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Purpose: In childhood cancer survivors, the most common late effect is thyroid dysfunction, most notably subclinical hypothy-
roidism (SCH). Our study evaluated the risk factors for persistent SCH in survivors.
Materials and Methods: Survivors (n=423) were defined as patients who survived at least 2 years after cancer treatment completion.
Thyroid function was assessed at this time and several years thereafter. Two groups of survivors with SCH were compared: those
who regained normal thyroid function during the follow-up period (normalized group) and those who did not (persistent group).
Results: Overall, 104 of the 423 survivors had SCH. SCH was observed in 26% of brain or nasopharyngeal cancer survivors (11 of
43) and 21.6% of leukemia survivors (35 of 162). Sixty-two survivors regained normal thyroid function, 30 remained as persistent
SCH, and 12 were lost to follow-up. The follow-up duration was 4.03 (2.155.78) years. Brain or nasopharyngeal cancer and Hodg-
kin disease were more common in the persistent group than in the normalized group (p=0.002). More patients in the persistent
group received radiation (p=0.008). Radiation to the head region was higher in this group (23942469 cGy) than in the normalized
group (8941591 cGy; p=0.003). On multivariable analysis, lymphoma (p=0.011), brain or nasopharyngeal cancer (p=0.039), and
head radiation dose 1800 cGy (p=0.039) were significant risk factors for persistent SCH.
Conclusion: SCH was common in childhood cancer survivors. Brain or nasopharyngeal cancer, lymphoma, and head radiation
1800 cGy were significant risk factors for persistent SCH.
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Subclinical Hypothyroidism in Cancer Survivors
circulating TSH. Primary hypothyroidism can be overt [reduc- the reference values were 80200 ng/dL, 0.952.23 ng/dL, and
ed levels of free thyroxine (fT4) and triiodothyronine (T3)] or 0.34.0 mU/L, respectively, as defined by our institution. SCH
subclinical (normal fT4 and T3 levels). In central hypothyroid- was defined as a condition in which TSH levels were higher
ism, the reduced thyroid hormone levels result from inade- than the reference value and T3 and T4 levels were within the
quate stimulation of the thyroid gland due to reduced TSH in range of the reference values. To detect thyroid disorders in sur-
cases where hypothalamic-pituitary disturbance is present.8-10 vivors, the thyroid function test (TFT) was performed 2 years
Overt hypothyroidism is usually treated via daily administra- after cancer treatment completion as a baseline test.7 Survivors
tion of thyroxine pills,8-10 and the distinction between it and with no thyroid disease-related symptoms received no addi-
subclinical hypothyroidism (SCH) is determined via biochem- tional TFTs as routine surveillance to comply with the Korean
ical measurement of fT4 and T3 concentrations in serum. There health insurance policy. Survivors with abnormal thyroid func-
is no standard management for patients with SCH and mildly tion were followed-up annually or biannually. If thyroid func-
high serum TSH concentrations, although treatment of patients tion became normal, they were designated as normalized. If
with concentrations of 10 mU/L or more is recommended.8-10 it did not, they were designated as persistent.
Pediatric endocrinologists are undecided as to how to treat As recommended by an endocrinologist, thyroid hormone
children with SCH, as controlled pediatric SCH studies are (levothyroxine) was prescribed for survivors whose TSH levels
rare. Two recent studies reported that untreated patients with were >810 mU/L, with consideration of their clinical symp-
SCH had normal TSH levels at follow-up.10,11 However, eluci- toms, signs, and developmental stage. Thyroid hormone re-
dation of the natural history of SCH as a late effect in childhood placement was tapered out after 612 months. If the TSH level
cancer survivors is lacking, despite its frequent occurrence in increased after tapering or discontinuing the treatment, the
such survivors.12,13 treatment was reinitiated. Thyroid function was monitored ev-
The aim of this study was to determine which children are at ery 12 years after short-term discontinuation of replacement
risk for persistent SCH after cancer treatment and who there- therapy. If the therapy was permanently discontinued, the sur-
fore should be treated early during the follow-up period. vivor was considered to be normalized.
