Factors predicting endocrine late effects in childhood cancer survivors from a Japanese hospital

Abstract

We retrospectively analyzed endocrine late effects in 81 childhood cancer survivor (CCS) patients who had been referred to our endocrinology department in Chiba Children’s Hospital between January 1, 2008 and December 31, 2016. Among 69 eligible patients (33 male, 36 female), endocrine late effects were identified in 56 patients (81.1%). The median age at the last visit to our endocrinology department was 17.4 years (range: 7.1–35.3 years). The most common primary cancer was acute lymphoblastic leukemia (22 patients, 31.8%). Forty-four patients (64%) were treated using radiation therapy. A primary brain tumor and high doses (≥6 g/m²) of cyclophosphamide were significantly associated with growth hormone deficiency (GHD). Our present study suggests that high doses of cyclophosphamide is a risk factor for GHD. Adult heights and pubertal growth spurts of patients treated with radiation therapy were significantly lower than patients not treated with radiation therapy. Our retrospective study reconfirmed that hematopoietic stem cell transplantation and chronic graft versus host disease (GVHD) were associated with elevated risks of primary hypothyroidism. However, it is unclear whether GVHD induces thyroid dysfunction. Gonadal radiation and busulfan were associated with primary hypogonadism as reported in previous studies. We found high doses of cyclophosphamide to be involved in pituitary disorders. We suggest that pediatric endocrinologists should discuss the potential effects of radiation therapy on adult height and pubertal growth spurt in CCS patients. Moreover, patients who have been treated with high doses of cyclophosphamide or have chronic GVHD require long-term follow-up for endocrine late effects.

THE SURVIVAL RATES for childhood cancer have recently improved [1], although childhood cancer survivor (CCS) patients may encounter late effects and related health problems decades after their first cancer treatment. Approximately 50% of CCS patients will experience endocrine late effects [2], and there is a growing interest in how these late effects influence the patient’s quality of life. While a large retrospective cohort study conducted by the Childhood Cancer Survivor Study has evaluated the endocrine late effects following childhood cancer treatment [3], a recent Japanese multicenter study too has examined the general health and endocrine late effects in CCS patients [4], although few previous reports have described the endocrine late effects in Japanese CCS patients [5-7]. Therefore, the present study investigated the endocrine late effects in CCS patients treated at our hospital and aimed to identify the predictive factors in this setting.

Materials and Methods

Patients

We reviewed records of 81 patients who had undergone cancer treatment and were then referred to our Department of Endocrinology between January 1, 2008 and December 31, 2016. However, we excluded 10 patients who had received treatment within the previous year (physiological amounts of steroid drugs, immunosuppressant drugs, or chemotherapy) and 2 patients who had died. Thus, this retrospective study included data from 69 patients (33 males and 36 females, Table 1). The retrospective protocol of this study was approved by the ethics committee of Chiba Children’s Hospital and complied with the principles of the Declaration of Helsinki.

Table 1 Patient characteristics

	Number of patients	(%)
Sex
Female	36	(52%)
Male	33	(48%)
Primary disease
Hematological disease	47	(68%)
Brain tumor	11	(16%)
Solid tumor	11	(16%)
Treatment
Chemotherapy	63	(91%)
Radiotherapy	44	(64%)
Surgery	14	(20%)

The median age at the first visit to our Department of Endocrinology was 10.2 years (range: 1.5–26.0 years), and the median age at the last visit was 17.4 years (range: 7.1–35.3 years). The median follow-up duration was 8.0 years (range: 0.33–21.6 years). The median age at the diagnosis of primary cancer was 4.3 years (range: 0–15.6 years). The diagnoses included hematological diseases (47 patients), brain tumors (11 patients), and solid tumors (11 patients). The hematological diseases included acute lymphoblastic leukemia (22 patients), acute myelocytic leukemia (12 patients), non-Hodgkin lymphoma (8 patients), aplastic anemia (3 patients), Wiskott-Aldrich syndrome (1 patient), and juvenile myelomonocytic leukemia (1 patient). The brain tumors included craniopharyngioma (5 patients), medulloblastoma (2 patients), primitive neuroectodermal tumors (2 patients), plexus papilloma (1 patient), and a germ cell tumor (1 patient). The solid tumors included rhabdomyosarcoma (3 patients), neuroblastoma (3 patients), Langerhans cell histiocytosis (3 patients), hepatoblastoma (1 patient), and a yolk sac tumor (1 patient).

