Renal Cell Carcinoma

Abstract

IMPORTANCE

Renal cell carcinoma (RCC) is a common malignancy, with an estimated 434 840 incident cases worldwide in 2022. In the US, it is the sixth most common cancer among males and ninth among females.

OBSERVATIONS

Clear cell RCC is the most common histologic subtype (75%−80% of cases) and is characterized by inactivation of the von Hippel Lindau (VHL) tumor suppressor gene. Many patients (37%−61%) are diagnosed with RCC incidentally on an abdominal imaging study such as ultrasound or computed tomographic scan, and 70% of patients have stage I RCC at diagnosis. Although its incidence has increased approximately 1% per year from 2015 through 2019, the mortality rate of RCC has declined about 2% per year in the US from 2016 through 2020. Patients with a solid renal mass or complex cystic renal mass should be referred to urology. Treatment options for RCC confined to the kidney include surgical resection with partial or radical nephrectomy, ablative techniques (eg, cryoablation, radiofrequency ablation, radiation), or active surveillance for some patients (especially those with renal masses <2 cm). For patients with renal masses less than 4 cm in size (48% of patients), partial nephrectomy can result in a 5-year cancer-specific survival of more than 94%. For advanced or metastatic RCC, combinations of immune checkpoint inhibitors or the combination of immune checkpoint inhibitors with tyrosine kinase inhibitors are associated with tumor response of 42% to 71%, with a median overall survival of 46 to 56 months.

CONCLUSIONS AND RELEVANCE

RCC is a common malignancy, that is often diagnosed incidentally on an abdominal imaging study. Seventy percent of patients are diagnosed with stage I RCC and 11% of patients with stage IV. First-line treatments for early-stage RCC are partial or radical nephrectomy, which can result in 5-year cancer-specific survival of more than 94%, ablative techniques, or active surveillance. New treatment options for patients with metastatic RCC include immune checkpoint inhibitors and tyrosine kinase inhibitors.

Renal cell carcinoma (RCC) is a common cancer, with an estimated lifetime prevalence of 2.3% for men and 1.3% for women in the US.¹ In 2023, there were an estimated 81 800 newly diagnosed cases of RCC in the US, making it the sixth most common cancer in males and ninth in females.¹ Insights into the molecular pathogenesis of RCC has led to the development of therapies that target its underlying pathophysiology and immunobiology. This review summarizes the epidemiology, clinical presentation, pathophysiology, and management of RCC (Box).

Box. Common Questions About Renal Cell Carcinoma.

How Are Most Renal Cell Carcinomas Identified?

Between 37% and 61% of renal cell carcinomas (RCCs) are identified incidentally. The classic triad of flank pain, a palpable abdominal mass, and hematuria occurs in less than 10% of patients with newly diagnosed RCC. Gross hematuria is reported in less than 25% of patients and occurs more often in advanced disease.

Can Patients With Renal Cell Carcinoma Be Cured?

The chance of cure depends on stage at presentation. For early-stage RCC partial or radical nephrectomy can result in more than a 94% cancer-specific survival. Other viable treatment options for patients with early-stage RCC include active surveillance or ablative therapy. Metastatic RCC is generally not considered curable but long-term treatment-free survival is possible.

What Systemic Treatments Are Available for RCC?

Systemic treatment is effective in patients with metastatic RCC. First-line treatment with combination immune checkpoint inhibition (dual blockade of cytotoxic T-lymphocyte-protein 4 and programmed cell death 1) or immune checkpoint inhibition with a tyrosine kinase inhibitor results in tumor response in approximately half of patients. Adjuvant pembrolizumab should be considered for patients with RCC after nephrectomy.

Methods

A PubMed search was performed using the search terms renal cell carcinoma and kidney cancer to identify clinical trials, systematic reviews, and meta-analyses in English published between January 1, 2013, and January 15, 2024. This search yielded 2469 clinical trials and 1184 meta-analyses or systematic reviews. Articles were selected for inclusion based on study design, study quality, relevance, and sample size. Additionally, cohort or observational studies were selected for inclusion by the authors based on their knowledge of the literature. A total of 89 studies were included, consisting of 6 epidemiological studies, 3 narrative reviews, 6 systematic reviews, 37 cohort studies, 19 clinical trials, 8 guideline, and 10 articles about pathophysiology or genetics.

