Out of a total of 408 DTC patients assessed, 78 (19.1%) presented IR to initial treatment. Twenty patients were excluded (less-than-total thyroidectomy (n = 2), non-radioiodine ablated (n = 8) and switch in laboratory assays during follow-up (n = 10), thus, data on remaining 58 patients was analyzed. (Fig. 1)
Demographic, clinical and pathological characteristics of 58 patients with DTC and IR to initial treatment are observed on Table 1. The majority of patients were female (83%) and < 55 years-old at diagnosis (76%). The most frequent histologic type was papillary thyroid carcinoma (96%), and among these, classical variant was the most prevalent (72%). Tumors were larger than 1 cm in 91% of the cases; lymph node involvement was found in 49%. Most patients (86%) were stage I according to AJCC/UICC. Three patients were treated with external beam radiotherapy due to extensive airway invasion. Characteristics of patients in both populations of IR (Tg (+) and TgAb (+)) were similar, except for a higher proportion of female patients in the TgAb (+) group (96 vs 74%, p 0.026).
Table 1
Clinical-pathological characteristics of 58 patients with differentiated thyroid cancer and indeterminate response to initial treatment
Group
|
Total
(n = 58)
|
TgAb (+)
(n = 24)
|
Tg (+)
(n = 34)
|
P
|
Age (years) (mean) (± SD)
< 55 years
≥ 55 years
|
44 (+/-12.7)
44 (76%)
14 (24%)
|
46.1 (+/-12.7)
|
42.4 (+/-12.7)
|
ns
|
Female/male
|
48 (83%) / 10 (17%)
|
23 (96%)/ 1 (4%)
|
25 (74%)/ 9 (26%)
|
0.026
|
Histology
|
|
|
|
|
Papillary carcinoma
Classic variant
|
42 (72%)
|
18 (75%)
|
24 (70%)
|
ns
|
Papillary carcinoma follicular variant
|
9 (16%)
|
4 (17%)
|
5 (15%)
|
ns
|
Other
|
7 (12%)
|
2 (8%)
|
5 (15%)
|
ns
|
Primary tumour diameter (mm) [range]
|
26 [4–90]
|
22.13 [8–50]
|
29.51 [4–90]
|
0.08
|
T1
|
21 (36%)
|
13 (54%)
|
8 (23%)
|
ns
|
T2
|
18 (31%)
|
6 (25%)
|
12 (35%)
|
ns
|
T3
|
9 (16%)
|
1 (4%)
|
8 (24%)
|
ns
|
T4
|
8 (14%)
|
3 (13%)
|
5 (15%)
|
ns
|
Tx
|
2 (3%)
|
1 (4%)
|
1 (3%)
|
ns
|
N0
|
23 (40%)
|
8 (33%)
|
15 (43%)
|
ns
|
N1a
|
12 (21%)
|
9 (38%)
|
3 (9%)
|
ns
|
N1b
|
17 (29%)
|
6 (25%)
|
11 (32%)
|
ns
|
Nx
|
6 (10%)
|
1 (4%)
|
5 (16%)
|
ns
|
M0
|
54 (93%)
|
22 (92%)
|
32 (94%)
|
ns
|
M1
|
1 (2%)
|
0
|
1 (3%)
|
ns
|
Mx
|
3 (5%)
|
2 (8%)
|
1 (3%)
|
ns
|
Risk of recurrence ATA
|
|
|
|
|
Low
|
20 (35%)
|
9 (37%)
|
11 (32%)
|
ns
|
Intermediate
|
24 (41%)
|
10 (42%)
|
14 (41%)
|
ns
|
High
|
13 (22%)
|
5 (21%)
|
8 (24%)
|
ns
|
Unknown
|
1 (2%)
|
0
|
1 (3%)
|
ns
|
Time of assessment of response to initial treatment (months) median [range]
|
16.31 [7.1–87]
|
16.51 [9.7–35]
|
15.88 [7.1–87]
|
ns
|
Tg (+): stimulated thyroglobulin 1–10 ng/ml or non-stimulated thyroglobulin detectable but < 1 ng/ml and |
TgAb (+): descending or stable levels of anti-thyroglobulin antibodies in absence of structural disease. |
In Tg (+) patients, average preablation Tg levels were 17.7 ng/ml (± 30); at assessment of response to initial treatment, the mean Tg level was 2.9 ng/ml (± 2.26). Mean TgAb levels in TgAb (+) patients was 471.6 UI/ml (± 636).
