title: Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation.
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.
authors.affiliation: Divisions 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.
authors.forename: H S
authors.initials: HS
authors.lastname: Chan
authors.forename: G
authors.initials: G
authors.lastname: DeBoer
authors.forename: J J
authors.initials: JJ
authors.lastname: Thiessen
authors.forename: A
authors.initials: A
authors.lastname: Budning
authors.forename: J E
authors.initials: JE
authors.lastname: Kingston
authors.forename: J M
authors.initials: JM
authors.lastname: O'Brien
authors.forename: G
authors.initials: G
authors.lastname: Koren
authors.forename: E
authors.initials: E
authors.lastname: Giesbrecht
authors.forename: G
authors.initials: G
authors.lastname: Haddad
authors.forename: Z
authors.initials: Z
authors.lastname: Verjee
authors.forename: J L
authors.initials: JL
authors.lastname: Hungerford
authors.forename: V
authors.initials: V
authors.lastname: Ling
authors.forename: B L
authors.initials: BL
authors.lastname: Gallie
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D019540:Area Under Curve; D016190:Carboplatin / Q000627:therapeutic use; D002675:Child, Preschool; D016572:Cyclosporine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D017674:Hypophosphatemia / Q000139:chemically induced; D007223:Infant; D007231:Infant, Newborn; D019572:Retinal Neoplasms / Q000188:drug therapy*; D012175:Retinoblastoma / Q000188:drug therapy*; D013713:Teniposide / Q000627:therapeutic use; D016896:Treatment Outcome; D014750:Vincristine / Q000627:therapeutic use; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014750:Vincristine; D016572:Cyclosporine; D013713:Teniposide; D016190:Carboplatin