Outcomes of Children and Adolescents with Well-Differentiated Thyroid Carcinoma and Pulmonary Metastases Following 131 I Treatment: A Systematic Review

Abstract

Background:

The optimal dose and efficacy of ¹³¹I treatment of children and adolescents with well-differentiated thyroid carcinoma (WDTC) and pulmonary metastases are not well established. A therapeutic challenge is to achieve the maximum benefit of ¹³¹I to decrease disease-related morbidity and obtain disease-free survival while avoiding the potential complications of ¹³¹I therapy.

Summary:

We systematically reviewed the published literature on children and adolescents with WDTC and pulmonary metastases treated with ¹³¹I to examine outcomes after ¹³¹I administration and the risks and benefits of therapy. After reviewing 14 published articles, 9 articles met our inclusion criteria encompassing 112 pediatric and adolescent patients with WDTC and pulmonary metastases 21 years of age or younger at diagnosis spanning a follow-up period of 0.6–45 years. ¹³¹I therapy after surgery and thyrotropin suppression resulted in complete, partial, and no disease response in 47.32%, 38.39%, and 14.29% of patients, respectively. Five studies provided data on disease response in relation to ¹³¹I dose. In general, nonresponders received the highest ¹³¹I doses and complete responders received a higher dose than partial responders. The disease-specific mortality rate was 2.68%. Survival was 97.32%. A second primary malignancy occurred in one patient. One out of 11 patients studied experienced radiation fibrosis.

Conclusions:

This review confirms that the majority of pediatric and adolescent patients with WDTC and pulmonary metastases treated with ¹³¹I do not achieve complete response to therapy, yet disease-specific morbidity and mortality appear to remain low. It is therefore prudent to use caution in the repeated administration of ¹³¹I to such patients to ensure that adverse effects of therapy do not cause more harm than good in a disease that has an overall favorable natural course. Long-term prospective studies are needed to analyze disease-specific morbidity and mortality, recurrence rate, dose-specific response, and dose-related adverse effects of ¹³¹I in this patient population.

Introduction

T hyroid carcinoma occurs rarely in the pediatric and adolescent population, with an annual incidence of 2.25/100,000 individuals under age 20 (1) accounting for only 1%–2% of childhood malignancies. Of these, the vast majority are well-differentiated thyroid carcinoma (WDTC) (2). While the long-term prognosis for such malignancies is excellent, several studies have demonstrated that pediatric WDTC often presents at a more advanced stage than the adult variant (3,4). In particular, pulmonary metastases occur in 9%–30% of pediatric patients with WDTC (5,6). In conjunction with total thyroidectomy and thyrotropin suppression with thyroxine, ¹³¹I therapy is a mainstay of treatment in such cases. The expected long lifespan of pediatric and adolescent patients creates the therapeutic challenge of achieving the maximum benefit of ¹³¹I to prevent disease-related morbidity and obtain disease-free survival while avoiding the complications of therapy over decades. This quandary, combined with the absence of long-term prospective studies on such patients who have received ¹³¹I, has led to a lack of consensus on the optimal ¹³¹I treatment in this patient population. We performed a systematic review of the current literature on children and adolescents with WDTC and pulmonary metastases treated with ¹³¹I to examine disease-related morbidity as well as the relationship between ¹³¹I administration and response to treatment, survival rate, and possible adverse events arising from ¹³¹I therapy.

Methods

OVID Medline, PubMed, Cochran database of systematic reviews, and Embase literature searches were performed by two independent reviewers to identify articles published since 1990 with data reported on outcomes of pediatric and adolescent patients with WDTC and pulmonary metastases treated with ¹³¹I. The electronic search was restricted to articles in English with data on humans. The search strategy included medical subject headings related to thyroid cancer and its treatment (thyroid neoplasms, iodine radioisotopes, and radioactive iodine) and pulmonary metastases and was restricted to children and adolescents. Fourteen articles were identified (4,7 –19). Of these, nine (4,11 –18) were included in our analysis after meeting the inclusion criteria listed in Table 1. Articles including patients with known exposure to radiation exposure, such as the Chernobyl accident, were excluded, because the biological behavior of WDTC after an unknown quantity of radiation exposure is not well defined. Data analyzed from the nine included studies and definitions are listed Table 2. As seen in Table 2, in these studies thyroglobulin levels <10 ng/mL in the hypothyroid state met the definition for complete response to therapy. Chest X-ray was the prevalent means of disease surveillance at the time many of the studies were published. Antithyroglobulin autoantibodies could not be evaluated as such data were not provided by the majority of studies reviewed.

