Is the Naproxen test suitable for differentiating between fever caused by malignancy or infection in a patient with stage IV renal cell carcinoma and impaired renal function, currently treated with pembrolizumab and lenvatinib?

The Naproxen Test is Not Recommended for Differentiating Fever Etiology in This Clinical Context

The Naproxen test should not be used in a patient with stage IV renal cell carcinoma and impaired renal function receiving pembrolizumab and lenvatinib, as NSAIDs like naproxen are contraindicated in patients with renal impairment and can cause significant nephrotoxicity, particularly when combined with nephrotoxic cancer therapies.

Critical Safety Concerns with Naproxen in This Patient

Renal Function Contraindication

• NSAIDs including naproxen are contraindicated or require extreme caution in patients with pre-existing renal impairment, as they can precipitate acute kidney injury through prostaglandin-mediated reduction in renal blood flow
• Lenvatinib itself causes proteinuria and renal dysfunction in a significant proportion of patients, with proteinuria being a common adverse event requiring monitoring 1, 2
• The combination of lenvatinib plus pembrolizumab has high rates of grade 3-4 adverse events (82.4%), with careful management of toxicities being essential for maintaining treatment exposure 3, 2

Drug Interaction Risks

• Adding an NSAID to a patient already receiving lenvatinib (which causes hypertension in 23% as grade 3-4 events) could exacerbate cardiovascular and renal complications 4
• The lenvatinib-pembrolizumab regimen requires dose reductions in 68.8% of patients due to treatment-related adverse events, and adding nephrotoxic agents would further compromise treatment tolerability 3

Alternative Approaches to Fever Evaluation

Comprehensive Infectious Workup

• Obtain blood cultures, urinalysis with culture, chest imaging, and site-specific cultures based on clinical suspicion
• Consider opportunistic infections given immunotherapy exposure with pembrolizumab
• Evaluate for catheter-related infections if central venous access is present

Malignancy-Related Fever Assessment

• Renal cell carcinoma itself can cause paraneoplastic fever through cytokine release (IL-6, TNF-alpha)
• Review imaging for disease progression, which would suggest tumor-related fever
• Check inflammatory markers (CRP, ESR) and lactate dehydrogenase, though these are nonspecific

Immunotherapy-Related Considerations

• Pembrolizumab can cause immune-related adverse events including pneumonitis, colitis, and hepatitis that may present with fever 1
• Monitor for signs of immune-mediated toxicity: diarrhea (which could indicate colitis rather than simple GI upset), dyspnea, or elevated liver enzymes
• Consider that fever may represent an immune-related adverse event requiring corticosteroid therapy rather than antibiotics

Clinical Decision Algorithm

If fever with localizing symptoms or signs of infection:

• Initiate appropriate antimicrobial therapy based on suspected source
• Obtain cultures before antibiotics when feasible
• Monitor renal function closely given baseline impairment

If fever without clear infectious source:

• Hold lenvatinib temporarily if fever is associated with other concerning symptoms (per prescribing information, dose modifications are frequently required) 1, 2
• Evaluate for immune-related adverse events with appropriate laboratory and imaging studies
• Consider empiric broad-spectrum antibiotics if neutropenic or clinically unstable
• If fever persists beyond 48-72 hours without identified source and patient is stable, imaging for disease progression is warranted

Critical monitoring parameters:

• Serial renal function tests (creatinine, proteinuria) given lenvatinib nephrotoxicity risk 1, 2
• Blood pressure monitoring (hypertension occurs in 23% as grade 3-4 with lenvatinib-pembrolizumab) 4
• Thyroid function (both drugs can cause thyroid dysfunction)

Why the Naproxen Test Lacks Clinical Utility Here

The theoretical basis of the naproxen test—that malignancy-related fever responds to NSAIDs while infectious fever does not—has poor sensitivity and specificity in modern oncology practice and does not change management. The risks of NSAID administration in this patient with renal impairment and concurrent nephrotoxic therapy far outweigh any potential diagnostic benefit. Direct evaluation for infection and disease progression provides definitive answers without additional toxicity risk.