Renal Cell Carcinoma Treatment Protocols

Treatment protocols for renal cell carcinoma are provided below, including treatment of localized and advanced disease and recommendations for patients with predominantly clear cell carcinoma and those with predominantly non–clear cell carcinoma. ^[1]

The therapeutic approach for renal cell carcinoma is guided by the probability of cure, which is related directly to the stage or degree of tumor dissemination. More than 50% of patients with early stage renal cell carcinoma are cured, but the outcome for stage IV disease is poor; thus, the approach is curative for early stage disease. ^[2]

Adjuvant treatment currently does not have a role in patients who have undergone a complete tumor resection; observation remains the standard of care after nephrectomy or clinical-trial enrollment. ^{[3, 4, 5, 6]}

See Renal Cell Carcinoma: Recognition and Follow-up, a Critical Images slideshow, to help evaluate renal masses and determine when and what type of follow-up is necessary.

Treatment recommendations for localized disease

Surgical resection is the preferred treatment for localized disease, ^[7] including radical or partial nephrectomy or nephron-sparing surgery. Radical nephrectomy is commonly preferred for treatment of tumors that extend into the inferior vena cava. ^[6]

Stage IA:

• Surgical resection with partial nephrectomy is preferred (open/robotic/laparoscopic) ^{[8, 9, 10, 11, 12]}
• If partial nephrectomy is not feasible or the tumor is centrally located, radical nephrectomy may be recommended
• Active surveillance is preferred in selected patients
• Thermal ablation may be considered for nonsurgical candidates ^[13]

Stage IB:

• Partial nephrectomy (open/robotic/laparoscopic) when feasible, or radical nephrectomy is the standard treatment

Stages II and III:

• Radical nephrectomy is the preferred treatment for most patients.
• Adjuvant pembrolizumab, q3wk or  400 mg q6wk until disease recurrence, unacceptable toxicity, or for up to 12 months, in patients at high risk of recurrence ^[14] (eg, stage II clear cell renal cell carcinoma with grade 4 or sarcomatoid features, or stage III clear cell disease ^[6] )

Treatment recommendations for advanced disease (stage IV, relapsed, or recurrent disease)

See the list below:

• Primary treatment includes consideration for cytoreductive nephrectomy for primary tumor before systemic therapy in patients with a resectable primary tumor ^[15]

• Cytoreductive nephrectomy is recommended in selected patients with favorable performance status ^[16]

Stage IV, relapsed, or recurrent disease with predominantly clear cell histology

First-line therapy for previously untreated patients with low or intermediate risk:

• Clinical trial or

• Sunitinib 50 mg/day PO for 28 d; every 6 wk (compared with interferon, it provides increased progression-free survival [PFS] and overall survival [OS]: PFS is 11 mo with sunitinib vs 5 mo with interferon alone; median overall survival is 26.4 mo vs 21.8 mo with interferon alone, and response is 47% with sunitinib vs 12% with interferon alone) ^{[17, 18]} or

• Avelumab 800 mg IV every 2 wk plus  axitinib 5 mg PO BID; continue until disease progression or unacceptable toxicity; in the JAVELIN Renal 101 trial (n=886), median PFS with avelumab plus axitinib was 13.8 mo compared with 8.4 mo for sunitinib (HR, 0.69; P < 0.001) ^[19]  or

• Pembrolizumab 200 mg IV q3wk or 400 mg IV q6wk plus  axitinib 5 mg PO BID ^[20]  or

• Sorafenib 400 mg (two 200 mg tablets) PO BID either 1 h before or 2 h after meals ^{[21, 22]} (this can be considered first-line therapy if the patient is not able to receive any of the other first-line therapies) or

• Pazopanib 800 mg/day PO either 1 h before or 2 h after meals ^[23] (it is superior to best supportive care with or without cytokines: PFS is 9.2 mo with pazopanib vs 4.2 mo without pazopanib, and OS is nonsignificantly superior with pazopanib, at 22.9 mo vs 20.5 mo) or

• High-dose interleukin (IL)-2 in selected patients (ie, excellent performance status and normal organ function): recombinant IL-2 600,000-720,000 IU/kg IV over 15 min every 8 h for 14 consecutive doses on days 1-5 and days 15-19; re-treat in responding patients and those with stable disease every 12 wk for up to three cycles ^[24] (this should be considered first-line therapy in carefully selected younger patients with good performance status) or

• Interferon alfa-2a 9 million units SC three times weekly for 1y plus bevacizumab 10 mg/kg every 2 wk ^{[25, 26]} (bevacizumab and interferon are superior to single-agent interferon: OS is nonsignificantly superior [18.3 mo vs 17.4 mo], and PFS [8.5 mo vs 5.2 mo] and objective response [25.5% vs 13.1%] are significantly superior) or

• Nivolumab 240 mg IV q2Weeks or 480 mg IV q4Weeks plus cabozantinib (Cabometyx) 40 mg PO qDay; continue cabozantinib until disease progression or unacceptable toxicity and continue until disease progression or unacceptable toxicity or up to 2 years for nivolumab (Note: Do not substitute Cabometyx tablets with Cometriq capsules) ^[27] and

• Supportive care: palliative radiation therapy, metastasectomy, and bisphosphonates for bony metastasis

First-line for previously untreated clear-cell renal cell cancer in patients with poor prognostic (high-risk) characteristics and patients with non–clear cell history:

