Renal Cell Carcinoma Guidelines

Guidelines Contributor : Bagi RP Jana, MD Associate Professor of Medicine (Genitourinary Oncology), Division of Hematology and Oncology, University of Texas Medical Branch

Classification

In 2016, the World Health Organization released an updated classification of renal cell tumors that expanded the subtypes of renal cell carcinoma (RCC) based on tumor histology, chromosomal alterations, and molecular pathways. The update included the following five newly recognized epithelial renal tumors ^[76] :

• Hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome–associated RCC
• Succinate dehydrogenase–deficient RCC
• Tubulocystic RCC
• Acquired cystic disease–associated RCC
• Clear cell papillary RCC

Other revisions to RCC classification included the following ^[76] :

• Clear cell RCC is characterized in >80% of sporadic cases by VHL gene mutations, hypermethylation of VHL gene promoter, and loss of heterozygosity

• Multilocular cystic clear cell RCC has been renamed as multilocular cystic renal neoplasia of low malignant potential due to its indolent behavior.

• Papillary renal cell carcinomas are histologically and cytogenetically defined by two main subtypes, type 1 and type 2, but they represent a heterogeneous disease that includes both indolent and agressive tumors. RCCs associated with hereditary leiomyomatosis are usually type 2 papillary RCC and have a poor prognosis with a high risk of dissemination.

• The oncocytic variant of papillary RCC should be reclassified as type 1 (mainly) or type 2 papillary RCC.

• The maximum size of papillary adenoma was 5 mm but is now ≤15 mm in its largest dimension.

• The main prognostic factors in chromophobe RCC are tumor stage, the presence of necrosis, a sarcomatoid and/or rhabdoid component, and small vessel invasion.

• The diagnosis of the highly aggressive collecting duct carcinoma is based on six histological features: medullary location, infiltrative growth pattern, tubular architecture, desmoplastic stromal reaction, high-grade atypia, and that the tumor is neither an RCC nor a transitional cell carcinoma.

Guidelines for the diagnosis and staging of renal cell carcinoma (RCC) have been issued by the following organizations:

• American Urological Association (AUA)
• National Comprehensive Cancer Network (NCCN)
• European Society for Medical Oncology (ESMO)
• European Association of Urology (EAU)

American Urological Association recommendations

The 2017 AUA guideline for the management of clinically localized sporadic renal masses suspicious for RCC in adults recommends that in patients with a solid or complex cystic renal mass, clinicians should perform high-quality, multiphase, cross-sectional abdominal imaging to optimally characterize and clinically stage the renal mass. ^[19] Characterization of the renal mass should include assessment of the following:

• Tumor complexity
• Degree of contrast enhancement (where applicable)
• Presence or absence of fat

According to the AUA guideline, a renal mass biopsy should be considered when a mass is suspected to be hematologic, metastatic, inflammatory, or infectious (Clinical Principle). In the setting of a solid renal mass, biopsy is not required for either of the following (Expert Opinion):

• Young or healthy patients who are unwilling to accept the uncertainties associated with biopsy
• Older or frail patients who will be managed conservatively independent of biopsy findings

When considering the utility of renal mass biopsy, patients should be counseled regarding its rationale, positive and negative predictive values, potential risks, and nondiagnostic rates (Clinical Principle). For patients with a solid renal mass who elect biopsy, multiple core biopsies are preferred over fine needle aspiration (Moderate Recommendation; Evidence Level: Grade C)

National Comprehensive Cancer Network recommendations

NCCN recommendations are categorized as follows ^[18] :

• Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate
• Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate
• Category 2B:Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate
• Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate

All NCCN recommendations are category 2A unless otherwise noted.

The NCCN  guidelines for kidney cancer recommend the following as part of the initial workup ^[18] :

• History and physical examination
• Complete blood count, comprehensive metabolic panel, and urinalysis
• Abdominal/pelvic CT or abdominal MRI, with contrast when clinically indicated
• Chest x-ray
• Bone scan, brain MRI, chest CT, if clinically indicated
• If multiple renal masses, ≤46 years, or family history, consider genetic evaluation

In addition, the NCCN recommends considering needle biopsy of small lesions if clinically indicated. The NCCN also recommends considering urine cytology and ureteroscopy if urothelial carcinoma is suspected (eg, a central mass is present).