Median time of follow-up was 74.7 months [range: 9.9–190], and it was longer in Tg (+) group (82 months) [range: 28–190] vs. TgAb (+) (62 months) [range: 10–162] (p < 0.05).
Regarding additional therapies, one patient with persistent TgAb (+) received a second dose of radioiodine (100 mCi 131I), with IR at last visit on follow-up. In the Tg (+) group, six patients received further therapies. All of them were treated with radioiodine; in two cases this was due to structural disease (and also were treated with external beam radiotherapy and percutaneous ethanol injection, respectively, as detailed below). In the remaining four, radioidine was prescribed because of a combination of detectable/rising Tg levels, and non-conclusive findings on whole body scan and/or neck ultrasound. At last follow up visit, two of these four patients had no evidence of disease while the remaining two had persistent IR.
At last visit on follow-up, 27 patients (46.5%) had no evidence of disease, 26 (44.8%) had IR, in 3 patients (5.1%) biochemical persistence was observed and 2 (3.4%) had structural disease. (Table 2).
Table 2. Status on last follow-up visit of 58 patients with differentiated thyroid cancer and indeterminate response to initial treatment
Tg (+): stimulated thyroglobulin 1-10 ng/ml or non-stimulated thyroglobulin detectable but <1 ng/ml.
TgAb (+): descending or stable levels of anti-thyroglobulin antibodies in absence of structural disease.
In the two patients with structural disease, it was detected 28 and 32 months after initial treatment respectively. Both patients belonged to the Tg (+) group. One patient had a stage II papillary thyroid cancer, tall-cell variant with a high risk of recurrence and his preablation Tg was 16.4 ng/ml. Ten months later, his stimulated Tg was 3.3 ng/ml; neck ultrasound and whole body radioiodine scan were negative for suspicious findings. Nineteen months later, his non-stimulated Tg levels began to steadily rise, up to a maximum of 15 ng/ml. At this moment, a 18FDG PET/CT scan revealed lung and mediastinal metastases. He received a therapeutic dose of radioiodine, and, due to progressive disease, external beam radiotherapy was administered. Rapid progression ensued and the patient died 64.5 months after diagnosis. The second patient with structural incomplete response had a stage I papillary thyroid cancer, classical variant. His preablation Tg was 49 ng/ml. Sixteen months after initial surgery, stimulated Tg was 1.5 ng/ml; neck ultrasound was negative and radioiodine whole body scan showed no foci of uptake. Ten months later, non- stimulated Tg rose to 7 ng/ml and cervical uptake on 18FDG PET/CT. A therapeutic dose of radioiodine was administered with a negative post dose scan and six months later, small volume lung metastases were found. He underwent percutaneous ethanol injection of the cervical lymph node, and both lung and neck foci of disease remain stable after 14 months.
When comparing patients who progressed from IR to incomplete response (both biochemical and structural), to those with no evidence of disease, it was found that those with adverse outcomes had significantly larger primary tumors (44.4 vs 11.5 mm, p 0.03), higher percentage of high-risk cases (60% vs 14.8%, p 0. 02), and higher preablation Tg levels (42.9 vs 10.1 ng/ml, p 0.03).
Patients in the TgAb (+) group had a higher proportion of IR at the end of follow-up (75% vs 23% in the Tg (+) group, p 0.0005) (Fig. 1, Table 2), which was due to the presence of detectable TgAb levels. Out of these, 83% had a descending trend, while the remaining 17% had stable levels of TgAb. Conversely, final excellent responses were more frequent in the Tg (+) group (65% vs 21% in the TgAb (+) group, p 0.0005).