• Temsirolimus 25 mg IV weekly until disease progression ^{[17, 18]} (compared with single-agent interferon, it significantly prolongs OS [10.9 mo vs 7.3 mo] and PFS [5.5 mo vs 3.1 mo]) when compared with single-agent interferon; consider as first option for patients with poor prognosis

• Nivolumab 3 mg/kg IV infused over 30 min, followed by ipilimumab 1 mg/kg IV infused over 30 min on the same day; repeat every 3 weeks for 4 doses; then  nivolumab as a single agent, 240 mg IV q2wk or 480 mg IV q4wk infused over 30 min; significantly prolongs OS at 18 mo compared with sunitinib (75% vs 60%, respectively) ^[28]

• Sunitinib, pazopanib, or sorafenib if the patient is not a candidate to receive temsirolimus

• Patients with predominantly sarcomatoid renal cancers may respond to combination chemotherapy

Subsequent targeted therapy after tyrosine kinase inhibitors (ie, axitinib, pazopanib, sorafenib, sunitinib):

• Sorafenib is superior to placebo in patients in whom interferon therapy failed: PFS improves (5.5 mo vs 2.8 mo), and OS trends better (17.8 mo vs 15.2 mo) or

• Everolimus 10 mg PO once daily, improves survival compared with placebo in patients in whom sunitinib or sorafenib therapy previously failed: PFS is statistically superior (4.9 mo vs 1.9 mo), and OS is better but not significantly so ^[29] or

• Axitinib 5 mg PO BID; comparable to sorafenib: Longer PFS (8.3mo vs 5-7mo) and similar OS (20.2 mo vs 19.2 mo) or

• Sunitinib 50 mg PO once daily; 6-week cycle (4 weeks on followed by 2 weeks off treatment, then repeat) or

• Pazopanib 800 mg PO once daily or

• Temsirolimus 25 mg IV once weekly or

• Bevacizumab 10 mg/kg IV q2 wk until disease progression or unacceptable toxicity

Subsequent targeted therapy after cytokine therapy:

• Axitinib 5 mg PO BID or

• Sorafenib 400 mg PO BID or

• Sunitinib 50 mg PO once daily; 6-week cycle (4 weeks on followed by 2 weeks off treatment, then repeat) or

• Pazopanib 800 mg PO once daily or

• Temsirolimus 25 mg IV once weekly or

• Bevacizumab 10 mg/kg IV q2 wk until disease progression or unacceptable toxicity or

• Subsequent cytokine therapy with IL-2

Subsequent targeted therapy after antiangiogenic therapy:

• Nivolumab 240 mg IV q2wk or 480 mg q4wk over 30 min until disease progression or unacceptable toxicity ^[30] or
• Cabozantinib (Cabometyx) 60 mg PO once daily ^[31] or
• Envatinib 18 mg plus  everolimus 5 mg PO once daily until disease progression or unacceptable toxicity ^[32]

Subsequent targeted therapy after ≥2 systemic therapies:

• Tivozanib 1.34 mg PO qDay on Days 1-21 of repeated 28-day cycles; continue until disease progression or unacceptable toxicity ^[33]

Stage IV, relapsed, or recurrent disease for patients with predominantly non–clear cell histology

Clinical trial (preferred) or:

• Temsirolimus 25 mg IV weekly; continue until disease progression ^{[34, 35]} or

• Sorafenib 400 mg PO (two 200 mg tablets) twice daily either 1 h before or 2 h after meals or

• Sunitinib 50 mg PO daily; 6-week cycle (4 weeks on followed by 2 weeks off treatment, then repeat) or

• Pazopanib 800 mg PO once daily either 1 h before or 2 h after meals or

• Axitinib 5 mg PO q12 h or

• Everolimus 10 mg PO once daily or

• Bevacizumab 10 mg/kg IV q2wk or

• Erlotinib 150 mg once daily (off-label use; not approved by the US Food and Drug Administration [FDA] for renal cell carcinoma) or

• Gemcitabine and doxorubicin for disease with sarcomatoid-only features: doxorubicin 50 mg/m² IV push on day 1 plus gemcitabine 1500 or 2000 mg/m² IV on day 1 every 2-3 wk with granulocyte colony-stimulating factor (G-CSF) support ^[36] or

• Supportive care

Supportive care for metastatic disease

Supportive care is essential for patients diagnosed with metastatic renal cell carcinoma and may include any of the following:

• Palliative radiation therapy
• Metastasectomy ^[16]
• Bisphosphonates for bony metastasis ^[37]

Special considerations

Tyrosine kinase inhibitors have the potential to cause hand-foot syndrome, which usually consists of blisters, hyperkeratosis in areas of friction, acral erythema with or without paresthesias, and pain in the palms and soles. For mild (grade I) changes, topical corticosteroids and moisturizers are helpful; dose reduction may be needed for grade II changes, and temporary discontinuance of the drug may be needed for grade III. This condition is more common with sorafenib (30-60%).

Other common adverse events seen with sorafenib are rash, upper and lower gastrointestinal distress (eg, diarrhea), fatigue, and hypertension. These typically range from grade I to III in severity. ^[38]

Mammalian target of rapamycin (mTOR) inhibitors have common toxicities, including skin rash, asthenia, loss of appetite, and nausea; anemia is common.