Treatment

The patients were treated based on applicable guidelines (e.g., the Tokyo Children’s Cancer Study Group protocol), although the recommended treatments evolved during the study period. The treatments included chemotherapy (63 patients), radiotherapy (44 patients), and/or surgery (14 patients). Chemotherapeutic agents used were classified into alkylating agents, anthracyclines, methotrexates, heavy metals, and asparaginase. We examined the doses of alkylating agents used in the study because they were widely used and induced DNA damage. Radiotherapy involved total body irradiation (TBI: 5–12 Gy) and local irradiation (18–58 Gy). Patients who underwent hematopoietic stem cell transplantation (HSCT) with TBI conditioning, received TBI 12 Gy (six fractions of 2 Gy each). Four patients underwent HSCT conditioning with total lymphoid irradiation (TLI: 3–7.5 Gy single irradiation). The highest dose of radiation used was 58 Gy (29 fractions of 2 Gy each) as local irradiation in a patient who had been diagnosed with craniopharyngioma. HSCT was performed for 41 patients, including 1 patient who completed the maximum number of HSCTs (four treatments). Hematopoietic stem cells were derived from the bone marrow (31 patients), cord blood (11 patients), and/or peripheral blood (11 patients). The conditioning regimen involved chemotherapy alone (14 patients) or chemotherapy plus TBI or TLI (27 patients). It is well known that myeloablative conditioning (MAC) has the risk of endocrine late effects, and therefore reduced intensity conditioning (RIC) has been developed as it reduces early morbidity and endocrine late effects [3, 8, 9]. RIC regimen consists of low doses of alkylating agents and fludarabine, along with a low dose of TBI in certain situations [10]. In this study, only one patient received HSCT with RIC. She had been diagnosed with aplastic anemia and underwent bone marrow transplantation along with a conditioning regimen of cyclophosphamide 200 mg/kg and anti-thymocyte globulin 10 mg/kg. Twenty-one patients (51.2%) had acute graft versus host disease (GVHD) and 27 patients (65.9%) had chronic GVHD.

Endocrinology parameters

Clinical examinations were performed to determine height and weight at the most recent visit. Body mass index (BMI) values were calculated for males who were >18 years old and females who were >16 years old. Obesity was defined as an excess weight of >20% of the ideal body weight or a BMI of >25 kg/m², and underweight status was defined as a reduced weight of <20% of ideal body weight or a BMI of <18.5 kg/m². Height was evaluated based on the standard deviation score (SDS) and a short stature was defined as any value <–2 standard deviations.

Growth hormone stimulation testing was performed for patients with a height that was 2 standard deviations below the SDS or for patients with a growth velocity of –1.5 standard deviations for >2 years. Growth hormone deficiency (GHD) in children was diagnosed based on a peak growth hormone (GH) level of <6 ng/mL when using insulin, arginine, clonidine, and dopamine, or a peak GH level of <16 ng/mL when using growth hormone releasing peptide-2. Severe adult GHD was diagnosed based on a peak GH level of <1.8 ng/mL when using insulin, arginine, clonidine, and dopamine, or a peak GH level of <9 ng/mL when using growth hormone releasing peptide-2 [11].

We correlated their thyroid function reference with this report [12]. Primary hypothyroidism was defined as a TSH level of ≥10 μIU/mL with a free T₄ level of <0.75 ng/dL. Central hypothyroidism was defined as an free T₄ level of <0.75 ng/dL and non-elevated TSH levels. Subclinical hypothyroidism was defined as a TSH level of ≥5 μIU/mL and a normal free T₄ level. Hyperthyroidism was defined as a TSH level of ≤0.10 μIU/mL and elevated free T₃ and/or free T₄ level. We checked for both thyroglobulin and thyroid peroxidase (TPO) autoantibodies in hypothyroidism cases, and thyrotropin receptor antibodies in hyperthyroidism cases. Thyroid ultrasonography was performed when: thyroid nodules were palpable, thyroid dysfunction was suspected based on the laboratory and physical findings, or the CCS patient was being transferred to receive treatment as an adult.

Tanner’s method was used to evaluate pubertal status. Laboratory data were checked to evaluate the serum levels of basal FSH, LH, and estradiol or testosterone. Puberty onset was defined as a testicular volume of >4 mL in boys [13] or when breast enlargement (Tanner 2) was detected in girls. We distinguished between primary and central hypogonadism based on the laboratory data. Treatment was considered for boys who had not experienced testicular enlargement by the age of 13 years and girls who had not experienced breast enlargement by the age of 12 years. We suspected precocious puberty when boys had a testicular volume of >4 mL by the age of 9 years or when girls had breast enlargement by the age of 7.5 years [14].

Statistical analysis

Relationships between clinical factors and endocrine late effects were evaluated using the chi-squared test and Fisher’s test. The Mann-Whitney U-test was used to assess inter-group differences. P values <0.05 were considered statistically significant. We selected factors for endocrine late effects by looking at previous studies. Multivariable logistic regression analyses were performed to identify factors that predicted endocrine late effects. The final multivariable model, using backward stepwise selection, included several factors significantly associated with endocrine late effects. All statistical analyses were performed using EZR (version 1.27; Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R software (The R Foundation for Statistical Computing, Vienna, Austria) that includes frequently used biostatistical functions [15].

Results

Endocrine late effects were identified in 56 patients (81.1%, Table 2), with no significant differences between male and female patients (27/33 [81.8%] vs. 29/36 [80.6%]). Hormone replacement therapy was provided to 39 patients (56.5%, 18 male and 21 female), and 12 patients (17.4%, 6 male and 6 female) received multiple hormone replacements.

