| IntroductionThyroid carcinoma is the most common malignancy of the endocrine system. According to 2014 cancer statistics in American, the largest annual increases cancer from 2006 to 2010 is thyroid carcinoma (5.4% and 6.5% in men and women, respectively). Well-differentiated thyroid cancers (DTC) account for a percentage of 90% thyroid cancer, primarily papillary (PTC) and follicular carcinomas (70%-75% and 15%-20%, respectively). Therapeutic approach for DTC is multifactorial, including surgery and thyroid hormone suppressive therapy, often followed by radioactive 131I treatment.Typically, differentiated thyroid carcinoma (DTC) has a slow clinical course, and the prognosis is generally favorable, particularly when the DTC is completely intrathyroid or has spread to only the cervical lymph nodes. Papillary and follicular carcinomas can carry 10-year overall survival rates of 93% and 85%, respectively. Although distant metastases are uncommon in DTC, with a prevalence of 4%-18%, over 50% of distant metastatic patients have lung metastases. Patients with lung metastases have better outcomes than those with metastases to bone or brain. Despite an excellent prognosis, the rate of death from thyroid cancer is steadily increasing. Recent advances indicated that distant metastatic diseases from DTC are associated with poor prognosis, while widespread metastatic disease is an independent predictor of a poor prognosis.Normally, the treatment option for DTC patients presenting with distant metastasis disease always performing a total thyroidectomy so as to facilitate radioactive iodine (RAI) therapy, followed by L-thyroxine therapy to suppress the thyroid-stimulating hormone (TSH).131I therapy is the primary modality in all patients with radioiodine-avid disease. Even after an adequate stimulation by TSH, only 42% of them achieve a cure after one or more times of 131I administration. Therefore, it is valuable to investigate the factors that may influence the efficiency of 131I for DTC patients with distant metastatic, including lung metastases (LM). To date, most studies have paid considerable attention to the investigation of outcomes of 131I for treatment of DTC with lung metastases and whether some factors, including age, pathological subtypes, distant metastases, CT findings, serum thyroglobulin (Tg) levels, radioioindine-avidity, and therapeutic doses of 131I, might have effects on radioiodine treatment. However, the correlations between these factors and their possibly influencing mechanisms on radioiodine treatment outcomes have not been completely elucidated. Few have described the effect of presenting times of lung metastasis by 131I imaging on clinical outcomes, and correlations between times of RAI therapy and outcomes. Thus, the characteristics of PTC patients presenting with lung metastases, also benefits and limits of RAI therapeutic times, still require further investigation.Our previous studies had investigated the potential contribution of 131I whole-body scan to the therapeutic benefits of patients those with lung metastases at the first diagnosis imaging and those with LM discovered after initial 131I treatment. In the present study, we retrospectively determine clinical outcomes among those groups with pulmonary metastases detected at various times on 131I imaging, discuss the factors that influence the time of lung metastasis detection, and examine potential factors that may affecting clinical outcomes. Since most patients with PTC lung metastases rountinely underwent at least once RAI therapy in clinical practices, we also assessed cumulative outcomes for patient performed more times of 131I treatments. Furthermore, benefits and limits of 131I treatment were investigated based on clinical outcomes and side-effects in patients with PTC lung metastases.Materials and MethodsSubjectsA retrospective review of 87 patients (20 males and 67 females) with PTC presenting with pulmonary metastasis diagnosed by 131I scanning at the Department of Nuclear Medicine, Henan Provincial People’s Hospital from June 2008 to June 2014 was performed. All 87 cases exhibited negative for serum anti-Tg antibodies (TgAb) in this study. The average age of collected patients was 42.9±16.1 years (rang 7-77), with 46 (52.9%) patients being under the age of 