Renal Cell Carcinoma Guidelines

Updated: Apr 03, 2017
  • Author: Kush Sachdeva, MD; Chief Editor: E Jason Abel, MD  more...
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Guidelines

Guidelines Summary

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 Orgnaization released an updated classification of renal cell tumors which expanded the subtypes of renal cell carcinoma (RCC) based on tumour histology, chromosomal alterations and molecular pathways,  5 newly recognized epithelial renal tumours included in the update are [69] :

  • 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 include [69] :

  • Clear cell RCC is characterised in >80% of sporadic cases by VHL gene mutations, hypermethylation of VHL gene promoter, and loss of heterozygosity
  • Multilocular cystic ccRCC has been renamed as multilocular cystic renal neoplasia of low malignant potential due to its indolent behaviour.
  • Papillary renal cell carcinoma are histologically and cytogenetically defined by two main subtypes, type 1 and type 2, but they represent a heterogeneous disease including both indolent and agressive tumors. RCCs associated with the 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 tumour 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.

 

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Diagnosis and Staging

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)
  • The European Society of Medical Oncology (ESMO)

American Urological Association recommendations

The 2009 AUA guideline for the management of the clinical T1 renal mass recommends a high-quality cross-sectional computed tomography (CT) or magnetic resonance imaging (MRI), first without and then with intravenous contrast if renal function is adequate. The objectives are as follows [21] :

  • Rule out angiomyolipoma
  • Evaluate for locally invasive features
  • Study the involved anatomy
  • Determine the status of the uninvolved kidney and its vasculature

According to the AUA guideline, a renal mass core biopsy via a percutaneous approach, with or without fine-needle aspiration, is indicated in patients for whom the results might affect approach to treatment. Biopsy is especially appropriate in patients with clinical or radiographic evidence of lymphoma, abscess, or metastasis. [21]

National Comprehensive Cancer Network recommendations

NCCN recommendations are categorized as follows [20] :

  • 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 2016 guidelines for kidney cancer recommend the following as part of the initial workup [20] :

  • History and physical examination
  • Complete blood count, comprehensive metabolic panel, and urinalysis
  • Abdominal/pelvic CT or abdominal MRI with or without contrast, depending on renal insufficiency
  • Chest imaging
  • Bone scan, if clinically indicated
  • Brain MRI, if clinically indicated

The NCCN guideline recommends abdominal MRI to assess suspected tumor involvement in the inferior vena cava, or as an alternative to CT for renal mass detection and staging in cases where the use of contrast is contraindicated because of allergy or renal insufficiency. [20]

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.

Lymph node dissection is described as prognostic rather than therapeutic in the NCCN guideline, which cites a 2009 randomized phase III trial in which adding lymph node dissection to radical nephrectomy made no significant difference in time to progression, progression-free survival, or overall survival. [20]

European Society of Medical Oncology recommendations

The ESMO 2016 updated clinical practice guidelines included the following recommendations for the diagnosis and staging of RCC [70] :

  • Diagnosis is usually suggested by ultrasound and further investigated by CT scan. Magnetic resonance imaging (MRI) may provide additional information in investigating local advancement and venous involvement by tumour thrombus.
  • Contrast-enhanced chest, abdominal, and pelvic CT is mandatory for staging; In case of an allergy to CT contrast medium,  a high-resolution CT scan of the chest without contrast medium, together with an abdominal MRI may be used.
  • Unless clinically indicated, the use of bone scan or CT (or MRI) of the brain is not recommended for routine clinical practice
  • Positron emission tomography is not a standard investigation in the diagnosis and staging of RCC
  • A diagnostic biopsy is required before treatment with ablative therapies; it is also indicated in patients with metastatic disease before initiating systemic treatment.
  • The final histopathologic diagnosis, classification, grading, and evaluation of prognostic factors should be based on the nephrectomy specimen when available
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Management of Clinical Stage I Renal Mass

The 2009 American Urological Association (AUA) guideline for management of the clinical T1 renal mass recommends reviewing all available treatment options and the associated benefits and risks with the patient. This review should include oncologic issues, renal functional issues, and potential complications. [21]

According to the AUA guideline, in patients with a T1 renal mass, nephron-sparing surgery is an overriding principle, as it offers the advantage of avoidance of dialysis and reduced risk of chronic kidney disease. Surgical excision by partial nephrectomy is a reference standard, but is greatly underutilized.

Both open and laparoscopic approaches may be considered, with open partial nephrectomy generally preferred for complex cases. If partial nephrectomy is not technically feasible, as determined by a urologic surgeon, then a radical nephrectomy should be considered as an alternate standard of care. [21]

Thermal ablation with cryoablation or radiofrequency ablation, performed either percutaneously or laparoscopically, is a less invasive option that may be preferable for patients at high surgical risk. The AUA guideline panel cautions that larger tumors (>3.5 cm) and those with uneven shape or infiltrative appearance may have increased risk of recurrence when managed with thermal ablation. [21]

The AUA recommends that tumor biopsy (preferably core biopsy) always be performed before thermal ablation, to define histology. Biopsy should also be considered after treatment, especially if there is reason to suspect recurrence.

