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Surgical Treatment for Renal Cell Carcinoma

• Renal cell carcinoma: Definition and Epidemiology
• Renal cell carcinoma: Pathology
• Renal cell carcinoma: Diagnostic workup
• Renal cell carcinoma: Surgical Treatment
• Renal cell carcinoma: Targeted therapy of advanced disease

Therapy

Overview of Treatment Options

Unilateral small kidney tumor:

Open partial nephrectomy, laparoscopic partial nephrectomy, or robot-assisted partial nephrectomy is the standard treatment, depending on the surgeon's technical expertise. Favorably located small tumors can be treated with radiofrequency ablation, microwave ablation, or cryotherapy. Active surveillance is an option for older patients with significant comorbidity.

Large unilateral kidney tumor:

Radical nephrectomy is the standard treatment for large tumors when partial nephrectomy is technically or oncologically unsuitable, and for tumors with extensive venous tumor thrombus. Favorably located large tumors may also be treated with partial nephrectomy. Depending on the disease stage and the surgeon's technical expertise, surgery may be performed laparoscopically, retroperitoneoscopically, with robot assistance, or by an open flank or transperitoneal approach.

Bilateral kidney tumors:

Partial nephrectomy should be attempted on both sides. If this does not appear technically feasible, partial nephrectomy is first performed on the technically simpler side. After recovery, residual renal function is evaluated by renal scintigraphy. If residual function on the operated side is sufficient, radical nephrectomy may be performed on the contralateral side. If residual function is inadequate, imperative partial nephrectomy of the contralateral kidney should be attempted using all available technical options; radical nephrectomy followed by dialysis is an alternative.

Metastatic renal cell carcinoma:

In metastatic disease, a multidisciplinary team should assess before treatment whether complete metastasectomy, local treatment of metastases, or cytoreductive nephrectomy is likely to provide meaningful benefit. Systemic therapy is generally the priority in patients with a high metastatic burden, poor performance status, or an unfavorable IMDC risk group (see the IMDC risk criteria). If surgery has removed all tumor manifestations, adjuvant pembrolizumab may be considered for clear cell histology. Metastases that cannot be removed surgically are treated systemically with combinations of immune checkpoint inhibitors and tyrosine kinase inhibitors or with immune checkpoint inhibitor combinations (see systemic therapy for metastatic renal cell carcinoma).

Radical Nephrectomy

Indication:

Radical nephrectomy is the standard treatment for large tumors or tumors with venous tumor thrombus.

Relative contraindications:

The availability of a suitable nephron-sparing partial nephrectomy for a small tumor is a relative contraindication to radical nephrectomy, particularly in patients with existing or impending renal insufficiency. Risk factors for future renal insufficiency after nephrectomy include elevated serum creatinine, proteinuria, diabetes mellitus, arterial hypertension, bilateral renal cell carcinoma, and familial renal cell carcinoma.

Surgical technique:

Radical nephrectomy may be performed laparoscopically, with robot assistance, or retroperitoneoscopically [for technique and complications, see radical nephrectomy]. Open flank, transperitoneal, or thoracoabdominal nephrectomy is an alternative, particularly for very large tumors. Minimally invasive nephrectomy has lower morbidity and is oncologically equivalent. No significant clinical differences have been demonstrated between the different approaches (EAU guideline).

Laparoscopic radical nephrectomy: the renal vein is transected with a linear stapling device.

Venous invasion:

For tumors with venous thrombus, secure vascular control to open the inferior vena cava and complete removal of the tumor thrombus are prerequisites for nephrectomy. Accurate determination of the cranial extent of the thrombus is essential for surgical planning:

• Level I: Tumor thrombus in the renal vein
• Level II: Tumor thrombus in the inferior vena cava below the liver
• Level III: Tumor thrombus in the intrahepatic inferior vena cava below the diaphragm
• Level IV: Tumor thrombus extending above the diaphragm

Adrenalectomy:

If adrenal involvement is detected, the adrenal gland is removed during surgery for the primary tumor. Routine adrenalectomy without radiologic evidence of tumor involvement is generally not indicated.

Lymphadenectomy:

Lymphadenectomy should not be performed for cT1–2 cN0 tumors because a large EORTC study did not demonstrate a survival benefit (Blom et al., 2009). Based on retrospective data, some authors advocate an extended lymphadenectomy for advanced tumors or enlarged lymph nodes, extending from the diaphragmatic crura to the origin of the inferior mesenteric artery. For left-sided tumors, the para-aortic lymph nodes are removed; for right-sided tumors, the paracaval lymph nodes are removed. The interaortocaval lymph nodes should be removed regardless of tumor side.

