Non-renal cell carcinoma of the kidney represents a diverse group of cancers that behave differently from the more common clear cell type, requiring specialized approaches to treatment and care that are continually evolving through clinical research.

Understanding Treatment Goals for Non-Clear Cell Kidney Cancer

When someone receives a diagnosis of non-renal cell carcinoma of the kidney, the path forward depends on many individual factors. Treatment aims to control symptoms, slow down how fast the cancer grows, and help people maintain the best possible quality of life. The approach doctors choose depends heavily on the specific type of non-clear cell cancer, how far it has spread, and the overall health of the patient.^[2]

Unlike clear cell kidney cancer, which accounts for about 75% to 80% of all kidney cancers, non-clear cell types make up roughly 20% to 25% of cases. This group includes several distinct subtypes such as papillary renal cell carcinoma (which grows in finger-like projections), chromophobe renal cell carcinoma (with larger cells and prominent borders), and rarer forms like collecting duct carcinoma and medullary carcinoma.^[2][5] Each subtype has its own biological characteristics and responds differently to treatment.

Medical societies and cancer centers have developed standard treatments that doctors can use as a starting point. However, because non-clear cell kidney cancers are less common, there is also ongoing research testing new therapies in clinical trials. These studies aim to find treatments specifically designed for the unique biology of each subtype, rather than simply applying treatments developed for clear cell cancer.^[2][9]

Standard Treatment Approaches

Surgery remains the cornerstone of treatment for many people with non-clear cell kidney cancer, especially when the tumor is caught early and hasn’t spread beyond the kidney. The surgical procedure, called a nephrectomy, can involve removing just the part of the kidney containing the tumor (partial nephrectomy) or the entire kidney (radical nephrectomy). Most people can live well with one functioning kidney, though careful monitoring is important afterward.^[13]

For cancers that have spread to other parts of the body, or when surgery isn’t possible, doctors often turn to medicines that travel through the bloodstream to reach cancer cells wherever they are. These are called systemic treatments. Historically, many doctors have used the same drugs developed for clear cell kidney cancer, even though the biology underlying non-clear cell types is different.^[8]

One category of these medicines is tyrosine kinase inhibitors, or TKIs for short. These drugs work by blocking signals that tell cancer cells to grow and by preventing new blood vessels from forming to feed the tumor. Common TKIs include sunitinib (often known by the brand name Sutent) and cabozantinib (Cabometyx). Sunitinib has been used for various non-clear cell subtypes, while cabozantinib has shown particular promise in papillary kidney cancer because it targets a protein called MET that is often involved in this subtype’s growth.^[8][9]

Another type of drug used is mTOR inhibitors, such as everolimus (Afinitor). These medicines block a pathway inside cells that helps them grow and divide. Everolimus is particularly considered for chromophobe kidney cancer because this subtype often has changes in genes that affect the mTOR pathway.^[9]

Immunotherapy represents another important treatment option. These medicines help the body’s own immune system recognize and attack cancer cells. Drugs like nivolumab (Opdivo) and ipilimumab (Yervoy) are checkpoint inhibitors that remove the “brakes” cancer cells put on the immune system. Pembrolizumab (Keytruda) is another checkpoint inhibitor used in kidney cancer treatment.^[11][13]

The duration of therapy varies widely depending on how well the treatment works and what side effects a person experiences. Some people stay on treatment for many months or even years if it continues to control their cancer without causing intolerable problems. Others may need to switch treatments if their cancer grows despite therapy or if side effects become too severe.

Side effects depend on the specific treatment but commonly include fatigue, diarrhea, skin rash, high blood pressure, and changes in appetite for targeted therapies. Immunotherapy can cause different side effects related to the overactive immune system, such as inflammation of organs like the colon, lungs, or liver. Doctors monitor patients carefully and can often manage side effects with additional medicines or by adjusting doses.^[13]

Emerging Treatments in Clinical Trials

Clinical trials are studies that test whether new treatments are safe and effective. For people with non-clear cell kidney cancer, participating in clinical trials can provide access to promising new therapies that aren’t yet widely available. These studies are crucial because standard treatments haven’t worked as well for non-clear cell types as they have for clear cell cancer.^[2]

One of the most significant recent developments has been the SUNNIFORECAST trial, which specifically studied people with non-clear cell kidney cancer. This was a landmark study because it was the largest randomized trial ever conducted specifically for these rarer subtypes. The trial tested a combination of two immunotherapy drugs—ipilimumab and nivolumab—compared to standard care with targeted therapy drugs.^[11]

In the SUNNIFORECAST study, which included 309 patients, those receiving the combination immunotherapy lived longer on average than those getting standard treatment. More than three-quarters of patients survived for one year with the immunotherapy combination, compared to about two-thirds with standard care. The average overall survival was two years and nine months with immunotherapy versus just over two years with standard treatment. Most patients in this trial had papillary kidney cancer, but the results appeared similar across different non-clear cell subtypes.^[11]

This trial was conducted across multiple countries and represented years of careful work. The immunotherapy combination was discontinued due to side effects in about 17% of patients, compared to 9% stopping standard treatment due to side effects. These findings have influenced how doctors think about treating non-clear cell kidney cancer, though more research continues.^[11]