For a T1a renal mass, the 2016 National Comprehensive Cancer Network (NCCN) guideline recommends partial nephrectomy, stating that radical nephrectomy should not be used when nephron-sparing procedures are possible. For clinical T1b tumors, the NCCN guideline states that the standard of care is either radical nephrectomy or partial nephrectomy (when possible). [20]

The NCCN guideline recommends considering ipsilateral adrenal gland resection for patients with large upper pole tumors or adrenal glands that appear abnormal on CT; if adrenal glands are uninvolved, adrenalectomy can be omitted. [20]

The 2016 European Society of 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. [70]

Active surveillance

The AUA guideline recommends active surveillance as an option for all patients with localized renal masses, and as the first choice for patients with decreased life expectancy or numerous comorbidities that would make them high risk for intervention. Larger tumors (>3-4 cm) and those with an aggressive appearance (eg, infiltrative growth pattern) may pose increased risk and should be managed in a proactive manner if possible. [21]

For patients who are candidates for intervention, counseling about active surveillance should include a frank discussion of the following:

  • The small but real risk of cancer progression
  • The lack of curative therapies if metastases develop
  • The possible loss of a chance for nephron-sparing surgery
  • The limited data on active surveillance

NCCN guidelines cite active surveillance as an option in selected patients with localized renal masses, and recommend it as a primary option in patients with a decreased life expectancy or extensive comorbidities. [20]  Similarly, 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. [70]

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Management of Clinical Stage II and III Renal Masses

Approximately 5% of patients with renal cell carcinoma (RCC) have inferior vena caval involvement. In these cases, the National Comprehensive Cancer Network (NCCN) guideline states that radical nephrectomy is preferred, and for stage II and III renal tumors it is the standard of care. [20]

The European Society of 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. [70]

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Primary Treatment of Stage IV Kidney Cancer

National Comprehensive Cancer Network (NCCN) recommendations for primary treatment of patients with stage IV kidney cancer are as follows [20] :

  • 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
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Molecular-Targeted Therapy in Metastatic Renal Cell Carcinoma

Targeted therapy can be considered the standard of care in patients with metastatic renal cell carcinoma. High-dose interleukin-2 (IL-2) should be considered when feasible.

The 2016 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. [20]  For previously untreated patients with predominantly clear cell cancer, considerations for first-line therapy are best supportive care and one of the following:

  • Sunitinib
  • Temsirolimus (category 1 recommendation for poor-prognosis patients; category 2B for selected patients in other risk groups)
  • Bevacizumab plus interferon (IFN) alfa
  • Pazopanib
  • High-dose interleukin-2 (for selected patients)
  • Axitinib
  • Sorafenib (for selected patients)

For patients with previously treated predominantly clear cell renal cell cancer, considerations for subsequent therapy vary according to the therapy previously given. Considerations after tyrosine kinase inhibitor therapy include any of the following:

  • Axitinib (category 1)
  • Cabozantinib (category 1)
  • Nivolumab (category 1)
  • Everolimus (category 1)
  • Sorafenib
  • Sunitinib
  • Pazopanib
  • Temsirolimus (category 2B )
  • Bevacizumab

Considerations after cytokine therapy include any of the following:

  • Axinitib (category 1)
  • Sorafenib (category 1)
  • Sunitinb (category 1)
  • Pazopanib (category 1)
  • Temsirolimus
  • Bevacizumab
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Long-Term Monitoring for Clinically Localized Renal Neoplasms

Active surveillance

In patients with a clinically localized renal neoplasm who have chosen active surveillance, the American Urological Association (AUA) [68]  and the National Comprehensive Cancer Network (NCCN) [20]  recommend similar follow-up measures. The NCCN monitoring schedule for active surveillance is as follows:

  • Physical exam and history every 6 mo for 2 y, the annually for up to 5 y
  • Comprehensive metabolic panel and other laboratory tests as indicated every 6 mo for the first 2 y, then annually up to 5 y
  • Abdominal CT or MRI within 6 mo of surveillance initiation, to establish a growth rate, and continued imaging (ultrasound, CT, or MRI) at least annually thereafter
  • In patients with biopsy-proven renal cell carcinoma or a tumor with oncocytic features, annual chest x-ray or CT to assess for pulmonary metastases
  • Pelvic imaging as clinically indicated
  • CT or MRI of the head or MRI of the spine as clinically indicated
  • Bone scan as clinically indicated

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. [68]  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. [68]

Other recommendations and options outlined in the guideline include the following [68] :

  • 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. [68]

NCCN postoperative guidelines

For stage I renal cell carcinoma, the NCCN recommends a complete history, physical examination, comprehensive metabolic panel, and other laboratory tests as indicated every 6 months for 2 years, then annually for 5 years.

The NCCN recommends a baseline abdominal CT, MRI, or ultrasound scan within 3-12 months postoperatively. If this scan is negative, patients who underwent partial nephrectomy may be considered for abdominal imaging annually for 3 y, based on individual risk factors. For patients who underwent radical nephrectomy, abdominal imaging after 12 mo may be performed at the clinician’s discretion. [20]

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- mo; then CT, MRI, 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- mo postoperatively, with CT or chest x-ray every 3- mo for at least 3 y, then annually up to 5 y, then as clinically indicated.
  • 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 [20] :

  • 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
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