Academic Background and Problem Statement

Fibroblast growth factor receptor inhibitors (FGFRi) are a class of targeted drugs used to treat intrahepatic cholangiocarcinoma (iCCA). Although FGFRi has shown significant efficacy in treating iCCA, the potential complications associated with their long-term use have not been fully studied. In particular, whether FGFRi is associated with the formation or progression of cataracts is of great importance in clinical practice. Cataracts are a common eye disease that can lead to vision loss or even blindness. Therefore, understanding whether FGFRi treatment is associated with cataract formation is crucial for optimizing patient treatment plans and improving quality of life.

Previous studies have shown that FGFR is widely expressed in ocular tissues, and FGFRi may cause various ocular adverse effects, such as dry eye, uveitis, and central serous retinopathy. However, research on the effects of FGFRi on the adult lens, particularly cataract formation, is very limited. Although cataracts were not listed as a common adverse event in FGFRi clinical trials, a few case reports and clinical studies have suggested that FGFRi may be associated with cataract formation. Therefore, this study aims to explore the incidence, clinical characteristics, and related risk factors of cataracts in iCCA patients treated with FGFRi through retrospective case analysis.

Source of the Paper and Author Information

This study was conducted by Isabell Kassaye, Adam Alyafaie, Karen Zhang, Jacob Lifton, John D. Gordan, Robin Kate Kelley, and Madeline Yung, all affiliated with the University of California, San Francisco (UCSF) Department of Ophthalmology and Hematology-Oncology. The study data were sourced from the UCSF Hepatobiliary Tissue Bank and Registry, covering iCCA patients treated with FGFRi between February 2015 and October 2021. The study was conducted from September 6, 2022, to May 4, 2023, with data analysis completed from May 5 to September 6, 2023. The results were published online on October 24, 2024, in JAMA Ophthalmology.

Study Design and Methods

This study is a retrospective case series aimed at describing the occurrence or progression of cataracts in iCCA patients treated with FGFRi. The study included 18 iCCA patients with FGFR2 gene abnormalities who underwent ophthalmic evaluation after FGFRi treatment. The primary outcome was the development or worsening of cataracts after FGFRi treatment. Cataracts were defined as: new-onset cataracts, worsening of pre-existing cataracts, indications for cataract surgery, or a decrease in best-corrected visual acuity (BCVA) by at least two lines.

The study employed univariate and multivariate statistical analysis methods to assess the association between cataract formation and clinical variables. Specific methods included t-tests, Fisher’s exact tests, and a bivariate logistic regression model to analyze the relationship between the total duration of FGFRi therapy, patient age, and cataract development.

Study Results

Among the 18 patients, 9 (50%) developed new or worsening cataracts in at least one eye after FGFRi treatment. Of the 17 eyes with cataracts, 8 (47%) required cataract surgery. One patient required emergency surgery due to cataract-associated phacomorphic glaucoma. The median time from the initiation of FGFRi treatment to cataract onset or worsening was 18 months (range: 1-23 months). Notably, 5 out of 9 patients (56%) were diagnosed with new or worsening cataracts after discontinuation of FGFRi.

Statistical analysis showed that the median duration of FGFRi treatment in patients who developed cataracts (13 months) was significantly longer than in those who did not (5 months). Bivariate regression analysis further indicated that the duration of FGFRi therapy was significantly associated with cataract development (OR=1.01, 95% CI: 1.00-1.02, p=0.048), while patient age was not significantly associated with cataract formation.

Discussion and Conclusions

This study is the first to systematically explore the relationship between FGFRi treatment and cataract formation. Although the retrospective design of the study precludes the establishment of causality, the results suggest that FGFRi treatment may be associated with the formation or progression of cataracts, particularly in patients with longer treatment durations. This finding contrasts with the lower incidence of cataracts reported in previous clinical trials, possibly due to the shorter follow-up periods in those trials, which may have missed cataracts occurring after treatment discontinuation.

The FGFR signaling pathway plays an important role in the development and maintenance of the lens, and FGFRi may impair lens structure by inhibiting this pathway, leading to cataract formation. Additionally, hyperphosphatemia, a common systemic adverse event of FGFRi, may also be associated with cataract formation. The study also found that some patients developed cataracts after discontinuation of FGFRi, suggesting that the long-term inhibitory effects of FGFRi may lead to compensatory responses in the lens, and the rebound of signaling pathways after discontinuation may further exacerbate cataract formation.

Based on these findings, the study recommends regular ophthalmic examinations during and after FGFRi treatment to detect and manage cataracts early. This is particularly important for improving the quality of life in iCCA patients, given their limited survival.

Highlights and Significance of the Study

The highlight of this study lies in its systematic revelation of the potential association between FGFRi treatment and cataract formation, filling a knowledge gap in this field. The results suggest that FGFRi treatment may increase the risk of cataracts, particularly in patients with longer treatment durations. This finding provides important guidance for clinical practice, recommending regular ophthalmic monitoring during and after FGFRi treatment.

Furthermore, the study proposes a hypothesis regarding the mechanism of cataract formation after FGFRi discontinuation, providing direction for further research on the effects of FGFRi on the lens. Although the study has a small sample size, its results have significant clinical implications, especially for iCCA patients, as cataract formation may further impact their quality of life.

Limitations of the Study

The limitations of this study include its retrospective design, incomplete data, and small sample size. As the study relied on medical records, ophthalmic evaluations for some patients may not have been systematic, potentially leading to an underestimation of cataract incidence. Additionally, the short survival of iCCA patients may have resulted in some patients dying before cataract development, further affecting the accuracy of the study results.

Despite these limitations, this study provides preliminary evidence of the relationship between FGFRi treatment and cataract formation, laying the groundwork for future prospective studies.