Childhood differentiated thyroid carcinoma: clinical course and late effects of treatment
Nies, Marloes
DOI:
10.33612/diss.145080681
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Chapter 9
CHAPTER 9
Summary and
9
SUMMARY
Clinical course and outcome of childhood differentiated thyroid cancer
In Chapter 2, we evaluated the clinical course of patients diagnosed with differentiated thyroid carcinoma (DTC) during childhood (i.e. diagnosed before the age of 19 years). Disease-specific survival of 170 patients was 100% after a median follow-up period of 13.5 years. One patient had died from a cause other than DTC. From 105 survivors, we obtained informed consent to review their medical record. After surgical treatment, almost one in three patients suffered from permanent complications such as hypoparathyroidism or recurrent laryngeal nerve injury. Patients with more advanced primary tumors, lymph node or distant metastases (DM) were treated with a higher number of radioactive iodine (131I) administrations and a higher cumulative dose of 131I. The majority of the patients remained in remission during follow-up, but 9% had
persistent disease and 8% experienced disease recurrence. Having a higher tumor, node or metastases stage was associated with having persistent disease.
A minority of patients with childhood DTC develops distant metastatic disease and no large scale studies have been conducted regarding long-term outcomes of these patients. When patients with an aggressive form of DTC do not respond to standard treatment, molecular targeted therapy may be beneficial. However, further development of targeted therapy requires better definition of the mutational landscape in patients with childhood DTC. In Chapter 3 we therefore described the clinical course and mutational landscape of patients diagnosed with DM from childhood DTC in a cohort of patients treated at the MD Anderson Cancer Center in the United States. We showed that distant spread of childhood DTC is persistent in nature, but mild in its course. The median overall survival was 50.7 years, with a median disease-specific survival of 52.8 years. Patients were treated with surgery and 131I, and – in exceptional
cases – with systemic therapy. Most patients with an identified oncogenic driver had a fusion involving the rearranged during transfection (RET) gene. The presence of fusions involving the neurotrophic tyrosine kinase receptor (NTRK) gene and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations was less pronounced. No clear genotype-phenotype associations were discovered.
Late effects of the administration of radioactive iodine
In Chapter 4, we evaluated female fertility in the Dutch nationwide cohort, using a fertility-focused questionnaire and measuring serum Anti-Müllerian Hormone (AMH, a marker of ovarian reserve), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2). The numbers of live births and of couples reporting problems with conceiving were comparable to the general population. AMH levels evaluated after a median follow-up period of 15.4 years did not differ significantly from the comparison group consisting of women not treated for cancer, even after adjusting for age. LH, FSH, and E2 levels were within reference ranges. Based on this
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broad evaluation of female fertility, we concluded that there is no evidence to suggest that long-term female fertility is impaired after the treatment of childhood DTC.
In the nationwide childhood DTC study, 17 males participated, four of whom agreed to participate in semen analysis. Because of this low number, and to obtain a representative number of males, we decided to evaluate male fertility in survivors of
adult DTC, as shown in Chapter 5. We examined 51 males who had had a follow-up period
of at least two years after their last administration of 131I. Depending on the cut-off for
‘low semen quality’, a minority of participants had low semen quality compared to a general population (1). However, reproductive characteristics and evaluation of LH, FSH, and Testosterone showed no overt disturbances.
Late effects of thyroid-stimulating hormone suppression therapy
A first evaluation of cardiac function in the current cohort of survivors of childhood DTC revealed the presence of diastolic dysfunction in one out of five survivors after a median follow-up of 17 years after diagnosis (2). When compared to age- and sex-matched controls, the median (left ventricular) diastolic function was lower in survivors. Systolic function was unaffected and no atrial fibrillation was observed. As diastolic dysfunction is associated with accelerated cardiac aging and an increased risk of cardiovascular disease, we re-evaluated 47 of the aforementioned survivors five years after their first cardiac evaluation, as described in Chapter 6. Paired analyses showed a significant decrease in diastolic function over these five years. Moreover, compared to the results of the first evaluation, the number of survivors with diastolic dysfunction had increased. When the decline in diastolic function of the current survivors was compared to the average decline based on age-categorized reference ranges, the decline among survivors was greater. Thereby, the significant increase of the N-terminal pro–B-type natriuretic peptide (NT-proBNP) between the two evaluations also indicated an increase in cardiac damage. In a multivariate linear regression analysis, body mass index and attained age were significantly associated with diastolic function, but thyroid-stimulating hormone (TSH) levels during follow-up were not.