Table 1.

Inclusion and Exclusion Criteria for Studies Reviewed

Inclusion criteria	Exclusion criteria
Age ≤21 years at diagnosis of WDTC	Known exposure to environmental radiation
Pulmonary metastases diagnosed at presentation or upon follow-up
Treatment with ¹³¹I
Data reported on clinical response
Data reported on mortality

WDTC, well-differentiated thyroid carcinoma.

Table 2.

Data Analyzed and Definitions

Data analyzed	Definitions
Follow-up period	Specific to individual study (see text)
¹³¹I dose	In millicuries
Response to treatment	Complete responders: patients with negative whole-body scans and tg levels < 10 ng/mL in the hypothyroid state
	Partial responders: patients with persistent, improved disease based on WBS or chest X-ray and/or improvement but not suppression of tg to < 10 ng/mL in the hypothyroid state
	Nonresponders: patients with persistence of disease without change or worsening of RAI uptake on WBS and/or increasing tg levels
Recurrence of disease 1 year after diagnosis and initial ¹³¹I therapy	Local: within the thyroid bed
	Regional: cervical lymph node
	Distant: pulmonary, bone
Long-term survival	Years since diagnosis
Mortality	Number who died in study period
Disease morbidity	Lung disease
Adverse effects of ¹³¹I	Radiation pneumonitis, SPM

tg, thyroglobulin; WBS, whole body scan; RAI, radioactive iodine; SPM, second primary malignancy.

Major Characteristics of the Studies Reviewed

The nine (4,11 –19) studies analyzed encompass 112 patients with WDTC and pulmonary metastases treated with ¹³¹I age 21 years or younger at diagnosis. Of these 112 patients, histopathological data were available on 74 patients. Of these, 68 patients (91.89%) had papillary carcinoma. All identified studies were retrospective. Pulmonary metastases in 14 of the 112 patients were diagnosed at follow-up. Table 3 shows data compiled from the studies.

Table 3.

Demographic, Histopathological, and Clinical Characteristics of 112 Pediatric and Adolescent Patients with Well-Differentiated Thyroid Carcinoma and Pulmonary Metastases from a Literature Review of Nine Published Studies

Author, year of publication	No. of patients	Upper age limit (years)	Histopathology	Range of f/u in years	Cumulative ¹³¹I dose (mCi)	Complete responders, n (%)	Partial responders, n (%)	Nonresponders, n (%)	Recurrence	Mortality	Survival
Samuel 1998 (11)	26	18	NA	0.7–26.6	125–1050^a	8 (30.7%)	17 (65.38%)	1 (3.85%)	1 regional, 1distant (same patient)	1	96.30%
Bal 2004 (12)	20	20	2 F, 18 P	0.5–24.3 (8.8^b)	60–1180^a (296^c,352^b)	14 (70%)	4 (20%)	2 (10%)	NA	0	100%
Dottorini 1997 (13)	16	18	2F, 14 P	0.83–24.2 (9.6^c)	59–841^a	2 (12.5%)	10 (62.5%)	4 (25%)	1 regional	0	100%
Brink 2000 (14)	12	17	12 P	1–45 (21.5^c, 19.3^b)	100–841^a (430^b)	7 (58.33%)	5 (41.67%)	0	2 regional	0	100%
Giuffrida 2002 (4)	10 (5 at presentation, 5 at f/u)	20	10 P	0.16–24.5 (7.7^b)	368.5+ to 136.5^b	6 (60%)	4 (40%)	0	NA	0	100%
Chow 2004 (15)	9 (4 at presentation, 5 at f/u)	21	1 F, 8 P	9.3–35	NA	5 (55.56%)	2 (22.22%	2 (22.22%)	NA	2	77.78%
Collini 2006 (16)	7 (4 at presentation, 3 at f/u)	17	1F, 6 P	8–29.75	NA	6 (85.71%)	0	1 (14.28%	NA	0	100%
Grigsby 2002 (17)	7	20	NA	NA	NA	5 (71.43%)	0	2 (28.57%)	2 distant	0	100%
Pazaitou-Panayiotou 2005 (18)	5 (3 at presentation, 2 at f/u)	20	NA	NA	80–100 initial + 200–1150 more for mets	0	1 (20%)	4 (80%)	NA	0	100%

Range.

