Study subjects
Inclusion criteria: (a) patients were required to be aged≥18 years; (b) patients underwent thyroidectomy for DTC; (c) patients had measurable, pathological and/or cytological confirmed CMLN from DTC, evidence of radioiodine refractory according to at least one criteria used in recent clinical trials as follows (i) at least one lesion never concentrate iodine-131, (ii) at least one lesion that has progressed within 12 months after RAI therapy despite iodine-131 avidity, or persistent disease after a cumulative dose of iodine-131 ≥ 600mCi; (iii) partial thyroidectomy leads to thyroid tissue residue, which affects the efficacy of RAI-131 (d) patients who had inoperable CMLN or refused to undergo repeated neck surgical dissection.
Exclusion criteria: (a) cognitive impairment due to neuropathy or psychosis, (b) severe coagulation disorders; (c) patients with severe heart failure/respiratory failure/ liver failure or renal failure, (d) being pregnant or breast feeding.
We performed a retrospective analysis of 18 patients (including 11 males and 7 females) with 36 CMLNs who underwent ultrasound guided 125I seed implantation in our hospital from June 2016 to November 2018. Of all cases, 17 had total thyroidectomy and 1 had partial thyroidectomy. BRAFV600E mutations was found in 17 patients. CMLNs were situated at levels I, II, III, IV, V, and VI respectively, in 0, 6, 12, 10, 1, and 7 cases. The median volume of the initial CMLNs was 522.8 mm3 (147.5, 2009.6) mm3. 3 cases showed obvious symptoms of neck compression due to tumor volumes > 10 000 mm3 and 2 had dysphagia due to esophageal narrowed under tumor compression. 2 case were tracheotomy. 1 case was bilateral vocal cord paralysis. 1 case had skin ulceration on surface of the lesion. The detailed clinical characteristics before implantation of 125I-seeds are listed in Table 1.
Table 1 Clinical characteristics regarding 18 patients of 36 CMLNs treated with implantation of 125I-seeds
Parameter
|
Characteristics
|
Result
|
Sex of patients (n = 18)
|
M/F
|
11/7A
|
Age of patients (n = 18)
|
|
52.2 ± 20.8 (27–87) B
|
Subtypes of DTC (n=18)
|
PTC/FTC
|
17/1(94/6) C
|
No. of neck surgeries performed (n=18)
|
<3/≥3
|
16/2(89/11) C
|
Cumulative dose of RAI-131 (n=18)
|
<600/≥600mci
|
14/4(78/22) C
|
BRAFV600E mutation (n=18)
|
P/N
|
17/1(94/6) C
|
No. of CMLNs (n=18)
|
|
|
|
1
|
8(44) C
|
|
2
|
4(22) C
|
|
≥3
|
6(34) C
|
Sides of CMLNs (n=36)
|
L/R
|
15/21(42/58) D
|
Level of CMLNs (n=36)
|
|
|
|
I
|
0(0) D
|
|
II
|
6(17) D
|
|
III
|
12(33) D
|
|
IV
|
10(28) D
|
|
V
|
1(3) D
|
|
VI
|
7(19) D
|
Largest diameter of CMLNs (n=36) (mm)
|
|
14.0(8.0, 22.5) E
|
Initial volume of nodule (n=36) (mm3)
|
|
522.8(147.5, 2009.6) E
|
M male, F female, PTC papillary thyroid carcinoma, FTC follicular thyroid carcinoma, P positive, N negative, L left, R right
A Number of patients
B Mean ± standard deviation, with range in brackets
C Number of patients, with percentage in brackets
D Number of CMLNs, with percentage in brackets
E Median, with P25 and P75 in brackets
Equipment
Siemens Acuson Sequoia 512 Ultrasound System (Siemens, Mountain View, CA, USA) with a 6L3 linear array transducer was used for guiding core needle biopsy (CNB) and 125I-seed implantation. Siemens Acuson Sequoia 512 Ultrasound System with a 15L8W linear array transducer or a Philips iU22 Ultrasound System (Philips Healthcare, Bothell, WA) with a L12-5 linear array transducer or a Mindray M9 Ultrasound System (Mindray, Shenzhen, China) with a L12-4 linear array transducer was used for image collection before implantation, as well as during follow-up. 125I seeds (radioactivity: 0.4 mCi, the average energy: 27–35 keV, half-life: 60.1 days, antitumor activity: 2.0 cm) in this study were provided by Shanghai Xinke Pharmaceutical Co., LTD.
