Risk Versus Reward: Managing Side Effects of Kidney Cancer Treatments

CURE, Kidney Cancer Special Issue 2022,

Advocacy Groups | <b>Kidney Cancer Assocation</b>

Newer drugs for kidney cancer have proven extremely effective but can cause unwanted symptoms that affect safety and quality of life.

When Marissa Willis began feeling pain on her left side in May 2013, she initially thought she might have pulled a muscle during one of her workouts.

At 38, the mother of two was in good health and exercised regularly. Yet when the pain persisted, Willis headed to her local urgent care center and was shocked when X-rays revealed a mass on her left kidney.

“I saw my primary care provider the next day for a sonogram, and the next two weeks were a whirlwind of appointments, scans and tests at the University of Kansas Medical Center,” says Willis, who lives in Blue Springs, Missouri. “Ten days later, I had a radical left nephrectomy to remove both the tumor and my left kidney.”

After her surgery, Willis was doing well until a follow-up imaging test 10 months later found a small spot on her lung.

“Since the spot was less than a centimeter, my oncologist decided it was reasonable to watch the mass and see if would grow,” Willis says.

Three years later, in 2017, an imaging test determined another spot on her lung was large enough to biopsy. Test results found the cancer had metastasized to her lung, and Willis began four cycles of high-dose interleukin-2, a form of immune-stimulation therapy.

It wasn’t until Willis was prescribed her current drug regimen of Votrient (pazopanib), a tyrosine kinase inhibitor that targets cancer-supporting blood vessels, that she began to experience side effects from her cancer treatment.

“I had never had high blood pressure before, but after being on Votrient for a short time, I was diagnosed with both hypertension and an underactive thyroid,” Willis says.

Although tyrosine kinase inhibitors and checkpoint inhibitors have proven to be extremely effective in treating patients with renal cell carcinoma, they also carry the possibility of side effects, which can be worrisome for patients.

In Willis’ case, her care team had discussed potential side effects with her in advance and monitored her bloodwork and blood pressure levels so that any changes with her health could be immediately addressed.

“My doctor put me on medication to lower my blood pressure and treat my underactive thyroid. I monitor my blood pressure daily and have my thyroid-stimulating hormones levels checked on a regular basis,” Willis says. “While I will be on both medications indefinitely, I’m happy to be living a pretty normal life.”

Risk Versus Benefits

Because treatments for kidney cancer, including immunotherapies and tyrosine kinase inhibitors, carry the risk of side effects, it’s important for patients and their oncology care team to weigh the risks versus the benefits of each treatment, according to Dr. Thomas Hutson, director of the urologic oncology program and co-chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center in Dallas and a professor of medicine at Texas A&M University School of Medicine in Bryan.

“Immunotherapies and (tyrosine kinase inhibitors) have shown success in treating metastatic cases by shrinking tumors and offering many patients remission and long-term survival,” Hutson explains. “Many of the common side effects tend to be fatigue, skin rashes and chronic muscle-related issues such as cramping or joint pain.”

Findings from a study published in the medical journal JAMA Oncology in 2021 showed that approximately 40% of patients taking checkpoint drugs as immunotherapy develop acute and chronic complications such gastrointestinal side effects, rash, arthritis or endocrine dysfunction.

If a patient encounters more severe side effects, Hutson says doctors will look at adjusting or lowering the dose of the medication, making the side effects manageable.

“Some patients are reluctant to lower their medication dose, mistakenly believing it will also lower the effectiveness of the medication,” Hutson says. “This isn’t the case, and when prescribing treatments, doctors take (into) consideration a patient’s quality of life. If the medications are taking too much of a toll on a patient and adversely affecting their health, a decision will be made about stopping the medication, since we don’t want to continue a high-dose drug regimen that will cause patients to suffer unnecessarily.”

Hutson tells patients their cancer journey is “a marathon, not a sprint,” and if they need to stop an immunotherapy or tyrosine kinase inhibitor drug — at least temporarily — they can later resume treatment on a lower dose or sometimes even a different drug.

He emphasizes that patients should always report side effects to their oncology team.

“Reducing dosages isn’t bad,” Hutson says. “In clinical trials, dose reductions are quite common, so we always tell patients the medication dose they start at may not be the same dose they stay on. In fact, two-thirds of all (patients with cancer) need to be switched to a lower dose. We strive to balance the side effects with safety and quality of life.”

Information from clinical trials shows that the rates of response and length of time to when there may be progression of a tumor do not seem to differ among patients who need a dose reduction due to side effects compared to those who may not.

In rare cases, Hutson notes that immunotherapy drugs, especially when combined, can trigger a more severe autoimmune response causing inflammation of the lungs, liver or colon.

This was the case for Chase Griffith, 45, of Dallas, who was diagnosed with kidney cancer in December 2018. After Griffith underwent a complete nephrectomy, his follow-up scans showed no sign of cancer — until April 2021, when an MRI and CT scan found that the cancer had metastasized to Griffith’s liver.

After meeting with doctors at The University of Texas MD Anderson Cancer Center in Houston and UT Southwestern Medical Center in Dallas, Griffith decided his best course of action was to begin a triple-medicine clinical trial using two immunotherapy drugs, Opdivo (nivolumab) and Yervoy (ipilimumab), combined with the tyrosine kinase inhibitor Cabometyx (cabozantinib).

The phase 3 clinical trial is comparing treatment with Yervoy and Opdivo followed by Opdivo alone to treatment with Yervoy and Opdivo followed by Opdivo with Cabometyx in patients with untreated renal cell carcinoma that has spread to other parts of the body.