Late effects on well-being and psychosocial development
In Chapter 7, survivors of childhood DTC were compared to age- and sex-matched controls regarding health-related quality of life (HRQoL) and the presence of fatigue, anxiety, and depression. Survivors’ thyroid cancer-specific complaints were also evaluated. The overall well-being of survivors did not differ from their controls, except for a slightly higher but statistically significant rate of physical problems and mental fatigue. The majority of the survivors reported none or few thyroid cancer-specific complaints. Extensive disease and treatment and unemployment were associated with worse well-being.
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To evaluate whether and to what extent the course of life was influenced by the diagnosis and treatment of childhood DTC, in Chapter 8 we evaluated the achievement of psychosocial developmental milestones of these survivors. Their psychosocial development was compared to age- and sex-matched controls and to survivors of other childhood cancers. Social, autonomy, and psychosexual development in childhood DTC survivors and controls was similar. Compared to survivors of other childhood cancers, social development in childhood DTC survivors was better. Development of autonomy and psychosexual development were similar in both groups. Overall, the diagnosis and treatment of childhood DTC did not seem to affect psychosocial development.
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DISCUSSION
The aim of this thesis was to evaluate the clinical course and late effects of childhood DTC. The ultimate aim of the studies was to provide an outlook for newly diagnosed patients, but also to provide relevant information for patients previously treated for childhood DTC. Finally, we aimed to contribute knowledge for developing future management guidelines to optimize care for patients diagnosed with childhood DTC.
Clinical course and outcome of childhood differentiated thyroid cancer
Deaths caused by childhood DTC have been consistently low, with survival rates higher than 95% after decades (3, 4). This high survival rate is confirmed in
Chapters 2 and 3. Even in children presenting with advanced disease, the survival
of children with DTC remains excellent (Chapter 3). This is unlike in adults, were the presence of local or distant metastases increases the risk of thyroid cancer-related deaths (5). Despite the high survival rate, long-term follow-up of childhood DTC patients is recommended because recurrence of the disease can occur decades after initial treatment (6). Follow-up is also required because thyroid hormone levels must be regularly evaluated, as life-long substitution of levothyroxine is necessary due to iatrogenic hypothyroidism after a thyroidectomy.
Because of the low mortality rate from childhood DTC, optimal treatment for these children involves balancing between reducing the chance of recurrent or persistent disease and limiting the risk of the negative consequences of treatment.
Optimization of treatment of childhood DTC starts with adequate and timely diagnosis of the disease. The Dutch pediatric guidelines indicate which diagnostic steps are appropriate at the right level of care: rare diagnoses are treated in referral centers to provide more experienced and multidisciplinary treatment (7). Initial thyroid surgery, consisting of a total thyroidectomy for the majority of children diagnosed with DTC, also has to be performed in dedicated centers, as advised by the pediatric management guidelines of the American Thyroid Association (ATA) (8).
Increasing evidence supports that a hemithyroidectomy may also be sufficient for childhood DTC patients who have a small, unifocal tumor, no extrathyroidal extension, and no lymph node metastases, or only a small number of lymph node metastases (9, 10). However, most children present with T3 or T4 tumors and locoregional lymph node metastases (3, 11) and require more aggressive surgery, as advanced disease is associated with a higher chance of recurrence or persistent disease (12, 13). Unfortunately, extensive surgery is correlated with the occurrence of more surgical complications. These occur to a lesser extent, however, when children are treated by high-volume surgeons (14-16). Minimizing surgical complications decreases long-term disease burden, such as voice problems caused by vocal cord paralysis. Other problems include parathyroid damage, which creates a need for daily medication, frequent laboratory controls, and additional clinical evaluation. Children
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with hypoparathyroidism, for instance, are at risk of nephrocalcinosis (17). To meet a higher quality standard, (surgical) treatment of children with DTC in the Netherlands has in recent years been centralized (7), which will benefit patient outcomes (18). However, to optimize treatment, not only surgery but all disciplines involved with childhood DTC management (e.g. endocrinology, nuclear medicine, pathology, and radiology) require a centralized experienced multidisciplinary management team to offer patient-tailored advice in individual situations.
