Long-term therapy related side effect on endocrine system among survivor with paediatric brain tumour and acute lymphoblastic leukaemia

Abstract

Background: Acute lymphoblastic leukaemia (ALL) and brain tumours are frequently seen in childhood malignancies. With the improved effectiveness of treatments, approximately 70–80% patients can be cured of their primary illness. However, therapy-related long-term sequelae among survivors are becoming a major concern. Traditional treatments include surgery, radiation and chemotherapy, and these have been shown to have prolonged side effects on the endocrine system, and symptoms may develop months or years after completion of treatment. Currently, the endocrine complications in survivors of brain tumours and ALL are under-studied in Hong Kong.

Objective: To evaluate the frequency and nature of endocrine complications in paediatric patients with brain tumours and ALL from 2000 to 2015 in Queen Mary Hospital, Hong Kong. Risk factors likely to be associated with these complications were also evaluated.

Method: 359 patients with acute lymphoblastic leukaemia, medulloblastoma, intracranial germ cell tumour, ependymoma and craniopharyngioma were reviewed retrospectively in a single centre within the study period and included 233 patients after screening for inclusion and exclusion criteria. Basic biological data, disease-related and treatment-related information were obtained from patients’ medical record. Endocrine dysfunction was defined by both clinical and laboratory evaluation. Details of endocrine complications, date of completed cancer treatment and diagnosis of complications were retrieved. Cox regression or Fisher’s exact test (2x2 table) was used, as these are appropriate for analysis of between-group differences in discrete variables. Odds ratios were calculated and reported as 95% confidence intervals for the prediction of incidence of different endocrine disorders. Patients who presented with endocrine complications before the start of cancer treatment were excluded from analysis.

Results: The most common complication was hypothyroidism (n=45), followed by hypogonadism (n=40). Other major complications included diabetes insipidus (n=29), growth hormone deficiency (n=28), hypoadrenalsim (n=23) and precocious puberty (n=8). Brain tumour patients are at significantly higher risk of developing endocrine complications in comparison to ALL patients (p < 0.0001, 63.2% vs. 13%). Gender, age at diagnosis, and tumour histology are not significantly associated with the complications. Brain tumour patients are also significantly associated with multiple endocrine complications. Craniopharyngioma patients had the highest association with endocrine deficiency, followed by germ cell tumour and medulloblastoma patients. Meanwhile, ependymoma patients had the least likelihood of having endocrine complication among all brain tumour patients. Radiotherapy and alkylating agents were risk factors in some of the endocrine complications. The use of alkylating agents was statistically significant associated with hypogonadism in both male and female (p=0.0035, odd ratio (OR) 3.956); meanwhile testicular radiotherapy (p=0.0001, OR 34.636) and TBI (p=0.0051, OR 9.058) were had greater association with primary hypogonadism, particularly in male patients. Both cranial radiotherapy (p <0.0001, OR 7.369) and brain surgery (p <0.0001, OR 7.77) were significantly associated for the prevalence of growth hormone deficiency. Cranial irradiation >40 Gy had significantly higher risk in developing hypothyroidism (p<0.0001, OR 7.6493) and hypoadrenalism (p=0.0002, OR6.32).

Conclusion: While endocrine complications can be caused by the tumour itself, current cytotoxic treatments are still contributory high risk factors. Endocrine complications are more frequent among brain tumour survivors than ALL survivors and hypothyroidism is the most common complication in local survivors. Patients who received radiotherapy and/or alkylating agents are at higher risk of endocrinopathies. It is hard to predict the onset time of post-treatment endocrine complications in a retrospective review. The early detection relies on regular screening, long-term multidisciplinary follow up and patient education.