Oncological results:

More precise estimates of survival can be obtained by considering multiple risk factors using the Stage, Size, Grade, and Necrosis (SSIGN) score [tables Assessing the SSIGN score and SSIGN score and survival].

Adjuvant therapy:

The risk of recurrence is increased in locally advanced or node-positive renal cell carcinoma. Adjuvant systemic therapy is approved only for pembrolizumab in patients with clear cell histology and a high risk of recurrence; structured surveillance remains the standard outside this setting.

Adjuvant therapy with checkpoint inhibitors:

KEYNOTE-564 was the first phase III trial to demonstrate improved disease-free survival (HR 0.72) and improved overall survival (91 % vs. 86 % at four years) with adjuvant pembrolizumab after surgery (Choueiri et al., 2024). Included patients had dedifferentiated tumors (grade 4), T3–4 or N+ disease, or had undergone complete resection of metastases. The FDA approved treatment in November 2021 and the EMA in February 2022. Potential disadvantages of early adjuvant pembrolizumab include overtreatment of patients without metastatic disease, undertreatment of patients with metastatic disease who do not receive a tyrosine kinase inhibitor, and high costs.

Adjuvant therapy with tyrosine kinase inhibitors:

Several randomized studies examined adjuvant signal transduction inhibitors in patients at high risk of progression after surgery. ASSURE (sunitinib vs. sorafenib vs. placebo) showed no significant benefit. PROTECT (pazopanib vs. placebo) improved progression-free survival (HR 0.69), but did not demonstrate a difference in overall survival. S-TRAC (sunitinib vs. placebo) demonstrated improved progression-free survival but no established overall survival benefit. Long-term tyrosine kinase inhibitor therapy has significant adverse effects. Adjuvant therapy with these agents is not recommended outside controlled trials, and available signal transduction inhibitors are not approved for adjuvant treatment.

Follow-up after radical nephrectomy:

According to the EAU and German S3 guideline recommendations, follow-up after radical nephrectomy should be based on symptoms and the risk of metastasis. The risk can be estimated using the Stage, Size, Grade, and Necrosis (SSIGN) score [tables SSIGN score and SSIGN score and survival].

For patients at low risk, follow-up is recommended for five years. Clinical examinations, laboratory tests, and ultrasound examinations are recommended at months 3, 6, 12, 24, 36, 48, and 60. The EAU guideline recommends CT only if symptoms suggest recurrence. The German S3 guideline recommends CT of the chest and abdomen at years 1, 2, and 4.

For patients at intermediate or high risk, follow-up is recommended for nine years. Clinical examinations, laboratory tests, and ultrasound examinations are recommended at months 3, 6, 12, 24, 36, 48, 60, 84, and 108. CT of the chest and abdomen is recommended at years 1, 2, 3, 4, 5, 7, and 9. For patients at high risk, additional chest CT is recommended at months 6 and 18. Bone scintigraphy or whole-body low-dose CT is indicated for bone pain.

Local recurrence:

A local recurrence without evidence of distant metastases should be surgically removed whenever possible. After complete resection, the five-year survival rate is approximately 50 %.

Partial Nephrectomy

Imperative indications:

Partial nephrectomy is imperative when radical nephrectomy would result in renal insufficiency requiring dialysis. If oncologically feasible, partial nephrectomy is strongly indicated for:

• RCC in a solitary kidney
• Compensated renal insufficiency (chronic kidney disease)
• Bilateral tumors
• Familial renal cell carcinoma
• Known conditions that may lead to future renal insufficiency (e.g., diabetes mellitus or renal artery stenosis).

Elective indications:

The German S3 guideline clearly favors partial nephrectomy for localized renal cell carcinoma. If technically feasible, partial nephrectomy should be performed for T1 tumors and may be performed for T2 tumors instead of radical nephrectomy. Retrospective comparisons of radical and partial nephrectomy for T1 tumors found better survival after partial nephrectomy. This may be explained by a reduction in cardiovascular disease associated with better renal function. The randomized EORTC study did not demonstrate a survival benefit (van Poppel et al., 2011).

Surgical technique:

Open partial nephrectomy is performed through a flank or transperitoneal approach. Laparoscopic or robot-assisted partial nephrectomy can be performed transperitoneally or retroperitoneoscopically. After exposure and control of the renal hilar vessels, the tumor is excised with or without temporary ischemia, depending on tumor size, location, complexity, and bleeding risk. A wide safety margin is not required; a macroscopically tumor-free resection margin is essential. Enucleation along the pseudocapsule is oncologically acceptable for tumors with suitable morphology (Minervini et al., 2012). For technical details, see open partial nephrectomy.

