The current analysis was undertaken to take advantage of the large number of adult survivors of childhood acute leukemia within the CCSS cohort, with a median follow-up of over 20 years, in order to investigate the effects of different combinations of radiotherapy exposures on adult height/BMI, hypothyroidism, and reproductive outcomes. Although the long-term effects of radiation exposure on these outcomes have long been recognized, we were able to make direct comparisons of risks associated with various combinations of radiation exposures including CRT and TBI, relative to a group of survivors not treated with radiation therapy. In a recent collaborative analysis between the CCSS and the Bone Marrow Transplant Survivor Study, the endocrine system was the organ system most commonly affected among childhood HCT survivors, with upwards of 30% of HCT survivors reporting severe endocrine conditions compared with 5% of non-HCT general cancer survivors (11
). However, that study did not investigate specific endocrine complications or radiotherapy exposures in detail (11
). Typically, most other existing studies of these endocrine-associated outcomes (discussed in detail below) have examined patients treated with conventional therapies and HCT/TBI in isolation, and have rarely examined both groups directly.
A variety of studies have documented that children treated for leukemia may develop adverse height and BMI outcomes. Prior reports, including those from the CCSS have identified younger age at diagnosis, female gender, and increased CRT dose as factors associated with short stature, with those exposed to any spinal radiotherapy and any TBI at even greater risk (12
). However, even those treated with chemotherapy alone may be at increased risk of short stature (13
). Although growth hormone supplementation was associated with an increased rate of short stature in our analysis, we suspect that this was a surrogate for survivors who were most affected, as most studies suggest that timely supplementation among growth hormone deficient children improves final height (18
Among non-HCT pediatric leukemia survivors, particularly girls and those younger at diagnosis, exposure to CRT has been an established risk factor for subsequent obesity (21
). Although the exact mechanism remains unclear, it is postulated that radiotherapy injures the hypothalamic pituitary axis, affecting growth hormone secretion and leptin sensitivity (22
). However, more contemporary therapy without CRT also has been associated with increased BMI in some but not all studies, suggesting a possible role for glucocorticoids and lifestyle factors (16
). Our current results suggest that children treated with CRT+TBI tended to have an intermediate BMI phenotype compared with CRT only (higher average BMI) and TBI only (lower average BMI). However, a more detailed examination of TBI exposed patients’ body composition has typically revealed significant central adiposity and decreased lean body mass even among those with low or normal BMI (28
). Although the mechanism by which this sarcopenic obesity develops remains unclear, central adiposity may be a more specific risk factor for cardiometabolic risk than BMI defined adiposity (31
A prior report from the CCSS found a clear dose-relationship between craniospinal radiotherapy and subsequent hypothyroidism among ALL survivors, with risk differences between <2000 vs. ≥2000 cGy CRT doses, and increased risk with any spinal radiotherapy (33
). An analysis of nearly 800 pediatric HCT survivors treated at a single US center found that approximately 30% of patients subsequently developed some form of hypothyroidism, with those treated with TBI and/or busulfan having the greatest risk compared with those receiving cyclophosphamide-based regimens only (34
). Risk with busulfan exposure alone without concurrent radiotherapy also has been reported in other HCT populations (35
). Although our study lacked complete information on survivors’ HCT conditioning regimen, inclusion of only those who were treated with TBI would have excluded most individuals treated with busulfan-containing regimens. Our study also was limited by lack of hormonal data, which made it impossible for us to differentiate between primary and central hypothyroidism. Nonetheless, other studies have suggested that following HCT, compensated primary hypothyroidism is the most common type of hypothyroidism to develop (34
Finally, previous CCSS studies have shown that both female leukemia survivors and female partners of male survivors in general have decreased rates of pregnancy compared with siblings (40
). Among all childhood cancer survivors, increased radiation doses to the hypothalamus/pituitary gland (e.g., from CRT or TBI) and to the reproductive organs (e.g., from TBI, SRT-related scatter, or any testicular radiotherapy), as well as increased alkylating chemotherapy doses all have been associated with decreased fertility in a clear dose-response fashion (41
). Larger studies of HCT survivors generally feature transplant recipients treated as adults and report very low rates of subsequent pregnancies (typically ≤ 5% prevalence) (43
). In one study, 11 out of 196 (6%) prepubertal HCT recipients reported subsequent pregnancies (45
), which is consistent with our results. Nevertheless, recovery of ovarian and testicular function has been reported to occur in small numbers of patients, even after TBI-based myeloablative HCT regimens (45
Although our outcomes were self- (or proxy-) reported, self-reported heights and weights have generally been well-validated and correlate closely with measured values (47
), and also were used to derive the general population adult normative values in this study (10
). A study of HCT survivors that used a similar questionnaire as the current study found that the validity of self-reported hypothyroidism compared with medical records was excellent, with sensitivity, specificity, and overall agreement greater than 95% (48
). The reliability of self-reported pregnancies is known to be variable, as studies from the general population suggest that nearly one-quarter of pregnancies as detected by laboratory testing are not recognized by parents (49
). Nevertheless, we are not aware of evidence suggesting that such awareness would differ across our exposure groups of interest.
Additional factors that should be considered when interpreting our findings include changes in radiation therapy over the past 20 years. Although methods for delivering TBI, CRT, and SRT have changed less relative to other radiation modalities, contemporary CRT/SRT may result in less scatter to surrounding tissue than the older conventional doses experienced by our cohort, and reduced intensity or non-myeloablative TBI doses now becoming more common were much less likely to have been used during our study period (4
). Finally, it is possible select post-HCT exposures such as chronic graft versus host disease may contribute to some of the adverse outcomes examined. However, restriction of our TBI exposed cohort to those who were more than 5 years from transplant make it less likely that most transplant-related exposures would be actively present at time of outcome. Furthermore, we would not expect such exposures to necessarily differ between those treated with CRT+TBI vs. TBI alone.
In summary, our study of a very large cohort of childhood acute leukemia survivors was able to quantify and discriminate between the effects of cranial, spinal, and total body irradiation with respect to specific endocrine outcomes. Although the majority of acute leukemia survivors no longer receive cranial or craniospinal radiotherapy routinely, they remain an important part of many higher risk protocols. TBI-based HCT regimens also remain a common frontline choice for relapsed or very high risk acute leukemias in children. Therefore, these results may help clinicians better counsel patients and families with regards to these common late effects.