Along with the disease burden caused by initial thyroid surgery, additional negative effects induced by treatment of childhood DTC may also arise. Long-term adverse consequences of cancer treatment are called late effects.
Late effects of the administration of radioactive iodine
Female fertility after radioactive iodine
Chapter 4 presents an elaborate assessment of reproductive characteristics and
ovarian reserve of female survivors of childhood DTC; the assessment showed no long-term impairment.
Scarce evidence obtained from previous studies performed in survivors of
childhood DTC presumed similar indications, but the small number of patients and
lack of well-defined outcomes hindered drawing firm conclusions (19, 20).
131I administration in women treated for adult DTC caused a decrease in levels of AMH
particularly pronounced in women aged 35 years and older (21-23), but after long-term follow-up normal AMH levels were found (24, 25). The clinical consequences of these studies solely reporting on AMH levels may be limited, since the assessment of AMH levels does not provide a complete evaluation of all aspects of (onco)fertility. Reviews and large-scale studies concluded that transient disturbances of fertility may occur after treatment with 131I in women treated for adult DTC, but long-term fertility is not
affected because gonadal function, the ability to conceive, birthrates, and pregnancy outcomes were not permanently impaired (26-29).
Two factors may explain the normal fertility in the survivors of childhood DTC: duration of follow-up and age at treatment. First, an increased follow-up duration may allow primordial follicles to develop into secondary and early antral follicles, resulting over time in a rise of AMH levels (30). The temporary disruption of the menstrual cycle seen up to one year in women treated with 131I could reflect damage to the secondary
and early antral follicles only (26). Secondly, the larger ovarian reserve in children will be relatively less impacted than the smaller number of oocytes present in adult women, manifested by a more pronounced decrease in AMH levels in women treated at ages 35 and older (21, 23, 28).
The research in Chapter 4 combined with extrapolated results from studies of adult DTC do not indicate that long-term female fertility is impaired after treatment of childhood DTC.
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Male fertility after radioactive iodine
To date, because of the small number of boys diagnosed with the disease, no studies have been performed to evaluate male fertility after childhood DTC. Thereby, earlier studies on male fertility after 131I administrations for adult DTC were limited by
a short-term follow-up, a limited study size, and an incomplete evaluation of fertility parameters (31-36). Chapter 5 presents an assessment of male fertility after adult DTC after long-term follow-up. All males were treated with a relatively high cumulative dose of 131I (100 mCi or more). Semen quality, reproductive hormones, and reproductive
characteristics were evaluated.
The normal long-term semen quality of the majority of the participants in
Chapter 5 may be a result of the long follow-up period in the study. Radiation may
initially impair semen quality, but spermatogenesis continues as long as spermatogonial stem cells are unaffected (37). In earlier studies in adult males treated with 131I for DTC, initial damage and some recovery of male fertility was seen after 131I treatment, but patients were followed up to a maximum of only 18 months after 131I administration (31-36). Unlike female fertility, male fertility is not dependent on
age, and spermatogenesis takes place up to the last decades of life (38). The long-term follow-up described in Chapter 5 may have provided time for recovery of the semen quality in the majority of male DTC patients.
Next to the comparison with adult DTC survivors, an indication of the possible damage to fertility in boys treated for DTC can be derived from other childhood cancer survivors treated with radiotherapy. The radiation dose to the testes in other childhood cancer radiotherapies is up to 10 or 100 times higher than the testicular dose from 131I
therapy (39-41), but even after high doses of radiotherapy, semen quality can recover (42). No clear radiation-induced threshold for permanent azoospermia is defined, but a higher dose of radiation leads to an increased recovery period. Studies in survivors of other childhood cancers showed that the effects of radiotherapy on gonadal tissue are similar in children and adults (43, 44). Compared to other (childhood) cancer patients receiving radiation to the testes, the damage to male fertility caused by 131I radiation is
probably of a smaller order.