Mean.

Median.

F, follicular carcinoma; P, papillary carcinoma; f/u, follow-up; NA, data not available.

Follow-up period

The studies' follow-up periods ranged from 0.6 to 45 years. Four studies (4,11,14,16) do not specify whether the follow-up period was after diagnosis or treatment. Three studies (12,13,15) specify the follow-up period as after diagnosis of WDTC. In two studies (17,18), the follow-up period was not separately specified for those patients with pulmonary metastases.

Radioactive Iodine Dose

Three of the articles analyzed (15 –17) did not provide data on ¹³¹I dose-specific to patients with pulmonary metastases. Of the remaining articles with reported data, the cumulative ¹³¹I dose administered ranged widely from 88 to 1230 mCi ¹³¹I over a variable and often nonspecified number of treatments. Of the nine studies reviewed, only one study (11) presented data on patients treated based upon dosimetric parameters. Of those patients, complete outcome/adverse event results were available for 14 patients. The authors found that the dosimetric parameters employed could not predict the disease response to therapy. The remainder of the patients reviewed were dosed via body weight or other measures specific to individual institutions. The units for the radioactive iodine (RAI) doses were given in GBq instead of mCi in the Dottorini study (13), which were converted to mCi (59–841 mCi).

Response to treatment

Of the 112 patients, 53 patients (47.32%) responded completely to therapy, 43 (38.39%) were partial responders, and 16 (14.29%) were nonresponders. Table 4 lists the mean cumulative ¹³¹I doses in mCi for complete responders, partial responders, and nonresponders for the five studies with available data (4,12,13,15,18). In general, nonresponders received the highest dose of ¹³¹I. Complete responders generally received a higher dose than partial responders. In one study (11), no correlation was observed between the cumulative ¹³¹I dose, the number of doses, and response of pulmonary metastases to therapy. The follow-up data could not be consistently correlated to treatment response. In the Samuel et al. study (11), 4 out of 8 of the complete responders and 15 out of 17 partial responders had a follow-up time of <10 years.

Table 4.

Mean ¹³¹ I Dose (mCi) in Relation to Disease Status in Five Published Studies

	Bal 2004 (12)	Dottorini 1997 (13)	Giuffrida 2002 (4)	Chow 2004 (15)	Pazaitou-Panayiotou 2005 (18)
CR	322.79	229.73	725	338	0
PR	230.75	244.05	305	NA	437.5
NR	1180	490.54	0	NA	1230

CR, complete responder; PR, partial responder; NR, nonresponder; NA, not available.

Recurrence

Four articles (11,13,14,17) encompassing 61 patients addressed recurrence in patients with pulmonary metastases after treatment with ¹³¹I. Six patients (9.8%) experienced recurrence. One patient (11) developed cervical nodal and bone metastases after an interval of 4 and 7 years, respectively. The specifics of this patient's treatment course and clinical status were not otherwise specified. Another patient who experienced a regional recurrence was not initially treated with a total thyroidectomy (13), the current standard of care. Two patients (14) experienced regional recurrence 1 and 3 years after total thyroidectomy.

Mortality

All studies commented on mortality rate. There were 3 deaths out of the 112 patients studied. In the studies analyzed, 97.32% of children were alive at the time of the individual study analysis and 2.68% had died. One death occurred in an 18-year-old patient 4 years after the onset of pulmonary metastases (11). Her initial response to ¹³¹I was noted to be poor although the timing and dose of ¹³¹I was not reported. She developed intratracheal disease requiring a tracheostomy and subsequent respiratory failure. Relation of the respiratory failure to her pulmonary metastases was not noted. A patient with follicular thyroid carcinoma died of airway obstruction secondary to unresectable local/regional disease 6 months after diagnosis (15). A third patient with papillary thyroid carcinoma experienced local/regional recurrence and diffuse bilateral lung metastases 11 years after diagnosis and died of respiratory failure (15).

