Navigating the Hidden Dangers of Fungal Infections in Cancer Patients: A Story of Precision Medicine That Could Save Lives
Imagine a young teenager fighting advanced cancer, only to face a potentially lethal fungal invasion. This isn't just a medical case—it's a real-life battle highlighting how tailored drug monitoring can turn the tide in complex treatments. But here's where it gets controversial: are we overlooking the power of personalized approaches in antifungal therapies? Let's dive in and explore this gripping case, where therapeutic drug monitoring (TDM) played a starring role.
Therapeutic Drug Monitoring-Guided Antifungal Therapy Under Tyrosine Kinase Inhibitor Treatment in Invasive Pulmonary Aspergillosis
By Ruiting Wen,¹,* Wentao Ni,²,* Xiaotong Gu,¹,³,* Boyu Liu,¹ Gali Bai,¹,⁴ Xiaohong Zhang¹
¹Department of Pharmacy, Peking University People’s Hospital, Beijing, People’s Republic of China; ²Department of Pulmonary and Critical Care Medicine, Peking University People’s Hospital, Beijing, People’s Republic of China; ³Department of Pharmacy, China Aerospace Science and Industry Corporation 731 Hospital, Beijing, People’s Republic of China; ⁴Department of Pharmaceutical Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Xiaohong Zhang, Department of Pharmacy, Peking University People’s Hospital, Beijing, 100044, People’s Republic of China, Email [emailprotected]; Ruiting Wen, Department of Pharmacy, Peking University People’s Hospital, Beijing, 100044, People’s Republic of China, Email [emailprotected]
Abstract: Treating invasive pulmonary aspergillosis (IPA)—a serious lung infection caused by Aspergillus fungus—in cancer patients poses significant challenges due to variations in how individuals process antifungal drugs and possible interactions between medications. This detailed case study involves a 14-year-old boy with advanced osteosarcoma who developed IPA following chemotherapy. His first antifungal, voriconazole, didn't yield the expected results, as TDM showed extremely low drug levels in his blood even after increasing the dose. Switching to isavuconazole led to a positive response, with steady blood concentrations within the desired range. Additionally, TDM revealed no significant drug interactions between isavuconazole and apatinib, but hinted at potential issues between voriconazole and anlotinib. This report underscores the value of personalized pharmacokinetic strategies in managing antifungal treatments for oncology patients, where TDM can guide decisions and fine-tune regimens for better outcomes.
Keywords: invasive pulmonary aspergillosis, voriconazole, isavuconazole, apatinib, pharmacokinetics
Introduction
Invasive pulmonary aspergillosis (IPA) represents a severe opportunistic fungal infection that threatens immunocompromised patients with advanced cancers, often weakened by radiation or chemotherapy.¹,² Prompt identification and effective antifungal treatment are critical to halt the infection's spread and avert fatalities. Current guidelines recommend voriconazole (VOR) and isavuconazole (ISA) as primary options for IPA management.³,⁴ The effectiveness and safety of these drugs depend heavily on their pharmacokinetic profiles—how the body absorbs, distributes, metabolizes, and eliminates them. Too little exposure can lead to treatment failure, while excessive amounts might cause harmful side effects. Furthermore, interactions between azole antifungals and anticancer drugs, mediated through liver enzymes like cytochrome P450 (CYP450), raise additional concerns. In light of these complexities, therapeutic drug monitoring (TDM)—regularly checking drug levels in the blood—emerges as a vital tool to optimize dosing, prevent toxicity, and identify unforeseen interactions.
And this is the part most people miss: TDM isn't just for experts; it's a practical way to personalize care, especially when standard doses don't fit due to individual differences.
We share a case here of IPA arising after chemotherapy for advanced osteosarcoma, where TDM informed treatment choices and uncovered potential drug interactions, emphasizing the need for customized pharmacokinetic approaches in antifungal therapy for cancer patients.
