Hearing loss and dental abnormalities were the most prevalent outcomes for the patients in our study, impacting >90% of survivors. Dental changes are not an unexpected outcome secondary to TBI and chemotherapy [11
]. Holtta et al. noted that children treated between the ages of 3.1–5 years had the most dramatic dental effects of their cancer therapy [12
]. Dental changes have been noted after less intense, non-ablative therapies, but not at the severity and frequency of the current transplant population [14
]. Laverdiere et al. [9
] reported on 63 patients treated for advanced stage neuroblastoma, in this group the dental complications were only noted in 13%, though the treatment of this cohort was more heterogeneous and only 56% of this cohort had an autologous transplant.
An obligatory component of treatment for high-risk neuroblastoma includes cisplatin and carboplatin, known ototoxins. Over 90% of the subjects in this study had documented hearing loss, with significant hearing loss (Grade 3–4) in 58% of the cohort. This finding is similar to or higher than previous literature [6
]. Flandin et al. [6
] reported significant hearing loss in only 15% of a cohort of neuroblastoma survivors treated with 360–400 mg/m2
of cisplatin (±TBI). However, Parsons et al. [17
] reported on a cohort of patients, most of whom had received two cycles of high-dose cisplatin in induction therapy followed by a non-TBI transplant regimen using intensified carboplatin (2 g/m2
). Grade 3–4 hearing loss in this cohort was 82%. Several factors may explain the high rate of significant hearing loss in our study population, notably high dose carboplatin. Moreover, schedule of drug administration may play a role. The patients in our current cohort received 200 mg/m2
per course. Data in the literature suggest that hearing loss may be more significant when cisplatin is administered in this manner rather than two courses of 100 mg/m2
]. Additionally, young age of exposure may also have contributed to the rate of significant hearing loss [20
]. The use of ototoxic antibiotics for supportive care on therapy must also be considered as a possible contributing factor. Unlike many of the other long-term sequelae identified in our cohort, exposure to TBI is not the primary causative factor for hearing changes, as there is no literature, which associates hearing loss with TBI in the absence of platinum drug exposure. Ototoxicity is a serious problem in this population of survivors. Gurney et al. [22
] recently reported that neuroblastoma survivors with significant hearing loss are at elevated risk for learning difficulties and psychosocial problems.
One of the most striking late effects in this cohort is short physical stature, as none of the subjects had attained a height within the average range for their age. Below average height was noted even when subjects were not diagnosed to be GHD. Despite adequate GH replacement in the patients with GHD, they do not grow as well as patients with isolated GHD, since their long bones have been irradiated as part of the treatment regimen [23
]. Reports on the long-term outcomes of neuroblastoma survivors who were treated with a single autologous transplant including TBI had similar rates of short physical stature [18
]. The incidence of hypothyroidism the present cohort is consistent with numerous reports in the literature that have reported the negative impact of TBI on thyroid function [6
]. In patients treated with a single TBI containing transplant the incidence of hypothyroidism was lower than our cohort, but the median follow up time was significantly shorter [18
From a nutritional perspective, our results demonstrated that this predominantly male cohort is underweight for age. This is consistent with the report by Meacham et al. [26
] which found that male survivors of neuroblastoma in the CCSS cohort were more likely to be underweight as adults compared to sibling controls. These patients warrant anticipatory guidance regarding balanced nutrition and further monitoring regarding health consequences of abnormal BMI.
Musculoskeletal changes are not unexpected in children treated with radiation, including an increased prevalence of osteochondromas [27
]. Taitz et al. [27
] noted the overall risk of osteochondromas to be 24% after TBI, especially when the child was under the age of 5-year at time of treatment. When compared to previous studies, a larger percentage of patients in this study (46%) developed bony changes consistent with osteochondromas [18
]. One possible explanation is that the majority of osteochodromas found in our cohort were identified on routine radiographs performed for other tests, rather than when these deformities became painful or interfered with functional mobility.
Our data do not show any significant cardiac changes in this population. However, given that these survivors are just now within the first decade post treatment, the absence of significant cardiac toxicities should be viewed with cautious optimism. Although the cumulative dose of anthracylines in this treatment regimen is not high, the additive risks of TBI and young age at exposure support the need for longer follow up of cardiac function. In addition, although there is only one second tumor (a pheochromocytoma), the actual incidence of secondary tumors may increase further with time. Secondary hematological malignancies were not seen in this cohort. Similarly, in follow-up of 97 patients treated according to this protocol, one patient has presented with a myelodysplastic picture [5
]. One factor that may account for the low risk of secondary hematologic problems seen to date is the decision to collect PBSC early in therapy, where exposure to DNA-damaging agents is less than at the end of induction.
In summary, 13 survivors have significant long-term effects involving multiple systems that have the potential to negatively impact quality-of-life. The importance of continued vigilance with this cohort is evidenced by the fact that these patients already face significant challenges in the first decade after transplant. Moreover, the present results support and extend previous observations that TBI is a major contributor to long-term, multi-organ toxicities [18
]. It will be critical to study in a comprehensive manner the newer cohort of advanced stage neuroblastoma survivors who have been managed without TBI. This study is somewhat limited as these data are largely descriptive, and the small number of patients does not allow for high-powered statistical analyses. However, unlike other descriptive studies on outcomes for patients with stage IV neuroblastoma, these patients were uniformly treated, and were followed by the same subspecialists for their late effects of treatment. This highlights the strength of a consistent, collaborative multidisciplinary approach to late effects research, particularly in populations with multiple chronic treatment related toxicities.