Kidney cancer accounts for approximately 3–4% of all adult cancers, with an estimated 81,000 new cases diagnosed annually in the United States. The kidneys filter blood, remove waste, and produce urine. Cancer can develop in the kidney tissues, the renal pelvis, or the ureter lining. Over the past two decades, significant advances in targeted therapy and immunotherapy have substantially improved outcomes, even for patients with metastatic disease.
Early-stage kidney cancer is often curable with surgery alone, while advanced kidney cancer now benefits from multiple lines of systemic therapy that have extended median survival from approximately 12 months to well over 3 years in many patients.
Types of Kidney Cancer
Renal Cell Carcinoma (RCC)
Renal cell carcinoma is the most common form of kidney cancer, representing about 85% of all kidney malignancies. RCC originates in the lining of the proximal convoluted tubule within the kidney. Several subtypes exist, each with distinct genetic characteristics and prognoses:
- Clear cell RCC — The most common subtype (70–80% of RCC cases). Often associated with VHL gene mutations. Generally responds well to targeted therapy and immunotherapy.
- Papillary RCC — Accounts for 10–15% of cases. Divided into Type 1 (better prognosis) and Type 2 (more aggressive). Associated with MET and fumarate hydratase gene alterations.
- Chromophobe RCC — Represents approximately 5% of cases. Generally carries a more favorable prognosis than clear cell or papillary subtypes.
- Collecting duct carcinoma — A rare and aggressive subtype accounting for less than 1% of RCC cases.
Transitional Cell Carcinoma (Urothelial Carcinoma of the Renal Pelvis)
Transitional cell carcinoma (TCC) of the renal pelvis accounts for 5–10% of kidney cancers. This cancer develops in the urothelial cells lining the renal pelvis and is biologically similar to bladder cancer. Risk factors include smoking, occupational chemical exposure, and chronic analgesic use. Treatment typically involves nephroureterectomy (removal of the kidney and entire ureter) and may include cisplatin-based chemotherapy.
Wilms Tumor (Nephroblastoma)
Wilms tumor is the most common kidney cancer in children, typically diagnosed between ages 3 and 4. It accounts for about 5% of all childhood cancers. Treatment outcomes are excellent, with overall survival rates exceeding 90% through a combination of surgery, chemotherapy (vincristine, actinomycin D, doxorubicin), and sometimes radiation therapy. The Children's Oncology Group (COG) protocols guide treatment based on tumor histology (favorable vs. anaplastic) and staging.
Risk Factors
- Smoking — Doubles the risk of kidney cancer. Responsible for approximately 20–30% of cases in men and 10–20% in women.
- Obesity — Excess body weight increases risk through hormonal changes (elevated estrogen and insulin levels).
- Hypertension — High blood pressure independently increases kidney cancer risk.
- Family history — First-degree relatives of kidney cancer patients face a 2–4 fold increased risk.
- Inherited syndromes — Von Hippel-Lindau (VHL) disease, hereditary papillary RCC, Birt-Hogg-Dubé syndrome, and hereditary leiomyomatosis and RCC (HLRCC).
- Chronic kidney disease — Patients on long-term dialysis face increased risk due to acquired cystic kidney disease.
- Occupational exposures — Trichloroethylene and other industrial solvents.
Staging and Diagnosis
Kidney cancer is staged using the TNM system. Diagnosis typically begins with imaging (CT scan with contrast or MRI) and may not always require biopsy before surgery, as imaging characteristics are often sufficient to guide treatment decisions.
| Stage | Description | 5-Year Survival |
|---|---|---|
| Stage I | Tumor ≤7 cm, confined to the kidney | ~93% |
| Stage II | Tumor >7 cm, confined to the kidney | ~70–75% |
| Stage III | Tumor extends into major veins, adrenal gland, or perinephric tissue; or 1 regional lymph node involved | ~53–60% |
| Stage IV | Tumor invades beyond Gerota's fascia, or distant metastases present | ~8–15% |
Surgical Treatment
Partial Nephrectomy (Nephron-Sparing Surgery)
Partial nephrectomy removes only the tumor and a margin of healthy tissue, preserving the remaining kidney function. It is the preferred approach for tumors ≤7 cm (T1 tumors) whenever technically feasible. Studies show equivalent cancer control to radical nephrectomy for appropriately selected patients, with the added benefit of preserving renal function and reducing long-term cardiovascular risk.
Partial nephrectomy can be performed via open surgery, laparoscopic surgery, or robot-assisted laparoscopic surgery. The robotic approach has gained widespread adoption due to improved visualization, reduced blood loss, and shorter hospital stays.
Radical Nephrectomy
Radical nephrectomy involves removal of the entire kidney, surrounding fat, Gerota's fascia, and sometimes the ipsilateral adrenal gland. It is indicated for large tumors (typically >7 cm), tumors with venous extension into the renal vein or inferior vena cava, and locally advanced disease. Minimally invasive (laparoscopic or robotic) approaches are standard when feasible.