Case Presentation
A 14-year-old male, previously diagnosed with osteosarcoma in his left tibia and lung metastases, had undergone surgeries on his left tibia (one year prior) and right upper lung lobe (five months earlier). Post-lung surgery, his chemotherapy regimen shifted to ifosfamide, vincristine, and trelizumab. Two months ago, he started anlotinib (12 mg daily), an innovative multi-target anti-angiogenic tyrosine kinase inhibitor (aa-TKI).⁵ During this period, he experienced neutropenia, though exact counts weren't recorded. One month ago, symptoms flared: fever peaking at 39.0°C, cough, and left back pain. A week later, he sought care at a local hospital, where thoracic computed tomography (CT) scans and metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage (BAL) fluid confirmed IPA caused by Aspergillus fumigatus (with 18 sequence reads). Cultures from BAL came back negative. Chemotherapy, excluding anlotinib, was halted. He received intravenous voriconazole (VOR, 200 mg every 12 hours) and liposomal amphotericin B (25 mg daily) for eight days, followed by caspofungin (50 mg daily) for another eight days due to uncontrolled fever. Despite methylprednisolone, his CT scans deteriorated, though his temperature normalized. He was then referred to our facility.
Upon arrival, his measurements included a weight of 47 kg, height of 1.75 m, and BMI of 15.35 kg/m². CT imaging displayed widespread consolidation in the left upper lobe with ground-glass opacities (Figure 1A). Blood tests showed a white blood cell (WBC) count of 12.00 × 10⁹/L (70.5% neutrophils, 13.7% monocytes), normal C-reactive protein, procalcitonin, liver enzymes, and kidney function. BAL microscopy, Gram stain, and cultures were negative, but galactomannan antigen in BAL was elevated (6.64), while serum levels were low (0.28). Based on the revised criteria from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group, this qualified as "probable" IPA.⁶ Given the prior treatment's ineffectiveness, anlotinib was paused. Intravenous VOR continued as monotherapy, with the dose bumped to 250 mg every 12 hours. Initial TDM on admission day 2 (VOR day 18) measured a serum VOR trough concentration (Cmin) of 0.93 μg/mL (target range: 2–6 μg/mL). Surprisingly, by day 10 (VOR day 26), it plummeted to 0.28 μg/mL, and CT scans showed little progress (Figure 1B), with WBC at 10.10 × 10⁹/L. The treating physician consulted a clinical pharmacist.
Suspecting the patient might be an ultra-rapid (UM) or rapid metabolizer (RM) of CYP2C19, the main enzyme breaking down VOR,⁷ the pharmacist proposed switching to ISA. Treatment began on admission day 16 with intravenous ISA (200 mg three times daily for loading, then 200 mg daily maintenance). To confirm adequate levels, TDM measured ISA Cmin at 2.43 μg/mL on day 22 (ISA day 7), aligning with averages from the SECURE trial (2.6 ± 1.0 μg/mL on day 7).⁸ WBC dropped to 5.94 × 10⁹/L. As this early reading might not reflect steady state, dosing continued unchanged, switching to oral form on day 23 for ease. After 14 days, Cmin hit 3.96 μg/mL, and CT scans on day 37 revealed significant improvement (Figure 1C).
With the antifungal response encouraging, the team planned to resume chemotherapy using another aa-TKI, apatinib (APA, 375 mg daily). APA's breakdown mainly involves CYP3A4/5 enzymes. Research indicates that ketoconazole or VOR can boost APA levels in animal models,⁹ raising questions about similar risks with ISA, potentially causing side effects like hand-foot syndrome, high blood pressure, protein in urine, or low neutrophils.¹⁰ To address this, the pharmacist conducted TDM for APA using liquid chromatography-tandem mass spectrometry, following established methods.¹¹ On day 39 (APA day 2), Cmin values were 3.82 μg/mL for ISA and 24.66 ng/mL for APA. By day 44 (APA day 7 at steady state), they stood at 4.12 μg/mL and 30.41 ng/mL. Since APA's dose-response link isn't fully defined, area under the curve (AUC0-24) was calculated: 116.5 mg·h/L for ISA and 5283 mg·h/L for APA, matching clinical trial data (ISA 200 mg daily: 106 ± 32.1 mg·h/L; APA 500 mg daily: 8991 ± 3139 mg·h/L).¹¹,¹² No adverse effects appeared, and he was discharged on day 45 with ISA (200 mg daily) and APA (375 mg daily) prescriptions (Figure 2). A week later at follow-up, Cmin levels were 3.40 μg/mL for ISA and 24.41 ng/mL for APA. He transferred to a local hospital, where ISA was stopped after 12 weeks, showing substantial CT improvement.