916 http://dx.doi.org/10.3349/ymj.2016.57.4.915
Hyun Joo Lee, et al.
alysis and regression analysis, diagnosis groups were categoriz- survivors (data not shown). The percentage of survivors with
ed into three groups: brain/naso, lymphoma, and other tumors. SCH was similar for all diagnoses (p=0.322, data not shown):
Variables that were significant in a univariate analysis, includ- leukemia, 35 of 162 (21.6%); NHL, 12 of 47 (25.5%); HD, 6 of 12
ing treatment modalities and age at diagnosis, were included (50.0%); brain/naso, 11 of 43 (25.6%); WT/NB/abdomen, 23
in the multivariable model. We calculated the odds ratios us- of 79 (29.1%); and sarcoma/others, 17 of 73 (32.3%, data not
ing logistic regression after adjustment for the risk factors of shown).
persistent SCH including age, gender, HSCT, head radiation, Our findings showed that SCH was the most common thy-
neck radiation, and chemotherapeutic agents such as enzymes roid hormone disturbance after cancer treatment (n=104). Ow-
and epipodophyllotoxins. All statistical analyses were perform- ing to losses (n=12) during follow-up, our study group ultimate-
ed by using SPSS version 21 for Windows (SPSS Inc., Chicago, ly comprised 92 childhood cancer survivors with SCH; their
IL, USA). characteristics are shown in Table 1. The number of male sur-
vivors was 61 (66.3%). The median ages at cancer diagnosis,
cancer treatment completion, initial TFT, and final TFT were
RESULTS 3.97 (1.808.11), 6.00 (2.9510.50), 9.75 (6.9214.59), and 14.42
(10.8219.15) years, respectively. The interval from comple-
Patient demographics tion of treatment to enrollment was 2.97 (2.334.95) years. The
Two years after cancer treatment completion, 116 of the 423 follow-up duration (initial TFT to final TFT) was 4.03 (2.15
childhood cancer survivors initially surveyed (27.4%) had hy- 5.78) years. The most common diagnosis was leukemia (n=32,
pothyroidism; 112 (26.5%) had primary hypothyroidism, and 34.8%), followed by WT/NB/abdomen (n=21, 22.8%). Most
four (0.94%) had secondary hypothyroidism. The four survivors survivors underwent chemotherapy (n=91, 98.9%), and 43 sur-
with secondary hypothyroidism were brain tumor survivors, vivors received HSCT (46.7%).
and all were cases of overt hypothyroidism. Eight of the 112
(7.1%) survivors with primary hypothyroidism had overt hy- Risk factors for persistent SCH: demographic findings
pothyroidism, whereas 104 (92.9%) had SCH. Six of the eight Sixty-two survivors with SCH regained normal thyroid function
(75%) survivors with overt hypothyroidism were brain tumor more than 2 years after cancer treatment completion (the nor-
http://dx.doi.org/10.3349/ymj.2016.57.4.915 917
Subclinical Hypothyroidism in Cancer Survivors
malized group), whereas 30 did not (the persistent group). L; p=0.001 via Mann-Whitney U-test, data not shown). In the
There were no differences in sex or any time variables (age at normalized group, the TSH level was significantly lower at the
diagnosis or age at cancer treatment completion) between the final follow-up than at the initial follow-up (2.88 mU/L vs. 4.86
normalized and persistent groups. There were, however, sig- mU/L; p<0.001 via Wilcoxon signed rank test) (Table 3). The fT4
nificant differences in terms of cancer type: leukemia (75.0%), level was significantly higher at the initial follow-up than at
WT/NB/abdomen (85.7%), and sarcoma/others (73.3%) were the final follow-up (1.18 ng/dL vs. 1.07 ng/dL; p=0.008 via Wil-
more common in the normalized group, whereas brain/naso coxon signed rank test); however, all were in the normal range.
(87.5%) and HD (66.7%) were more common in the persistent In the persistent group, the TSH level was also lower at the fi-
group. The fT4 levels were statistically similar in all survivors nal follow-up than at the initial follow-up (4.70 mU/L vs. 7.71
regardless of cancer type (p=0.176) (Table 2). TSH levels were mU/L; p<0.001 via Wilcoxon signed rank test).
significantly higher in survivors of brain/naso cancer than in In the persistent SCH group, 23 (76.7%) survivors received
survivors of the other cancer types (p=0.010). As for the treat- thyroid hormone replacement therapy. The mean TSH levels
ment modality, fT4 was significantly higher in patients treated tended to be higher in the replacement group than in the non-
with HSCT than in those without HSCT (p=0.021), and fT4 was replacement group, though not significant [8.79 (5.4612.71)
significantly lower in patients treated with radiation (p=0.044); mU/L vs. 6.27 (4.907.12) mU/L; p=0.149 via Mann-Whitney U-
however, the fT4 levels in all groups were within the normal test], and fT4 levels were not different [1.11 (0.951.28) ng/dL
range. vs. 1.09 (0.941.20) ng/dL; p=0.756 via Mann-Whitney U-test,
The initial TSH level was significantly higher in the persistent data not shown]. Survivors with good clinical status did not re-
group than in the normalized group (7.71 mU/L vs. 4.86 mU/ ceive hormone replacement therapy, and their TSH level did
918 http://dx.doi.org/10.3349/ymj.2016.57.4.915
Hyun Joo Lee, et al.
