTOR inhibitors: Fatigue, rash, hyperglycemia, dyslipidemia
• Others related to disease progression
FOLLOW-UP
Patient Monitoring
• Depends on stage of disease and treatment
– Usually chest and abdominal imaging every 3–6 mo if not being treated
– Imaging every 3–4 cycles if underactive systemic treatment
– Serum chemistries and liver function tests as routine
Patient Resources
• Kidney Cancer Association www.kidneycancer.org
• National Cancer Institute, Kidney Cancer www.cancer.gov/cancertopics/types/kidney
REFERENCES
1. McDermott DF, Rini BI. Immunotherapy for metastatic renal cell carcinoma. BJU Int. 2007;99:1282–1288.
2. 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.
3. 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.
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. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as 2nd-line treatment for advanced renal cell carcinoma: Overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14(6):552–562.
6. Flanigan RC. Debulking nephrectomy in metastatic renal cell carcinoma. Clin Cancer Res. 2004;10:6335S–6341S.
7. Lara PN Jr, Tangen CM, Conlon SJ, et al. Predictors of survival of advanced renal cell carcinoma: Long-term results from SWOG Trial S8949. J Urol. 2009;181(2):512–516.
ADDITIONAL READING
• Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335:865–875.
• NCCN Guidelines. Available at http://www.nccn.org/clinical.asp (Acessed August 20, 2014)
See Also (Topic, Algorithm, Media)
• Renal Cell Carcinoma, General
• Renal Cell Carcinoma, Localized (T1–T2)
• Renal Cell Carcinoma, Locally Advanced (T3–T4)
• Renal Cell Carcinoma, Metastatic (N+, M+) Image 
• Renal Cell Carcinoma, Pediatric
• Reference Tables: TNM: Kidney Cancer
CODES
ICD9
• 189.0 Malignant neoplasm of kidney, except pelvis
• 196.2 Secondary and unspecified malignant neoplasm of intra-abdominal lymph nodes
ICD10
• C64.1 Malignant neoplasm of right kidney, except renal pelvis
• C64.9 Malignant neoplasm of unsp kidney, except renal pelvis
• C77.2 Secondary and unsp malignant neoplasm of intra-abd nodes
CLINICAL/SURGICAL PEARLS
• Cytoreductive surgery should be considered for M1 disease.
• Only high-dose IL-2 provide durable complete response (CR).
• No targeted agents show significant complete response (CR).
• Patients achieving response with targeted agents such as TKI have a response duration of ∼8–10 mo (medium <12 mo) with continuous therapy treatment.
• Combination therapies are being explored.