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Managing adverse events associated with targeted therapies used to treat metastatic renal cell carcinoma
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The introduction of targeted therapies in the management of metastatic renal cell carcinoma has markedly increased the treatment options available for these patients. These agents are now used in the first-line and second-line treatment settings, and beyond, to improve patient outcomes. Although many of these agents were approved on the basis of an improvement in progression-free survival, a recent analysis of a real-world patient population found that the use of targeted therapy has led to improved survival as well.
Two main types of oral, small molecule targeted therapies are used in the treatment of renal cell carcinoma. Tyrosine kinase inhibitors (TKIs) designed to inhibit the VEGF receptor (VEGFR) include sunitinib (Sutent, Pfizer), sorafenib (Nexavar, Bayer), pazopanib (Votrient, Novartis), axitinib (Inlyta, Pfizer), cabozantinib (Cometriq/Cabometyx, Exelixis) and lenvatinib (Lenvima, Eisai). A second class of agents are the mTOR inhibitors, which include temsirolimus (Torisel, Pfizer) and everolimus (Afinitor, Novartis). Despite the benefit these agents have brought to patients with metastatic renal cell carcinoma, these agents are also associated with adverse events that can be significant and/or serious in nature . Effective management of these adverse events is critical to ensure that patients can continue treatment for as long as the drug is effective, while minimizing dose reductions or delays. Some of the more common adverse events that are associated with VEGFR TKI targeted agents in renal cell carcinoma, and their management, are described below.
Diarrhea
Diarrhea events reported in the prescribing information of each VEGFR TKI approved for the treatment of advanced renal cell carcinoma.
| Sunitinib | Sorafenib | Pazopanib | Axitinib | Cabozantinib | Lenvatinib* | |
| All-grade diarrhea, % | 66% | 43% | 52% | 55% | 74% | 81% |
| Grade 3/4 diarrhea, % | 10% | 2% | 4% | 11% | 11% | 19% |
*Administered in combination with everolimus.
These agents were not studied in head-to-head trials. Comparisons between agents cannot be made.
Diarrhea is one of the most frequently reported adverse events with TKI therapy. Although diarrhea is generally mild or moderate in severity, if it is not efficiently managed, it can become more serious. Diarrhea can dramatically and negatively affect the patient’s quality of life, and result in more serious effects such as weight loss, dehydration and abdominal pain and cramping.
Management of diarrhea involves four strategies — changing diet, addressing dehydration, intervening pharmacologically and adjusting dose. Patients may be advised to avoid high-fiber and other foods that aggravate diarrhea, and instead favor foods associated with slower gastrointestinal motility (such as the BRAT diet consisting of bananas, rice, apples and toast). Oral rehydration is necessary, even for mild symptoms, and IV rehydration may be required in severe cases. Over-the-counter anti-diarrhea agents, such as loperamide, can be an effective intervention to mitigate and lessen diarrhea. In cases of grades 3 or 4 diarrhea, dose modifications and/or treatment interruptions may be required and can be performed according to manufacturer’s recommendations.
Dermatological events
Selected all-grade dermatological events reported in the prescribing information of each VEGFR TKI approved for the treatment of advanced renal cell carcinoma.
| Sunitinib | Sorafenib | Pazopanib | Axitinib | Cabozantinib | Lenvatinib* | |
| All-grade rash, % | 29% | 19% | NR | 13% | 23% | 35% |
| All-grade hand-foot skin reaction, % | 29% | 21% | NR | 27% | 42% | NR |
*Administered in combination with everolimus.
Abbreviation: NR, not reported.
These agents were not studied in head-to-head trials. Comparisons between agents cannot be made.
A wide range of skin and subcutaneous events have been reported in clinical studies of VEGFR TKIs, including in part rash, dry skin, erythema, pruritus, hand-foot skin reaction (HFSR), acne and alopecia, among others. Among these dermatological events, rash and HFSR seem to be the most significant.
Symptomatic relief using topical therapies is the most common management strategy for dermatological events arising as VEGFR TKI adverse events. Topical therapies may include intensified skin moisturizers, emollients and urea-containing lotions. It is important to distinguish cases of mild or moderate rash from serious cases of hypersensitivity rash, the latter of which required dose adjustments, interruptions or discontinuations. Patients can be advised on strategies to help prevent HFSR, which focus on removal of calluses, use of cushions, and topical creams and ointments.
Hypertension
Hypertension events reported in the prescribing information of each VEGFR TKI approved for the treatment of advanced renal cell carcinoma.
| Sunitinib | Sorafenib | Pazopanib | Axitinib | Cabozantinib | Lenvatinib* | |
| All-grade hypertension, % | 34% | 9% | 40% | 40% | 39% | 42% |
| Grade 3/4 hypertension, % | 13% | 4% | 4% | 16% | 16% | 13% |
*Administered in combination with everolimus.
These agents were not studied in head-to-head trials. Comparisons between agents cannot be made.
Prompt identification of VEGFR TKI-associated hypertension is important to prevent more serious complications such as intracranial hemorrhage and heart failure. Home blood pressure monitoring may help in the earlier detection of hypertension. If patients are advised to monitor their blood pressure at home, they should be provided with individualized systolic and diastolic thresholds to use as guidance for when to contact their provider.
Hypertension is generally managed with standard anti-hypertensive agents, administered on an individualized basis according to the severity of that patient’s hypertension as well as other cardiovascular risk factors present. Both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can be used. Dose adjustments (either delays, reductions or discontinuations) may be required in cases of severe hypertension.