Table 2 Numbers and proportions of endocrine late effects

Endocrine late effects	Number of patients	(%)
Growth hormone deficiency	13	18.8%
Hypothyroidism	14	20.2%
Thyroid-stimulating hormone deficiency	5	7.2%
Primary hypothyroidism	4	5.8%
Subclinical hypothyroidism	5	7.2%
Hyperthyroidism	2	2.9%
Hypogonadism	25	36.2%
LH/FSH deficiency	4	5.8%
Primary hypogonadism	21	30.4%
Central precocious puberty	8	11.6%

LH, luteinizing hormone; FSH, follicle-stimulating hormone

Body type and growth

At the most recent visit, 6 patients were considered obese and 23 patients (11 male and 12 female) were considered underweight, based on their body type. The 6 obese patients included 1 male patient and 5 female patients. Twenty-eight patients were judged to have a short stature, including 8 patients who received growth hormone replacement therapy.

All 13 patients who were diagnosed with GHD had also received growth hormone replacement therapy (Table 3), and their median height SDS value at the last visit was –2.43 (range: –4.91 to +0.6). Three of these patients were diagnosed with severe adult GHD and continued their growth hormone replacement therapy. Six of the thirteen patients had a primary brain tumor and 6 patients received a high dose of cyclophosphamide (>6 g/m²) each. Both, the primary brain tumor patients and patients who received high doses of cyclophosphamide, were independently associated with GHD in the multivariable model, which included brain tumor, HSCT, acute GVHD, and a high dose of cyclophosphamide (Table 4), although there was no significant difference in cranial irradiation.

Table 3 Univariate predictors of growth hormone deficiency

	GHD (n = 13)	Non-GHD (n = 56)	Odds ratio	95% CI	p-value
Sex			1.984	0.577–6.824	0.272
Male	8	25
Female	5	31
Primary cancer
Hematological disease	6	41	0.314	0.091–1.084	0.059
Brain tumor	6	5	8.743	2.101–36.378	0.001
Solid tumor	1	10	0.383	0.045–3.296	0.367
Age at primary cancer diagnosis			0.917	0.170–4.930	0.919
<10 years old	11	48
≥10 years old	2	8
Treatment
Cranial radiation	9	26	2.250	0.618–8.198	0.212
Hematopoietic stem cell transplantation	5	36	0.347	0.100–1.205	0.088
Acute GVHD	1	20	0.150	0.018–1.240	0.048
Chronic GVHD	4	23	0.638	0.175–2.322	0.493
Chemotherapy
Alkylating agents	6	43	0.302	0.083–1.099	0.060
Cyclophosphamide	6	30	0.667	0.188–2.362	0.528
≥6 g/m2	6	8	5.250	1.346–20.475	0.011
Busulfan	3	11	1.398	0.317–6.168	0.657
Ifosfamide	0	8
Anthracyclines	6	41	0.317	0.087–1.154	0.073
Methotrexates	5	27	0.714	0.201–2.532	0.601
Heavy metals	2	8	1.150	0.211–6.256	0.871
Asparaginase	4	23	0.674	0.181–2.512	0.555

GHD, growth hormone deficiency; CI, confidence interval; GVHD, graft versus host disease

Table 4 Independent predictors of growth hormone deficiency

	Odds ratio	95% CI	p-value
Primary cancer
Brain tumor	15.700	2.970–83.100	0.011
Cyclophosphamide (≥6 g/m2)	7.990	1.500–42.600	0.015

CI, confidence interval

Adult height was identified based on a growth of <1 cm/year and was evaluated in 37 patients. The adult height SDS of patients treated with radiation therapy (median: –1.98 SDS [range: –4.34 to +3.47]; p = .033) was significantly lower than patients not treated with radiation therapy (median: –0.45 SDS [range: –2.25 to +2.09]) (Fig. 1). We also examined the pubertal growth spurt based on the heights at the start of puberty and adulthood. The pubertal growth spurt of patients treated with radiation therapy (median: 11.9 cm [range: 2.2–30.7 cm]; p = .008) was significantly lower than patients not treated with radiation therapy (median: 21.3 cm [range: 15.2–31.6 cm]) (Fig. 2).

Fig. 1

Range of adult height with and without radiation.

The adult height based on the standard deviation score (SDS) of patients treated using radiation therapy was significantly lower than that of patients not treated using radiation therapy

Fig. 2

Range of pubertal growth spurt with and without radiation.