not exceed 10 mU/L throughout the follow-up period. Table 5. Thyroid Function According to Radiation Site and Dose
Radiation dose (cGy, meanSD)
Risk factors for persistent SCH: treatment factors Radiation site Normalized SCH Persistent SCH p value
More survivors treated with radiation than without radiation (n=62) (n=30)
showed persistent SCH (21 of 48, 43.8% vs. 9 of 44, 20.5%; p=
Head 893.51591.1 23942468.8 0.003
0.017); the numbers of survivors previously receiving HSCT
Neck 115.2357.4 6261467.7 0.086
(p=0.378) or chemotherapy (p=0.326) were similar in both gr-
Chest 196563.9 260869.2 0.841
oups (Table 1). There were no group differences in the types of
Abdomen 302.6836.9 323776.6 0.535
chemotherapeutic agents used with two exceptions: more sur-
Extremity 220621.6 110338.7 0.882
vivors showed normalized SCH when treated with enzyme
Testis 115.2357.4 110338.7 >0.999
(e.g., L-asparaginase) than those treated without enzyme [21 of
Spine 462.1920.7 13191603 0.001
25 (84.0%) vs. 41 of 67 (61.2%); p=0.038], whereas epipodophyl-
Total radiation
lotoxin usage tended to be higher in the persistent group [25 of 1266.31707 28832303.8 0.001
dose per survivor
63 (38.1%) vs. 5 of 29 (20.7%); p=0.098] (Table 4).
SCH, subclinical hypothyroidism.
Radiation doses to the head region were significantly higher
in the persistent group (23942469 cGy) than in the normalized (28832304 cGy vs. 12661707 cGy; p=0.001) (Table 5).
group (8941591 cGy; p=0.003), as were doses to the spine region
(13191603 cGy vs. 462921 cGy; p=0.001) (Table 5). Sixteen Time trend of thyroid function normalization
of the 37 (43.2%) survivors who had received head radiation The median interval from time of cancer treatment completion
1800 cGy still had SCH at the final follow-up. In contrast, all to time of normalization of thyroid function was 8.84 years
four survivors (100%) who had received head radiation of <1800 (95% confidence interval, 7.1010.58 years). When the survi-
cGy returned to normal at the final follow-up (p=0.031, data not vors were split into three cancer type groups (brain tumor sur-
shown). vivors, lymphoma survivors, and survivors of other cancers),
Radiation doses to the neck region were also higher in the there was a tendency of difference in the normalized propor-
persistent group than in the normalized group, although the tion of SCH among the three groups (p=0.094) (Fig. 1). Brain tu-
difference was not significant (6261468 cGy vs. 115357 cGy; mor survivors did not regain normal thyroid function during
p=0.086) (Table 5). All of the four survivors who had received the follow-up compared to the survivors in the other groups
neck radiation 1500 cGy still showed SCH at the final follow- (p=0.039).
up. Seven of the nine survivors (77.8%) who had received neck
radiation <1500 cGy recovered normal thyroid function (p= Multivariable analysis of the risk factors for persistent
0.009, data not shown). The total radiation dose per survivor SCH
was higher in the persistent group than in the normalized group Lymphoma (odds ratio, 6.71; p=0.011), and brain/naso (odds
http://dx.doi.org/10.3349/ymj.2016.57.4.915 919
Subclinical Hypothyroidism in Cancer Survivors
100 roid gland and is categorized as SCH or, if more severe, overt
hypothyroidism. Central hypothyroidism is caused by damage
80 to the hypothalamus-pituitary gland axis and can result in loss
of endocrine function. In our study, SCH was the most com-
Normalized proportion
920 http://dx.doi.org/10.3349/ymj.2016.57.4.915
Hyun Joo Lee, et al.