Anorexia and weight loss
Anorexia or weight decreased events reported in the prescribing information of each VEGFR TKI approved for the treatment of advanced renal cell carcinoma.
| Sunitinib | Sorafenib | Pazopanib | Axitinib | Cabozantinib | Lenvatinib* | |
| All-grade anorexia/weight decreased, % | 48% | 29% | 22% | 25% | 31% | 34% |
| Grade 3/4 anorexia/weight decreased, % | 3% | 3% | 2% | 2% | 2% | 3% |
*Administered in combination with everolimus.
These agents were not studied in head-to-head trials. Comparisons between agents cannot be made.
In patients with renal cell carcinoma treated with VEGFR TKIs, anorexia may arise from a variety of causes. Often, anorexia arises from a loss of appetite that may be related to treatment-related nausea, vomiting, oral pain, diarrhea and loss or disturbance of taste. Anorexia-related symptoms, which include weakness, fatigue, depression, tooth loss and organ damage, can significantly affect a patient’s quality of life and dramatically affect a patient’s overall health and function.
Management of anorexia is not a one-size-fits-all approach, but can be guided by a few principles. For example, pharmacological interventions may be effective, including megestrol acetate; eicosapentaenoic acid diester; medroxyprogesterone acetate; and mixtures of beta-hydroxy-beta-methylbutyrate, glutamine and arginine. Simple dietary advice, including eating small amounts several times a day and incorporating nutrient liquids may also be helpful.
Fatigue
Fatigue events reported in the prescribing information of each VEGFR TKI approved for the treatment of advanced renal cell carcinoma.
| Sunitinib | Sorafenib | Pazopanib | Axitinib | Cabozantinib | Lenvatinib* | |
| All-grade fatigue, % | 62% | 46% | 19% | 39% | 56% | 73% |
| Grade 3/4 fatigue, % | 15% | 10% | 2% | 11% | 9% | 18% |
*Administered in combination with everolimus.
These agents were not studied in head-to-head trials. Comparisons between agents cannot be made.
Often overlooked, fatigue can be an important adverse event that significantly affects the patient’s quality of life. Fatigue can include physical, emotional and/or cognitive exhaustion. Fatigue may be difficult to manage particularly in cancer patients, in which its etiology can be complex and due to the disease itself as well as anti-cancer treatments, or it can also reflect an underlying disorder (such as anemia or depression).
The first step in managing fatigue is to identify and address treatable causes, such as anemia, thyroid dysfunction, depression or sleep disorders. Beyond that, the primary intervention to manage fatigue is educating the patient and caregiver on coping strategies for fatigue. These may include conserving energy, rescheduling activities to occur at times of peak energy and good sleep practices.
Mucositis and stomatitis
Mucositis and/or stomatitis events reported in the prescribing information of each VEGFR TKI approved for the treatment of advanced renal cell carcinoma.
| Sunitinib | Sorafenib | Pazopanib | Axitinib | Cabozantinib | Lenvatinib* | |
| All-grade mucositis† and/or stomatitis, % | 47% | NR | NR | 30% | 41% | 44% |
| Grade 3/4 mucositis† and/or stomatitis, % | 3% | NR | NR | 2% | 3% | 2% |
*Administered in combination with everolimus.
†Also reported as mucosal inflammation.
Abbreviation: NR, not reported.
These agents were not studied in head-to-head trials. Comparisons between agents cannot be made.
Inflammation and ulceration of the mucous membranes lining the gastrointestinal tract (mucositis) or specifically of the mouth (stomatitis) is a painful adverse event in some patients. The pain can be so intense it subsequently results in difficulty speaking or eating, which may in turn lead to dehydration and weight loss.
A number of interventions are used to address this distressing adverse event. Patients are generally advised to switch to a nonalcoholic mouthwash and to avoid foods that are particularly salty, sour or spicy. Dexpanthenol sugar-coated tablets or cream may be used to help protect the mucus membrane, and topical steroids may help to reduce inflammation. In some cases, proton-pump inhibitors may be effective to treat stomatitis and mucositis particularly involving the esophagus. In severe cases, narcotic analgesics may be required for pain relief.
Summary
The adverse events described here represent just a few of the more common ones that have been reported in clinical trials of VEGFR TKIs. Many other adverse events have been reported to varying degrees, including nausea, vomiting, cardiac and liver dysfunction, arterial and venous thromboembolic events, and gastrointestinal perforation. A common theme for management of all adverse events arising during treatment is that early intervention is key to minimizing the severity of the toxicity. This is important as mild or moderate adverse events are more manageable, whereas grade 3 or 4 severe adverse events often require dose adjustments, including dose reductions or delays, which may in turn reduce the overall efficacy the patient might achieve. In cases of severe toxicity, or when adverse events recur despite dose adjustments, treatment discontinuation is considered and may be appropriate according to the manufacturer’s recommendations.
References:
Pal SK, Ghate SR, Li N, et al. Real-world survival outcomes and prognostic factors among patients receiving first targeted therapy for advanced renal cell carcinoma: a SEER-Medicare database analysis. Clin Genitourinary Cancer. 2017;15(4):e573-e582.
Eisen T, Sternberg CN, Robert C, et al. Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst. 2012;104(2):93-113.
Sutent (sunitinib malate) capsules [prescribing information]. New York, NY; Pfizer Labs, a Division of Pfizer, Inc.; November 2017.
Nexavar (sorafenib) tablets [prescribing information]. Whippany, NJ; Bayer HealthCare Pharmaceuticals Inc.; December 2017.
Votrient (pazopanib) tablets [prescribing information]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; May 2017.
Inlyta (axitinib) tablets [prescribing information]. New York, NY; Pfizer Labs, a Division of Pfizer, Inc.; August 2014.
Cabometyx (cabozantinib) tablets [prescribing information]. South San Francisco, CA; Exelixis, Inc.; December 2017.
Lenvima (lenvatnib) capsules [prescribing information]. Woodcliff Lake, NJ; Eisai Inc.; November 2017.