The pubertal growth spurt based on the heights at the start of puberty and adulthood, revealed a significantly smaller pubertal growth spurt in patients treated using radiation therapy

Thyroid function

Sixteen patients had thyroid disorders. Fourteen patients had hypothyroidism, including five with central hypothyroidism, four with primary hypothyroidism, and five with subclinical hypothyroidism. Eleven patients received levothyroxine treatment. Table 5 shows the characteristics of patients with primary and subclinical hypothyroidism. Nine patients had been diagnosed with primary cancer before the age of 10 years, nine patients had undergone HSCT, and seven patients developed chronic GVHD. HSCT and chronic GVHD were significantly associated with primary and subclinical hypothyroidism (p < .05). Eight patients had undergone radiation therapy. We found positive results for both thyroglobulin and TPO autoantibodies in only 1 patient. The primary cancers in patients with central hypothyroidism were four craniopharyngiomas and one suprasellar germ cell tumor. Two patients with hyperthyroidism were diagnosed with Graves’ disease based on positive results for TSH receptor antibodies, and 1 of the 2 patients had undergone HSCT. Four patients had thyroid nodules identified during their long-term follow-up, which was diagnosed as adenomatous goiter [16], and all of these patients had undergone HSCT before the age of 10 years.

Table 5 Univariate predictors of primary and subclinical hypothyroidism

	Hypothyroidism (n = 9)	Euthyroid (n = 53)	Odds ratio	95% CI	p-value
Sex			2.240	0.506–9.911	0.279
Male	6	25
Female	3	28
Primary cancer
Hematological disease	7	38	1.382	0.257–7.423	0.705
Brain tumor	1	5	1.200	0.124–11.659	0.059
Solid tumor	1	10	0.538	0.060–4.802	0.573
Age at primary cancer diagnosis
<10 years old	9	45			0.590
≥10 years old	0	8
Treatment
Cranial radiation	8	27	6.686	0.799–316.194	0.069
Hematopoietic stem cell transplantation	9	31			0.021
Acute GVHD	4	17	1.694	0.403–7.120	0.469
Chronic GVHD	7	20	5.775	1.091–30.579	0.025
Chemotherapy
Alkylating agents	8	37	3.243	0.373–28.228	0.264
Cyclophosphamide	7	28	4.750	0.540–41.802	0.129
≥6 g/m2	4	9	4.222	0.883–20.190	0.058
Busulfan	3	11	2.018	0.415–9.815	0.378
Ifosfamide	2	6	2.278	0.371–13.991	0.364
Anthracyclines	7	39	1.077	0.197–5.892	0.932
Methotrexates	4	27	0.681	0.163–2.841	0.597
Heavy metals	2	7	1.755	0.301–10.231	0.528
Asparaginase	3	23	0.587	0.132–2.613	0.481

GHD, growth hormone deficiency; CI, confidence interval; GVHD, graft versus host disease

Gonadal function

Thirty-three patients had gonadal disorders (13 male and 20 female), including 4 patients with central hypogonadism, 21 patients with primary hypogonadism, and 8 patients with central precocious puberty. Sex hormone replacement had been performed for 24 patients (7 male and 17 female), although 2 female patients stopped receiving this therapy since they underwent menstruation and defaulted the treatment. The primary cancers in patients with central hypogonadism were three craniopharyngiomas and one germ cell tumor. Sixteen patients had been diagnosed with their primary cancer before the age of 10 years (Table 6). Seventeen patients were treated using gonadal radiation therapy and 18 patients had undergone HSCT. Eighteen patients received alkylating agents and there was significant difference using busulfan. All 8 patients treated with busulfan received a high dose (>100 mg/m²) through MAC. Gonadal radiation and busulfan were independent risk factors for primary hypogonadism in the multivariable model which included gonadal radiation, HSCT, and busulfan (Table 7). The patients with central precocious puberty included 5 boys and 3 girls, with 5 patients undergoing cranial radiation therapy and only 1 patient having a primary brain tumor.

Table 6 Univariate predictors of primary hypogonadism

	Primary hypogonadism (n = 21)	Normal gonadal function (n = 28)	Odds ratio	95% CI	p-value
Sex			0.324	0.099–1.056	0.058
Male	7	17
Female	14	11
Primary cancer
Hematological disease	19	19	4.500	0.857–23.641	0.060
Brain tumor	2	2	1.368	0.177–10.601	0.763
Solid tumor	0	7
Age at primary cancer diagnosis			0.533	0124–2.294	0.394
<10 years old	16	24
≥10 years old	5	4
Treatment
Gonadal radiation	17	13	4.904	1.312–18.327	0.014
Hematopoietic stem cell transplantation	18	14	6.000	1.437–25.053	0.009
Acute GVHD	10	6	3.333	0.960–11.568	0.053
Chronic GVHD	14	7	6.000	1.724–20.879	0.003
Chemotherapy
Alkylating agents	18	17	5.824	1.123–30.203	0.024
Cyclophosphamide	13	12	2.600	0.705–9.592	0.146
≥6 g/m2	6	3	3.500	0.738–16.604	0.103
Busulfan	8	1	17.455	1.938–157.209	0.002
Ifosfamide	2	3	0.917	0.137–6.139	0.928
Anthracyclines	18	24	3.000	0.308–29.183	0.325
Methotrexates	13	15	1.733	0.507–5.928	0.379
Heavy metals	1	4	0.319	0.033–3.112	0.305
Asparaginase	14	12	3.402	0.846–15.741	0.072