Principles of partial nephrectomy: the tumor is resected after vascular control and, if necessary, with renal ischemia. The vessels and collecting system are closed with a running suture. The bulldog clamp is removed from the renal artery. During renorrhaphy, the organ defect is approximated with interrupted sutures and clips, and the sutures are tied over a bolster (e.g., resorbable cellulose or a flap of perinephric fat).

Comparative studies:

Compared with open surgery, minimally invasive procedures reduce postoperative pain, length of hospital stay, and morbidity related to the surgical approach. Compared with conventional laparoscopy, robot-assisted partial nephrectomy facilitates tumor dissection, reconstruction, and suturing, and enables complex partial nephrectomy for central or hilar tumors. Oncological outcomes are comparable with appropriate patient selection. Blood loss, complication rates, and warm ischemia time depend substantially on tumor complexity and surgeon experience (Xia et al., 2017).

Management of bilateral renal cell carcinoma:

The simpler partial nephrectomy is performed first to avoid dialysis due to transient ischemia of a solitary functioning kidney. After full recovery, residual renal function is assessed by renal scintigraphy. If it is sufficient, complex or central contralateral tumors may be treated with radical nephrectomy. If residual function is inadequate, imperative partial nephrectomy should be attempted if technically feasible.

Oncological results:

The randomized EORTC study of 541 patients confirmed the oncological safety of partial nephrectomy for small resectable renal tumors (van Poppel et al., 2011). Tumor progression and cancer-specific mortality were rare in both study arms; a significant overall survival benefit from partial nephrectomy was not demonstrated. Prognosis after partial nephrectomy is determined primarily by tumor stage, tumor size, grade, histologic subtype, and distant metastases (see tables SSIGN score and SSIGN score and survival). Local recurrence is uncommon but is more likely with higher tumor stage, unfavorable tumor biology, and positive surgical margins.

Significance of positive surgical margins:

According to the German S3 guideline, partial nephrectomy may be performed without frozen-section examination if complete macroscopic tumor removal is achieved intraoperatively. Microscopic positive surgical margins primarily increase the risk of local recurrence; their effects on metastatic risk and overall survival are smaller. Prophylactic completion nephrectomy is not recommended for a microscopic R1 resection without imaging evidence of residual tumor. Instead, intensified risk-adapted follow-up is indicated; further local treatment or nephrectomy is performed if local recurrence is confirmed (German S3 guideline).

Follow-up after partial nephrectomy:

After a close-margin or R1 resection, abdominal CT three months after surgery is useful as a baseline for postoperative changes. Follow-up after partial nephrectomy should be based on symptoms and the risk of metastasis. Risk can be estimated using the Stage, Size, Grade, and Necrosis (SSIGN) score [tables SSIGN score and SSIGN score and survival]; see also follow-up recommendations after radical nephrectomy.

Alternative Treatment Options for Localized Small Renal Tumors

Options include active surveillance and thermal ablation, such as cryotherapy, radiofrequency ablation, or microwave ablation. The German S3 guideline recommends tumor biopsy before invasive ablation. Complication rates for ablative procedures are low to moderate and depend substantially on tumor size, location, and technique. Comparative long-term data are unavailable.

Cryotherapy:

Cryotherapy is delivered percutaneously or laparoscopically. Rapid tissue cooling, gradual thawing, and repeated freeze-thaw cycles are essential for cell destruction. The frozen tissue is resorbed and replaced by granulation tissue. Laparoscopic cryotherapy offers several advantages: the mobilized kidney can be cooled more effectively, the risk of injury to adjacent organs is minimized, and the ice ball can be visualized in relation to the tumor margins.

Radiofrequency and microwave ablation:

Peripheral small tumors can be treated with radiofrequency or microwave ablation. Compared with cryotherapy, monitoring the treatment effect is more difficult.

Active surveillance for T1a renal cell carcinoma:

Active surveillance is an option for small renal tumors in older patients with significant comorbidity. For tumors smaller than 3–4 cm, 22–46 % of renal tumors are benign. Among renal cell carcinomas, fewer than 10 % are poorly differentiated [table Renal tumor pathology by tumor size]. Active surveillance should be reconsidered if the primary tumor grows significantly or exceeds 3–4 cm.

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