Figure 1 Thoracic CT features of the patient during different antifungal therapy. (A1 and A2) day 2 of admission (voriconazole day 18); (B1 and B2) day 13 of admission (voriconazole day 29); (C1 and C2) day 36 of admission (isavuconazole day 23).
Figure 2 The timeline of antifungal and TKI therapy, and trough concentrations.
Abbreviations: ANL, anlotinib; VOR, voriconazole; AMB, amphotericin B; CAS, caspofungin; ISA, isavuconazole; APA, apatinib.
Discussion
To the best of our knowledge, this report is the first to detail TDM-guided antifungal management amid new-generation aa-TKI use in IPA patients with cancer. By using TDM for efficacy and safety checks, it shines a light on the critical role of individualized antifungal approaches in oncology.
IPA is a formidable complication in cancer care, with rising death rates.² Voriconazole, a top choice, shows wide variability in how patients handle it, primarily metabolized via liver CYP2C19. Genetic variations in CYP2C19 greatly influence exposure.⁴ Guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) note that ultra-rapid or rapid metabolizers often fall short of target levels with standard doses, recommending alternatives like ISA, liposomal amphotericin B, or posaconazole.⁷ In this instance, insufficient VOR levels—likely from quick metabolism—may explain the initial setbacks. A CYP2C19 genotype test could confirm this, but it wasn't available locally, and VOR was discontinued. Interestingly, the higher VOR Cmin on admission (0.93 μg/mL) might stem from interactions with anlotinib. Studies link CYP2C19 variants to anlotinib levels and reactions,¹³ but its role as a CYP2C19 inhibitor remains unclear. No prior reports exist on VOR-anlotinib interactions, calling for more research into mechanisms.
But here's where it gets controversial: should genetic testing be mandatory before starting azoles, or do we risk overcomplicating treatment for everyone? What do you think—could this lead to better outcomes or unnecessary delays?
ISA, a newer triazole, matches VOR's effectiveness in IPA trials.⁶ It offers perks like predictable dosing, less variability, and fewer interactions.¹⁴ While TDM isn't always needed, it's useful for detecting DDIs, though official thresholds for ISA efficacy and safety are pending.²,³ Some suggest aiming for 2–5 μg/mL Cmin.¹⁵ Here, TDM ensured stable ISA levels, correlating with better results and less fluctuation than VOR, showing ISA's reliability.
Emerging aa-TKIs like anlotinib and APA are key for advanced bone and soft tissue cancers, backed by trials.¹⁶,¹⁷ Both rely on CYP3A4/5, so interactions with azoles are a worry. Preclinical data predict or show increased exposure with azoles,⁸,¹⁸ yet our case saw stable levels and no reactions, with AUCs in line with trials, suggesting low DDI risk. That said, measurements weren't continuous post-discharge, a limitation. More robust studies are needed.
And this is the part most people miss: while this case points to minimal interaction between ISA and APA, it contrasts with potential VOR-anlotinib issues. Could this spark a debate on which combinations are safer? Share your thoughts in the comments—do these findings change how you view antifungal-cancer drug pairings?
Conclusion
As novel aa-TKIs gain traction in cancer therapy, customizing antifungal treatments for IPA becomes essential to balance effectiveness and safety. This example illustrates minimal pharmacokinetic interference between ISA and APA, but possible concerns with VOR and anlotinib, aided by TDM. Comprehensive investigations into azole-aa-TKI interactions are warranted.
Data Sharing Statement
Supporting data for this study can be obtained from the corresponding author (Ruiting Wen) with a reasonable request.
Consent Statement
The patient provided informed consent for TDM and publication of results. Since this is a case report (not a clinical trial), no ethics board review was sought, as serum monitoring is standard care at our hospital.
Funding
Supported by Peking University People’s Hospital Scientific Research Development Funds (RDL2022-42, RDE2023-05).