Of course, characteristics of each cancer and its treatment need to be recognized, since consequences for male fertility may differ. For instance, it is unknown whether the expression of the sodium iodine symporter (NIS) in germinal and Leydig cells facilitates the uptake of 131I in the testes (45). Additionally, treatment of DTC is
accompanied by periods of hyper- and hypothyroidism which also have a transient negative effect on semen quality (46, 47).
Although future studies face logistical challenges in acquiring a representative number of participants, research regarding male fertility after childhood DTC is essential for drawing ultimate conclusions. To gather an adequate sample size, (inter) national collaboration is needed. Until then, patients should be informed about
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the low risk of poor long-term semen quality. Since we do not know which patients are at risk, fertility preservation should be discussed and offered as a precaution to all postpubertal boys and to adults receiving doses of 131I equal to or higher than 100
mCi. In prepubertal boys, performing testicular sperm extraction or testicular tissue freezing is too great an intervention for the possible minimal effect of 131I administration
on fertility. When semen is cryopreserved, it is highly recommended that the patient is euthyroid upon preservation, since we found that hypothyroid patients did not preserve semen of optimal quality.
Short-term fertility after 131I administration
Short-term disruption of female and male fertility is observed after the administration of 131I. A disruption of the menstrual cycle or decrease in semen quality may transiently
reduce the chance of conceiving. For females, the tendency in most studies is that 131I
does not affect pregnancy outcomes or the health of children (26, 27), but a single study observed an increase in miscarriages the first year after 131I administration
(48). For males, it is unknown if the increased DNA fragmentation and chromosomal abnormalities that are observed in spermatozoa up to one year after 131I administration
(32, 49) have clinical consequences or impair the health of conceived children. However, no evidence exists that their children experience health problems (19, 50). Guidelines cautiously advise to avoid (conceiving) pregnancies 6 to 12 months after
131I administration (8), but to date, there is no convincing evidence to assume that 131I
impairs pregnancy (outcomes). Males with a short-term desire to have children may benefit from cryopreserving their semen.
Salivary gland function after radioactive iodine
Salivary gland function was also evaluated in our cross-sectional nationwide study by performing sialometry, sialochemistry, and analysis of the completed xerostomia inventory. Almost half of the survivors of childhood DTC had impaired salivary gland function, and one in three survivors reported complaints of xerostomia (51). The extent of damage to the stimulated salivary secretion and the occurrence of complaints of xerostomia increased with a higher cumulative dose of 131I. Salivary gland dysfunction
(SGD) can be explained by the presence of the sodium iodine symporter in the salivary glands, which facilitates uptake of (radioactive) iodine. In adults, salivary gland function also decreases after treatment with 131I (52, 53). SGD can cause a range of difficulties
such as problems with swallowing, chewing or speaking. SGD is also associated with a higher risk of dental caries, halitosis, and oral candidiasis (54). Xerostomia or SGD can be treated (symptomatically), but prevention of SGD should be the main focus. Stimulation of the salivary glands during 131I treatment, such as eating sour candy or
drinking lemon juice, has been advised to prevent SGD, but no specific studies have been performed to evaluate the effectiveness of these precautions in children (8).
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Secondary primary malignancies after radioactive iodine
Children or young adults who have been treated for DTC may have a slightly higher risk of developing SPM (55, 56). One study found that survivors of childhood DTC who died predominantly died of SPM (56). 131I is also associated with a slightly higher incidence of
SPM in survivors of adult DTC (57-59). The SPM found in patients treated with 131I mainly
concerns rare cancers, such as salivary gland carcinomas (55, 59). It is the question if this increase represents a likely threat to DTC patients (60). Moreover, it could be that DTC patients have a genetic predisposition for the development of cancer(s). In the cohort of 105 patients described in Chapter 2, three patients were diagnosed with a SPM. However, studies to evaluate SPM require large cohorts, emphasizing the need for international collaboration.