Epidemiology

Globally, there were 434 840 incident cases of RCC in 2022. RCC is most common in Europe, Oceania, and North America,² potentially in part due to higher incidental detection rates of renal masses on abdominal imaging studies.^3–5 It is the 15th most common cause of cancer-related death worldwide, with more than 179 000 deaths reported in 2020.² Despite the increasing, incidence of about 1% per year from 2015 through 2019, the mortality rate from RCC has declined about 2% per year in the US from 2016 through 2020, partially due to improvements in therapy.

Peak RCC incidence occurs between the ages of 60 and 70 years and is more common in males than females (a ratio of approximately 3:2).⁶ Multiple risk factors associated with it have been identified, and most risk factors have a dose-response relationship with increasing exposure, including systolic hypertension (relative risk [RR], 1.4; 95% CI, 0.9–2.1), diastolic hypertension (RR, 2.3;95% CI, 1.2–4.4), smoking (RR, 1.6; 95% CI, 1.3–1.9), kidney disease (RRs or up to, 12.3 for patients undergoing dialysis;95% CI, 8.4–17.1), and environmental exposures such as heavy metals and industrial solvents (the RR varies by exposure length and agent).^7–10 More than 16% of cases worldwide are associated with obesity (RR, 1.9; 95% CI, 1.3–2.7), although patients with obesity are less likely to present with an advanced stage than are patients with normal weight (odds ratio [OR], 0.61; 95% CI, 0.49–0.79).^11,12 RCC is also associated with several hereditary cancer syndromes (described below).

Subtypes and Genetics of RCC

RCC arises from epithelial cells of the renal cortex. The diagnosis is primarily determined by histological review with the assessment of morphology and immunohistochemistry. Immunohistochemical markers suggestive of RCC include presence of the renal lineage marker paired box protein 8 (PAX8) and carbonic anhydrase IX, a transmembrane protein specific for clear cell RCC.¹³

Elucidation of the molecular underpinnings of RCC has led to the identification of a group of molecularly defined RCCs based on specific genomic alterations that cannot be diagnosed morphologically. For example, the earlier morphological subdivision of papillary RCC into types 1 and 2 are now molecularly classified into papillary RCC and classified RCCs such as fumarate hydratase-deficient RCC or hereditary leiomyomatosis and RCC syndrome–associated RCC. There are now more than 20 subtypes of malignant renal cell tumors recognized by the World Health Organization (WHO) classification system.¹⁴

The 3 dominant histological subtypes are clear cell (75%−80%), papillary (10%−15%), and chromophobe (5%).¹⁵ Clear cell RCC is named for its golden yellow clear cytoplasm.¹⁵ Loss of the von Hippel Lindau (VHL) tumor suppressor gene occurs in up to 90% of clear cell RCC tumors, with VHL inactivation leading to activation of hypoxia and angiogenesis pathways.¹⁶ VHL inactivation results in highly vascular tumors with a high risk of bleeding. VHL inactivation usually occurs through a combination of a deleterious mutation and loss of a portion of chromosome 3p, home to VHL, as well as several other commonly mutated genes (Figure 1A). The VHL gene is part of a complex that marks subunits of a hypoxia-inducible factor (HIF) family of transcription factors (HIF1α, HIF2α, and HIF3α) for degradation.¹⁷ This oxygen-dependent interaction between the VHL protein and HIFα is the primary mechanism by which mammalian cells sense oxygen and respond to hypoxia (Figure 1B).^18–20

Figure 1.

Need title

A, Chromosome 3p is a key genomic locus that is deleted in clear cell renal cell carcinoma (RCC) and contains key tumor suppressor genes. B, Regulation of the hypoxia response through the VHL-HIFα pathway. The biochemical interaction between the VHL protein (pVHL) complex and HIFα subunits are governed by the hydroxylation of HIFα subunits by a family of oxygen-dependent HIF prolyl hydroxylases (PHDs). In normoxic conditions, PHDs hydroxylate HIFα facilitate their binding to pVHL and target the HIFα subunits for degradation.¹⁷ In contrast, under hypoxia, or in the case of VHL inactivation, HIFα subunits stabilize and heterodimerize with the aryl hydrocarbon receptor nuclear translocator s protein (ARNT, also known as HIF1β) and act as a transcription factor for hypoxia-responsive genes, thereby increasing glycolysis-promoting angiogenesis via upregulation of vascular endothelial growth factor A (VEGFA), and increasing cellular growth through upregulation of platelet-derived growth factor (PDGF) and transforming growth factor (TGFα).¹⁶ C, Clear cell RCC therapeutic targets and mechanism of action.