Disclosure
Ruiting Wen, Wentao Ni, and Xiaotong Gu equally contributed as co-first authors. Ruiting Wen and Xiaohong Zhang equally contributed as co-corresponding authors. No authors report conflicts of interest related to this article.
References
Wang Y, Cui X, Tian R, Wang P. The epidemiological characteristics of invasive pulmonary aspergillosis and risk factors for treatment failure: a retrospective study. BMC Pulm Med. 2024;24(1):559. doi:10.1186/s12890-024-03381-3
Zhang F, Li T, Bai Y, et al. Treatment strategies with combined agency against severe viral pneumonia in patients with advanced cancer. J Transl Int Med. 2024;12(3):317–320.
Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24(1):e1–e38. doi:10.1016/j.cmi.2018.01.002
Chen K, Zhang X, Ke X, et al. Individualized medication of voriconazole: a practice guideline of the division of therapeutic drug monitoring, Chinese Pharmacological Society. Ther Drug Monit. 2018;40(6):663–674. doi:10.1097/FTD.0000000000000561
Shen G, Zheng F, Ren D, et al. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol. 2018;11(1):120. doi:10.1186/s13045-018-0664-7
Donnelly JP, Chen SC, Kauffman CA, et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020;71(6):1367–1376. doi:10.1093/cid/ciz1008
Moriyama B, Obeng AO, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2C19 and voriconazole therapy. Clin Pharmacol Ther. 2017;102(1):45–51. doi:10.1002/cpt.583
Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a Phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760–769. doi:10.1016/S0140-6736(15)01159-9
Lou D, Cui X, Bao SS, et al. Effects of ketoconazole, voriconazole, and itraconazole on the pharmacokinetics of apatinib in rats. Drug Dev Ind Pharm. 2019;45(4):689–693. doi:10.1080/03639045.2019.1569042
Geng R, Song L, Li J, Zhao L. The safety of apatinib for the treatment of gastric cancer. Expert Opin Drug Saf. 2018;17(11):1145–1150. doi:10.1080/14740338.2018.1535592
Ding J, Chen X, Dai X, Zhong D. Simultaneous determination of apatinib and its four major metabolites in human plasma using liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. J Chromatogr B. 2012;895–896:108–115. doi:10.1016/j.jchromb.2012.03.027
Bergmann F, Wölfl-Duchek M, Jorda A, et al. Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions. J Antimicrob Chemother. 2024;79(5):1169–1175. doi:10.1093/jac/dkae088
Tan T, Han G, Cheng Z, et al. Genetic polymorphisms in CYP2C19 cause changes in plasma levels and adverse reactions to anlotinib in Chinese patients with lung cancer. Front Pharmacol. 2022;13:918219. doi:10.3389/fphar.2022.918219
Zhang T, Shen Y, Feng S. Clinical research advances of isavuconazole in the treatment of invasive fungal diseases. Front Cell Infect Microbiol. 2022;12:1049959. doi:10.3389/fcimb.2022.1049959
Risum M, Vestergaard MB, Weinreich UM, et al. Therapeutic drug monitoring of isavuconazole: serum concentration variability and success rates for reaching target in comparison with voriconazole. Antibiotics. 2021;10(5):487. doi:10.3390/antibiotics10050487
Liao Z, Li T, Zhang C, et al. Clinical study of apatinib in the treatment of stage IV osteogenic sarcoma after failure of chemotherapy. Cancer Biol Med. 2020;17(2):501–512. doi:10.20892/j.issn.2095-3941.2019.0397
Tang L, Niu X, Wang Z, et al. Anlotinib for recurrent or metastatic primary malignant bone tumor: a multicenter, single-arm trial. Front Oncol. 2022;12:811687. doi:10.3389/fonc.2022.811687
Bu F, Cho YS, He Q, et al. Prediction of pharmacokinetic drug-drug interactions involving anlotinib as a victim by using physiologically based pharmacokinetic modeling. Drug Des Devel Ther. 2024;18:4585–4600. doi:10.2147/DDDT.S480402
This case raises intriguing questions: Is TDM the future of antifungal therapy, or are we over-relying on it? Do these findings challenge the status quo on drug combinations in cancer care? We'd love to hear your opinions—agree, disagree, or share your own experiences in the comments!