45 years. The mean follow-up after the diagnosis of lung metastases by 131I imaging was 49.8±12.7 months, ranging from 13 to 72 months. The 87 patients were divided into three groups based on the time when lung metastases were detected by 131I imaging:1) at the initial postoperative RAI treatment (n=62); 2) immediately following RAI thyroid remnant ablation, at the second RAI imaging (n=15); and 3) during follow-up (n=10). This retrospective review protocol was approved by the Institutional Review Board at Henan Provincial People’s Hospital, and all patients gave informed consent.PTC Treatment and PreparationAll 87 patients underwent total or near-total thyroidectomy. Eighty-five patients underwent central-compartment (level VI) lymph node dissection (therapeutic or prophylactic level VI neck dissection for patients with clinically involved or uninvolved central or lateral neck lymph nodes). In addition,19 underwent bilateral neck node dissection,35 underwent unilateral neck node dissection, and six underwent metastasectomy after RAI treatment. Three patients received external beam radiation therapy; one had 125I seeds implanted in the lung metastasis; and no patient received chemotherapy according to the data collected. All patients had no contractions to RAI.Prior to 131I thyroid ablation therapy, all patients underwent a pretherapeutic imaging and laboratory work-up, routinely including tests of the 24-h thyroid radioiodine uptake (TRIU) (while pretreatment diagnostic RAI scans were not performed in all patients), measurements of serum levels of TSH, Tg and TgAb, chest x-ray or CT, high-resolution neck ultrasonography (US), and function tests of liver and kidney. Occasionally, MR imaging or FDG PET-CT scanning was performed in some patients if needed. RAI ablating remnant or metastatic foci require TSH stimulation. A TSH of>30 mlU/L is related to increased 131I uptake in remnant throid or tumors. To acheive adequate endogenous TSH elevation for optimal ablation treatment or follow-up 131I imaging, LT4 was not administrated for 4 weeks after thyroidectomy in patients for thyroid remnant ablation, and was withdrawn for 3 weeks in patients for ablating persistent metastases. A low iodine diet for 2 weeks is necessary for patients undergoing RAI remnant ablation. Specifically for patients with CTs performed using iodinated contrast, RAI should be administered at least 3 months later. Posttherapeutic 131I planar whole-body scan (Rx-WBS)+chest (including neck) SPECT/CT were conducted 6 days after ablative 131I administration.Postoperative 131I ablating thyroid remnant (or known or suspected persistent neoplastic foci) treatment was performed generally 4 weeks after surgery, and specifically should be prolonged by 1 or 2 weeks if serum TSH was below an determined level (>30 mU/L) before administration of 131I. If ablation therapy had to be delayed beyond 6 weeks, levothyroxine (LT4) treatment was initiated and then withdrawn. Empiric fixed 131I activity used for thyroid remnant ablation in our department was 3.7 GBq (100 mCi) in patients without metastases, 4.44 GBq (120 mCi) in those with lymph node metastases, and 5.55 GBq (150 mCi) in those with lung metastases based on preoperative work-up and/or postoperative pathological and/or pretherapeutic imaging findings. Thyroid hormone suppression therapy was initiated or resumed on the third or fifth day after 131I administration.131I ablating persistent pulmonary metastases, prepared by 3-week LT4 withdrawal, was routinely performed 6 months after their last 131I treatment session with empirically administratered doses of 7.40 GBq (200 mCi) 131I. Thyroid hormone suppression therapy was initiated or resumed 24h or 72h after 131I administration. 