CCND1, cyclin D1; CTLA4, cytotoxic T-lymphocyte–protein 4; CUL2, Cullin 2; EPO, erythropoietin; rbx1, ring-box 1; mTORC1, mammalian target of rapamycin 1; PD-1, programmed cell death 1; PD-L1, PD ligand 1; TCR, T-cell receptor.

Hereditary Renal Cancer Syndromes

Although most cases of RCC are sporadic, approximately 5% to 16% of stage III or IV cases are secondary to hereditary renal cancer syndromes.²¹ An inherited predisposition should be considered for patients with an RCC diagnosed before age 50 years, bilateral RCC, or multiple tumors in one kidney. Numerous hereditary renal cancer syndromes exist including VHL disease (2% of all cases), hereditary leiomyomatosis and RCC syndrome, hereditary papillary renal cell carcinoma syndrome, and Burt Hogg Dubé syndrome.²² Other hereditary cancer syndromes are associated with RCC, including hereditary paraganglioma-pheochromocytoma syndrome (secondary to germline mutations in succinate dehydrogenase [SDH] sub-unit genes SDHB, SDHC, SDHD). Recognition of these syndromes suggests the need for screening for other associated cancers, and consideration of genetic counseling of family members.

Clinical Presentation

The classic triad of flank pain, a palpable abdominal mass, and hematuria occurs in less than 10% of patients with newly diagnosed RCC.²³ Because the retroperitoneal space can accommodate substantial tumor growth prior to symptom onset, only large RCCs are detected by palpation. Currently, the widespread use of abdominal imaging leads to incidental RCC detection in 37% to 61% of cases.^3–5 With increased incidental detection, gross hematuria is currently reported in less than 25% of patients and occurs more often in advanced disease.^3,5 Approximately 1.3% of patients with gross hematuria are diagnosed with RCC.²⁴

Paraneoplastic Syndromes

Paraneoplastic syndromes occur in 10% to 40% of patients with RCC and are not consistently associated with higher stage or grade across studies.²⁵ Common paraneoplastic manifestations include fever (8%) hypercalcemia (1%−30%), anemia (22%−52%), thrombocytosis (8%−12%), erythrocytosis (2%−4%), and hypertension (3%−18%).^3,26–28 Paraneoplastic erythrocytosis is associated with elevated erythropoietin levels, which is produced by RCC tumor cells upon VHL inactivation.¹⁶ Stauffer syndrome, a paraneoplastic syndrome first described in 1961, is characterized by elevated liver enzymes in approximately 3% of patients with RCC; hepatosplenomegaly without liver metastases can also occur with this syndrome.^26,27 Paraneoplastic syndromes may resolve in up to 52% of patients after nephrectomy or systemic treatment of RCC,^26,28,29 and persistence of paraneoplastic symptoms after nephrectomy may indicate residual disease.

Radiological Considerations

A proposed algorithm, adapted from the American College of Radiology guidelines for workup of an incidental renal mass is presented in Figure 2.³⁰ Multiphase cross-sectional computed tomographic (CT) imaging or magnetic resonance imaging (MRI) using contrast is recommended to evaluate a renal mass that is detected by ultrasound or found incidentally on CT or MRI performed for other indications. A CT renal mass protocol (sensitivity 88%, specificity 75%) differs from a standard contrasted CT scan of the abdomen in that contrasted images are captured at an early arterial phase that optimally visualizes the renal parenchyma.³¹ RCC characteristically appears on CT scans as a solid or cystic mass, possibly with heterogeneous features such as calcifications (20%); the hypervascular clear cell RCC typically enhances after contrast administration.³²

Figure 2.