GHD, growth hormone deficiency; CI, confidence interval; GVHD, graft versus host disease

Table 7 Independent predictors of primary hypogonadism

	Odds ratio	95% CI	p-value
Treatment
Gonadal radiation	8.700	1.550–48.900	0.014
Chemotherapy
Busulfan	29.100	2.360–360.000	0.009

CI, confidence interval

Other outcomes

Seven patients had central diabetes insipidus and were treated using desmopressin. The primary cancers included craniopharyngioma (4 patients), Langerhans cell histiocytosis (2 patients), and a germ cell tumor (1 patient). Six of these patients had been treated using other hormone replacements.

Discussion

The increasing survival rate of CCS patients has highlighted the importance of additional treatments and prediction factors of endocrine late effects of cancer. For example, Hudson et al. [17] reported that, among CCS patients, the prevalence of any chronic health condition was 95.5% at the age of 45 years, with 80.5% of these conditions being considered serious or life-threatening. In this study, endocrine late effects were identified in 56 patients (81.1%). We reconfirmed that CCS patients had high risk for endocrine late effects. The present study revealed that short stature and growth retardation were the most common endocrine late effects, and GHD is known to be common in patients who receive cranial irradiation for brain tumors [18, 19]. Furthermore, as seen in previous reports [19, 20], the risk of GHD was elevated when the patient’s cancer was diagnosed before the age of 10 years.

The risk of GHD was not significantly associated with cranial radiation therapy, although it was associated with lower values for adult height and pubertal growth spurt. These results suggest that this type of radiation therapy might damage the patient’s spine and long bones, in addition to their hypothalamus-pituitary axis, which would lead to the GHD. The spine has increased vulnerability to radiation therapy during puberty [21], and it is important to have a follow-up for any patients who have received radiation therapy at the age of >10 years. Further studies should also consider assessing the effects on bone mineral density and bone age. Interestingly, the incidence of GHD was higher in patients treated with a high dose (≥6 g /m²) of cyclophosphamide. There is little understanding of the influence of alkylating agents on the pituitary. Some previous studies reported that cyclophosphamide induced oxidative stress in the brain of mice [22, 23], and Ayoka et al. reported that the parenchymal cells appeared scanty and hypertrophied in the pituitary of mice exposed to cyclophosphamide [24]. We deduced that the alteration of the histoarchitecture of the pituitary may lead to GHD.

All 9 patients with primary hypothyroidism and subclinical hypothyroidism had undergone HSCT. Interestingly, the prevalence of primary hypothyroidism is 23.1–45.1% among CCS patients who have undergone HSCT [25, 26], which suggests that HSCT is a possible risk factor for primary hypothyroidism. Other studies have indicated that related risk factors include TBI [27, 28] or chemotherapy for transplantation conditioning [29-31]. We reconfirmed that chronic GVHD was significantly associated with primary and subclinical hypothyroidism, and previous studies have also reported this [32, 33]. However, Savani et al. [34] could not confirm that chronic GVHD was a risk factor for thyroid damage. Hence, further studies are needed in order to confirm that GVHD contributed to primary and subclinical hypothyroidism.

However, the present study failed to detect a significant relationship between primary hypothyroidism and cranial radiation therapy or chemotherapy. This is because the follow-up duration in our study was shorter. Several studies reported that the risk of primary hypothyroidism increased with time [35, 36]. For this reason, the CCS patients should have a long-term follow-up even if their thyroid function is normal.

We unexpectedly found that both patients with Graves’ disease had not undergone radiation therapy. This result was surprising, as the risk of Graves’ disease is increased by radiation therapy [37], and Sklar et al. [36] have reported that a radiation dose of >35 Gy was associated with the development of Graves’ disease. However, there is speculation that Graves’ disease in patients who underwent HSCT is related to the donor’s T-cells and B-cells attacking the recipient’s thyroid gland [38, 39], which suggests that it involves chronic GVHD. In our study, both the patients with Graves’ disease had undergone HSCT and only one of them developed chronic GVHD.

We reconfirmed that gonadal radiation (p = 0.014) and busulfan (p = 0.009) were independently associated with primary hypogonadism, and previous studies have indicated these association [6, 30, 39]. We did not identify significant differences between the use of cyclophosphamide and age at the primary cancer diagnosis, although previous studies have indicated that a higher risk of ovarian dysfunction is associated with TBI before the age of 10 years in CCS patients [40, 41], and a high dose of cyclophosphamide could cause disorders in spermatogenesis [42, 43]. Nevertheless, this discrepancy may be related to the fact that our children’s hospital generally treated CCS patients before they had developed sufficient gonadal function for testing. In contrast, Leydig cell function is thought to be maintained in male patients who underwent HSCT and received a radiation dose of <20 Gy [30, 44], and only relatively mild damage is caused by alkylating agents, with a limited need for testosterone replacement therapies [45, 46]. Nevertheless, the functioning of germ cells and Sertoli cells is known to be adversely affected by low-dose alkylating agents and radiation [43, 47], which suggests that adolescent and adult patients require a careful follow-up.

