Demographic and treatment characteristics of the survivor and sibling cohorts are summarized in . Compared with siblings, survivors were younger and more likely male, but similar in the proportion of self-reported White, non-Hispanic race/ethnicity. Compared with survivors analyzed in this study, survivors with incomplete or unknown radiotherapy exposure data (n=572) were more often male (59.3%), non-White (25.7%), and treated before 1981 (53.5%), but were similar in the proportion who relapsed.
Characteristics of 5-year acute lymphoblastic leukemia survivors and a sibling comparison group.
Fifty-six survivors reported developing hypothyroidism compared with 50 siblings during follow-up. However, among these individuals only 26 survivors and 25 siblings reported recently taking thyroid hormone replacement. Twenty-three survivors reported a history of hyperthyroidism compared with 19 siblings. Two of these survivors and 3 of these siblings had subsequent thyroidectomies; 1 survivor and 3 siblings with hyperthyroidism also reported recently taking anti-thyroid medications.
The overall cumulative incidence of hypo- and hyperthyroidism among survivors 15 years following original ALL diagnosis was 1.6% (95% CI 1.1, 2.1) and 0.6% (95% CI 0.3, 1.1), respectively. Compared with siblings, survivors were significantly more likely to report both hypo- (HR 2.6, 95% CI 1.8, 3.8) and hyperthyroidism (HR 2.0, 95% CI 1.1, 3.9). Both male and female survivors were more likely to report hypothyroidism compared with same-sex siblings, and as expected, female siblings were more likely to report hypothyroidism compared with male siblings (). However, only female survivors were more likely than same-sex siblings to report hyperthyroidism; male survivors and male siblings had similar risk (). Overall, no apparent plateau in risk of either hypo- or hyperthyroidism was seen among survivors during the follow-up period.
FIGURE 1 Cumulative incidence of hypothyroidism among 5-year acute lymphoblastic leukemia (ALL) survivors versus siblings, stratified by sex. Outcomes censored by alternative thyroid conditions, leukemia recurrence, second malignancy, hematopoietic cell transplant, (more ...)
FIGURE 2 Cumulative incidence of hyperthyroidism among 5-year acute lymphoblastic leukemia (ALL) survivors versus siblings, stratified by sex. Outcomes censored by alternative thyroid conditions, leukemia recurrence, second malignancy, hematopoietic cell transplant, (more ...)
Compared with survivors who received only chemotherapy, those who received ≥20 Gy cranial radiotherapy in addition to any dose of spinal radiotherapy had the highest risk of reporting subsequent hypothyroidism (HR 8.3, 95% CI 3.3, 20.5; ). Survivors who received <20 Gy cranial radiotherapy with or without spinal radiotherapy and those who received ≥20 Gy cranial radiotherapy alone were not at significantly increased risk of subsequent hypothyroidism. There was no difference in risk between female survivors treated without radiotherapy and female siblings; however, male survivors treated without radiotherapy had a borderline increased risk versus male siblings (p=0.053). Results were similar if analysis was restricted only to those survivors who reported being on thyroid hormone supplementation (). The radiation exposures to the thyroid and pituitary glands were similar between survivors with hypothyroidism who reported being on thyroid hormone compared to those who were not on hormonal treatment (data not shown).
Pituitary and thyroid dosimetry and corresponding risk of hypothyroidism, stratified by radiotherapy exposure and adjusted for diagnosis year and age, race/ethnicity, and sex.
Survivors exposed to craniospinal radiotherapy also were at increased risk of subsequent hyperthyroidism compared with those treated with chemotherapy alone (HR 6.1, 95% CI 1.1, 34.2; ). Those treated with cranial radiotherapy alone had a 3-fold increased risk compared with those treated with chemotherapy only, but estimates were imprecise. In both hypo- and hyperthyroid analyses, other treatment and demographic characteristics such as age and year of diagnosis, and race/ethnicity were not independently associated with an altered risk of either thyroid condition among ALL survivors.
Risk of hyperthyroidism, stratified by radiotherapy exposure and adjusted for diagnosis year and age, race/ethnicity, and sex.
When treatment exposures were re-categorized by pituitary and thyroid gland-specific radiation dosimetry, only pituitary doses ≥20 Gy combined with thyroid doses ≥10 Gy were associated with a significantly increased risk of hypothyroidism (HR 9.9, 95% CI 4.0, 24.8) compared with survivors treated with chemotherapy only; there was no difference in risk if 10–14 Gy and ≥15 Gy thyroid doses were analyzed separately. In analysis of hyperthyroidism, only survivors exposed to pituitary doses ≥20 Gy combined with thyroid doses ≥15 Gy were at increased risk (HR 8.4, 95% CI 1.3, 53.5) versus chemotherapy only.
Twenty (0.6%) survivors reported developing a thyroid nodule at a mean of 14 years (range, 0–22 years) after ALL diagnosis; 18 had received some form of cranial or craniospinal radiotherapy. Among these 20 survivors, 4 reported subsequent hyperthyroidism, 3 reported subsequent hypothyroidism, and 3 reported subsequent thyroid cancer. Overall, 13 survivors developed thyroid cancer as their first subsequent malignancy: 11 papillary carcinomas (including 3 with the follicular variant type), 1 follicular adenocarcinoma, and 1 unknown histology. On average, these 13 survivors developed thyroid cancer at a median age of 25 years (range 14–40) and a median interval of 22 years (range 9–29) following ALL diagnosis. All 13 had received some form of CNS radiation with 10 having received spinal radiation. The median radiation dose to the thyroid gland was 13.4 Gy (range 0.1–21.4), and among patients who had received spinal radiotherapy, all received at least 10 Gy to the thyroid. Overall, the SIR of thyroid cancer among survivors was 4.8 (95% CI 2.6, 8.2; )), but this was primarily associated with craniospinal radiotherapy (SIR 30.3, 95% CI 14.5, 55.7). Survivors who received only cranial radiotherapy were not at increased risk and there was no difference in risk by gender.
Risk of thyroid cancer among 5-year acute lymphoblastic leukemia survivors without prior relapse, hematopoietic cell transplant, thyroidectomy, or other secondary malignancies.