Pulmonary fibrosis after radioactive iodine
Pulmonary fibrosis is a rare but serious side effect of 131I administration in patients
with lung metastases (61). In Chapter 3 we described one patient who died from pulmonary fibrosis as a complication of 131I administration. The ATA pediatric guidelines
advise adjusting the dose of 131I when significant (diffuse) lung uptake is present on
the diagnostic whole-body scan in patients with lung metastases (8).
Bone marrow suppression after radioactive iodine
131I has a suppressing effect on the bone marrow (62, 63). Moreover, the concentration
of 131I in bone metastases can also cause bone marrow toxicity. However, long-term
bone marrow suppression after administration of 131I is rare (8). No studies have been
performed in children with DTC to evaluate long-term bone marrow suppression following 131I administration. In the Dutch cohort, no long-term bone marrow
suppression was observed (unpublished results).
Considerations regarding 131I administration in childhood DTC
To improve the recurrence free survival of children with DTC, 131I was routinely
administered to those having residual disease after their initial thyroid surgery (64). In line with this, 131I administration in addition to initial thyroid surgery is considered
beneficial in high risk patients with (inoperable) lymph node metastases or with distant metastases (8). However, large-scale studies have shown conflicting results regarding the potential decrease in recurrences ascribed to administration of 131I (56,
65, 66). Some studies show that recurrence rates are not changed by administration of
131I, while others report that 131I does decrease the chance of recurrence.
Therefore, in children with DTC who have (inoperable) local or distant metastases, administration of 131I is more easily justified than in patients with small initial tumors,
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refraining from administration of 131I can be considered (8). Further, when giving 131I,
the size of the dose or the number of doses of 131I can be adjusted per patient.
SGD is a late effect of 131I administration that is the most prominent. Possible
long-term damage to fertility is not an argument for administering less, or no 131I. It
should be discussed whether the increased risk of late effects is acceptable when administering (more) 131I. Whenever 131I is administered, children and their caregivers
must be able to make an informed decision.
Late effects of TSH suppression therapy
Cardiac function after TSH suppression therapy
The decreased diastolic function initially found in childhood DTC survivors (2) further deteriorated in the five years following the initial evaluation, as shown in
Chapter 6. The first evaluation did not identify arrhythmias or systolic function defects.
The substantial incidence of diastolic dysfunction in this relatively young group of survivors with no pronounced cardiovascular risk factors requires follow-up, since the presence of diastolic dysfunction is associated with a higher risk of accelerated cardiac aging.
No explanation has yet been found for the cardiac damage in these survivors of childhood DTC. Diastolic dysfunction is also seen in other (childhood) cancer survivors, but the etiology in these patients lies within the cardiotoxic effects of chemotherapy or damage caused by the irradiation (67-69). The most plausible cause of the diastolic dysfunction in survivors of childhood DTC is the TSH suppression therapy, since TSH suppression therapy is strongly associated with (reversible) diastolic dysfunction in survivors of adult DTC (70-73): prolonged subclinical hyperthyroidism is associated with impaired diastolic function due to slowed myocardial relaxation (80). Survivors of adult DTC have an increased risk of cardiovascular disease and cardiovascular mortality when they are being treated with TSH suppression therapy (74). However, in contrast with results in survivors of adult DTC, in the first and second evaluations of the described survivors of childhood DTC, TSH levels were no significant predictor of diastolic function. This could be attributed to the limited availability of TSH measurements during follow-up, resulting in an incomplete representation of actual TSH levels and suppression in this retrospective study. The median of the available TSH values during the total follow-up period of 23 years was not in the suppressed range. Hypothetically, TSH suppression during the first years after initial treatment may have initiated cardiac damage. Prospective research is needed to identify if and when suppressed TSH levels initiate diastolic dysfunction in survivors of childhood DTC. Although survivors did not have a known cardiovascular disease, our findings seem clinically relevant seen the substantial impairment of diastolic function at this relatively young age. Thereby, this prospective research can also assess the possible effects on cardiac functioning of hypothyroidism induced during the treatment
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of children, as hypothyroidism also effects cardiac functioning in adults (75, 76). In adults, it is advised to limit thyroid hormone withdrawal because of its risk of cardiac impairment (75). As the effects of the administration of 131I on cardiac function have
not been well-established or evaluated, they require attention in future research (77). It is important to assess if or when diastolic dysfunction becomes clinically relevant by repeating the cardiac evaluation of these survivors. Thereby, the pathophysiological mechanism causing the diastolic dysfunction needs to be understood. Future research should assess whether treatment of childhood DTC should be adjusted. Cardiac screening seems required, with the intensity to be determined by future research.