The NCCN guideline recommends lymph node dissection in patients with enlarged lymph nodes (palpable or visible or detected on preoperative imaging). To obtain needed staging information, lymph node dissection may also be performed on patients whose lymph nodes appear normal.

European Society for Medical Oncology recommendations

The ESMO updated clinical practice guidelines include the following recommendations for the diagnosis and staging of RCC. ^[77]

Diagnosis is usually suggested by ultrasound and further investigated by CT scan. If RCC is suspected, the following laboratory examinations should be performed:

• Serum creatinine
• Hemoglobin
• Leukocyte and platelet counts
• Lymphocyte-to-neutrophil ratio
• Lactate dehydrogenase
• C-reactive protein (CRP)
• Serum-corrected calcium

Contrast-enhanced chest, abdominal, and pelvic CT is mandatory for accurate RCC staging. Bone scan or brain CT (or magnetic resonance imaging) is not recommended for routine clinical practice unless indicated by clinical or laboratory signs or symptoms.

Renal tumor core biopsy has high sensitivity and specificity for histopathologic confirmation of malignancy. It is especially recommended before ablative therapy and in patients with metastatic disease before systemic treatment is started.

The Union for International Cancer Control tumor, node, and metastasis (TNM) staging system should be used for staging and risk assessment.

European Association of Urology

EAU guidelines on diagnosis and staging of RCC include the following recommendations ^[78] :

• Use multi-phasic contrast-enhanced CT of abdomen and chest for the diagnosis and staging of renal tumors.
• Omit chest CT in patients with incidentally noted cT1a disease due to the low risk of lung metastases in this cohort.
• Use MRI to better evaluate venous involvement, reduce radiation exposure, or avoid intravenous CT contrast medium.
• If the results of contrast-enhanced CT are indeterminate. use non-ionizing modalities, including MRI and contrast-enhanced ultrasound, for further characterization of small renal masses, tumor thrombus, and differentiation of unclear renal masses.
• Do not routinely use bone scan and/or PETCT for staging of RCC.
• Perform a renal tumor biopsy before ablative therapy and systemic therapy without previous pathology.
• Perform a percutaneous biopsy in select patients who are considering active surveillance.
• Do not perform a renal tumor biopsy of cystic renal masses.
• Use a core biopsy technique rather than fine needle aspiration for histological characterization of solid renal tumors.

EAU recommendations on staging and risk assessment of RCC include the following ^[78] :

• Use the current TNM classification system.
• Use the World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading system and classify RCC type.
• Use prognostic models in localized and metastatic disease.
• Do not routinely use molecular markers to assess prognosis.

In patients with a clinical T1a renal mass for which intervention is indicated, the American Urological Association (AUA) guideline recommends prioritizing partial nephrectomy, as it minimizes the risk of chronic kidney disease (CKD) or CKD progression and is associated with favorable oncologic outcomes, including excellent local control (Moderate Recommendation; Evidence Level: Grade B). ^[19]

Thermal ablation may be considered as an alternate approach for the management of cT1a renal masses < 3 cm in size. Before ablation, a tumor mass biopsy should be performed, to provide pathologic diagnosis and guide subsequent surveillance (Expert Opinion). Counseling about thermal ablation should include information that tumor persistence or local recurrence occurs more commonly after primary thermal ablation than after surgical extirpation, but may be addressed with repeat ablation if further intervention is elected (Strong Recommendation; Evidence Level: Grade B). ^[19]

Thermal ablation may be performed using radiofrequency or cryoablation. A percutaneous technique is preferred over a surgical approach whenever feasible, to minimize morbidity. (Conditional Recommendation; Evidence Level: Grade C). ^[19]

For a pathologic T1a renal mass, National Comprehensive Cancer Network (NCCN) lists the following as treatment options ^[18] :

• Partial nephrectomy (preferred)
• Radical nephrectomy (if partial not feasible or central location)
• Active surveillance in selected patients
• Ablative techniques in selected patients

For pT1b disease, the NCCN recommends either partial or radical nephrectomy. ^[18]