An elevated risk of central precocious puberty is associated with cranial radiation doses of >18 Gy in CCS [48, 49]. However, in the present study, only 2 of the 5 patients with central precocious puberty had received a cranial radiation dose of >18 Gy. Nevertheless, careful follow-up is still needed for patients who receive low-dose radiation therapy, as patients who received only TBI for transplantation conditioning too, subsequently developed central precocious puberty [50]. Moreover, the risk is higher for patients who receive radiation therapy before the age of 5 years [51, 52], and 4 of our 5 patients with central precocious puberty had received radiation therapy before the age of 5 years.

The present study has some limitations. First, our study was retrospective and was performed in a single hospital. Second, the present study involved CCS patients who had been previously treated and referred to our center by their oncologists, which explains the relatively high prevalence of endocrine late effects. Third, approximately one-half of our patients were relatively young and had insufficient gonadal function for testing. Finally, we evaluated only a small sample of patients with relatively short follow-up periods (median: 8.0 years, range: 0.3–21.6 years), and endocrine late effects are known to increase over time in CCS patients [53]. Therefore, CCS patients should have long-term follow-up, even if they have not yet developed endocrine late effects.

In conclusion, there were no novel findings in the present study, although the incidence of endocrine late effects in CCS patients reported in previous studies were reconfirmed by us. We found that radiation therapy was associated with decreased values for pubertal growth spurt and adult height. Thus, we suggest that pediatric endocrinologists should discuss the potential effects of radiation therapy with their CCS patients. Additionally, our retrospective study suggests that a high dose of cyclophosphamide is associated with GHD. Furthermore, we reconfirmed that chronic GVHD was associated with an elevated risk of primary and subclinical hypothyroidism in CCS patients. Finally, CCS patients who had been treated with a high dose of cyclophosphamide or had chronic GVHD should have long-term follow-ups for endocrine late effects. Further study is needed to evaluate the effect of a high dose of cyclophosphamide for GHD and the association between chronic GVHD and primary hypothyroidism.

Disclosure

None of the authors have any potential conflicts of interest associated with this research.

