Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation

• Published in: Clinical cancer research Vol. 2; no. 9; pp. 1499 - 1508
• Main Authors: CHAN, H. S. L, DEBOER, G, HUNGERFORD, J. L, LING, V, GALLIE, B. L, THIESSEN, J. J, BUDNING, A, KINGSTON, J. E, O'BRIEN, J. M, KOREN, G, GIESBRECHT, E, HADDAD, G, VERJEE, Z
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-09-1996
• Subjects: Antineoplastic agents; Antineoplastic Agents - therapeutic use; Area Under Curve; Biological and medical sciences; Carboplatin - therapeutic use; Chemotherapy; Child, Preschool; Cyclosporine - adverse effects; Cyclosporine - pharmacokinetics; Cyclosporine - therapeutic use; Drug Therapy, Combination; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Humans; Hypophosphatemia - chemically induced; Infant; Infant, Newborn; Medical sciences; Pharmacology. Drug treatments; Retinal Neoplasms - drug therapy; Retinoblastoma - drug therapy; Teniposide - therapeutic use; Treatment Outcome; Vincristine - therapeutic use; Weight Loss - drug effects; Human; Antineoplastic agent; Nervous system diseases; Drug combination; Retinopathy; Intraocular; Toxicity; Bilateral; Malignant tumor; Apocynaceae; Eye disease; Alkaloid; Chemotherapy; Treatment; Vinca; Dicotyledones; Angiospermae; Phase II trial; Phase I trial; Spermatophyta; Pharmacokinetics; Retinoblastoma; Child; Platinum II Complexes
• ISSN: 1078-0432; 1557-3265

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.