Ablative Therapies
For patients who are poor surgical candidates or have small tumors (≤3–4 cm), ablative therapies offer a less invasive alternative:
- Cryoablation — Uses extreme cold (argon gas) delivered through a probe to freeze and destroy tumor tissue. Can be performed percutaneously or laparoscopically.
- Radiofrequency ablation (RFA) — Uses high-frequency electrical current to heat and destroy cancer cells. Typically performed percutaneously under CT guidance.
- Microwave ablation — An emerging technique using microwave energy to generate heat, with potential advantages in treating larger tumors compared to RFA.
Ablation is associated with slightly higher local recurrence rates compared to surgery but offers an important treatment option for elderly patients or those with significant comorbidities.
Targeted Therapy for Advanced Kidney Cancer
Targeted therapies have revolutionized the treatment of advanced and metastatic RCC. These drugs target specific molecular pathways critical to cancer growth, particularly the VEGF (vascular endothelial growth factor) and mTOR (mammalian target of rapamycin) signaling pathways.
VEGF-Targeted Agents (Tyrosine Kinase Inhibitors)
- Sunitinib (Sutent) — A multi-targeted TKI that inhibits VEGFR, PDGFR, and KIT. Long established as a standard first-line therapy for clear cell RCC, demonstrating median progression-free survival of approximately 11 months.
- Pazopanib (Votrient) — An oral TKI with a side effect profile that some patients tolerate better than sunitinib. The COMPARZ trial demonstrated non-inferiority to sunitinib in first-line treatment.
- Cabozantinib (Cabometyx) — Inhibits VEGFR, MET, and AXL. Used in both first-line (in combination with nivolumab) and subsequent-line settings. The METEOR trial showed improved PFS and OS compared to everolimus after prior anti-VEGF therapy.
- Axitinib (Inlyta) — A potent VEGFR inhibitor commonly used in combination with immune checkpoint inhibitors in the first-line setting.
- Lenvatinib — Used in combination with pembrolizumab or everolimus. The CLEAR trial demonstrated superior outcomes with lenvatinib plus pembrolizumab compared to sunitinib.
mTOR Inhibitors
- Everolimus (Afinitor) — An oral mTOR inhibitor used after failure of VEGF-targeted therapy. The RECORD-1 trial demonstrated improved PFS compared to placebo.
- Temsirolimus (Torisel) — An intravenous mTOR inhibitor that showed survival benefit in poor-risk patients in the Global ARCC trial.
Immunotherapy
Immune checkpoint inhibitors have transformed the treatment landscape for advanced RCC and are now part of standard first-line combination regimens:
- Nivolumab (Opdivo) — A PD-1 checkpoint inhibitor. The CheckMate 025 trial established nivolumab as superior to everolimus in previously treated RCC patients, with improved overall survival and fewer side effects.
- Ipilimumab (Yervoy) — A CTLA-4 checkpoint inhibitor used in combination with nivolumab. The CheckMate 214 trial showed the nivolumab plus ipilimumab combination significantly improved overall survival compared to sunitinib in intermediate- and poor-risk patients, with 5-year OS rates of approximately 43%.
- Pembrolizumab (Keytruda) — A PD-1 inhibitor used in combination with axitinib or lenvatinib as first-line treatment.
Current First-Line Treatment Recommendations
For patients with advanced or metastatic clear cell RCC, the NCCN guidelines recommend the following preferred first-line regimens based on IMDC risk category:
| Risk Category | Preferred Regimens |
|---|---|
| Favorable risk | Pembrolizumab + axitinib; Pembrolizumab + lenvatinib; Cabozantinib + nivolumab |
| Intermediate/Poor risk | Nivolumab + ipilimumab; Pembrolizumab + axitinib; Pembrolizumab + lenvatinib; Cabozantinib + nivolumab |
Active Surveillance
Active surveillance (watchful waiting with serial imaging) is an appropriate option for small renal masses (≤2–3 cm) in elderly patients or those with significant comorbidities. Studies show that most small renal masses grow slowly (average growth rate of 2–3 mm per year), and delayed intervention does not compromise oncologic outcomes in carefully selected patients.
Follow-Up and Survivorship
After treatment, patients require regular follow-up including imaging surveillance (CT or MRI), blood tests (renal function, complete blood count), and monitoring for treatment side effects. The frequency and duration of surveillance depend on the initial stage and treatment received:
- Low-risk (T1) — Imaging every 6–12 months for the first 3 years, then annually for at least 5 years.
- Intermediate-risk (T2–T3) — Imaging every 3–6 months for the first 3 years, then every 6–12 months through year 5, then annually.
- High-risk (T4 or metastatic) — Imaging every 3–6 months for at least 5 years.
Kidney cancer survivors should maintain a healthy weight, manage blood pressure, avoid smoking, and have regular renal function monitoring, particularly if they have undergone radical nephrectomy.