Treatment of pediatric brain tumors is an evolving field. With improvements in mortality, more attention has been focused on maximizing quality of life (QOL) and minimizing effects of therapy. There are efforts to tailor treatment protocols and reduce radiation doses in patients with more favorable molecular subtypes . Advances in radiation therapy, including PRT, promise to reduce radiation doses delivered to normal tissues. Data is needed to further evaluate whether PRT is superior to XRT in terms of reducing clinically meaningful long-term sequelae of radiation and whether dose reductions can achieve similar survival rates.
Two prior studies done by Eaton et al. and Bielamowicz et al. directly examined the differences between PRT and XRT [11, 15]. Eaton et al. found that PRT was associated with lower incidence of hypothyroidism and sex hormone deficiency, reduced need for endocrine replacement therapy, and greater height SDS at follow up. Bielamowicz et al. focused on hypothyroidism, specifically looking at central and primary hypothyroidism, and while not statistically significant, the data suggested a trend towards decreased risk of both primary and central hypothyroidism.
This study extends the work of Bielamowicz et al. to examine the incidence of primary and central hypothyroidism, GHD, and AI at a single institution among patients who have undergone both PRT and XRT. There was a higher incidence of hypothyroidism among patients who underwent XRT even after accounting for age at diagnosis, sex, race/ethnicity, and CSI radiation dose. More specifically there was higher incidence of primary and central hypothyroidism among XRT vs. PRT patients. Difference in the incidence of primary hypothyroidism supports prior hypotheses that spinal RT using protons may spare normal healthy tissues such as the thyroid, heart, and lungs that are distant from the target volume. Difference in the incidence of central hypothyroidism, while statistically insignificant, should cautiously be noted. This suggests that pituitary gland may have less radiation exposure after posterior fossa boost in patients treated with PRT CSI compared to XRT CSI. There was no significant difference between the incidences of AI or GHD between the two groups. Thus, the overall risk of HPA dysfunction remains similar despite use of PRT, and shows that the relative sensitivity of the growth hormone and ACTH producing pituitary tissue to RT is high even with lower overall dosage. This is consistent with the study done by Merchant et al., which suggested that the dose to the HPA was large enough with both PRT and XRT to cause GHD .
While there remained lower rates of hypothyroidism with PRT compared to XRT due to the difference in targeted dosage to the thyroid gland, the length of follow up was unable to ascertain the potential difference in outcomes of secondary thyroid cancer progression. Thyroid cancer is a known complication of spinal RT following medulloblastoma due to mutational transformation of the surviving thyroid tissue following irradiation . XRT therapy for medulloblastoma was previously shown to have an 18 fold increase in observed to expected case ratio in thyroid cancer incidence, typically occurring at more than 5–10 years from exposure . A concern however is that at higher targeted doses to the thyroid of > 2 Gy, the relative incidence of thyroid cancer is flat due to higher rate of cell destruction within the thyroid gland, while at lower doses between 0.2-2 Gy, there is a linear increase in the rate of thyroid cancer [22, 23]. This effect is caused by lower rates of cell destruction and sterilization of thyroid tissue at lower doses of RT but predisposing those tissues to malignant transformation. While lower overall doses of thyroid targeted RT with PRT may allow for reduced thyroid hormonal dysfunction, theoretically this actually may increase the overall incidence of secondary thyroid cancer. Although prior models have suggested a lower overall projected incidence of all cause secondary cancers with PRT vs. XRT among medulloblastoma survivors, the true rate of secondary thyroid cancer with PRT in this population is unknown and deserves long term follow up studies to determine outcomes .
This single-site, retrospective cohort study evaluated a large cohort of pediatric patients with medulloblastoma, where follow up laboratory studies and endocrinology referrals have become more standardized. The criteria used to diagnose hypothyroidism, were strictly defined, similar to the study done by Bielamowicz et al., and did not include cases of subclinical hypothyroidism unless started on thyroid replacement therapy. With PRT now in use at our institution for over ten years, there are patients who have had significant follow up time to allow for the development of endocrine sequelae. Prior studies have shown that the majority of endocrinopathies may occur in the subsequent 6 years from tumor therapy [33, 34], but endocrine complications have been reported decades later [35, 36], so re-assessing this cohort in the future may still be beneficial and may clarify what impact, if any, length time bias has on these outcomes. While this study’s median follow up was 5.6 years and likely reports a majority of outcomes for those individuals with > 5 years of follow up, it is possible that for patients with follow up time < 5 years and particularly < 2 years (all patients treated with PRT), the incidence of endocrine dysfunction may be underreported [17, 18, 37].
A limitation of this study was that some patients that had received XRT were not included in the analysis due to lack of timely and regular endocrine testing in the early 2000s. An additional limitation relates to the stimulation testing for GHD and AI. In most situations, stimulation testing was only performed if clinically indicated (obvious abnormalities in growth patterns, abnormal IGF testing, abnormal cortisol testing or symptoms of AI), which could explain lower incidence of GHD in our study. However, in later years more standardized referral to endocrinology and serial testing was adopted, and thus closer monitoring of endocrine function may have improved the findings in this study. In fact, rates of AI in our study were higher than the published literature, which could be related to more proactive screening protocols in recent years.
Ultimately, the results of this study add to the evidence that PRT results in less harm to non-target organs such as the thyroid and possibly the pituitary gland, leading to improved endocrine outcomes. Specifically in our study, there is a decreased risk of any hypothyroidism overall, and primary hypothyroidism in particular, with PRT in comparison to XRT. We observed similar rates of GHD and AI with PRT and XRT. However, further studies are needed to investigate longer-term effects of PRT and verify whether this finding remains statistically significant in a cohort followed decades after completion of therapy. Further studies must also be performed to assess whether lower radiation doses achieved with PRT will impact the rate of thyroid malignancy and reduce the risk of late effects on the heart and lungs.