Disease morbidity (lung disease)

Only one study (11) reported on pulmonary function test performance or results. Spirometry studies to assess pulmonary function were completed for 10 patients. Of these 10 patients, 6 showed evidence of restrictive lung disease (RLD). One showed evidence of severe RLD, 3 showed moderate RLD, 2 showed mild RLD, and the remaining 4 were normal. One of the patients with normal pulmonary function had complete response to therapy; the remaining nine were partial responders. The individual treatment courses, including ¹³¹I doses, were not provided. The follow-up of these patients ranged from 0.7 to 16.2 years.

Adverse effects of ¹³¹I therapy

Six articles (12 –14,16 –18) encompassing 83 patients addressed the presence or absence of possible adverse events as a result of RAI administration. One study (18) noted that no pulmonary fibrosis was observed as a result of ¹³¹I therapy although details of specific testing for pulmonary fibrosis were not stated. Six patients were evaluated by ^99mTc-diethylenetri-amine pentaacetic acid aerosol clearance studies for chronic radiation fibrosis (11). Of these, one patient showed evidence of radiation injury or pneumonitis with persistent restrictive disease leading to early bronchiectasis. Information regarding ¹³¹I therapy was not provided for this patient. In the Dottorini et al. study (13), one case of gastric cancer occurred 8 years after the administration of 459 mCi of ¹³¹I given in 6 doses to a female partial responder. The cancer was treated successfully by surgery with no relapse after 7 years of follow-up.

Conclusions

The incidence of thyroid carcinoma in children and adolescents is low. When it occurs, there are several known important differences from WDTC in adults that are particularly evident in prepubertal children (20). In comparison with adults, pediatric patients present more frequently with cervical node or distant metastases, most commonly functional pulmonary metastases (6,21,22). In addition, childhood WDTC typically presents with a larger mean papillary tumor volume (6,23). Several studies have shown that sodium iodine symporter expression is greater than in adult WDTC, possibly accounting for more successful treatment with ¹³¹I (24 –26). Paradoxically, both the recurrence rate (27) and long-term survival rate are higher in childhood WDTC (28 –30).

The high incidence of pulmonary metastases in children and adolescents with WDTC, which, nevertheless, has an overall favorable prognosis, makes treatment of such patients with ¹³¹I a therapeutic challenge. A balance must be achieved in the attempt to prevent disease-related morbidity and obtain disease-free survival while avoiding adverse complications of therapy. To date, no consensus has been reached on the optimal ¹³¹I therapy in such patients, including cumulative dose and number and timing of treatments. Multiple reviews have examined the outcome and treatment of children and adolescents with WDTC (20,31 –36). In this study, we performed the first systematic review of that subset of children and adolescents with WDTC and pulmonary metastases treated with ¹³¹I to better define the relationship between ¹³¹I treatment and outcome in such patients.

The published data are limited by several factors. First, it is known that the biologic activity of WDTC is different in prepubescent and adolescent individuals (20), but the available data often do not stratify patients by age or pubertal status. Clinical data dated back as far as 30 years, a time when treatment standard of care was different than current (i.e., total thyroidectomy was not advocated in all cases; external beam radiation was sometimes used). It was necessary to extract data on patients with pulmonary metastases from the larger published population of patients with WDTC, an objective not possible for all study parameters. The range of follow-up varied greatly within the studies and patient outcomes often could not be correlated to follow-up time. In addition, the shortest follow-up period was 0.6 years, which is too brief a time interval to meaningfully evaluate outcome. In many instances, the data did not permit clinical response to be correlated with ¹³¹I dose. It is possible that pulmonary metastases not diagnosed at the time of presentation may have been present but not apparent due to a lack of uniform remnant ablation. Data on thyrotropin levels over time were not available. Therefore, noncompliance with thyroxine therapy could not be eliminated as an influence on patient outcome.

