1. Identify patients with RCC who are candidates for active surveillance.

2. Describe the available systemic therapies for patients with metastatic RCC.

3. Discuss the role of surgery in managing metastatic RCC.

4. Design a multimodal management plan for patients with metastatic RCC.

5. Compare and contrast cryotherapy and radiofrequency ablation in the management of small RCCs.

Surveillance of the Small Renal Mass
Jeffrey A. Cadeddu, MD, Associate Professor, Department of Urology and Radiology, University of Texas Southwestern Medical Center, Dallas

Background: lesions of interest—renal masses <4 cm in diameter (T1a lesions); types of renal cortical tumors—benign tumors include angiomyolipomas and oncocytomas; malignant tumors include conventional renal cell carcinomas (RCCs), two types of papillary RCCs, chromophobe RCCs, collecting duct carcinomas, and medullary carcinomas; presentation—50% to 60% of renal tumors <4 cm in diameter not associated with symptoms (ie, incidentalomas); incidence—rapidly increasing for localized and increasing more slowly for regional tumors and distant metastases; increase in incidentalomas attributable to increased use of imaging studies for various abdominal complaints; mortality rates—slight increases during last decade; malignancy—≈20% of incidental tumors ≤3 cm in diameter and up to 18% of those ≤7 cm in diameter are benign; larger tumors (class T2 and above) typically malignant; recurrence primarily associated with conventional clear-cell carcinoma (represents ≈50% of T1 lesions) and type-2 papillary tumors

Needle biopsy: 10% to 15% of biopsies have false-negative or nondiagnostic findings; tumor seeding not concern; consider biopsy when—high suspicion for benign disease; tumor likely has low metastatic potential (eg, patient has history of chromophobic or papillary RCC); patient is poor candidate for surgery or has high risk for chronic kidney disease; note— active surveillance often appropriate in these cases

Conventional treatment options: radical nephrectomy; partial nephrectomy; ablation; choice of approach driven by tumor location and need to preserve kidney function; effect on kidney function—radical nephrectomy increases risk for chronic kidney disease 8-fold; nephron-sparing techniques associated with lower risk

GFR, morbidity, and mortality: mortality rates increase with decreasing GFR; moderate decreases in GFR associated with 20% increase in mortality rate and 40% increase in cardiovascular events; impaired renal function also increases risk for hypertension and serologic abnormalities

Active surveillance: rationale—20% of small renal tumors benign, and 30% have low metastatic potential; detecting incidentalomas has not affected stage migration or mortality rates; standard surgical treatments increase risk for chronic kidney disease (associated with increased morbidity and mortality); most incidentalomas grow slowly (eg, 1-4 mm/yr) and have low rate of metastasis; study—106 patients with T1a lesions; 33% of tumors showed no growth over 2 yr; median growth ≈2 mm/yr; of lesions that eventually required removal, 85% malignant, but metastasis seen only in one case (poor surgical candidate; tumor 8 cm when removed); autopsy studies—67% to 74% of RCCs undetected until death (ie, high rate of clinically insignificant disease); competing risk analysis—26,000 patients; those with T1a lesions have 5% risk for death within 5 yr; patients with T2 lesions have 27% risk for death within 5 yr; patients >70 yr of age much more likely to die of other cause, regardless of tumor size; disease-free survival—for patients with T1a tumors, tumor size does not affect treatment outcome; tumors ≤5 cm in diameter associated with 96% disease-free survival; risk for non–organ-confined disease does not increase until tumor diameter \>5 cm

Patient selection criteria: patients with asymptomatic T1a cortical tumors (no evidence of metastatic disease or fat invasion); poor surgical candidates (eg, multiple comorbidities); even patients \>70 yr of age in good health; poor renal function at baseline; no history of previous RCC

Informed consent: important to discuss option of active surveillance with appropriate patients; avoiding discussion constitutes breach in informed consent

Surgery for Renal Cell Cancer in the Age of Targeted Therapy
Bradley C. Leibovich, MD, Associate Professor, Department of Urology, Mayo Clinic College of Medicine, Rochester, MN

Renal cell carcinoma: ≈36,000 cases diagnosed annually (≈10,000 metastatic at time of diagnosis); surgery may be curative, but ≈40% of patients subsequently develop metastatic disease; median survival of patients with metastatic disease, 6 to 10 mo; ≈12,000 deaths annually

Managing metastatic RCC: surgical resection of primary cancer and metastases; radiation therapy has some benefit for bone and brain metastases (otherwise, relatively ineffective); immunotherapy only for patients with clear-cell histology; stem cell transplantation rarely performed; off-label use of interferon common; high-dose interleukin (IL)-2, only immunotherapy approved for use; targeted therapies include vaccine therapy and monoclonal antibodies