The 2019 European Society for Medical Oncology (ESMO) guidelines also recommend partial nephrectomy as the preferred option in tumors measuring up to 7 cm. Partial nephrectomy is also recommended in patients with compromised renal function, solitary kidney, or bilateral tumors, with no tumor size limitation. ^[77]

Active surveillance

AUA recommendations regarding active surveillance include the following ^[19] :

• Active surveillance is an option for patients with small solid or Bosniak 3/4 complex cystic renal masses, especially those < 2 cm (Conditional Recommendation; Evidence Level: Grade C).
• For patients with a solid or Bosniak 3/4 complex cystic renal mass, active surveillance/expectant management should be prioritized when the anticipated risk of intervention or competing risks of death outweigh the potential oncologic benefits of active treatment (Clinical Principle).
• For patients with a solid or Bosniak 3/4 complex cystic renal mass in whom the risk/benefit analysis for treatment yields equivocal results and who prefer active surveillance, repeat imaging should be performed in 3-6 months to assess for interval growth; renal mass biopsy may be considered for additional risk stratification (Expert Opinion).
• Active treatment is recommended for patients with a solid or Bosniak 3/4 complex cystic renal mass in whom the anticipated oncologic benefits of intervention outweigh the risks of treatment and competing risks of death; in this setting, active surveillance with potential for delayed intervention may be pursued only if the patient understands and is willing to accept the associated oncologic risk (Moderate Recommendation; Evidence Level: Grade C).

ESMO guidelines recommend active surveillance as an option in elderly patients with significant comorbidities or with a short life expectancy and tumors measuring < 40 mm. ^[77]

For stage II renal tumors, the National Comprehensive Cancer Network (NCCN) guideline recommends partial nephrectomy or radical nephrectomy as primary treatment. For stage III, the NCCN guideline recommends radical nephrectomy, or partial nephrectomy if clinically indicated. Examples of cases in which partial nephrectomy is appropriate include the following:

• Unilateral stage I-III tumors where technically feasible
• Uninephric state
• Renal insufficiency
• Bilateral renal masses
• Familial RCC
• Patients at relative risk for developing progressive chronic kidney disease due to young age or medical risk factors (ie, hypertension, diabetes, nephrolithiasis)

The European Society for Medical Oncology (ESMO) guideline recommends laparoscopic radical nephrectomy for T2 tumors (> 7 cm). For locally advanced RCC (T3 and T4), open radical nephrectomy is the standard of care, though a laparoscopic approach can be considered. However, systemic adrenalectomy or extensive lymph node dissection is not recommended when there is no evidence of adrenal or lymph node invasion. There is no recommended adjuvant treatment. Adjuvant and neoadjuvant treatment should not be considered outside of clinical trials. ^[77]

National Comprehensive Cancer Network (NCCN) recommendations for primary treatment of patients with stage IV kidney cancer are as follows ^[18] :

• Potentially surgically resectable primary tumor and a solitary metastatic site: Radical nephrectomy plus surgical metastatectomy, with consideration of first-line systemic therapy if relapse occurs
• Potentially surgically resectable primary with multiple metastatic sites: Cytoreductive nephrectomy in selected patients prior to systemic therapy, followed by first-line systemic therapy
• Surgically unresectable primary: First line systemic therapy

European Society for Medical Oncology (ESMO) recommendations for management of advanced or metastatic RCC are as follows ^[77] :

