Late Effects of the Neuroendocrine System
Children who undergo hematopoietic stem cell transplantation (HSCT) with total-body irradiation (TBI) have a significant risk of both GHD and the direct effects of radiation on skeletal development. Risk is increased with single-dose as opposed to fractionated TBI, pretransplant cranial irradiation, female gender, and posttreatment complications such as graft-versus-host disease (GVHD).[11,12,13] Regimens containing busulfan and cyclophosphamide appear to increase risk in some studies,[13,14] but not others. Hyperfractionation of the TBI dose markedly reduces risk in patients who have not undergone pretransplant cranial radiation for CNS leukemia prophylaxis or therapy. The late effects that occur after HSCT have been studied and reviewed by the Late Effect Working Party of the European Group for Blood and Marrow Transplantation. Among 181 patients with aplastic anemia, leukemias, and lymphomas who underwent HSCT before puberty, an overall decrease in final height-SDS value was found compared with height at transplant and genetic height. The mean loss of height is estimated to be approximately 1 height-SDS (6 cm) compared with the mean height at time of HSCT and mean genetic height. The type of transplantation, GVHD, GH, or steroid treatment did not influence final height. TBI (single-dose radiation therapy more so than fractionated dose radiation therapy), male gender, and young age at transplant, were found to be major factors for long-term height loss. Most patients (140 of 181) reached adult height within the normal range of the general population.[17,18]
GHD should be treated with replacement therapy. Some controversy surrounds this, with a concern over increased risk of primary tumor recurrence and second malignancies. Most studies, however, are limited by selection bias and small sample size. One study evaluated 361 GH-treated cancer survivors enrolled in the CCSS and compared risk of recurrence, risk of secondary neoplasm, and risk of death among survivors who did and did not receive treatment with GH. The relative risk (RR) of disease recurrence was 0.83 (95% CI, 0.37-1.86) for GH-treated survivors. GH-treated subjects were diagnosed with 15 second malignant neoplasms, all solid tumors, for an overall RR of 3.21 (95% CI, 1.88-5.46), mainly because of a small excess number of second neoplasms observed in survivors of acute leukemia. With prolonged follow-up, the elevation of second cancer risk due to GH diminished. Compared with survivors not treated with GH, those who were treated had a twofold excess risk of developing a second neoplasm (RR = 2.15; 95% CI, 1.33-3.47, P < .002), and meningiomas were the most commonly observed (9 of 20 tumors). A review of existing data suggests that treatment with GH is not associated with an increased risk of CNS tumor progression or recurrence, or new or recurrent leukemia. In general, the data addressing second malignancies should be interpreted with caution given the small number of events.