Algorithm for Evaluation of a Renal Mass

Compared with a CT scan, an MRI of the abdomen (sensitivity 80%−88%, specificity 89%−90%) has improved the ability to detect venous involvement, including identification of tumor thrombus in the main renal vein and inferior vena cava, which can aid surgical planning.^32,33

Staging and Grading of RCC

At the time of diagnosis, 70% are stage I RCC, and 11% are stage IV (Table 1).^34–36 The prognosis is associated with stage (size of tumor, spread to lymph nodes, and metastases; see Table 1) and grade.³⁷ Grade is a measure of histological tumor aggressiveness. The World Health Organization (WHO) and International Society of Urologic Pathology’s 4-level grading system is widely used and correlates more reliably with prognosis in clear cell and papillary RCC compared with the formerly used Fuhrman grading system.³⁸

Table 1.

Overview of Stage Definitions and Prognosis of Renal Cell Carcinoma

Stage	Extent of Disease	Diagnosis, %34	Typical treatment	5-Year cancer-specific survival, %34–36
I	≤7 cm, limited to kidney	70	Surgery	94–97
II	>7 cm tumor, limited to kidney	11	Surgery	90
III	Extends to perinephric tissues or major veins or involves regional lymph node	8	Surgery	63–78
IV	Extends to beyond Gerota fascia (including into ipsilateral adrenal) or distant metastases	11	Systemic therapy	27–28

Metastatic Sites

Metastatic disease (M1) occurs in approximately 10% of patients with newly diagnosed RCC and an additional 10% of patients with localized RCC will develop metastatic disease at a later time.³⁹ The most common sites of RCC metastases are lung (70%), lymph node (45%), bone (32%), liver (18%), adrenal gland (10%), and brain (8%).⁴⁰ RCC also metastasizes to atypical sites such as thyroid, pancreas, breast, skin, and muscle.^40,41

Treatment of Localized RCC

Surgery with partial or radical nephrectomy is the preferred treatment for RCC confined to the kidney. Other treatment options can include active surveillance and ablative techniques, depending on patient comorbidities and patient preferences.

Partial and Radical Nephrectomy

Radical nephrectomy includes resection of the kidney and perirenal fat, and sometimes includes resection of the ipsilateral adrenal gland and a regional lymph node dissection. Partial nephrectomy is a nephron-sparing approach that involves tumor resection and preservation of the remaining noncancerous portion of the kidney. Both radical and partial nephrectomies can be performed using open laparoscopic or robotic surgical techniques. In general, oncological outcomes are similar with partial nephrectomy compared with radical nephrectomy in patients with T1 (≤7 cm) RCC and therefore partial nephrectomy is preferred in these cases.⁴² In a retrospective cohort study of 662 patients with RCC undergoing partial or radical nephrectomy, partial nephrectomy was associated with decreased risk of chronic kidney disease (80% probability of freedom from estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m² vs 35% at the 3-year follow-up, P < .001).⁴³ For larger tumors, partial nephrectomy with open, laparoscopic, or robotic assistance may be possible depending on tumor location and complexity.⁴⁴ Radical nephrectomy is preferred for tumors with extension to the inferior vena cava.⁴²

Small Renal Masses

Up to 20% of small renal masses (≤4 cm) are misclassified radiographically as malignant and are pathologically benign.⁴⁵ For patients who undergo surgery for small renal masses, partial nephrectomy is preferred and has a 5-year cancer-specific survival of 94% to 97%. Alternatively, some patients with small renal masses may undergo active surveillance, defined as initial monitoring of tumors with serial ultrasound or abdominal CT scans (3 months, 6 months; every 6 months for up to 3 years; followed by annual surveillance), with ablation or nephrectomy recommended with growth of the tumor. In studies of active surveillance, the average tumor growth rate is 0.56 cm per year. Pathological examination of the tumor for individuals who undergo delayed nephrectomy after active surveillance is no more likely to result in upstaging than those who undergo nephrectomy soon after diagnosis.⁴⁶ Active surveillance is most commonly recommended for patients with substantial comorbidities and limited life expectancy.^39,47 Renal mass biopsy performed with imaging guidance (ultrasound or CT) is increasingly used for risk stratification of patients with small renal masses less than 3 cm, those with a cystic component, or those with higher surgical risk.^48–50 There is no increased risk of tumor upstaging (OR, 0.90; 95% CI, 0.6–1.34) or cancer recurrence (OR, 1.04; 95% CI, 0.57–1.89) in patients who undergo renal mass biopsy compared with those who do not.⁵⁰ A systematic review that included 20 studies with 2979 patients and 3113 biopsies reported a nondiagnostic biopsy in 14% of cases, hematoma in 5%, and clinically significant pain in 1%.⁵¹