• Cytoreductive nephrectomy is recommended in patients with good performance status (PS), except in intermediate/poor-risk patients with asymptomatic primary tumors when medical treatment is required.
• Radiation therapy (RT) can be used to treat unresectable local or recurrent disease and in patients unsuitable for surgery due to poor PS or unsuitable clinical condition. RT is an alternative if radioablation is not appropriate
• Image-guided RT techniques such as volumetric-modulated arc therapy (VMAT) or stereotactic body radiotherapy (SBRT) are needed to enable a high dose to be delivered.
• RT is an effective treatment for palliation of local and symptomatic metastatic RCC or to prevent the progression of metastatic disease in critical sites such as bones or brain.
• For RCC with brain metastases, corticosteroids can provide temporary relief of cerebral symptoms. Whole-brain radiotherapy (WBRT) of 20-30 Gy in 4-10 fractions is recommended for effective symptom control. For good-prognosis metastatic RCC patients with a single unresectable brain metastasis, sterotactic radiosurgery (SRS) with or without WBRT should be considered.
• For first-line systemic treatment, vascular endothelial growth factor receptor (VEGFR)–targeted agents and tyrosine kinase inhibitors (TKIs) are recommended options for good- and intermediate-risk patients. Tivozanib is approved by the European Medicines Agency (EMA) for good-risk patients.
• First-line treatment for advanced clear cell RCC, irrespective of the International Metastatic RCC Database Consortium (IMDC) risk group, is with the combination of a programmed death 1 (PD-1) inhibitor and a VEGFR-targeted agent: axitinib/pembrolizumab, cabozantinib/nivolumab, or lenvatinib/pembrolizumab (FDA-approved but not EMA-approved). There is no preferred PD-1 inhibitor–VEGFR TKI combination and indirect comparisons across trials are not recommended.
• Ipilimumab/nivolumab is recommended as first-line treatment for IMDC intermediate- and poor-risk patients, but not for the good-risk group.
• Immune checkpoint inhibitor (ICI)–based therapy is particularly active in sarcomatoid renal tumors and should be strongly recommended above single-agent VEGFR TKI therapy.
• Sunitinib, pazopanib, and tivozanib are alternatives to PD-1 inhibitor–based first-line combinations when immune therapy is contraindicated or not available. Cabozantinib is also an alternative in IMDC intermediate- and poor-risk disease, for those patients that cannot receive first-line PD-1 inhibitor-based therapy.
• Sunitinib or pazopanib are potential alternatives to PD-1 inhibitor-based combination therapy in IMDC favorable-risk disease due to a lack of clear superiority for PD-1-based combinations over sunitinib in this subgroup of patients, and the non-inferior effectiveness of sunitinib and pazopanib demonstrated by the COMPARZ trial.
• Surveillance is an alternative approach in a small subset of patients. This requires careful consideration.
• Only ICI-based combinations with a survival advantage are recommended in the first-line setting. Axitinib/avelumab and bevacizumab/atezolizumab are not yet associated with an overall survival advantage and are therefore not recommended.
• Cessation of ICIs should be considered after two years of therapy.
• Lenvatinib/everolimus should not be regarded as a standard first-line treatment for metastatic disease but can be recommended as a subsequent therapy after first-line treatment, along with other agents.
• For second-line treatment, following TKIs, nivolumab, cabozantinib, or tivozanib are recommended.
• The combination of lenvatinib and everolimus following TKIs is FDA- and EMA-approved and is recommended after the nivolumab/ipilimumab combination.
• If none of those drugs is available, either everolimus or axitinib can be used.
• In patients already treated with two TKIs, either nivolumab or cabozantinib is recommended.

European Association of Urology (EAU) recommendations for management of advanced or metastatic RCC are as follows ^[78] :

• To control local symptoms, offer ablative therapy, including metastasectomy, to patients with metastatic disease and favorable disease factors and in whom complete resection is achievable.
• Offer stereotactic radiotherapy for clinically relevant bone or brain metastases for local control and symptom relief.
• Do not offer TKI inhibitors to patients with metastatic RCC who have no evidence of disease after metastasectomy.
• Do not offer chemotherapy to patients with metastatic RCC.

The EAU bases its recommendations on systemic therapy for metastatic RCC on International Metastatic RCC Database Consortium (IMDC) risk level. Standard of care regimens for IMDC favorable risk are as follows:

• Nivolumab/cabozantinib
• Pembrolizumab/axitinib 
• Pembrolizumab/lenvatinib

Standard of care regimens for IMDC intermediate and poor risk are as follows:

• Nivolumab/cabozantinib
• Pembrolizumab/axitinib 
• Nivolumab/ilipilimumab

EAU recommendations for targeted therapy of metastatic RCC are as follows ^[78] :

• Offer nivolumab or cabozantinib for immune checkpoint inhibitor–naive VEGF agent–refractory clear-cell metastatic RCC after one or two lines of therapy.   
• Offer VEGF TKIs as second-line therapy to patients whose disease is refractory to nivolumab/ipilimumab, pembrolizumab/axitinib, nivolumab/cabozantinib, or pembrolizumab/lenvatinib.