References

• 1   Hampton  T (2005) Cancer treatment’s trade-off: years of added life can have long-term costs. JAMA 294: 167–168.
• 2   Brignardello  E,  Felicetti  F,  Castiqlione  A,  Chiabotto  P,  Corrias  A, et al. (2013) Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics. Eur J Endocrinol 168: 465–472.
• 3   Oeffinger  KC,  Mertens  AC,  Sklar  CA,  Kawashima  T,  Hudson  MM, et al. (2006) Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355: 1572–1582.
• 4   Ozono  S,  Ishida  Y,  Honda  M,  Okamura  J,  Asami  K, et al. (2014) General health status and late effects among adolescent and young adult survivors of childhood cancer in Japan. Jpn J Clin Oncol 44: 932–940.
• 5   Miyoshi  Y,  Ohta  H,  Hashii  Y,  Tokimasa  S,  Namba  N, et al. (2008) Endocrinological analysis of 122 Japanese childhood cancer survivors in a single hospital. Endocr J 55: 1055–1063.
• 6   Maeda  N,  Kato  K,  Matsuyama  T,  Kojima  S,  Ohyama  K (2003) High-Dose Busulfan is a major risk factor for ovarian dysfunction in girls after stem cell transplantation. Clin Pediatr Endocrinol 12: 13–18.
• 7   Ishiguro  H,  Yasuda  Y,  Tomita  Y,  Shinagawa  T,  Shimizu  T, et al. (2007) Gonadal shielding to irradiation is effective in protecting testicular growth and function in long-term survivors of bone marrow transplantation during childhood or adolescence. Bone Marrow Transplant 39: 483–490.
• 8   Ishida  H,  Adachi  S,  Hasegawa  D,  Okamoto  Y,  Goto  H, et al. (2015) Comparison of a fludarabine and melphalan combination-based reduced toxicity conditioning with myeloablative conditioning by radiation and/or busulfan in acute myeloid leukemia in Japanese children and adolescents. Pediatr Blood Cancer 62: 883–889.
• 9   Bitan  M,  He  W,  Zhang  MJ,  Abdel-Azim  H,  Ayas  MF, et al. (2014) Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens. Blood 123: 1615–1620.
• 10   Martino  R,  Iacobelli  S,  Brand  R,  Jansen  T,  van Biezen  A, et al. (2006) Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 108: 836–846.
• 11  Growth hormone research society workshop on adult growth hormone deficiency (1998) Consensus guidelines for the diagnosis, treatment of adults with growth hormone deficiency: summary statement for the growth hormone research society workshop on adult growth hormone deficiency. J Clin Endocrinol Metab 83: 379–381.
• 12   Iwaku  K,  Noh  JY,  Minagawa  A,  Kosuga  Y,  Suzuki  M, et al. (2013) Determination of pediatric reference levels of FT3, FT4 and TSH measured with ECLusys kits. Endocr J 60: 799–804.
• 13   Tanner  JM,  Whitehouse  RH (1976) Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 51: 170–179.
• 14  The study group of hypothalamic and pituitary disorder in Ministry of Health, Labor, and Welfare (2003) Diagnostic guidelines of central precocious puberty. http://square.umin.ac.jp/kasuitai/doctor/guidance/adolescence.pdf: accessed 2 June 2019 (In Japanese).
• 15   Kanda  Y (2013) Investigation of the freely-available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48: 452–458.
• 16   Shimazaki  S,  Kazukawa  I,  Ishida  M,  Minagawa  M (2018) Thyroid nodules and long-term follow-up among childhood cancer survivors who underwent hematopoietic stem cell transplantation. Clin Pediatr Endocrinol 27: 75–79.
• 17   Hudson  MM,  Ness  KK,  Gurney  JG,  Mulrooney  DA,  Chemaitilly  W, et al. (2013) Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309: 2371–2381.
• 18   Laughton  SJ,  Merchant  TE,  Sklar  CA,  Kun  LE,  Fouladi  M, et al. (2008) Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 26: 1112–1118.
• 19   Chemaitilly  W,  Li  Z,  Huang  S,  Ness  KK,  Clark  KL, et al. (2015) Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude lifetime cohort study. J Clin Oncol 33: 492–500.
• 20   Clement  SC,  Schoot  RA,  Slater  O,  Chisholm  JC,  Abela  C, et al. (2016) Endocrine disorders among long-term survivors of childhood head and neck rhabdomyosarcoma. Eur J Cancer 54: 1–10.
• 21   Bleyer  A,  Choi  M,  Wang  SJ,  Fuller  CD,  Raney  RB (2009) Increased vulnerability of the spinal cord to radiation or intrathecal chemotherapy during adolescence: a report from the Childrens Oncology Group. Pediatr Blood Cancer 53: 1205–1210.
• 22   Zhai  J,  Zhang  F,  Gao  S,  Chen  L,  Feng  G, et al. (2018) Schisandra Chinese extract decreases chloroacetaldehyde production in rats and attenuates cyclophosphamide toxicity in liver, kidney and brain. J Ethnopharmacol 210: 223–231.
• 23   Zarei  M,  Schivanandappa  T (2016) Neuroprotective effect of decalepis hamiltonii on cyclophosphamide-induced oxidative stress in the mouse brain. J Basic Clin Physiol Pharmacol 27: 341–348.
• 24   Ayoka  OA,  Ojo  OE,  Imafidon  EC,  Ademoye  KA,  Oladele  AA (2016) Neuro-endocrine effects of aqueous extract of Amaranthus viridis (Linn.) leaf in male wistar rat model of cyclophosphamide-induced reproductive toxicity. Toxicol Rep 3: 608–619.
• 25   Baker  KS,  Ness  KK,  Weisdorf  D,  Francisco  L,  Sun  CL, et al. (2010) Late effects in survivors of acute leukemia treated with hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivors Study. Leukemia 24: 2039–2047.
• 26   Leung  W,  Ahn  H,  Rose  SR,  Phipps  S,  Smith  T, et al. (2007) A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine 86: 215–224.