Ablative techniques such as cryotherapy or radiofrequency ablation are alternatives to surgical resection and are most commonly used for patients with comorbidities and high surgical risk who have tumors less than 3 cm. Ablation can be performed with or without (in cases with imaging characteristics highly suspicious of RCC) an antecedent renal mass biopsy. Risks of ablative techniques include bleeding (2%−4%), ureteral injury (2%), urine leak (0%−4%), and urinary tract infection (2%).⁵² Stereotactic body radiotherapy is an ablative therapy that is increasingly used for patients who are not candidates for surgery with stage I through III RCC. An individual patient data meta-analysis reported 5-year outcomes of 199 patients who underwent stereotactic ablative body radiotherapy for primary RCC.⁵³ The local relapse rate was 5.5%, eGFR decreased by 14 mL/min per 1.73 m², and adverse events included fatigue (27%), nausea (13%), and chest wall pain (6%).^53,54

Large Renal Masses

Biopsy is not required prior to surgical resection of larger renal tumors (>4 cm) with radiological findings consistent with RCC. However, biopsy should be considered for certain tumors such as those involving the renal sinus to rule out urothelial carcinoma or lymphoma. Many patients with large kidney tumors are cured after surgical resection with cancer-specific survival rates of 90% for stage II and 63% to 78% for stage III RCC at 5 years.^34–36 Among patients who relapse after nephrectomy, most relapses (74%) occur within 5 years of surgery yetvery late (>10 years) recurrences are possible.⁵⁵ The presence and extent of inferior vena cava tumor thrombus increases surgical complexity, often requires assistance of a cardiovascular surgeon, and has a surgery-related mortality of up to 10%.^42,56 A study of 87 patients who underwent surgery for RCC reported that those with a level I tumor thrombus (involving the inferior vena cava at the level of the renal vein) had a 5-year disease-specific survival of 71% compared with 35% for patients with a level IV tumor thrombus (involving the suprahepatic inferior vena cava or right atrium).⁵⁷ Ablative techniques are not currently recommended for stage T1b or higher, based on a lack of long-term high-quality studies and possible decreased cancer-specific mortality in 242 patients who had undergone ablative therapy compared with 5521 patients who had undergone partial nephrectomy in a Surveillance, Epidemiology, and End Results–matched cohort study (HR for death, 2.50; 95% CI, 1.08–5.63; P = .03).⁵⁸

Systemic Therapy in Localized RCC after Nephrectomy

Systemic therapy is currently used as adjuvant therapy after nephrectomy for localized RCC. The immune checkpoint inhibitor pembrolizumab ( Figure 1C) demonstrated a disease-free and overall survival benefit for patients with intermediate- and high-risk clear cell RCC. In the KEYNOTE-564 study,^59,60 994 patients were randomized to 1 year of pembrolizumab or placebo. The estimated proportion who remained alive and recurrence free 30 months after undergoing nephrectomy was 77% (95% CI, 73%−81%) in the pembrolizumab group vs 68% (95% CI, 64%−72%) in the placebo group (HR, 0.72; 95% CI, 0.59–0.87). In contrast, the randomized clinical trials of perioperative nivolumab and atezolizumab did not show a recurrence-free survival benefit, suggesting that the response to pembrolizumab may not be a class effect of all immune checkpoint inhibitors.^61–63 The overall survival benefit of pembrolizumab compared with placebo was the first report of a systemic adjuvant therapy improving survival in localized RCC and represents a new standard option for adjuvant treatment of intermediate- and high-risk localized clear cell RCC.⁶⁰

Management of VHL Disease–Associated RCC

Patients with RCC and VHL disease often have indolent, bilateral, and multifocal tumors. Typically, small RCCs in VHL disease are monitored with serial ultrasound or MRI imaging every 3 to 6 months until they reach 3 cm, at which point they are treated with partial nephrectomy or ablative therapy, whenever possible. This conservative approach to delay nephrectomy in patients with VHL disease is undertaken to decrease the lifetime risk of chronic kidney disease given the high likelihood of future development of RCCs.