For stage IV RCC that is relapsed, includes multiple metastatic sites, or is surgically unresectable, the National Comprehensive Cancer Network (NCCN) guideline gives several targeted therapy agents a category 1 recommendation (ie, based on high-level evidence, with uniform NCCN consensus that the intervention is appropriate) for this group of patients. ^[18]  For patients with predominantly clear cell cancer, considerations for first-line therapy are best supportive care and one of the following:

• Clinical trial
• Pazopanib (category 1, preferred)
• Sunitinib (category 1, preferred)
• Bevacizumab + interferon alfa-2b (category 1)
• Temsirolimus (category 1 for poor-prognosis patients, category 2B for selected patients of other risk groups)
• Axitinib
• Cabozantinib (for poor- and intermediate-risk groups)
• High-dose IL-2 for selected patients (with excellent performance status and normal organ function)
• Active surveillance for select, asymptomatic patients)

For patients with previously treated predominantly clear cell RCC, NCCN considerations for subsequent therapy include the following:

• Clinical trial
• Cabozantinib (category 1, preferred)
• Nivolumab (category 1, preferred)
• Axitinib (category 1)
• Lenvatinib + everolimus (category 1)
• Everolimus
• Pazopanib
• Sorafenib • Sunitinib
• Bevacizumab (category 2B)
• High-dose IL-2 for selected patientsj (category 2B)
• Temsirolimus (category 2B)

For patients with non–clear cell histology, NCCN recommendations for systemic therapy include the following:

• Clinical trial (preferred)
• Sunitinib (preferred)
• Axitinib
• Bevacizumab
• Bevacizumab + erlotinib for selected patients with advanced papillary RCC, including hereditary leiomyomatosis–associated RCC (HLRCC)
• Bevacizumab + everolimus for selected patients with advanced papillary RCC including HLRCC
• Cabozantinib
• Erlotinib
• Everolimus
• Lenvatinib + everolimus
• Nivolumab
• Pazopanib
• Sorafenib
• Temsirolimus (category 1 for poor-prognosis patients; category 2A for other risk groups)

Active surveillance

In patients with a clinically localized renal neoplasm who have chosen active surveillance, the American Urological Association (AUA) ^[75]  and the National Comprehensive Cancer Network (NCCN) ^[18]  recommend similar follow-up measures. The NCCN monitoring schedule for active surveillance in patients with pT1a disease is as follows ^[18] :

• History and physical examination annually
• Laboratory tests annually, as clinically indicated
• Abdominal imaging: Abdominal CT or MRI with contrast if no contraindication within 6 mo of surveillance initiation, then CT, MRI, or US at least annually
• Chest imaging: Chest x-ray or CT at baseline and annually as clinically indicated to assess for pulmonary metastases
• Consider renal mass biopsy at initiation of active surveillance or at follow-up, as clinically indicated
• Follow-up may be individualized based on surgical status, treatment schedules, side effects, comorbidities, and symptoms

Followup after renal surgery

As many as one third of patients with clinically localized disease may develop metastatic disease after nephrectomy, so they should be monitored carefully. In 2013, the AUA released a set of new guidelines addressing the follow-up and surveillance of clinically localized renal cancers treated with surgery or renal ablative procedures, biopsy-proven untreated clinically localized renal cancers followed on surveillance, and radiographically suspicious but biopsy-unproven renal neoplasms. ^[75]  Of the 27 statements in this guideline, the only one considered a grade A recommendation (standard of care) is that patients with a history of renal neoplasm who present with acute neurologic signs or symptoms should undergo prompt neurologic cross-sectional CT or MRI scanning of the head or spine, based on localization of signs and symptoms. ^[75]

Other recommendations and options outlined in the guideline include the following ^[75] :

• Bone scan can be performed in patients with an elevated alkaline phosphatase level or clinical symptoms such as bone pain and/or radiographic findings suggestive of a bony neoplasm