• 27   Berger  C,  Le-Gallo  B,  Donadieu  J,  Richard  O,  Deverqie  A, et al. (2005) Late thyroid toxicity in 153 long-term survivors of allogeneic bone marrow transplantation for acute lymphoblastic leukemia. Bone Marrow Transplant 35: 991–995.
• 28   Faraci  M,  Barra  S,  Cohen  A,  Lanino  E,  Grisolia  F, et al. (2005) Very late nonfatal consequences of fractionated TBI in children undergoing bone marrow transplant. Int J Radiat Oncol Biol Phys 63: 1568–1575.
• 29   Michel  G,  Socie  G,  Gebhard  F,  Bernaudin  F,  Thurnet  I, et al. (1997) Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation – a report from the Societe Francaise de Greffe de Moelle. J Clin Oncol 15: 2238–2246.
• 30   Afify  Z,  Shaw  PJ,  Clavano-Harding  A,  Cowell  CT (2000) Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide. Bone Marrow Transplant 25: 1087–1092.
• 31   Sanders  JE,  Hoffmeister  PA,  Woolfrey  AE,  Carpenter  PA,  Storer  BE, et al. (2009) Thyroid function following hematopoietic cell transplantation in children: 30 years’ experience. Blood 113: 306–308.
• 32   Isshiki  Y,  Ono  K,  Shono  K,  Onoda  M,  Yokota  A (2016) Autoimmune thyroid dysfunction after allogenic hematopoietic stem cell transplant. Leuk Lymphoma 57: 1227–1229.
• 33   Au  WY,  Lie  AK,  Kung  AW,  Liang  R,  Hawkins  BR, et al. (2005) Autoimmune thyroid dysfunction after hematopoietic stem cell transplantation. Bone Marrow Transplant 35: 383–388.
• 34   Savani  BN,  Koklanaris  EK,  Le  Q,  Shenoy  A,  Goodman  S, et al. (2009) Prolomged chronic graft-versus-host disease is a risk factor for thyroid failure in long-term survivors after matched sibling donor stem cell transplantation for hemtologic malignancies. Biol Blood Marrow Transplant 15: 377–381.
• 35   Mostoufi-Moab  S,  Seidel  K,  Leisenning  WM,  Armstrong  GT,  Oeffinger  KC, et al. (2016) Endocrine abnormalities in aging survivors of childhood cancer survivor study. J Clin Oncol 34: 3240–3247.
• 36   Sklar  CA,  Whitton  J,  Mertens  A,  Stovall  M,  Green  D, et al. (2000) Abnormalities of the thyroid in survivors of Hodgkins disease: data from childhood cancer survivor study. J Clin Endocrinol Metab 85: 3227–3232.
• 37   Hanock  SL,  Cox  RS,  McDougall  IR (1991) Thyroid diseases after treatment of Hodgkins disease. N Eng J Med 325: 599–605.
• 38   Tatevossian  R,  Blair  JC,  Plowman  PN,  Savage  MO,  Shankar  AG, et al. (2004) Thyrotoxicosis after matched unrelated bone marrow transplantation. J Pediatr Hematol Oncol 26: 529–531.
• 39   Sklar  C,  Boulad  F,  Small  T,  Kernan  N (2001) Endocrine complications of pediatric stem cell transplantation. Front Biosci 6: G17–G22.
• 40   Sarafoglou  K,  Boulad  F,  Gillio  A,  Sklar  C (1997) Gonadal function after bone marrow transplantation for acute leukemia during childhood. J Pediatr 130: 210–216.
• 41   Matsumoto  M,  Shinohara  O,  Ishiguro  H,  Shimizu  T,  Hattori  K (1999) Ovarian function after bone marrow transplantation performed before menarche. Arch Dis Child 80: 452–454.
• 42   Green  DM,  Liu  W,  Kutteh  WH,  Ke  RW,  Shelton  KC, et al. (2014) Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude lifetime cohort study. Lancet Oncol 15: 1215–1223.
• 43   Meistrich  ML (2013) Effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil Steril 100: 1180–1186.
• 44  Sanders JE (2004) Endocrine complications of high-dose therapy with stem cell transplantation. Pediatr Transplant 8 (Suppl 5): 39–50.
• 45   Romerius  P,  Stahl  O,  Moell  C,  Relander  T,  Cavallin-Ståhl  E, et al. (2009) Hypogonadism risk in men treated for childhood cancer. J Clin Endocrinol Metab 94: 4180–4186.
• 46   Greenfield  DM,  Walters  SJ,  Coleman  RE,  Hancock  BW,  Eastell  R, et al. (2007) Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study. J Clin Endocrinol Metab 92: 3476–3482.
• 47   Kenney  LB,  Cohen  LE,  Shnorhavorian  M,  Metzqer  ML,  Lockart  B, et al. (2012) Male reproductive health after childhood, adolescent, and young adult cancers: a report from the Children’s Oncology Group. J Clin Oncol 30: 3408–3416.
• 48   Gan  HW,  Phipps  K,  Aquilina  K,  Gaze  MN,  Hayward  R, et al. (2015) Neuroendocrine morbidity after pediatric optic gliomas: a longitudinal analysis of 166 children over 30 years. J Clin Endocrinol Metab 100: 3787–3799.
• 49   Chemaitilly  W,  Merchant  TE,  Li  Z,  Barnes  N,  Armstrong  GT, et al. (2016) Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes. Clin Endocrinol (Oxf) 84: 361–371.
• 50  Rossetti F, Messina C, Rebuffi L, Colleselli P, Pozzan GB, et al. (1991) Precocious puberty following BMT. Bone Marrow Transplant 8 (Suppl 1): 43.
• 51   Armstrong  GT,  Whitton  JA,  Gajjar  A,  Kun  LE,  Chow  EJ, et al. (2009) Abnormal timing of menarche in survivors of central nervous system tumors: a report from the childhood cancer survivor study. Cancer 115: 2562–2570.
• 52   Oberfield  SE,  Soranno  D,  Nirenberg  A,  Heller  G,  Allen  JC, et al. (1996) Age at onset of puberty following high-dose central nervous system radiation therapy. Arch Pediatr Adolesc Med 150: 589–592.
• 53   Diller  L,  Chow  EJ,  Gurney  JG,  Hudson  MM,  Kadin-Lottick  NS, et al. (2009) Chronic disease in the childhood cancer survivor study cohort: a review of published findings. J Clin Oncol 27: 2339–2355.