• biochemical incomplete response
• radioiodine treatment
• differentiated thyroid cancer
• structural incomplete response

Background: Initial therapy for differentiated thyroid cancer (DTC) aims to cure patients and reduce the risk of persistent/recurrent disease. However, some patients are found to have persistent or recurrent disease during follow-up. According to the recommendations of the most recent 2015 ATA guidelines, risk of recurrence should be reassessed at each clinical follow-up based on clinical, biochemical, and imaging evaluation. While the risk of recurrence over time is almost negligible in patients with an excellent response (ER) to initial therapy, it can vary in patients with a biochemical incomplete and indeterminate response (BiR/InR) depending on several epidemiologic and pathologic factors, including ATA risk category. In patients who develop BiR after initial treatment, the risk of structural disease during follow-up is about 20%, whereas it decreases to about 15% in patients who develop InR. In addition, structural incomplete response (SiR) to initial therapy is observed in 2%–6% of low-risk ATA patients, 19%–28% of intermediate-risk ATA patients, and 67%–75% of high-risk ATA patients. Lymph nodes and lung metastases are the main sites of SiR.
The management of patients with BiR/InR after initial therapy is controversial because they have persistent Tg or TgAb but no evidence of structural disease. Despite the recommendations of the ATA consensus guidelines, empiric treatment with radioiodine (131I) is often used in clinical practice to treat these patients, although the data on the efficacy of this treatment are controversial. There are several potential (not mutually exclusive) approaches for SiR patients, including active surveillance, surgery, radioiodine treatment, minimally invasive techniques, and systemic drugs. However, there are no prospective randomized trials evaluating the efficacy of different treatment modalities. For lymph node metastases, studies directly investigated the role of repeated radioiodine treatment are limited. On the other hand, lung metastases should be treated with repeated radioiodine treatments as long as they continue to take up radioiodine because the rate of disease control is high.
Objective: The aim of our study was to evaluate the impact of radioiodine treatment(s ) on the clinical outcome of DTC patients, analyzing 2 groups of patients separately: BiR/InR and SiR patients after the initial therapy.
Patients and methods: Between 2009 and 2012, 220 patients who had already undergone total thyroidectomy ± lymph node dissection and at least one 131I treatment received the second 131I treatment, at the Endocrine Unit of the University Hospital of Pisa. Patients were divided into two groups according to their disease status after the initial therapy: BiR/InR patients [153/220 (69.5%)] and SiR patients [67/220 (30.5%)]. As recommended by the “ongoing risk re-stratification” studies, definition of ER, BiR/InR, and SiR, was applied to all patients during the study period, after further treatments at each follow-up visit. Patients were followed until data lock (April 2023).
Results:
1) Bir/InR patients (n=153)
At the first evaluation after initial treatment (median: 7 months), most cases already had BiR/InR [145/153 – 94.8% (BiR: 58 - 37.9%; InR: 87 - 56.9%)], ER occurred in 8 (5.2%) patients, and BiR/InR was detected later during follow-up. After the second 131I treatment (median 8 months), 11.8% of patients showed ER, 17% SiR, while BiR/InR persisted in 71.2%. Less than half (38.5%) of SiR patients had radioavid metastases. The remaining 61.5% had no 131I uptake in metastases detected by other imaging modalities, mostly neck US. Overall, 6.5% (10/153) of BiR/InR cases had radioiodine-avid metastases after the second 131I treatment. Patients who had SiR after the second 131I treatment had larger tumor size, more aggressive histology and more severe vascular invasion than patients with BiR/InR and ER. Median levels of LT4-Tg, rhTSH-Tg, and TgAb were also significantly higher in patients who developed SiR than in patients in whom BiR/InR persisted (3.73 µg/L vs 2.05 µg/L, p=0.04; 8.85 µg/L vs 3.75 µg/L, p=0.03; 1295.5 UI/mL vs 210.2 UI/mL, p=0.04).
About half of the BiR/InR patients (71/153 - 46.4%) received additional treatments after the second 131I treatment. At the last evaluation (median 9.9 years), BiR/InR persisted in 57.5%, while 26.2% and 16.3% of patients had ER and SiR, respectively.
2) SiR patients (n=67)
Patients with lymph node (n=36) or lung metastases (n=23) were more common and were included in the analysis.