In addition, since the analyzed publications were all retrospective, there are no controlled data on the effects of ¹³¹I therapy in this patient population. Only 2/3 of the studies analyzed recurrence rate, an important outcome parameter thus far underinvestigated in the literature. The lack of consensus on ¹³¹I treatment was evidenced by wide dosage range of ¹³¹I administered and no consistent protocol for dose determination, frequency of administration, or total number of doses administered. From the data analyzed, although over half of the patients studied did not achieve a complete response to therapy, the disease-specific mortality rate remained low at 2.68%. While this is reassuring, the often short follow-up periods must be considered. However, it is interesting to note that one reported patient received no ¹³¹I treatment for pulmonary metastases and remained alive at last follow-up at the age of 35 years, 24 years after the diagnosis of metastatic disease with stable residual pulmonary disease (14). In addition, a report published by Vassilopoulou-Sellin et al. (37) in 1995 featured a child with papillary carcinoma and pulmonary metastases present at diagnosis who was treated with RAI as late as 10 and 30 years after diagnosis. The patient's clinical status and chest X-rays remained stable throughout. In addition, the five studies that provided data on dose in relation to clinical outcome demonstrate that the patients receiving the highest doses of ¹³¹I were those who did not respond to therapy. Thus, it remains to be shown from future prospective studies whether it is prudent to repeatedly administer RAI to a patient population with seemingly little morbidity or mortality despite persistent disease.

A 2003 study by Rubino et al. (38) investigated the role of ¹³¹I treatment on second primary malignancy (SPM) risk as an effect of age in patients found to have thyroid cancer. For the entire cohort (mean age at thyroid cancer diagnosis of 44 years), each 27 mCi of ¹³¹I was found to increase the relative risk for new solid tumors by 3.5% and for leukemia by 39% (38). However, in a subgroup analysis of the 210 patients aged <20 years at thyroid cancer diagnosis who were treated with ¹³¹I, no carcinogenic effect of ¹³¹I was found (relative risk = 1.1). With a pooled cohort follow-up period of only 13 years, it is difficult to definitively conclude that there is no increased risk of SPM in pediatric patients. Our review revealed one case of gastric carcinoma after a cumulative ¹³¹I dose of 459 mCi. However, not all studies provided data on SPM occurrence.

In 2000, La Quaglia et al. (9) published a large retrospective study on 83 patients <21 years of age with differentiated thyroid cancer and distant metastases, which highlighted the need for long-term follow-up. This study did not meet our inclusion criteria and therefore was not included in our analysis (response to treatment was not characterized). Sixty-six percent of the patients were treated by total thyroidectomy. All 83 patients received ¹³¹I as part of initial treatment with a median total dose of 155 mCi (range, 20–770 mCi; mean, 227 mCi). Thirty-one percent of patients had disease progression with a median time to progression of 2.4 years. While overall survival was 100% (median follow-up, 7.6 years; range, 1–42.1 years), progression-free survival was 76% at 5 years and 66% at 10 years after diagnosis. Patients in this study had more recurrences detected with increased length of follow-up but a continued 100% survival rate.

In conclusion, this review clearly highlights the need for long-term prospective studies on the outcome of children and adolescents with WDTC and pulmonary metastases treated with RAI to enable the creation of an evidenced-based treatment protocol for such patients. Such prospective studies are necessary to determine the amount of RAI needed to provide the greatest benefit in treating a disease with a known favorable outcome without causing harm as a result of therapy. In the meantime, a consensus should be developed based upon existing outcome data for standardized ¹³¹I therapy in this patient population. Molecular and genetic studies are needed to evaluate the difference between complete, partial, and nonresponders to therapy.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

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Outcomes of Children and Adolescents with Well-Differentiated Thyroid Carcinoma and Pulmonary Metastases Following 131 I Treatment: A Systematic Review

Abstract

Background:

Summary:

Conclusions:

Introduction

Methods

Major Characteristics of the Studies Reviewed

Follow-up period

Radioactive Iodine Dose

Response to treatment

Recurrence

Mortality

Disease morbidity (lung disease)

Adverse effects of 131I therapy

Conclusions

Footnotes

Disclosure Statement

References

Adverse effects of ¹³¹I therapy