Rationale for immunotherapy: RCC immunogenic; ≈0.5% of patients with metastatic disease experience spontaneous remission (likely mediated by immune response) after removal of primary tumor; increased risk for RCC (and other cancers) in immunodeficient patients; tumor-infiltrating lymphocytes present (but often nonfunctional); molecular basis of down-regulated immune function under investigation; IL-2 and interferon improve immune function

Traditional immunotherapies: interferon—response rate low (10%-15%) and duration of response generally <2 yr; subcutaneous injections given 3 times/week at home; treatment associated with negative impact on quality of life (QOL); high-dose IL-2—intravenous infusion given for 15 min every 8 hr for 5 days; 4 treatment cycles; patients very ill during treatment, but QOL returns quickly; low response rate (7% complete response; 8% partial response), but 60% of complete responders achieve long-term (\>10 yr) remission

Targeted therapies: most clear-cell RCCs have mutation in VHL tumor-suppressor gene and elevated levels of hypoxia-inducible factor (HIF); sorafenib, sunitinib, and temsirolimus interfere with VHL-HIF pathway and inhibit angiogenesis

Sorafenib: oral medication; multiple tyrosine kinase inhibitor; primarily inhibits vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF); efficacy—treatment associated with modest improvement in progression-free survival, compared to placebo (5.5 mo vs 2.8 mo); because of study’s design, efficacy likely underestimated, but complete response rare

Sunitinib: targets receptors for PDGF and VEGF; multiple tyrosine kinase inhibitor; typically given in 50-mg dose daily for 4 wk, followed by 2 wk off; efficacy—outperformed interferon (partial response seen in 31% vs 6% of patients); associated with lower rate of progressive disease and longer median progression-free survival (11 mo vs 5 mo)

Temsirolimus: inhibits mammalian target of rapamycin (mTOR); efficacy—patients with advanced metastatic disease and no previous systemic therapy randomized to temsirolimus, interferon, or combination therapy; temsirolimus modestly superior to interferon; effect of combination therapy similar to that of temsirolimus alone

Bevicizumab: monoclonal antibody against VEGF; efficacy—when added to interferon, bevicizumab increases progression-free survival (10 mo vs 5.5 mo with interferon alone) among patients with metastatic RCC who have undergone nephrectomy

Summary of targeted therapies: relatively well-tolerated; higher response rates compared with older therapies, but complete response rare; most study participants previously had undergone nephrectomy; no reported treatment-related mortality; response rate increases if patients appropriately selected (eg, those with alveolar pattern of clear-cell RCC); new drugs in development

Effect of surgery: debulking tumor volume removes immunosuppressive factor and may improve performance status before initiating systemic therapy; also used for symptom palliation; sequential therapy—nephrectomy before interferon therapy increases survival, compared to interferon alone (12.6 mo vs 7.8 mo); nephrectomy appears to improve response to systemic therapy (thereby improving survival); retrospective analysis of data suggests nephrectomy plus IL-2 therapy associated with longer survival than nephrectomy plus interferon therapy; nephrectomy alone does not substantially increase survival

Patient selection: ≥75% of total tumor volume (primary plus metastases) resectable; all metastases present in central nervous system must be treated and stable; good performance status; clear-cell histology (if tissue sample available); note— listed criteria do not apply when surgery palliative, for control of paraneoplastic syndrome, or if tumor thrombus involved

Lymphadenectomy: role debated; speaker considers appropriate when performing cytoreductive nephrectomy; predictors of node-positive disease—high-grade primary tumor; presence of sarcomatoid features; tumor diameter \>10 cm; pathologic stage pT3 or pT4; presence of tumor necrosis; ≈10% of patients with ≥2 features have node-positive disease; 53% of patients with all 5 features have node-positive disease; affected lymph nodes—little information about pattern of nodal disease with RCC; common “landing sites” include paracaval and interaortocaval nodes for right-sided tumors and para- aortic nodes for left-sided tumors (significant disease in paraortic nodes may warrant dissection of interaortocaval nodes as well); dissection—remove all gross adenopathy when possible; improves survival of patients with metastatic RCC treated with immunotherapy; associated with improved survival even among patients with pathologically node-negative disease

Adrenal gland involvement: preserve adrenal gland if no disease evident on computed tomography (CT); adrenal insufficiency—occurs in 20% of patients with metastatic RCC (avoid removal when possible); adrenal gland involvement —typically arises from hematogenous spread, not contiguous extension; both glands have same rate of involvement, regardless of location of primary tumor; note—removing adrenal gland may decrease efficacy of immunotherapy