In 2021, the oral medication, belzutifan, was approved for use in patients with clear cell RCC specifically associated with VHL disease. Belzutifan is a small molecule inhibitor of HIF2α, a key driver of VHL-associated RCC (Figure 1C).⁶⁴ The phase 2 study of belzutifan included 61 patients with VHL disease and at least 1 clear cell RCC of 1 cm or more. The objective response rate (defined as a reduction in maximal tumor diameter of at least 30%) was 59% in RCC tumors, 38% in central nervous system hemangioblastomas, and 90% in pancreatic neuroendocrine tumors.^65,66 The 2-year follow-up demonstrated durable responses, a decreased number of VHL-related surgeries (resection or ablation of RCC, central nervous system hemangioblastomas), and associated complications (chronic kidney disease, pancreatic insufficiency, neurological deficit) in patients with VHL disease treated with belzutifan.⁶⁷

Management of Advanced and Metastatic RCC

Risk Stratification

The International Metastatic RCC Database Consortium (IMDC) identified 6 independent risk factors associated with lower survival: neutrophil count higher than upper limit of normal, hemoglobin below lower limit of normal, platelet count higher than upper limit of normal, calcium higher than upper limit of normal, Karnofsky performance status less than 80%, and time less than 1 year from diagnosis to systemic therapy.⁶⁸ Among 645 patients with metastatic RCC, overall median survival was 22 months (95% CI, 20.2–26.5 months), with a 2-year overall survival rate of 75% for favorable risk (0 risk factors), 53% for intermediate risk (1–2 risk factors), and 7% for poor risk (≥3 risk factors).⁶⁹ An updated study from 2023 reported that 728 patients with metastatic RCC treated with modern systemic combination therapies including dual immune checkpoint inhibitors or an immune checkpoint inhibitor combined with a tyrosine kinase inhibitor had an 18-month overall survival of 90% to 93% for patients with a favorable risk, 78% to 83% with an intermediate risk, and 50% to 74% with a poor risk.⁶⁸ These survival rates are markedly improved compared with survival prior to use of immune checkpoint therapies, but longer-term population-level survival rates reflecting outcomes of modern therapy are awaited.

Systemic Therapy

Cytotoxic chemotherapy used for many other types of cancers is generally not effective in metastatic RCC. Systemic therapy for metastatic RCC instead includes immunotherapy and targeted therapy including tyrosine kinase inhibitors that impair angiogenesis and block vascular endothelial growth factor (VEGF) receptor–cell signaling pathways (Figure 1C). Current immunotherapies include antibodies that bind to and block the interaction between programmed cell death 1 (PD-1) (expressed on activated T cells) and programmed cell death ligand 1 (PD-L1) and PD-L2 (expressed on tumor cells and antigen-presenting cells, as well as the cytotoxic T-lymphocyte–protein 4 (CTLA4; expressed on T cells) interaction with CD80 and CD86 on antigen-presenting cells (see Figure 1C). Immune checkpoint inhibitors can restore the effectiveness of CD8 cytotoxic T cells against RCC, causing an antitumor immune response, even in widespread RCC.

In the setting of metastatic RCC, long-term treatment-free survival remains elusive for most patients but is possible with a complete response to immunotherapy-based systemic therapy or in the setting of oligometastatic disease when surgical resection or ablation of metastases can render a patient disease free. In such cases, patients may have a disease-free survival of approximately 22% to 27% at 3 years.⁷⁰ Follow-up of patients treated with the original cytokine-based immunotherapy high-dose interleukin 2 showed a complete response in 5% of patients. Of these, 59% remained alive and cancer free without subsequent therapy after a median follow-up of 10.5 years, suggesting long-term cure.^71,72 First-line treatment of advanced and metastatic RCC is currently immune checkpoint inhibitor–based combination therapy, either with 2 immune checkpoint inhibitors or with 1 immune checkpoint inhibitor combined with a tyrosine kinase inhibitor (Figure 1C). However, resection of metastatic lesions, imaging surveillance, and single-agent therapy with an immune checkpoint inhibitor or a tyrosine kinase inhibitor remain appropriate for carefully selected patients with metastatic RCC, such as those with favorable-risk disease, limited metastatic disease, or comorbidities that preclude combination therapy, such as baseline autoimmune disease or uncontrolled hypertension. Multiple combination therapies have demonstrated improved overall survival compared with the prior standard therapy of the single-agent tyrosine kinase inhibitor sunitinib (previously shown to prolong survival over placebo), including ipilimumab plus nivolumab, nivolumab plus cabozantinib, and pembrolizumab plus either lenvatinib or axitinib.

