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Localized Kidney Cancer Treatment

Active Surveillance

• Offer for cT1a mass (< 2cm)
• Likelihood that mass is benign (nomogram): 35-45% if < 1cm, 20-25% if 1-2cm, 15-20% if 2-4cm, 10% if 4-6cm, 5% if > 6cm
• Risk of metastasis at 3yrs: 0% if < 2cm, < 2% if < 4cm
• Size matters: 20-30% < 4cm and 40% < 2cm are benign, most masses grow at 0.09-0.34cm/yr
• Good candidate: old/frail, life expectancy < 5yrs, high comorbidity or operative risk, poor functional status
• Bad candidates: for patients w/ > 2cm, higher stage, growth rate > 5mm/yr, changes in patient/tumor factors
• Imaging: recommended q6-12 month intervals with CT, MR, or US, variation in size 3mm or less does not necessarily indicate interval growth, should also obtain chest imaging and labs annually
• Indications to treat: becomes > 2-3cm, interval growth > 0.5cm/yr, infiltrative appearance, change in clinical stage, becomes symptomatic, aggressive features on imaging

Focal Ablation

• Criteria: cT1a < 3cm (100% success, vs 81% success if > 3cm)
• Anatomy selection: posterolateral tumor, > 0.5cm from UPJ or renal pelvis, > 1cm from bowel
• Overall survival at 5yr: 95% for < 3cm vs 79% for > 3cm, cancer specific survival 95-98%
• Biopsy obtained at time of ablation
• Efficacy: assess with lack of contrast enhancement on post-treatment imaging, check at 3-6mo then annually for at least 5yrs
• Recurrence: 6% (vs 3% for PN or 1% for RN), can be treated with repeat ablation
• RadioFrequency: 460-500kHz leads to frictional heating, needs to reach 70 degrees for adequate kill (don't go above 105C can cause gas pockets), use multi-tine probe for improved delivery, more difficult to monitor effects in real time
• Cryoablation: temperatures below -20-40C leads to coagulation necrosis + edema during thaw, also causes thrombosis, form ice ball ~1cm outside renal mass to ensure adequate margin, perform double freeze/thaw cycle
• Temperature sink created by proximity to large vessels, can decrease efficacy of treatments
• Complications: overall 5-6%, hemorrhage 11-27%, transfusion 0-3%, obstruction, pneumo/hemothorax, renal failure, pancreatitis, lumbar radiculopathy

Surgical Considerations

• AUA recommendation: masses > 2cm, surgical candidate, not ablation candidate
• Eventual need for dialysis: 1-12%
• Lymph node dissection: has not been shown to increase cancer-specific or overall survival
• GFR: tumor removal should have minimal effect on GFR (removed tissue is already abnormal/nonfunctional)
• Recurrence: 1-2%, cancer free survival 90+%
• Postop complication risk calculator
• Postop nomograms: UISS, MSK, SSIGN (clear cell only), ASSURE
• Timing for bilateral tumors: perform partial nephrectomy first (then contralateral radical nephrectomy), provides maximal renal parenchyma for recovery and decreased dialysis risk

Partial Nephrectomy

• Best for cT1a, but can consider for cT1b-T2
• Indications: solitary kidney (only 25-30% kidney required to avoid dialysis), bilateral tumors, familial RCC, CKD, proteinuria, risk for contralateral renal disease or tumors
• Limit warm ischemia time to maximize nephron preservation
• Highest risk option for transfusions and GU complications
• Enucleation: noninferior to obtaining margin, margin width nonrelevant, key factor is maintaining margin-negative disease
• Positive margin: majority of patients will remain disease free, if radical nephrectomy is performed then residual disease found in < 16%

Radical Nephrectomy

• Option if worried about increased risk
• Indications: high tumor complexity, risky partial nephrectomy, normal contralateral kidney
• Higher risk of worsening GFR
• Less complications than partial nephrectomy: bleeding (1% vs 3%), urine leak (0% vs 4%), reoperation (2% vs 4%)

Management of complicated localized RCC situations

Locally Invasive (T4)

• < 2% prevalence, may present with pain due to invasion
• Only 40% of suspected invasion are confirmed on pathology
• En bloc resection recommended, but prognosis is overall poor (10-20% survival at 12 months)

Clinical Node Disease (cN1)

• Only 30-43% have pathology-confirmed nodal disease
• Likelihood based on pathologic size: 20% for 7mm, 29% for 10mm, 90% for 30mm
• > 40% nodal involvement if 2+ features: tumor > 10cm, cT3-4, tumor grade 3-4, sarcomatoid features, and histologic necrosis
• Lymphadenectomy: beneficial to confirm staging but no proven survival benefit
• Templates: paraaortic and interaortocaval nodes on L, paracaval and interaortocaval nodes on R, remove from diaphragmatic crus down to common iliac artery

