A Cautionary Tale: Dosing Chemotherapy in Infants With Retinoblastoma

Thisyear,8,000childrenwillbediagnosedwithretinoblastoma(RB) worldwide.Thisrarechildhoodcancer isa threatnotonly tosightbutalso to life. The majority of children diagnosed with RB live in economically underdeveloped countries where fewer than half can be expected to survive into adulthood. In contrast, in the United States, where only a few hundred children develop RB each year, almost all will be cured of RB. Before the 1990s, treatment of intraocular RB consisted largely of surgery (enucleation) and external-beam radiotherapy (EBRT). These therapies cured patients and salvaged vision. However, late effects including severe orbital hypoplasia with attendant cosmetic deformity, and a threefold increase in the rate of second tumors was found among children carrying the RB mutation. In the early 1990s, pediatric oncologists learned that certain chemotherapeutic agents, notably carboplatin and etoposide, were useful in the treatment of brain tumors. These same drugs were able to effectively reduce the volume ofintraoculardiseaseinchildrenwithbilateralRBandtheageofchemoreduction was born. The term chemoreduction refers to the use of chemotherapytoreducetumorvolumetoallowsuccessful treatmentwithfocal ophthalmic therapies such as cryotherapy, thermotherapy, laser, and scleral radioactive plaques. The best results are obtained when experienced oncologic ophthalmologists provide focal therapy. In the article that accompanies this editorial, Qaddoumi et al report their experience with carboplatin and vincristine in 60 patients with intraocular RB. In a retrospective review, they found an alarmingly high rate of sustained severe ototoxicity, a rate markedly different from three previously published reports from Dutch, American, and French investigators. Smits et al reported their observations of the hearing status of 25 children with RB with a median age at initiation of treatment of 7 months and a median follow-up of 25 months. No hearing loss was detected except for a single patient with a 13q deletion who had severe hearing loss before treatment. Lambert et al reported their data for 116 patients with intraocular RB who received carboplatin-containing regimens. The median age at the initiation of therapy was 10 months, and the median follow-up was 40 months. Again, no patient with a normal initial audiogram developed hearing loss. Of the 14 children with abnormal audiograms initially, only three remained persistently abnormal. Lastly, Jehanne et al analyzed the data of 175 children with RB treated at the Institut Curie. The median age at diagnosis in this study was 4 months, and the median follow-up was 60 months. Although ototoxicity was found in eight children (one of whom had hearing loss before therapy), only two had hearing loss that required hearing aids. Jehanne et al concluded that ototoxicity was uncommon and might be associated with an as yet unpredictable individual susceptibility to carboplatin. Recently, specific genotypes associated with higher rates of cisplatin-induced hearing loss have been identified. How does one reconcile the previous reports in which more than 300 young children were treated with carboplatin, without significant problems with hearing loss, with the present report of Qaddoumi et al in which nine of 60 patients require hearing aids? Differences in length of follow-up cannot be the reason, given that the median time from start of treatment to detection of hearing loss was 8 months in the present study. Although different audiologic methods were used to evaluate the patients and a lower threshold to define hearing loss was used in this report, the number of patients requiring hearing aids is clearly higher. Radiation therapy has been reported to contribute to the severity of platinum-related hearing loss. Twenty-eight of 60 patients (47%) in the present report received EBRT compared with 79 of 316 patients (25%) in the Dutch, American, and French series. However, Qaddoumi et al did not find an association between EBRT and hearing loss in their univariate analysis, possibly as a result of insufficient sample size. The authors note that the only risk factor identified as a significant predictor of sustained hearing loss was younger age at the start of chemotherapy. Therein may be the answer: Qaddoumi et al are the only investigators administering chemotherapy to infants based on body-surface area (BSA). The three prior reports all specified per-kilogram dosing ofchemotherapyforpatientsweighingless than10kilograms(oryounger than age 36 months for the patients treated by Lambert et al). Several carboplatin dosing formulas, developed based on the known relationship between renal function and drug exposure, are currently used in children, with each formula mathematically taking into account changes in renal function that occur during normal growth. Although these formulas have been validated in children, none have been validated in infants, and there is reason to believe that such validation, especially in infants younger than age 6 months, could fail. Moreover, the common practice of normalizing infant chemotherapeutic doses to body weight instead of BSA results in a net decrease in dose, offsetting not only differences in drug disposition (pharmacokinetics) but also potential differences in end organ sensitivity (pharmacodynamics). The differences in doses administered can be significant. For example, the carboplatin dose for an averagesize 3-month-old would be approximately 100 mg if calculated based on body weight (18.6 mg/kg) in contrast to the 170 mg dose (560 mg/m or glomerular filtration rate based) when normalized to BSA. Such cautionary advice in dosing young infants was highlighted in an excellent review by Kearns et al, in which the authors warn that failure to account for the ontogeny of organ function “can result in the exposure of infants to potentially toxic serum levels of drugs.” Similar experience with BSA-based dosing in young infants indeed has occurred in children treated for cancer, most recently in a study of infants with leukemia that used per meter square dosing of chemotherapy in an effort to improve event-free survival, only to determine that the approach resulted in a 25% induction mortality rate. These distinctions are more than academic as a new treatment named chemosurgery is gaining popularity in the treatment of Editorials