• For patients with a history of low-risk (pT1, N0, Mx) renal cell carcinoma that was managed surgically, chest x-rays should be performed annually for 3 years and then only as clinically indicated to assess for pulmonary metastases

• For moderate- to high-risk patients managed surgically (pT2-4, N0, Nx or any N+), the panel recommends baseline abdominal imaging (CT or MRI) within 3 to 6 months following surgery, with continued imaging every 6 months for at least 3 years and annually thereafter to year 5

• For patients on active surveillance, the panel recommends abdominal imaging (CT or MRI) within 6 months of active surveillance initiation to establish a growth rate, and then annually thereafter

• Following ablation, patients should undergo cross-sectional CT or MRI, with and without IV contrast, at 3 and 6 months to assess treatment success, and annually thereafter for 5 years

Spontaneous regression has been reported anecdotally in renal cell carcinoma. As many as 10% of patients with metastatic disease show no progression for more than 12 months. All systemic therapies are associated with treatment-related toxicity and low response; therefore, close observation is an option for asymptomatic metastatic disease. Once evidence of progression or symptoms appears, appropriate therapy should be initiated. Careful surveillance of patients with end-stage renal disease by ultrasonography and CT scanning is recommended. ^[75]

NCCN postoperative guidelines

In patients who have undergone ablative techniques for stage I RCC, the NCCN recommends the following:

• Complete history and physical examination annually
• Laboratory tests annually, as clinically indicated
• Abdominal imaging: Abdominal CT or MRI at 3–6 mo following ablative therapy unless otherwise contraindicated then CT or MRI (preferred), or US annually for 5 y or longer as clinically indicated; if there are imaging or clinical concerns for recurrence, then more frequent imaging, renal mass biopsy, or further treatment may be indicated.
• Chest imaging: Chest x-ray or CT annually for 5 y for patients who have biopsy-proven low-risk RCC, nondiagnostic biopsies, or no prior biopsy

In patients who have undergone partial or radical nephrectomy for stage pT1a or pT1b RCC, the NCCN recommends the following:

• Complete history and physical examination annually
• Laboratory tests annually, as clinically indicated
• Abdominal imaging: Baseline abdominal CT or MRI (preferred), or US within 3–12 mo of surgery, then annually for 3 y or longer as clinically indicated; a more rigorous imaging schedule or technique modality can be considered in cases with positive margins or adverse pathologic features (eg, sarcomatoid, high-grade [grade 3/4], positive margins)
• Chest imaging: Chest x-ray or CT annually for at least 5 y, then as clinically indicated. A more rigorous imaging schedule or technique modality can be considered in cases with positive margins or adverse pathologic features ^[18]

For stage II or III renal cell carcinoma, the NCCN recommends following radical nephrectomy with a history and physical examination every 3-6 mo for 3 y, then annually for up to 5 y, then as clinically indicated. A comprehensive metabolic panel (and other tests as indicated) is recommended every 6 mo for 2 y, annually up to 5 y, then as clinically indicated.

Imaging studies are as follows:

• Baseline abdominal CT or MRI scanning should be performed within 3-6 mo; then CT, MRI (preferred), or ultrasound every 3-6 mo for at least 3 y, annually up to 5 y, then as clinically indicated

• A baseline chest CT should be performed within 3-6 mo postoperatively, with CT (preferred) or chest x-ray every 3- mo for at least 3 y, then annually up to 5 y, then as clinically indicated, based on individual patient characteristics and tumor risk factors

• Additional imaging (ie, bone scan, brain imaging) as symptoms warrant

• Pelvic imaging, CT or MRI of the head or MRI of the spine, or bone scanning, is peformed as clinically indicated

For relapsed or stage IV and surgically unresectable disease, the NCCN recommendations are as follows ^[18] :

• History and physical exam every 6-16 w in patients receiving systemic therapy, or more often as clinically indicated

• Laboratory studies as required for the therapeutic agent the patient is receiving

• Baseline chest, abdominal, and pelvic CT or MRI, with follow-up imaging every -16 w as clinically indicated

• Consider CT or MRI of the head, at baseline and as clinically indicated, with annual surveillance scans at the clinician’s discretion

• Spine MRI as clinically indicated

• Bone scan as clinically indicated