Bone mineral density after TSH suppression therapy
In adult patients with DTC, TSH suppression therapy is associated with lower bone mineral density: exogenous subclinical hyperthyroid state induced by TSH suppression therapy is associated with increased bone resorption and low bone density (78). This effect is seen especially in postmenopausal women (79, 80). In survivors of childhood DTC, cross-sectional studies have shown no impairment of BMD (81, 82). However, due to large inter-individual differences in BMD, cross-sectional studies do not adequately assess individual changes in BMD. Currently, a longitudinal assessment of BMD is being performed in the childhood DTC cohort.
Considerations regarding TSH suppression therapy in childhood DTC
Based on expert opinions, the ATA pediatric guidelines recommend aiming for a more suppressed TSH in childhood DTC patients who are considered to be at higher risk of recurrence (8) because in adult DTC series, a suppressed TSH was associated with a lower risk of recurrence (71, 83). This finding can be explained by the fact that TSH has a proliferative effect on the thyroid tissue. However, the actual data proving the added value of TSH suppression therapy in children is lacking. Therefore, it is necessary to evaluate its benefits, especially since this unsubstantiated therapy may cause adverse effects. Caregivers must be aware of the emergence of possible diastolic dysfunction in survivors of childhood DTC.
Molecular landscape of childhood differentiated thyroid carcinoma
Knowledge about the molecular landscape in childhood DTC may provide additional tools to understand differences in characteristics between patients, although univocal associations between mutations and clinical characteristics were found neither in the study described in Chapter 3, nor previously (84-86). This might be due to the small sample sizes of individual studies, illustrating the need for meta-analyses or collaborations to obtain larger study sizes.
Molecular targeted therapy is successfully administered in exceptional cases in which patients with widespread, aggressive DTC do not respond to standard treatment
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(87-89). In the coming years, the role of this therapy will be further identified. It should be evaluated whether these treatments should remain applicable in patients with advanced disease, or whether these systemic therapies should be favored above standard therapy for their outcomes and late effects.
Late effects on well-being and psychosocial development
Quality of life (QoL), levels of fatigue, and feelings of anxiety or depression are not impaired in adult survivors of childhood DTC. Most survivors will not be hindered in reaching social, autonomic, and psychosexual developmental milestones during their journey into adulthood. Thyroid cancer-specific complaints were evaluated and showed no abnormalities (Chapters 7 and 8).
Although this generally mild course of DTC provides some leeway in treatment and prognosis, it does not mean all patients will experience this in a similar way. Caregivers of DTC patients have been found to misjudge the impact of DTC on patients’ lives (90, 91). As physicians focus on the positive outlook of the disease, some patients have conflicting emotions about their own experiences, and report that they are not fully understood (90-92).
Childhood DTC may not change the achievement of developmental milestones, but the effects on these survivors may be more subtle, as we found slightly more specific complaints of physical problems and mental fatigue. These results could indicate that childhood DTC does not greatly impact well-being in the long-term, but they could also mean that we are not taking into account some specific issues that arise in this group of survivors. The members of the focus group participating in the development of the thyroid cancer-specific questionnaire were all adults upon DTC diagnosis (93). Generally, it seems that a diagnosis of DTC at an older age has a more negative effect on well-being than diagnosis at a younger age (94-96).