Researchers are also exploring whether combining immunotherapy with targeted therapy drugs might work even better than either approach alone. Several clinical trials are testing combinations like cabozantinib plus nivolumab or other checkpoint inhibitors paired with TKIs. The idea is that targeted drugs might make tumors more visible to the immune system, while immunotherapy helps destroy cancer cells.^[6][12]

Another exciting area of research focuses on understanding the specific genetic changes in each subtype of non-clear cell kidney cancer. Scientists use advanced testing called next-generation sequencing to look at all the genes in a person’s tumor. This can reveal mutations or alterations that might be targeted with specific drugs.^[6]

For example, some papillary kidney cancers have changes in a gene called MET. Clinical trials have tested drugs specifically designed to block MET signaling. While these haven’t all succeeded, they represent the kind of precision medicine approach researchers are pursuing—matching specific drugs to specific genetic changes rather than treating all non-clear cell cancers the same way.^[6][9]

Eligibility for clinical trials depends on many factors including the specific subtype of cancer, whether it has spread, what treatments a person has already received, and overall health status. Trials are conducted at cancer centers in many locations including the United States, Canada, Europe, and other regions. Doctors can help patients find appropriate trials, and there are online databases that list active studies.^[13]

Some trials are testing drugs that target other specific molecular pathways. For instance, drugs targeting genetic changes in fumarate hydratase or succinate dehydrogenase genes are being explored for the rare hereditary kidney cancer syndromes associated with these genes. Other studies look at different combinations of existing drugs to see if they work better together.^[22]

The field is moving toward designing clinical trials that separate patients by their specific subtype rather than lumping all non-clear cell cancers together. This allows researchers to better understand how each subtype responds and to develop truly tailored treatments. However, because each subtype is rare, these studies can take longer to complete as they need to enroll enough patients to draw meaningful conclusions.^[6][12]

Most common treatment methods

• Surgery (Nephrectomy)
  • Partial nephrectomy removes the tumor and surrounding tissue while preserving kidney function
  • Radical nephrectomy removes the entire kidney and sometimes nearby structures
  • Remains the primary treatment for localized non-clear cell kidney cancer
• Targeted therapy with tyrosine kinase inhibitors
  • Sunitinib blocks signals for cancer growth and new blood vessel formation
  • Cabozantinib targets MET protein particularly relevant in papillary kidney cancer
  • These drugs are taken as pills and used when cancer has spread or surgery isn’t possible
• mTOR inhibitor therapy
  • Everolimus blocks the mTOR pathway inside cancer cells
  • Particularly considered for chromophobe kidney cancer due to genetic characteristics
  • Administered as oral medication
• Immunotherapy
  • Checkpoint inhibitors like nivolumab, ipilimumab, and pembrolizumab help immune system attack cancer
  • Combination of ipilimumab and nivolumab showed improved survival in SUNNIFORECAST trial
  • Given through intravenous infusions at regular intervals
• Platinum-based chemotherapy
  • Recommended specifically for collecting duct and medullary kidney cancers
  • Works by directly damaging cancer cells’ ability to divide
  • Administered through intravenous infusion
• Combination therapy approaches
  • Pairing immunotherapy with targeted therapy drugs being studied in clinical trials
  • Aim to make tumors more responsive by attacking through multiple mechanisms
  • Results from ongoing studies will help determine best combinations

Living with Non-Clear Cell Kidney Cancer

Managing life after diagnosis involves more than just medical treatments. Taking care of the remaining kidney tissue is crucial for long-term health. People can live normal lives with one kidney or with part of a kidney removed, as long as the remaining tissue functions well. However, protecting that remaining kidney function becomes a priority.^[17][18]

Staying at a healthy weight helps reduce strain on the kidneys. Being significantly overweight puts extra work on these organs and is also a risk factor for kidney cancer itself. Regular physical activity, even gentle exercise like walking, can help maintain a healthy weight and improve overall well-being.^[17][19]

Smoking is one of the strongest risk factors for kidney cancer and also increases the chance of cancer returning. Quitting smoking is one of the most important steps someone can take to protect their health. Many resources and support programs exist to help people quit, and healthcare providers can recommend medications or counseling that make stopping easier.^[17][18]

Diet plays a role in kidney health. While people with healthy remaining kidney function may not need major dietary changes, it’s often helpful to reduce salt intake. Too much salt makes kidneys work harder. Processed foods like chips, canned soups, and cured meats are high in salt. Eating plenty of fruits and vegetables while limiting heavily processed foods supports overall health.^[18]

Regular follow-up appointments are essential. Doctors monitor kidney function through blood and urine tests. They also perform imaging tests to check for any signs of cancer returning. The frequency of these appointments typically depends on the cancer stage and treatment received. Even years after successful treatment, some monitoring continues because kidney cancer can sometimes return.^[15][18]

Emotional well-being matters just as much as physical health. A cancer diagnosis can trigger anxiety, depression, sadness, anger, or feelings of isolation. These emotional responses are completely normal. Many cancer centers offer counseling services, support groups, or can connect patients with others who have gone through similar experiences. Speaking with a mental health professional or joining a support group helps many people cope with the challenges of living with cancer.^[19]

Managing treatment side effects requires open communication with the healthcare team. Most side effects can be reduced or controlled with medications or dose adjustments. People shouldn’t try to tough it out alone—reporting problems promptly allows doctors to help maintain quality of life during treatment.^[13]