Researchers hope to determine if the addition of Cabometyx to the usual treatment will make the therapy more effective at stopping the growth of tumor cells.

“When I went in to get my third dose of the treatment regimen, I had bloodwork done and my oncologist found that (my) liver enzymes were off the charts,” Griffith recalls. “Basically, the immunotherapy caused my immune system to attack my healthy liver tissue.”

Doctors told Griffith they would immediately stop the therapy and begin a course of steroids to suppress the immune response. Because Griffith had been cautioned ahead of time about potential side effects, he wasn’t surprised and believed he was in good hands with his oncology team.

“I was put on 200 milligrams a day of prednisone that I took for several months before doctors began tapering me off the medication,” Griffith says. “I got down to 10 milligrams in February of this year and started having the same side effects, including insomnia and an elevated heart rate. After going to an urgent care center, I learned that my liver enzymes were even higher than before.”

Griffith was hospitalized and given both prednisone and the high-level immunosuppressant CellCept (mycophenolic mofetil), which is often prescribed to prevent organ rejection after transplantation. He remained on the drugs for several months.

Because he has chromophobe renal cell carcinoma, a rare form of kidney cancer, Griffith knows his doctors are using novel approaches to create targeted therapies that stop or slow the growth of his cancer.

“This past February, doctors started me on another (tyrosine kinase inhibitor), lenvatinib (Lenvima), and an mTOR (inhibitor) therapy, everolimus, that have resulted in a 20% shrinkage in my tumor,” Griffith says. “Today, I feel good, and my doctor says I have no new tumors and that my existing tumors have stabilized.”

Frequent Communicatoin Is Key to Managing Side Effects

According to Laura Wood, an oncology nurse and former renal cancer center research coordinator at Cleveland Clinic Taussig Cancer Center, high blood pressure, or hypertension, can be a side effect of some of the multikinase inhibitors used to treat kidney cancer since they act by affecting the blood vessels in tumors and can also have effects on normal blood vessels that regulate blood pressure.

These drugs include Sutent (sunitinib malate), Lenvima and Inlyta (axitinib). In addition, Wood notes that a class of drugs known as mTOR inhibitors, including everolimus, rapamycin (sirolimus) and temsirolimus (CCI-779), can often cause side effects such as elevated blood sugar, cholesterol and triglycerides.

“We tell patients in advance they shouldn’t be surprised if they develop any of these conditions while undergoing cancer treat- ment,” Wood says. “They’re very manageable conditions, and (the patient’s) bloodwork and symptoms improve after adjustments are made to their cancer treatment and medications are given to treat the side effects. Some side effects may result in long-term symptoms which require ongoing discussions with your oncology team or other specialists to manage.”

Wood says it’s crucial for health care providers to provide patients with kidney cancer with early and ongoing education regarding potential side effects and for patients to report these as soon as possible to obtain relief and avoid any organ damage or other long-term problems.

Reporting side effects can also help researchers better understand side effects and develop additional strategies on how to best manage them.

In 2017, the Severe Immunotherapy Complications Service was launched at Massachusetts General Hospital in Boston to treat and study patients with immune complications from immune checkpoint inhibitors. Many other cancer centers have similar programs and multidisciplinary teams to manage immune-related side effects.

Dr. Naomi B. Haas, an oncolo- gist and director of the prostate and kidney cancer program at Penn Medicine and a professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, notes that in rare cases, side effects might even be considered something of a positive.

Haas cites an analysis of clinical trials conducted at Dana-Farber Cancer Institute in Boston showing that patients with advanced kidney cancer who were diagnosed with high blood pressure and prescribed medications called angiotensin system inhibitors, including angiotensin-converting enzyme inhibitors and angiotensin system blockers, lived longer and had better outcomes than patients who weren’t diagnosed with hypertension and treated with those medications.

Even when patients experience milder side effects, Haas says they should discuss changes with their oncology team.

The Kidney Cancer Association offers a printable side effect tracker on its website, www.kidneycancer.org, to make it easier for patients to track their symptoms and inform their oncology team about symptom severity and how often symptoms are occurring.

“In some cases, patients can lose their sense of taste and say their food tastes like cardboard,” Haas says. “As a result, they aren’t going to eat as much and will ultimately lose weight, which we don’t want.”

To address this, Haas says oncologists will typically ask a patient to cease taking their medication for a few days to determine whether it’s the drug or the disease that’s causing the problem. If it’s the medication, Haas notes that drugs such as mirtazapine can be prescribed to help stimulate a patient’s appetite.

Diarrhea is another common side effect that Haas says can impact both a patient’s physical and emotional health. Haas says patients should never be embarrassed to discuss any changes in their health with their oncology team.

“We don’t want patients to be miserable or afraid to venture out socially because they’re experiencing diarrhea,” Haas says. “We can prescribe probiotics and advise changes to their diet to remedy their situation. In severe cases, we might begin steroid therapy.”

In cases of renal cell carcinoma, although side effects can initially seem scary, Haas says most are treatable and are outweighed by the benefits patients receive from tyrosine kinase inhibitors and checkpoint inhibitors.

Willis says she has been feeling “pretty good” over the last 2-and- a-half years, especially since her side effects are much more manageable now.

“I know my body well enough on (treatment) now that I’m living a pretty normal life,” she says. “Ironically, being active, working out, that helps energy levels and those side effects. ... I’ll be on this indefinitely, probably until either I don’t need it, or it stops working.”

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