Thirty-six patients received the second 131I because of the presence of lymph node metastases. Seventeen (47.2%) of them showed radioiodine uptake at the first post-therapeutic whole body scan (pt-WBS) and in 10/17 (58.8%) the neck US was concordant with the pt-WBS. After the second 131I treatment, 7/17 (41.2%) patients with uptake at the first pt-WBS continued to take up radioiodine in the lymph node and in 2/17 (11.8%) patients lung uptake appeared for the first time. Conversely, in 8 (47.1%) cases, no radioiodine uptake was detected in the pt-WBS. In the group of patients with no uptake after the first 131I treatment (n=19), radioiodine uptake in the lymph nodes was observed in 5 (26.3%) cases. The pt-WBS persisted negative in 14 cases with lymph node metastases (73.7%), although neck US was positive. At the last evaluation (median 10.8 years after the initial diagnosis), 8 (22.2%) patients had ER, 9 (25%) had BiR/InR, and 19 (52.8%) had SiR. Only 6 out of 36 patients (16.7%) with lymph node metastases after initial treatment were cured by radioiodine treatments alone, however in all cases the maximum diameter of the lymph node metastases was < 1 cm.
Twenty-three patients received the second 131I because of lung metastases. Nineteen out of 23 patients (82.6%) had radioiodine-avid lung metastases at the first pt-WBS. Conversely, in 4 patients (17.4%) in whom metastases were detected preoperatively (3 patients) or early after initial therapy (1 patient), the lung lesions showed no 131I uptake after the first radioiodine treatment. After the second 131I treatment, radioiodine uptake persisted in 15 cases (79%) of 19 patients with lung uptake at the first pt-WBS, while it was negative in 4 patients who had an ER (n=3) and BiR (n=1) after the second 131I treatment. Among the 4 patients without uptake at the first pt-WBS, the second pt-WBS continued to show the absence of radioiodine uptake in 1 patient (radioiodine refractory), while in 3 patients lung radioiodine avid lesions were detected at the pt-WBS. At the last evaluation (median 10.9 years after diagnosis), 9 (39.1%) patients achieved ER, 5 (21.8%) BiR/InR and 9 (39.1%) SiR. Of the 9 patients who achieved ER, 7 were treated with radioiodine alone. Thus, in 30.4% (7/23) of patients with lung metastases after initial treatment, repeated radioiodine treatments were able to cure the disease. Considering all patients with lymph node or lung metastases after initial therapy (n=59), 13 (22%) obtained an ER at the end of follow-up with repeated radioiodine treatments alone. Vascular invasion was present in 50% of SiR patients and 50% of BiR/InR patients at the last evaluation, compared to only 11.8% of ER patients (p=0.024). Moreover, patients with SiR at the last evaluation had a larger median tumor size [3 (1.95-6.25) cm] than those with BiR/InR [2.1(1.35-3.25) cm ] and ER [1.7 (1.05-2.3) cm] (p=0.013). Patients with SiR at the last evaluation showed higher Tg values before the second radioiodine [(19.7 (0.95-224.5) µg/L] than those with BiR/InR [0.97 (0.54-1.4) µg/L] and ER patients [0.56 (0.27-0.72) µg/L].
Conclusions: Our study indicates that the second 131I treatment in patients who had a persistent BiR/InR after initial therapy, should neither totally “a priori” avoided nor unconditionally performed in all cases. The presence of detectable Tg or TgAb values alone is not necessarily indicative of radioiodine avid structural disease, since our data demonstrated that only a minority of cases who performed the second 131I treatment showed a radioiodine uptake in metastatic lesions. Therefore, the poor prognostic factors at diagnosis (i.e. tumor size, aggressive histologies, vascular invasion, higher values of Tg and/or TgAb) should be considered to better identify those cases with a higher probability of having a benefit from a second radioiodine treatment. Moreover, our results confirmed the usefulness of performing repeated 131I treatments in patients with either lymph node or lung metastases able to take up the radioiodine, leading to the disappearance of the structural disease in about one third of these patients. Also in these groups of patients, the presence of vascular invasion, larger tumor size and higher Tg values before the second 131I treatment are excellent predictors of structural disease persistence.