Clinical pearls: surgery remains cornerstone of management for metastatic RCC; presence of tumor thrombus associated with poor survival (proceed to surgery quickly); tyrosine kinase inhibitors safe and tolerable, but IL-2 is only systemic therapy associated with cure; resection beneficial in patients with metastatic RCC

Surgery as monotherapy: factors associated with poor prognosis—symptomatic disease; bone or liver metastases; multiple sites of metastasis; short interval (<2 yr) between primary disease and metastasis or metastasis present at initial diagnosis (intermediate risk); tumor thrombus; nuclear grade ≥4; histologic tumor necrosis; effect on survival—3- and 5-yr survival doubles after complete resection, compared to partial resection; lowest scores on scoring algorithm associated with best outcomes (median survival, 5.3 yr)

High-risk localized disease: careful observation required after resection; ongoing trials of adjuvant therapies (eg, monoclonal antibodies, sorafenib, sunitanib)

Management approach: assess need for biopsy; resect localized disease (or consider other options for small renal masses); consider trial of adjuvant therapy for patients with high-risk disease; when possible, completely resect metastatic disease and consider trial of adjuvant therapy; if complete resection not possible—assess appropriateness of cytoreductive nephrectomy; follow nephrectomy with adjunctive therapy; if patient is poor candidate for nephrectomy—assess risk; treat high- risk patients with temsirolimus (Toricel); treat low-risk patients with sunitanib (Sutent) or sorafenib (Nexavar)

Cryotherapy and RFA for Small Renal Tumors
J. Kellogg Parsons, MD, MHS, Assistant Professor, Department of Surgery, Cancer Prevention and Control Program, University of California, San Diego, School of Medicine

Rationale for minimally-invasive management: many renal tumors detected incidentally (often small and low-stage); incidence increasing; although partial nephrectomy (open or laparoscopic) preferred for removing tumors <4 cm in diameter, not all patients candidates

Indications: tumor characteristics—lesion enhances on CT; <4 cm in diameter; exophytic lesions generally preferred; safe distance from hilum, ureter, and other important structures; patient characteristics—poor surgical candidate or declines nephrectomy; multiple tumors and/or genetic syndromes (controversial; ablation may complicate partial nephrectomy if needed in future)

Clinical practice: 93% of academic centers use minimally-invasive ablative techniques (79% perform cryotherapy; 55% perform radiofrequency ablation [RFA]); remaining centers cite insufficient data demonstrating efficacy as reason for not using techniques

Cryosurgery: combination of argon and helium gases introduced by 17-gauge needle; physiology—repeated freezing and thawing results in cellular damage, coagulative necrosis, vascular injury, and ischemia; killed cells release antigens, which may potentiate immune response against tumor; technique—typical treatment consists of 2 freeze-thaw cycles; freeze cycle uses temperatures of -19°C to -40°C for 8 to 10 min; ice ball should extend 1 to 3 cm beyond tumor margin (coldest at center); thaw cycle lasts 5 to 6 min; possible to follow ablation in real time with ultrasonography (US); kill zone—extends laterally more than anteriorly from needle tip (needle placement important); multiple needles often used to achieve overlapping kill zones; approach—percutaneous (best for posterior tumors) with optional guidance by CT, US, or magnetic resonance imaging (MRI); partnering with interventional radiologist recommended; laparoscopic (best for anterior or medial tumors; consider proximity to hilum and major vasculature) with optional intraoperative US; follow-up —CT or MRI; lesions tend to shrink over time; inconclusive whether continued enhancement indicates residual tumor

Radiofrequency ablation: device—14- to 17.5-gauge probes; power up to 200 W, generating temperatures up to 105°C; treatment cycle—device-dependent (follow manufacturer’s recommendations); margins—irregular; cannot be followed in real time; approach—percutaneous (posterior tumors); laparoscopic (anterior and medial tumors); follow-up—CT or MRI; fibrotic mass tends to persist; inconclusive whether continued enhancement indicates residual tumor

Limitations of data: most outcome data from single-institution case series; no head-to-head comparison of cryosurgery and RFA, and no direct comparison of either technique to observation or to surgery; most patients (in studies) had multiple comorbidities that precluded surgery (question remains about clinical need for treatment); long-term efficacy not defined; outcome measures—study found poor correlation between postablative imaging (ie, enhancement) and pathology; unknown whether cytoreduction alters natural history of disease and patient survival; no long-term outcome data

Complications: cryosurgery—pain at insertion site most common; rare complications include renal hemorrhage or abscess; RFA—pain at insertion site; rare complications include urinoma, ureteral stricture, and bowel injury; overall— generally safe and well-tolerated