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Topotecan-based regimen improves ocular salvage, vision preservation in advanced retinoblastoma
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The combination of systemic vincristine, topotecan and carboplatin with aggressive focal therapies improved ocular salvage and preserved vision in patients with advanced retinoblastoma, according to study results published in the Journal of Clinical Oncology.
Further, this approach limited the use of radiation therapy.
Because most patients who present with localized intraocular disease have excellent survival, the focus of treatment for retinoblastoma is ocular salvage and vision preservation, Rachel C. Brennan, MD, assistant member in the department of oncology at St. Jude Children’s Research Hospital, and colleagues wrote.
“The goals of chemoreduction are to reduce tumor burden and facilitate local control with focal therapy,” the researchers wrote. “The selection and duration of systemic chemotherapy are based on the intraocular disease burden, laterality and potential for preservation of vision.”
Vincristine, carboplatin and etoposide is the most commonly administered systemic chemotherapy combination used to treat advanced intraocular retinoblastoma.
However, efforts to minimize the risk for etoposide-related secondary leukemia have yielded promising preclinical results with the combination of topotecan and carboplatin.
Brennan and colleagues evaluated the efficacy of systemic topotecan in combination with vincristine and carboplatin to treat 27 patients with bilateral retinoblastoma (median age, 8.4 months).
Treatment included two courses of topotecan plus vincristine, followed by three alternating administrations of carboplatin and vincristine for two courses and topotecan plus vincristine for one course, with optional periocular carboplatin. Focal treatments — including cryotherapy, laser photocoagulation, thermotherapy and plaque radiotherapy — could be administered after cycle 2 of chemotherapy.
Of the 51 eyes included in the analysis, 78% were considered Reese-Ellsworth classification groups IV and V and 69% were International Classification of Retinoblastoma groups C to E.
Researchers evaluated EFS, defined as avoidants of external-beam radiation therapy and enucleation.
All patients were alive after a median follow-up of 7.4 years (range, 2.7-10).
The 10-year EFS and ocular survival were the same per patient (69.2%; 95% CI, 0.16-1) and per eye (82.4%; 95% CI, 0.49-1).
Stratification by group demonstrated an ocular survival of 78% (standard error [SE] ± 21%) in eyes classified in Reese-Ellsworth group IV to V and 74% (SE ± %) for International Classification group C to E eyes.
In addition, cumulative incidence of external-beam radiotherapy was 5.9% (SE ± 3%) at 10 years for the Reese-Ellsworth group IV to V and the International Classification group E.
Ten eyes were enucleated, which included one eye at diagnosis, one eye due to neovascular glaucoma after therapy, one eye with hemorrhage related to tumor response during therapy, three eyes in two patients who developed progressive disease during therapy, and four with progressive disease after therapy.
Vision testing that occurred when patients were aged a median of 7 years (range, 5-10) showed 83% of patients with documented vision of 20/70 or better in one eye and 75% of patients with 20/40 vision in one eye.
All patients experienced neutropenia, 25 patients experienced with thrombocytopenia and 23 patients experienced anemia.
Other nonhematologic events included diarrhea, mucositis, anorexia, dehydration, emesis, rash and nonneutropenic fever.
“The incorporation of topotecan into first-line therapy for patients with advanced bilateral intraocular retinoblastoma and the improved rates of ocular salvage with useful vision clearly support the efforts to translate preclinical research into effective patient care,” Brennan and colleagues wrote. “Topotecan in combination with carboplatin, vincristine, and aggressive focal therapy should be considered as first-line therapy for patients with advanced intraocular disease to achieve globe salvage with measurable vision.” – by Kristie L. Kahl
Disclosure: Brennan reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
Back to TopGregory H. Reaman
Although retinoblastoma occurs infrequently and accounts for only approximately 3% of childhood cancer, its successful treatment is associated with an enormous burden, which has a severely disabling impact on the quality of life of successfully treated infants and children. This is particularly true in children with more advanced tumors and, particularly, in children with bilateral disease.
Multimodality therapy has dramatically improved survival outcomes; however, the early and progressive decrease in visual acuity associated with external beam radiotherapy and the total loss of vision in children whose management has required enucleation represent significant prices to pay for putative therapeutic success. The situation is especially desperate for children with bilateral disease for whom, until recently, blindness was a nearly expected complication of therapy. Efforts to reduce the rate of enucleation and the need for external beam radiotherapy with both local therapies — laser, cryotherapy, subtenon carboplatin, and plaque brachytherapy — and effective systemic chemotherapy regimens have been central to clinical research efforts in this disease. Effective and commonly used drugs to treat retinoblastoma include vincristine, carboplatin and etoposide.
The preclinical data demonstrating the synergistic effect of combination topotecan and carboplatin and its use in place of etoposide reduces the risk for treatment-associated second malignancies in the disease. Brennan and colleagues provide convincing evidence of the transformative results of systemic topotecan and carboplatin with focal therapy including periocular carboplatin, which provides high intraocular concentrations without systemic toxicity, in not only extending survival, but doing so with preservation of vision by reducing the rates of enucleation and need for external beam radiotherapy.
The complex management associated with the treatment decisions and delivery require expert, multidisciplinary teams that include ocular oncologists. The results reported mandate a new paradigm for the management of patients with advanced and bilateral disease and predict a brighter future for children afflicted with this disease.
Disclosure: Reaman reports no relevant financial disclosures.
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