large-scale retrospective study conducted in Israel; however, firmed that brain/naso tumors, lymphoma, and head radiation
most of its subjects had autoimmune thyroiditis.11 The rate of doses 1800 cGy were all significant risk factors for SCH. Brain
recovery in the meta-analysis was 21.950%, and progression tumor survivors have an increased risk of endocrine, psychiat-
to overt hypothyroidism was 028.8%.6 In the Israeli study, SCH ric, cognitive, neurological, and developmental disorders ow-
prevalence was 3.3% (n=3938), and 70.1% of patients with SCH ing to previous radiotherapy.3,4 The threshold dose for pituitary-
had normal TSH levels in subsequent tests.11 hypothalamus hypothyroidism was 5000 cGy in the studies on
Thyroid dysfunction in childhood cancer survivors is a well- the cranial irradiation.27-29 When the radiation dose to the pitu-
known late effect.3,7,26 Primary hypothyroidism is the most com- itary gland was increased from 2000 to 4500 cGy, the risk of hy-
mon abnormal thyroid-related response to thyroid irradiation.4 pothyroidism increased from 9% to 52%.29 As for direct thyroid
Risk factors for hypothyroidism include neck, craniospinal, and radiation, the thresholds are less clear; however, radiation dos-
total body irradiation3,4 yet apparently not chemotherapy.4,13 es greater than 30004000 cGy are generally accepted as a th-
Compared with primary overt hypothyroidism, SCH in child- reshold.29,30 Nevertheless, the threshold for SCH has not yet
hood cancer survivors is less understood. The percentage of been established. A large study on the general health status of
long-term survivors of Hodgkin lymphoma (n=55) who devel- cancer survivors reported that exposure of the hypothalamus-
op SCH is 20%. pituitary axis to 1800 cGy disrupted this axis in >50% of sur-
Data on the natural history of SCH in childhood cancer sur- vivors.31 However, it regarded all physical and laboratory find-
vivors are limited. A previous study showed impaired thyroid ings including growth, pubertal progress, menstrual history,
function in 24% of survivors (71 of 291) during a median follow- insulin-like growth factor 1 (IGF-1), cortisol, estradiol, TSH, and
up period of 6.1 years13 yet did not address SCH status after this fT4 by screening studies as outcome measurements and did
time. Ishiguro, et al.12 found that 26.5% of patients (39 of 147) not specify the kind, proportion, or severity of axis disruption.31
who underwent bone marrow transplantation developed SCH. Therefore, the radiation dose for inducing SCH could not be
Their TSH levels decreased from the upper normal range 8 confirmed. In this study, radiation exposure of 1800 cGy or more
years after bone marrow transplantation to the mid to normal to the head region posed the risk of persistent SCH, and this
range thereafter. However, the proportion of patients who recov- dose was lower than the dose causing overt hypothyroidism.
ered from SCH was not presented. Whether cancer survivors who develop SCH during follow-
In our study, 12 (2.8%) of the 423 childhood cancer survivors up should receive treatment is an unanswered question. Our
had overt hypothyroidism, mainly the brain/naso survivors. study provides suggestions based on the presence of risk fac-
SCH was the most common thyroid dysfunction in the 423 sur- tors. However, it had several limitations. First, the study cohort
vivors (104, 24.6%), as well as in the 123 survivors with thyroid was prospective, whereas the analysis was retrospective. Sec-
abnormalities (104, 84.5%). Among the study cohort (n=92), ond, follow-ups regularly occurred every 6 months; however,
67.4% of patients with SCH regained normal thyroid function. several survivors were lost during follow-up. Third, the dura-
This result is similar to those in other pediatric studies on pa- tion of the follow-up was 4.2 years, yet the range was variable.
tients with autoimmune disease or healthy thyroids.6,11 In our Fourth, certain cancer types had an insufficient number of sur-
study, 6085% of leukemia, NHL, and WT/NB/abdomen sur- vivors for analysis. Fifth, survivors with normal thyroid function
vivors regained normal thyroid function, whereas only 12.5 at the initial follow-up did not receive additional TFTs in com-
33.3% of brain/naso and HD survivors did so; this difference pliance with the Korean health insurance policy. Sixth, thyroid
was significant (p=0.002) (Table 2). Although the proportion autoantibodies as a risk factor for progression to thyroid dis-
of leukemia survivors with SCH was substantial (21.6%, which ease were not examined owing to the retrospective nature of
was much higher than in a normal pediatric cohort), most ex- our analysis. Despite these limitations, our study is one of the
hibited normalized thyroid function at the final follow-up. The few studies on SCH in childhood cancer survivors, and it pro-
percentages of brain/naso survivors with SCH or overt hypo- vides new data for Korean survivors. We showed that a sub-
thyroidism were 25.6% (11 of 43) and 20.9% (9 of 43), respec- stantial number of leukemia and WT/NB/abdomen survivors
tively; however, most of them did not recover a euthyroid sta- developed SCH, and our follow-up data described the natural
tus. Collectively, these data show that SCH is frequently found course of SCH in survivors.
in childhood cancer survivors regardless of cancer type. Leu- In conclusion, SCH is a frequent late effect in childhood can-
kemia and WT/NB/abdomen survivors can be managed with- cer survivors. Most leukemia and WT/NB/abdomen survivors
out further treatment, whereas brain/naso survivors should re- with SCH recovered spontaneously. There was an increased
ceive thyroid hormone replacement as soon as possible, even risk of persistent SCH in survivors with brain/naso, lymphoma,
if they have SCH rather than overt hypothyroidism. or head radiation at doses 1800 cGy.
The risk factors for persistent SCH are similar to those for
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