The dual-immune checkpoint inhibitors combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) is approved by the US Food and Drug Administration (FDA) as first-line treatment for patients with intermediate or poor-risk metastatic clear cell RCC. In these patients, this regimen had an objective response rate of 42% and improved overall survival compared with sunitinib in patients with intermediate- and poor-risk RCC (HR, 0.69; 95% CI, 0.59–0.81).^73,74 The 5-year overall survival probability was 43% (compared with 31% with sunitinib). With ipilimumab plus nivolumab, the complete response rate was 10% and 58% of patients with a response remained progression-free at 5 years.^75,76 The use of ipilimumab and nivolumab for patients with favorable-risk metastatic RCC remains controversial because response rates are lower with ipilimumab plus nivolumab than with sunitinib (30% vs 52%), but complete response rates are higher (12% vs 7%) and long-term survival was similar (5-year overall survival 63% vs 55%; HR, 0.82; 95% CI, 0.60–1.13).^73,74

Another option for patients with metastatic RCC regardless of the IMDC risk group is combination therapy with PD-1 axis blockade plus VEGF–receptor tyrosine kinase inhibitors (Figure 1C). These regimens have a higher objective response rate than ipilimumab plus nivolumab, exceeding 55% to 71% in most studies, although the regimens have not been directly compared.^77–79 Immune checkpoint inhibitor therapy plus tyrosine kinase inhibitor combinations can result in high response rates (eg, 55% in the CheckMate 9ER trial⁷⁸ using combination cabozantinib with nivolumab), rapid disease control (median time to response, 2.8 months) and symptom palliation in many patients.⁸⁰ However, most patients experience adverse effects with tyrosine kinase inhibitor therapy such as hypertension and diarrhea (Table 2). Ultimately, treatment decisions for metastatic RCC should be individualized and should consider disease-related symptoms, comorbidities such as autoimmune disease or uncontrolled hypertension, and patient-risk tolerance given the higher rate of adverse events in combination regimens. Up to 43% of patients with metastatic RCC are not treated with systemic therapy,⁸¹ often because they are considered unlikely to derive benefit or tolerate the adverse effects of these medications. In addition, the high cost of immune checkpoint inhibitors and tyrosine kinase inhibitors and their availability remain an issue globally.⁸²

Table 2.

Renal Cell Carcinoma Drugs With Common Adverse Events

Category	Drugs	Target or mechanism	Route	Selected adverse events within drug class (≥20%, any grade)a
Antiangiogenesis	Axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, sunitinib, tivozanib	Multikinase inhibitors including VEGF receptor	Oral	Hypertension, fatigue, hand foot syndrome, diarrhea, nausea, hypothyroidism, myelosuppression, stomatitis, proteinuria
	Bevacizumab	Antibody to VEGF	IV
	Belzutifan	Hypoxia inducible factor 2α inhibitor	Oral	Anemia, fatigue, headache, dizziness, nausea, peripheral edema, arthralgia, hypoxia
Immune checkpoint inhibitors	Avelumab, nivolumab, pembrolizumab	Anti-programmed cell death protein	IV	Fatigue, rash, pruritus, colitis, endocrinopathy, arthralgia
	Ipilimumab	Anti-cytotoxic T lymphocyte-associated protein 4;	IV
mTOR inhibitors	Everolimus	mTOR	Oral	Hyperglycemia, hyperlipidemia, stomatitis, diarrhea, fatigue, edema, rash, anemia, thrombocytopenia
	Temsirolimus	mTOR	IV
Other	High-dose interleukin 2	Cytokine or immunotherapy	IV	Capillary leak syndrome, fever, hypotension, nausea and vomiting, acute kidney injury, arrhythmias, flu-like symptoms, flushing

Abbreviations: VEGF, vascular endothelial growth factor; IV, intravenous; mTOR, mammalian target of rapamycin.

