Incidence of BM in DTC was relatively lower compared with that in other malignant cancers such lung cancer and breast cancer[20, 21]. Besides, BM often occurs in medullary and undifferentiated thyroid cancer, and limited characteristics about BM in DTC have been reported. Despite several case reports and cohort studies[23–25], little was known about its incidence, risk factor and prognosis in DTC. In this population-based study, we analyzed the trend in incidence, survival, risk factors and prognostic factors of BM in newly diagnosed DTC patients, aiming to promote understanding on the current situation and the association between clinical pattern and BM. To the best of our knowledge, this study included largest sample size of DTC patients with BM compared with previous ones.
In the present study utilizing SEER database, BM accounts for 0.36% (244/67176) among entire group and 34.76% (244/702) among subset with metastatic diseases in newly diagnosed DTC patients, which was lower than the proportion (2.0%) in study of Yorihisa et al. and the proportion (5.51%) in study of Marie-odile et al. Sample size in these two studies was relatively small and they only included patients in a single institution; therefore the results in the above studies were not representative. In addition, the above two studies were conducted with date in early period, while our study focused on patients diagnosed during 2010 to 2016. With the advancement of screening methods, early detection of asymptomatic thyroid cancer and timely interventions such as surgery have substantially enhanced the prognosis of thyroid tumor patients. Therefore, the frequency of bone metastases in DTC patients may have reduced compared with early decades.
To explore the trend of incidence of BM in DTC patients, Jointpoint regression analysis was introduced, and result indicated that the age-adjusted incidence of BM in DTC was relatively stable during study period, which was not reported before. Besides, incidence of thyroid cancer was in constant increasing during 1974 to 2013 in United States.
By using multivariable logistic regression, we recognized predictors of BM in newly diagnosed DTC. Older age, black race, male gender, follicular histology, more advanced T stage, radiation therapy, no surgery, and chemotherapy were significantly associated with of presence of BM in DTC patients at diagnosis. In a meta-analysis that enrolled 34 articles with 73,219 patients, age ≥ 45 years, male gender, and follicular histology were demonstrated to be significant predictors of distant metastasis, which was consistent with our analysis . Follicular thyroid cancer was characterized with higher invasion and distant metastasis compared with papillary thyroid cancer; therefore BM rate was higher correspondently. According to a population analysis included patients with DTC during 1988–2009 in SEER database, patients with distant metastasis tended to have received radiation therapy and not to have had surgery. However, as it was discussed, SEER database did not provide information about specific anatomic sites of distant metastasis at that time, so the detailed data for BM was not getable in their analysis.
Furthermore, the optimal performance of multivariable logistic regression model in the entire cohort was authenticated by ROC analysis, in which the AUC value was 0.893. Besides, the nomogram established in this study is an efficient tool to help doctors decision-making owing to its user-friendly interface and optimal predictive ability. Nevertheless, we were not capable of figuring out the most common site for BM because there was no data documented in SEER database until now.
Prognostic factors for overall survival and cancer-specific survival of DTC patient with BM was analyzed using the multivariable Cox model. Results revealed that patients with multiple metastatic sites have higher hazard ratio for overall survival and cancer-specific survival, which was in coherence with previous studies[10, 30]. Meanwhile, significant decrease in the hazard ratio for overall survival and cancer-specific survival was found in patients with total thyroidectomy and radioisotopes radiation therapy. Surgery was the mainstay of therapy for thyroid cancer patients, especially in patients without distant metastasis. Surgical options include thyroid total thyroidectomy or lobectomy, and it was still in controversy on how to choose optimal surgical procedure because of the difficulty in balancing surgical effect and complication. Total thyroidectomy reduces recurrence and allows early detection of recurrence in the neck using ultrasonography compared with lobectomy, thereafter improving the prognosis compared with others. The most used radioisotope in DTC was radioiodine, but its using was still of wide divergence, partially due to the lack of evident prospective randomized controlled trials. Patients with BM could benefit from radioiodine in both suppressing the progression of tumor and reducing recurrence of primary carcinoma as we concluded. It was testified in some retrospective studies that application of radioiodine could improve survival of DTC patients[9, 34, 35] as well as BM patients. Especially, radioiodine therapy was effective in the ablation of thyroid remnant after surgery. External beam radiation therapy (EBRT) was not associated with positive outcomes in our analysis. Inversely, a retrospective study enrolled 74 BM patients has demonstrated that EBRT significantly increased survival. Nevertheless, EBRT was reported to have acute toxicities such as esophageal stricture, so it was used under relatively strict indication. Besides, combining radioiodine and external beam radiation therapy seems advantageous in some cases. However, the treatment effect of total thyroidectomy and radioiodine in DTC patients with BM need to be further explored in the future study. Other factors did not exhibit prognostic value in our analysis, but their role has been demonstrated in other studies. Older age, higher T stage, positive lymph node, and black race were predictors of positive outcome[24, 25]. Further study is necessary to shed light on their prognostic value in BM.
Although this was a population-based study that enrolled largest cohort of DTC patients with BM, limitations in this study was unneglectable. Because it was a retrospective study based on current database record, some parameters were unavailable. Firstly, the further detailed information of BM like specific sites was not available in SEER database, which limited further analysis. Secondly, onset of BM during follow-up period was not presented and we only had information on synchronous metastasis, so the incidence may be underestimated. Thirdly, more detailed information about radiation or chemotherapy such as chemotherapy regimens, doses, and the specific number of cycles were not recorded in SEER database. Fourthly, except the survival, other outcomes such as complications of exposures or interventions were not reported. We could only assess the prognosis by survival data. Finally, data on specific metastatic sites including lung, bone, liver and brain was available in SEER database since 2010, leading to some inevitable bias. Therefore, more convincible clinical studies especially the randomized clinical trials were necessitated in the future.
In summary, results of this population-based study highlighted the incidence, predictors and prognostic factors of BM in newly diagnosed DTC patients. The age-adjusted incidence of BM in DTC was relatively stable during study period. Older age, male gender, black race, follicular histology, more advanced T staging, no surgery, radiation therapy, and chemotherapy were significant predictors for the presence BM in DTC patients. Thus, timely, and appropriate screenings for patients with these risk factors are recommended. Moreover, in DTC patients with BM, presence of total thyroidectomy and radioisotopes radiation therapy exhibited significant benefit on overall survival (OS) and cancer-specific survival (CSS) while multiple metastatic sites could serve as indicator of poor prognosis, which provided evidence for clinical practice.