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The adverse events of chemotherapy for retinoblastoma: what are they? Do we know?

E XTERNAL BEAM RADIATION (EBR) IS AN EFfective treatment for intraocular retinoblastoma, as it has been shown to save children’s vision as well as their lives. While once standard therapy, and despite its success, EBR has largely been abandoned, owing to the concern of secondary malignancies, and has been replaced with systemic multiagent chemotherapy. It is unusual in cancer treatment that the decision for successful treatment be based not on the immediate result (eliminating the cancer), but rather on complications that may develop many ( 30) years later. Nonetheless, in the last 10 years there has been a shift in treatment preference, and numerous authors have reported favorable outcomes using various drug regimens. It has been demonstrated that Reese-Ellsworth groups I-V can be successfully treated with either EBR or multiagent systemic chemotherapy followed by focal treatments. Patient and ocular survival appear identical in all cases despite the approach, but a lighter drug regimen often calls for additional radiation. Knowledge of adverse effects is therefore critical in deciding which therapy is best for the patient. With more than 95 articles describing experiences with chemotherapy and retinoblastoma, one would expect there to be extensive reporting on the adverse effects of these drugs, but surprisingly, little has been published on toxicity, and what has been published is widely variable and often difficult to quantify. The information that does exist is relatively short-term, as there are few children treated with modern chemotherapy who are older than 10 years. What do we know about the short-term adverse effects of systemic chemotherapy for retinoblastoma? While some have described them as “serious” or “life-threatening,” others have classified them as “well tolerated” or “mild.” Even articles written by the same authors at the same institution cite different incidences and use different terminology when reporting on toxicity. Shields et al reported in 2002 that “no patient developed serious side-effects of chemotherapy such as renal toxicity, hearing loss or second cancers,” but in the same year reported systemic infection in 3% of patients and prolonged bone marrow suppression in 7%. In 1996, the same authors reported systemic toxic effects as “temporary abdominal pain, nausea, vomiting, constipation, hair loss, and transient myeloid suppression” occurring in all patients. Considering that EBR, a treatment that works equally well in controlling tumor growth, has been abandoned owing to its associated adverse effects, it is puzzling that the incidence and severity of the adverse events associated with systemic chemotherapy remain unclear, and it is only rational that the subject be further investigated. Through a recent review of the published literature worldwide, we identified 61 articles published within the last 10 years regarding use of chemotherapy to treat intraocular retinoblastoma. Review articles were not included. Of these, 27 were excluded owing to their lack of toxicity reporting. This left only 34 articles reporting on any adverse event, whether the results were qualitative or quantitative. Fourteen articles employed the standard 3-drug regimen of carboplatin, vincristine, and etoposide; 3 articles employed the 3-drug regimen plus cyclophosphamide; 1 article employed the 3-drug regimen plus cyclosporin; 3 articles employed a 2-drug regimen of carboplatin and etoposide; 2 articles employed a 2-drug regimen of carboplatin and vincristine; and 2 articles employed a 1-drug regimen of carboplatin alone. Nine articles assigned patients to multiple treatment arms. The number of days per cycle that each drug was administered varied, but most studies used a standard regimen of carboplatin at 560 mg/m/d (18.7 mg/kg/d for younger children), etoposide at 150 mg/m/d (5 mg/kg/d for younger children) and vincristine at 1.5 mg/m/d (0.05 mg/kg/d for younger children). Dosage of carboplatin ranged from 90 mg/m/d to 1000 mg/m/d, dosage of etoposide ranged from 100 mg/m/d to 300 mg/m/d, dosage of cyclophosphamide ranged from 150 mg/m/d to 600 mg/m/d, and mean dosage of cyclosporin ranged from 8 mg/kg/d to 39 mg/ kg/d. The number of cycles of chemotherapy administered varied according to patient, but ranged from 1 to 13. While 1 article’s sole objective was to evaluate adverse events during the chemotherapeutic treatment of retinoblastoma, and 2 articles reported on the ototoxic effects of carboplatin, the others included, at most, a short paragraph or table relating to toxicity. Our original goal was to provide a quantitative as well as a qualitative review of the literature; however, a metaanalysis in its true form was not possible owing to the ambiguity of toxicity data. Eight papers reported adverse events qualitatively, giving few or no numeric values (eg, some patients experienced gastrointestinal toxicity, few required transfusions). Authors also used different terminology to describe the same adverse event, which made it difficult to categorize the data. Incidences of adverse events commonly reported in the articles that predominantly reported toxicity quantitatively are summarized in Table 1 and Table 2, and the ranges of incidences from 2and 3-drug regimens are shown in the Figure. Even when numeric values were used, it was impossible to make significant comparisons, because levels of severity were rarely