Adrenal involvement

• Seen in < 10% RCC
• Perform adrenalectomy if concern for involvement on preoperative imaging
• Consider if mass > 5cm or upper pole location

IVC Thrombus

• Prevalence: seen in 4-10% RCC
• Symptoms: lower extremity edema, right-sided varicocele, varicocele that does not collapse when supine, dilated abdominal veins, proteinuria, pulmonary embolus, right atrial mass, or nonfunctional kidney
• Staging: within renal vein (0), adjacent to renal vein ostium (I), extendeding below hepatic veins (II), intrahepatic below diaphragm (III), above diaphragm (IV)
• Bland thrombus: will not enhance on contrasted imaging, differentiating from tumor thrombus
• Anticoagulation: prophylactic dosing only, treatment dosing if bland thrombus present
• Preoperative renal artery embolization: not recommended, minimal proven benefit
• Success rates: 45-70% can be cured with nephrectomy + thrombectomy alone (no adjuvant therapy), but immediate postoperative mortality rates 5-10%, 1-2% risk of embolization to pulmonary arteries
• Palliative thrombectomy: may have some benefit even in poor surgical candidates due to treatment of bothersome symptoms
• Systemic therapy: can consider for large tumors to shrink enough to more safely perform surgery

Local Recurrence

• Prevalence: 2-4% of cases (1-10% for partial nephrectomy), more likely with locally advanced disease, node-positive disease, or adverse pathologic features
• Timing: 60-80% local recurrences occur simultaneously with metastatic disease, majority of other recurrences recur within 3yrs of initial resection
• Isolated recurrence: curable with local resection for 30-40%, but may be difficult due to lack of tissue planes

Adjuvant therapy

• Overall, no proven benefit for completely resected disease (questionable benefit to sunitinib from S-TRAC trial)
• Up to 20-40% will develop metastasis post-nephrectomy although this is based on old data

Metastatic RCC Management

Surgical management options

• Timing of cytoreductive nephrectomy: controversial, consider up-front immunotherapy followed by nephrectomy if good response
• Oligometastatic disease: treat surgically whether synchronous or metachronous, brain/bone mets can be treated with XRT, better prognosis if initially M0 (metachronous) as opposed to M1 (synchronous mets), lung oligomets have better prognosis than other sites
• Nonoligometastatic cytoreductive nephrectomy indications: low/favorable risk candidates, especially if ECOG 0/1, no brain mets, and only mets are in the lung
• Palliative CRN indications: pain, hematuria, systemic symptoms, paraneoplastic symptoms
• Brain metastases: respond best to surgery or XRT

Current targeted therapies

• anti-VEGF: sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, lenvatinib, bevacizumab
• mTOR inhibitors: temsirolimus, everolimus
• anti-PD1: nivolumab, pembrolizumab
• anti-PDL1: avelumab
• anti-CTLA-4: ipilimumab
• TKI side effects: hand/foot syndrome, GI distress, elevated LFTs, hypothyroid, pancytopenia, stroke, MI, worse wound healing (stop prior to elective surgery)
• mTOR inhibitor side effects: rash, stomatitis, asthenia, GI distress, pancytopenia, elevated LFTs, hyperglycemia, hyperlipidemia, rare bowel perforation, rare interstitial pneumonitis

Current recommendations

• Treatment naive, good risk: targeted agent alone, or axitinib + pembrolizumab/avelumab
• Treatment naive, intermediate/poor risk: nivolumab + ipilimumab or axitinib + pembrolizumab/avelumab
• Failed sunitinib/sorafenib: everolimus
• Failed anti-VEGF therapy: everolimus + lenvatinib, nivolumab, cabozatinib
• Failed first-line therapy: axitinib
• non-ccRCC: refer for clinical trial, sunitinib, cabozatinib, everolimus +/- levnvatinib

MSK model for predicting outcomes with chemotherapy or cytokine therapy

• Predictors: Karnofsky score < 80, elevated LDH (> 1.5x normal), low Hgb, elevated calcium (> 10), lack of prior nephrectomy
• 0 risk factors = median overall survival 20mo
• 1-2 risk factors = median overall survival 10mo
• 3+ risk factors = median overall survival 4mo

IMDC model for predicting outcomes with VEGF-targeted therapy

• Predictors: Karnofsky score < 80, neutrophilia, low Hgb, elevated calcium (> 10), thrombocytolosis, < 1yr from diagnosis to starting VEGF therapy
• 0 risk factors = median overall survival 43mo
• 1-2 risk factors = median overall survival 23mo
• 3+ risk factors = median overall survival 8mo

Prior therapies (mainly historical interest)

• IFN-a: response rate 10-25%, durable response < 2%
• IL-2: response rate 15-20%, complete regression 7-9%
• IFN-a + IL-2: response rate 19%, no overall significant difference in survival
• Conventional chemotherapy: response rate 5-6%
• Hormone therapy: response rate 2%