Managing Toxicities in Advanced RCC: Insights From an Expert Panel

In a recent Oncology Nursing News case-based roundtable discussion, oncology nurse practitioners and physician assistants convened to discuss the evolving therapeutic landscape for patients with advanced renal cell carcinoma (RCC).

Moderated by Jared Thorley, MSN, NP, a family nurse practitioner at Intermountain Health in Salt Lake City, Utah, the panel examined frontline systemic therapy options, dosing modifications, and adverse event (AE) management strategies. The discussion highlighted how nursing intervention, patient education, and multidisciplinary collaboration are central to maintaining patients on life-prolonging therapies while optimizing quality of life.

Selecting Frontline Systemic Therapies

Frontline management of advanced clear cell RCC—representing the vast majority of metastatic cases—increasingly relies on combination regimens recommended by National Comprehensive Cancer Network (NCCN) guidelines. These include immunotherapy (IO) doublets, such as nivolumab (Opdivo) plus ipilimumab (Yervoy), and IO combined with tyrosine kinase inhibitors (TKIs), such as Lenvatinib (Lenvima) plus pembrolizumab (Keytruda), cabozantinib (Cabometyx) plus nivolumab, or axitinib (Inlyta) plus pembrolizumab.

When choosing between regimens, the roundtable panel noted several high-level practice considerations:

• Upfront Treatment Intent: A majority of the roundtable participants advocated for utilizing the most aggressive, highly effective treatment option upfront rather than saving it for subsequent lines, citing high patient attrition in later lines of therapy.
• Risk Stratification and Clinical Factors: Selection between an IO-IO versus an IO-TKI combination is guided by the International Metastatic RCC Database Consortium (IMDC) risk stratification, which categorizes patients into favorable, intermediate, or poor risk based on key prognostic indicators.
• Comorbidities and Disease Burden: Clinicians must evaluate patient performance status, comorbidities, and disease kinetics. For instance, rapid symptom control is often best achieved with highly active IO-TKI combinations, whereas patients with pre-existing uncontrolled hypertension or significant cardiovascular risk may benefit from an IO-IO approach.

Managing the 'Big Three' Frontline Toxicities

Thorley categorized the most prevalent and challenging treatment-related AEs in clinical practice as "the big three": hypertension, diarrhea, and fatigue. Effectively managing these toxicities requires a structured approach to maintain dose intensity:

1. Hypertension Dosing and Management Strategies: Hypertension is a hallmark class effect of TKIs, such as lenvatinib, cabozantinib, and axitinib. In the phase 3 CLEAR trial evaluating lenvatinib plus pembrolizumab, any-grade hypertension occurred in 57.4% of patients, with 29% experiencing grade 3 or higher events.

• Prioritize Antihypertensives First: The panel reached a strong consensus to add or optimize antihypertensive therapies (using up to three agents) before reducing the TKI dose, aiming to maintain maximum treatment efficacy.
• Proactive Monitoring: Nurses should counsel patients to log their blood pressure daily at home and report elevations before they escalate.

2. Differentiating and Managing Diarrhea and Colitis

Nurses must distinguish between TKI-induced diarrhea and immunotherapy-related colitis.

• TKI-Induced Diarrhea: Typically presents early in the treatment course. Management involves holding the TKI (such as lenvatinib) for grade 2 or higher diarrhea, initiating supportive care (loperamide, hydration, and a BRAT diet), and resuming at a reduced dose once symptoms improve to grade 1 or baseline. Standard lenvatinib dose reductions proceed from 20 mg daily to 14 mg, 10 mg, and 8 mg.
• IO-Mediated Colitis: Often presents later and is characterized by inflammatory processes. Workup includes checking C-reactive protein and fecal calprotectin while ruling out infectious causes. Management requires holding immunotherapy and initiating systemic corticosteroids (oral prednisone or IV methylprednisolone).

3. Addressing Subjective Fatigue

Fatigue is highly prevalent across all regimens and is heavily subjective.

• Thorough Clinical Investigation: Nurses must look beyond subjective patient complaints to assess the functional impact of fatigue on daily activities.
• Supportive Interventions: Supportive care referrals can assist with prescribing low-dose steroids or psychostimulants (e.g., methylphenidate) to alleviate severe fatigue.

The Value of Multidisciplinary Support

Successful AE management is deeply rooted in patient education and interdisciplinary collaboration. Panelists noted the invaluable role of clinic pharmacists who provide dedicated, in-depth toxicity counseling and distribute structured education packets to patients. Establishing open communication channels, such as patient portal systems, ensures that toxicities are caught at early, manageable grades, preventing unnecessary treatment discontinuations and hospitalizations.