^aThese medications may have high rates of adverse events, with individual variability in the frequency of cardiovascular, dermatologic, endocrine and metabolic, gastrointestinal, hematologic, hepatic, neuromuscular, renal, and respiratory adverse events. Selected adverse events that can occur in 20% or more of treated persons are shown (for rates of individual medications, see LexiComp, UpToDate Lexidrug, https://www.uptodate.com/contents/table-of-contents/drug-information, Last accessed May 4, 2024).

Cytoreductive Nephrectomy

Cytoreductive nephrectomy (the removal of a primary renal tumor in the setting of distant metastases) is no longer recommended for most patients with advanced or metastatic RCC based on results from the CARMENA⁸³ study. This trial of 450 patients with metastatic clear cell RCC found that the overall survival with systemic therapy alone (sunitinib) was not inferior to cytoreductive nephrectomy followed by sunitinib (stratified HR for death, 0.89; 95% CI, 0.71–1.10; upper bound of 95% CI for noninferiority ≤1.20) with median overall survival of 18 months for sunitinib alone and 13.9 months in the nephrectomy plus sunitinib group.⁸³ This study was performed before FDA approval and widespread use of immune checkpoint inhibitors in RCC. Therefore, cytoreductive nephrectomy maystill have a role in selected patients, such as those with good-risk disease, limited burden of metastatic disease outside of the kidney, or responsive to systemic therapy.

Systemic Toxicity

Patients with RCC who are being treated with systemic therapy benefit from a multidisciplinary team that can help manage potential immune–related adverse events that include but are not limited to cardiovascular, dermatologic, gastrointestinal, hematologic, endocrinologic, hepatic, and renal adverse events (Table 2). For example, in the Checkmate 214 trial, which randomized 1096 patients with advanced RCC to ipilimumab plus nivolumab or sunitinib, 27% had diarrhea that was related to treatment.⁸⁰ Immunosuppression, typically with corticosteroids, can halt or reverse the immune–related adverse event, and early recognition or consultation with oncology is recommended.⁸⁴ Patients treated with VEGF–receptor tyrosine kinase inhibitors have more predictable and less severe adverse events. For example, hypertension associated with VEGF–receptor tyrosine kinase inhibitors occurs in 35% to 55% of patients with RCC taking these medications.^77–79 Table 2 summarizes common adverse events of FDA-approved drugs for RCC (see also LexiComp, UpToDate Lexidrug, https://www.uptodate.com/contents/table-of-contents/drug-information, Last accessed May 4, 2024).

Predictive Biomarkers of Response

Clinically useful biomarkers of treatment response to guide RCC therapy have not been identified and next-generation sequencing of DNA or RNA rarely informs treatment selection. Lack of a predictive biomarker is consistent with the fact that the genomic profile of clear cell RCC primarily consists of tumor suppressor gene loss instead of oncogene activation. Although clear cell RCC has only a low to moderate number of mutations, it is one of the more immunotherapy-responsive cancers. Multiple studies have reported molecular subtypes within clear cell RCC based on gene expression profiling of angiogenesis and inflammatory gene signatures that have been retrospectively shown to be associated with progression-free survival with use of immune checkpoint inhibition or angiogenesis inhibitors.⁸⁵ However, these gene expression profiling subclassifications of RCC have not been validated prospectively for clinical use.

Limitations

This review has several limitations. First, it is not a systematic review and the quality of included literature was not formally evaluated. Second, relevant articles may have been missed. Third, long-term survival data for immune checkpoint therapies are not currently available. Fourth, the use of predictive biomarkers requires prospective validation.

Conclusions

RCC is a common malignancy, that is often diagnosed incidentally on an abdominal imaging study. At diagnosis, RCC is stage I in 70% of patients and stage IV in 11% of patients. Preferred treatments for early-stage RCC are partial or radical nephrectomy, which can result in 5-year cancer-specific survival of more than 94%; ablative techniques; or active surveillance. New treatment options for patients with metastatic RCC include immune checkpoint inhibitors and tyrosine kinase inhibitors.