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Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation
H S Chan1, G DeBoer, J J Thiessen
1Divisions of Hematology-Oncology and Clinical Pharmacology and Toxicology, Department of Pediatrics, Hospital for Sick Children Research Institute, 555 University Avenue, Toronto, Ontario M5G 1X8 Canada.
Abstract:
Chemotherapy without radiation has not controlled most intraocular retinoblastoma, perhaps because of the common high expression of multidrug resistance P-glycoprotein that we found in retinoblastoma. Cyclosporin blocks P-glycoprotein-induced efflux of vincristine and teniposide in vitro, and possibly modulates responses to carboplatin. To avoid eye irradiation in bilateral retinoblastoma patients with RB1 germline mutations, which incurs a high second malignancy rate, we added cyclosporin A to a vincristine-teniposide-carboplatin protocol and consolidated chemotherapy responses with focal therapy. We scored patients requiring irradiation, enucleation, or focal ablation of central vision as failures. In 21 study patients, the overall relapse-free rate at a median follow-up of 3.3 years was 76%, with a rate of 92% for newly diagnosed and 50% for previously treated, relapsed retinoblastoma. Our results for the most unfavorable tumors with vitreous seeds (86% at 3.5 years) are better than published success rates of irradiation for similar tumors, or irradiation with the same chemotherapy without cyclosporin (45% at 2. 6 years). These results also exceeded our historic success rate with similar chemotherapy without cyclosporin, focal therapy, and/or radiation in 19 equivalently poor-risk patients (relapse-free rate 37% at a median follow-up of 5.6 years, P = 0.032), 16 of whom were previously untreated (relapse-free rate also 37%, P = 0.012). A better outcome occurred with higher cyclosporin blood levels and projected tissue exposure. Cyclosporin did not enhance the usual chemotoxicity. This clinical study suggests that cyclosporin improves the long-term response of retinoblastoma to chemotherapy, possibly by more than one mechanism.
Insights
Adding cyclosporin A to chemotherapy improved retinoblastoma outcomes. This approach reduced the need for radiation and enucleation, showing promise for controlling intraocular retinoblastoma.
Area of Science:
- Ophthalmology
- Oncology
- Pharmacology
Background:
- Intraocular retinoblastoma often resists chemotherapy due to P-glycoprotein.
- Radiation therapy for retinoblastoma, especially in bilateral cases with RB1 mutations, carries a high risk of secondary malignancies.
- P-glycoprotein efflux of chemotherapy drugs can be blocked by cyclosporin.
Purpose of the Study:
- To evaluate the efficacy of adding cyclosporin A to a chemotherapy regimen for intraocular retinoblastoma.
- To reduce the need for radiation therapy and associated risks in retinoblastoma patients.
- To assess the impact of cyclosporin A on relapse-free rates and treatment outcomes.
Main Methods:
- A vincristine-teniposide-carboplatin chemotherapy protocol was administered with cyclosporin A.
- Focal therapy was used to consolidate chemotherapy responses.
- Patients requiring irradiation, enucleation, or focal ablation of central vision were considered treatment failures.
Main Results:
- The overall relapse-free rate was 76% at a median follow-up of 3.3 years.
- For newly diagnosed retinoblastoma, the relapse-free rate was 92%, and for previously treated, relapsed cases, it was 50%.
- Outcomes for unfavorable tumors with vitreous seeds (86% relapse-free at 3.5 years) surpassed historical rates for similar tumors treated with irradiation or chemotherapy without cyclosporin.
Conclusions:
- Cyclosporin A, when added to chemotherapy, significantly improves long-term response rates in retinoblastoma.
- This combination therapy potentially offers a way to avoid radiation and reduce secondary malignancy risks.
- Higher cyclosporin blood levels correlated with better outcomes, suggesting a dose-dependent effect.