Renal Cell Carcinoma Treatment Protocols 

Updated: May 17, 2016
  • Author: Kush Sachdeva, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
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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. [7]

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, the patient may be recommended for radical nephrectomy
  • Active surveillance is preferred in selected patients
  • Thermal ablation may be considered for nonsurgical candidates [13]

Stage IB:

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

Stages II and III:

  • Radical nephrectomy is the preferred treatment

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

See the list below:

  • Primary treatment includes cytoreductive therapy for potentially surgically resected primary and metastatic disease before systemic therapy in patients with a potentially resectable primary tumor and multiple resectable metastases [14]
  • Surgical resection is recommended in selected patients with good performance status [15]
  • Medically or surgically unresectable nonsurgical treatment is recommended, and clinical trials should be considered

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

First-line therapy for previously untreated patients 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 11mo 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) or
  • Sorafenib 400 mg (two 200 mg tablets) PO BID either 1 h before or 2 h after meals [16, 17] (this can be considered first-line therapy if the patient is not able to receive any of the other first-line therapies) or
  • Temsirolimus 25 mg IV weekly until disease progression [18, 19] (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 or
  • Pazopanib 800 mg/day PO either 1 h before or 2 h after meals [20] (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 [21] (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 [22, 23] (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) 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; continue until disease progression [18, 19] (this significantly prolongs OS [10.9m o vs 7.3 mo] and PFS [5.5 mo vs 3.1 mo] when compared with single-agent interferon) or
  • 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 [24] o r
  • 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 or

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 3 mg/kg IV q2wk until disease progression or unacceptable toxicity [25]  or
  • Cabozantinib (Cabometyx) 60 mg PO once daily [26]
  • Lenvatinib 18 mg plus  everolimus 5 mg PO once daily until disease progression or unacceptable toxicity [27]

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

Clinical trial (preferred) or the following options

  • Temsirolimus 25 mg IV weekly; continue until disease progression [28, 29] 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 q2 wk 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/m 2 IV push on day 1 plus  gemcitabine 1500 or 2000 mg/m 2 IV on day 1 every 2-3 wk with granulocyte colony-stimulating factor (G-CSF) support [30] or
  • Supportive care: palliative radiation therapy, metastasectomy, [15] and bisphosphonates for bony metastasis [31] and

Supportive care for metastatic disease

Supportive care is essential for patients diagnosed with metastatic renal cell carcinoma and can include palliative radiation therapy, metastasectomy, or bisphosphonates for bony metastasis.

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. [32]

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

Prognosis

See the list below:

  • Stage I (T1N0): 5-y survival > 90%
  • Stage II (T2N0): 5-y survival 75-95%
  • Stage I or II RCC that invades the urinary collecting system have a significantly worse prognosis
  • Stage I (T1N0) with invasion of the urinary collecting system: 10-y survival 43%
  • Stage II (T2N0) with invasion of the urinary collecting system: 10-y survival 41%
  • Stage III (T3N0 or T3N1) who undergo nephrectomy: 5-y survival 59-70%

The size of the primary tumor remains a prognostic factor. The 10-y survival rates for tumors of varying sizes are as follows:

  • < 4 cm: 77%
  • 4-7 cm: 54%
  • >7 cm: 46%
  • Median survival for patients with stage IV disease is 16-20%, and 5-y survival is < 10%
  • Newer therapies have reported median survival >2 y