Thereby, although overall well-being was similar between survivors and controls, QoL was more variable in survivors, as they had a wider distribution toward worse QoL. This could indicate that a subgroup of survivors is more affected in their well-being. Future research regarding well-being in survivors of childhood DTC should address relevant topics and identify those survivors most at risk of having poor QoL. We further elaborate on this subject in the paragraph ‘future perspectives’.
Children are not small adults
DTC in children requires a different approach than DTC in adults. A younger age upon DTC diagnosis is associated with more aggressive or more advanced disease (97, 98). Thereby, the distribution of different somatic mutations varies between childhood and adult DTC (99-109). Moreover, after treatment, more recurrence or persistent disease is seen in children, but deaths are less common (5, 56, 60, 110). Late effects of treatment may be caused by similar mechanisms in children and adults,
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but consequences may differ depending on the stage of life in which the patient is treated. Some of the differences between children and adults in the presentation and clinical course might be explained by the different oncogenic drivers of adult and childhood DTC.
A gap exists in knowledge concerning the disease characteristics of patients in the transition phase from childhood to adulthood. There is no biological or psychological cut-off point after which a patient with DTC should be considered an adult. Some young adults diagnosed with DTC may have disease with the same characteristics as childhood DTC (i.e. advanced disease with a mild disease course and molecular profile in line with other childhood DTC patients), but will be treated as an adult. To prevent mismanagement, the recognition of patterns of disease can only be provided by experienced caregivers, resulting in optimal treatment
Future perspectives
In all studies that are performed in patients with childhood DTC, achieving an adequate sample size is a challenge because of the rarity of the disease. Therefore, national and international collaborations are essential for future studies. Herein lies a challenge, because collaborations require that cultural, logistical or financial differences between physicians, hospitals or countries are overcome. Examples of (inter)national collaborations are the European Reference Network on Rare Endocrine Conditions, European Thyroid Association Taskforce for Children with Thyroid Nodules and Thyroid Cancer, and the North American Child and Adolescent Thyroid Consortium.
Regarding late effects after childhood DTC, the increase in diastolic dysfunction in this relatively young group of survivors requires attention. Longitudinal research is needed to evaluate the clinical significance of this finding, but should also focus on preventive and therapeutic interventions. It is also important to evaluate possibilities for preventing and managing SGD in these survivors.
With regard to well-being, patient meetings may serve multiple purposes. First, gatherings can function as a place where patients are informed about various aspects of their rare disease. Secondly, they can (anonymously) address their thoughts regarding subjects for future research on late effects. Third, patient information meetings could also offer an opportunity for patients to meet other patients with this rare disease. Lastly, provision of patient information regarding current knowledge is crucial to ensure that patients in general understand the importance of participating in studies. Of course, structured focus groups to assess problems arising in patients and survivors of childhood DTC can also be instituted.
Other future research should focus on optimizing treatment outcomes with minimal late effects. The role of 131I administration and TSH suppression therapy in
childhood patients of all risk factor categories should be re-established, by comparing long-term outcomes between treatments. Prospective studies are most desirable
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for assessing these endpoints. Shared (inter)national databases with well-defined definitions can overcome the sample size issues. Databases can serve prospective and retrospective research, where retrospective research could reveal risk factors for late effects of childhood DTC treatment. By adding data from (young) adult DTC patients to the databases, more insight can be gained into the structural differences in disease characteristics and outcomes between age groups.
Survivors of childhood DTC may benefit from care for late effects in specialized late effects outpatient clinic, as developed for other childhood cancer survivors in the Netherlands and many other countries.
CONCLUSION
As most children with DTC will survive their disease, it is important to keep late effects in mind during treatment or follow-up. A multidisciplinary team should balance the disease outcome and the burden of the disease and its treatment, requiring individual decisions for every patient. Regarding late effects of treatment, our research showed that survivors of childhood DTC are at risk for diastolic dysfunction, requiring follow-up to assess its consequences. Although subtle or transient changes may occur, no overt permanent damage of male or female fertility was observed. In general, QoL and psychosocial development do not seem to be harmed by childhood DTC or its treatment.
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