131I ScanningPostt herapeutic 131I planar whole-body scan (Rx-WBS) was conducted 6 days after ablative 131I administration using a dual-head gamma-camera, Infinia Hawkeye 4 (GE Healthcare). With patients in the same position, SPECT/CT was performed during the same session as WBS over the chest (including neck) and other suspected increased uptake areas seen on WBS. The standard for determining the presence of metastatic foci or positive on Rx-WBS and SPECT/CT:Any focal or diffuse 131I uptake outside the thyroid bed higher than the surrounding background and inconsistent with physiologic activity (131I uptake in salivary glands, urinary collecting system, and gastrointestinal tract) was defined as metastatic foci uptake of 131I.Serum Tg AssaySerum Tg and TgAbs were measured routinely both 1 day just before 131I administration (4 weeks LT4 withdrawal) and during the follow-up (5 months after 131I treatment) on LT4 treatment by electro-chemiluminescence immunoassay (Cobas E411, Roche, Mannheim, Germany). The comparison of Tg concentrations in assessment of the therapy response should be conducted with patients on the same situation (while on and/or off LT4).Follow-upAfter abation therapy, regular check-ups including neck US, Tg and TgAb (while on LT4) were performed every 6-12 months. If needed,131I imaging [74-185 MBq] and the TSH-stimulated (withdrawal of LT4 for 3-4 weeks or TSH>30 mIU/L) serum Tg levels, even chest x-ray (or CT) and FDG PET/CT, were performed during follow-up based on the findings of regular check-ups. Specifically, patients with a complete clinical cure and those not considered for RAI therapy can be assessed while receiving LT4 treatment. No diagnostic 131I imaging was performed before RAI ablation of a normal thyroid remnant or in patients with known metastatic disease before 131I therapy.Evaluation of Therapeutic EfficacyThe treatment efficacy was evaluated by 131I Rx-WBS and SPECT/CT, Tg levels (both on and off LT4), and radiographic findings. For patients with negative Tg during treatments, the assessments of efficacy were based on findings of 131I Rx-WBS and SPECT/CT and chest x-ray or CT. The findings of each 131I Rx-WBS and SPECT/CT were used to measure the efficacy of the last treatment session.The efficacy following one or more times of treatment was divided into four types according to therapy results:(1) Complete remission (CR):Evidence for identification of CR comprises the absence of extra-thyroid uptake on 1311 Rx-WBS and SPECT/CT (and/or normal neck US or CT), Tg< 1 ng/mL during TSH suppression and stimulation without interfering TgAbs, and no recurrence within at least 1 year follow-up.(2) Partial remission (PR):Evidence for PR comprises persistent Tg level≥ 1 ng/mL but a decline≥25% after treatment, and persistent metastatic foci uptake but a decline of uptake intensity and/or a shrinkage of metastatic foci and/or a decreased foci number on 131I Rx-WBS and SPECT/CT.(3) No change (NC):Evidence for NC comprises a decline of serum Tg level<25% after treatments, and no change on 131I Rx-WBS and SPECT/CT.(4) Progressive disease (PD):Evidence for PD comprises an increase of Tg level and an enlargement of metastatic foci and/or an increased foci number on 131I Rx-WBS and SPECT/CT, or absence of 131I uptake in newly presenting metastatic foci, or patient death.In this study, both CR and PR were identified to be effective.For investigation of possible factors influencing the treatment efficacy, the following data were collected and analyzed:age, gender, size (refers to the maximal diameter in the metastatic foci) and number of lung metastases by chest CT, and whether pulmonary metastases could be visualized on the post-ablation 131IWBS or SPECT-CT.131I repeatedly ablating persistent lung metastasesPTC pulmonary metastases should be treated with RAI therapy if demonstrated continuously to be iodine avid and clinically responsible to 131I treatment. Whether or not and how often to give RAI are decisions that must be individually tailored on the basis of the disease response to therapy, the rate of disease progression in between treatments, age of the patient, and the presence of other metastatic lesions. The time interval beteween two treatemts is typically 6-12 months and the doses of RAI to administer is empiric fixed activities of 7.4 Gq (200mCi) in our clinical practice.Statistical analysisStatistical descriptions were given as mean±standard deviation (SD) and median. The Student’s t-test, chi-square test were used when appropriate to evaluate statistical significance of the data. Multi-variance Binary logistic regression analysis was performed to assess the effect of variables. Statistical significance was accepted at p≤0.05. Statistics were calculated using SPSS version 11.5.ResultsDescription of the study populationThe clinical characteristics of 87 cases of PTC with lung metastases discovered by 131I imaging are summarized in table 1. There were no statistical significance of gender, age at diagnosis of LM (<45yrs vs>45yrs), site of metastases (lung only, lung+lymph node, multiple metastases), metastases on chest X ray and/or CT (yes vs no) and 24h TRIU among three groups (P>0.05). Treament outcome analysis based on various times of pulmonary metastases presenting on 131I Rx WBSThe 131I therapy efficacy on patients presenting with lung metastases was analyzed (Table 2). The cure (effective) rate was 12.9%(51.6%),6.7%(46.7%), and 0.0%(20.0%) in 3 groups, respectively. The clinical outcome results showed that patients with lung metastases detected at the initial RAI treatment (Fig.l) had better outcomes than those presenting during follow-up (Fig.2) (P< 0.05), while had no significant difference compared to those detected at post-ablation 131 I imaging (see Table II, Fig 3).TSH-suppressed serum Tg levels analysisThe suppressed serum Tg levels were analyzed among those 3 groups (see table 2). Six months after first time 131I ablating thyroid remnant treatment, the median Tg level was 148.6,165.8, and 254.5(ng/mL) in 3 groups, respectively. However, there were no statistical significance of Tg levels among three groups (P> 0.05). Six months after first time 131I ablating persistent pulmonary metastases treatment, the median serum Tg levels was markedly decreased from 148.6 ng/mL to 37.5 ng/mL in group 1,165.8ng/mL to 98.6 ng/mL in group 2 (P < 0.05), while had no significant difference although a little bit decline of from 254.5 ng/mL to 203.2 ng/mL in group 3 (P> 0.05).Cumulative outcomes of RAI repeatedly ablating persistent lung metastasesThe 87 patients underwent RAI treatment for 2-6 times, with a median cumulative postoperative RAI dose of 11.1 (range 7.4-22.2) GBq.Fifteen patients had 2 131I treatment,38 had 3,27 had 4,7 had 5 and 4 had 6 treatments). The overall effective rate was 57.47% (50/87). The cumulative effective rate was 21.83%(19/87) for 2 treatment,32.18%(28/87) for 3 treatments,40.23%(35/87) for 4,54.02%(47/87) for 5, and 57.47%(50/87) for 6 treatments, respectively. There were statistically significant differences in cumulative effective rate (x2= 5.74,P<0.001) among different number of repeated treatments, but there were no significant differences between 5 and 6 treatments (x2= 0.261, P=0.506).Influencing factors analysisComparison of 131I treatment outcomes according to possibly influencing factors showed that, there was a higher effective rate in patients whose metastatic LMs could be visualized on the first thyroid remnants ablation 131I WBS or SPECT-CT than those whose metastatic LMs could not (89.3% vs 70%) (P= 0.018), in patients whose serum Tg levels, measured six months after first time 131I ablating persistent pulmonary metastases treatment, had a decline of≥25% than those whose Tg did not (Table 3).According to Binary Logistic regression analysis, whether metastatic LMs could be visualized on the first post-surgical ablation 131I WBS (or SPECT-CT) or not, and a≥25% decline of serum Tg after first time 131I ablating persistent metastases treatment, were found to be significant factors influencing treatment outcomes, suggesting that patients with lung metastases detected at the initial RAI treatment and markedly decreased Tg after first RAI ablating persistent metastases therapy were more likely to have better outcomes of 131I therapy (Table 4).ConclusionsRAI is effective for treatment of radioiodine-avid lung metastases, particularly if detected earlier. For patients with metastases detected during the follow-up period, RAI treatment is not ideal. Dynamic monitoring of serum Tg levels and lesion changes are more objective measures of the effectiveness of RAI treatment. For patient underwent more times of 131I treatments, cumulative outcomes should be also assessed to investigage benefits and limits of 131I treatment based on clinical outcomes and side-effects in patients with PTC lung metastases. Our data suggest that patients with lung metastases detected at the initial RAI treatment and markedly decreased Tg after first RAI ablating persistent metastases therapy were more likely to have better outcomes of 131I therapy. |
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