Pre‑implantation assessment
Before 125I seed implantation, all the CMLNs were evaluated by conventional ultrasound (US) combined with contrast-enhanced ultrasound (CEUS). For each CMLN, three orthogonal diameters (the largest diameter and two perpendicular diameters) were measured by US. Volume was calculated with the equation of V = πabc/6 (where V represents volume; a is the largest diameter; b and c are the other two perpendicular diameters). CEUS provided visualization of blood supply region and enhancement pattern of the lesion. The ultrasound contrast agent we used was Sulphur hexafluoride (SonoVueR, Bracco. International, Milan, Italy). Bolus injection of SonoVue (2.4 ml) through elbow vein was performed for a single CEUS and each imaging acquisition lasted at least 3 min. Then, situated level, adjacent structures, volume and flow perfusion of each CMLN were recorded in details. Thyroglobulin (Tg) test and routine analysis of blood were also performed before implantation.
Implantation procedure
The procedure was carried out by an experienced US physician with more than 20 years experiences in interventional US. Patients were placed in the supine position with their necks extended. Local infiltration anesthesia with 1% lidocaine was injected at subcutaneous puncture site and periphery of the lesion. Number and distribution of 125I seeds to be implanted were designed according to the volume and location of each CMLN. An interstitial needle (18 Gauge) was gradually inserted into the lesion, and the seeds were implanted using turntable implantation gun guided by US. Every seed was placed at 0.5cm–1.0cm intervals. According to the principles of the Paris system, the distribution of the seeds should be arranged in a straight line and parallel to each other. The seeds should be about 0.3cm-0.5cm away from edge of lesion and at least 1cm away from cervical vital structures such as vessels, esophagus, trachea, recurrent laryngeal nerves, etc. Refer to the Halarism’s experienced formula: total activity (A) mCi =Da×5, Da denotes the mean sum value of length (L), width (W) and height (H) of the targeted lesion as (L+W+H) /3 (unit is cm). Number of seeds to be implanted were obtained by the equation: total activity (A) ÷ the average activity of a single 125I seed = the number of seeds required [20, 21]. Postoperative observation was conducted for 2 hours. We paid attention to possible complications such as bleeding and hematoma during or immediately after implantation.
Follow-up
Follow-up consisted of US, CEUS, routine hematology, and thyroglobulin (Tg) levels at 1-3, 6, 9 and 12 months and every 6 months thereafter. If Tg levels were significantly elevated, for instance doubled, additional systemic examination was performed to determine whether there was a distant metastasis.
The volume of each CMLN was evaluated by US and we calculated volume reduction rate (VRR) during follow-up as VRR = ([initial volume – final volume] × 100)/initial volume[22]. Blood perfusion of CMLN was evaluated by CEUS. Variation of enhancement pattern of nodule before and after implantation was monitored. Hyper-enhancement before implantation while non-enhancement or hypo-enhancement during follow-up suggested the treatments effective[23, 24]. For those with no changes in CEUS before and after implantation, VRR should be combined with serum Tg values to evaluation. There were the following situations: (a) if VRR ≥ 50%, the treatment was deemed to be effective; (b). if VRR < 50%, but the serum Tg level reduction was more than 50% compared with pre-implantation, “wait and watch” would be recommended; (c). if VRR and the serum Tg level reduction were both less than 50%, further US-guided CNB should be performed to determine whether there was active lesion residue, (d). volume of nodules increased from the original during follow-up, indicating treatment failure. Common symptoms and severity of adverse radiation events were classified by the criteria of Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC).
Statistical analysis
Statistical analysis was performed using SPSS statistical software (Version 23.0). Continuous data following normal distribution were represented as `x ± s (the range), and if not, as median (P25, P75). The Wilcoxon signed-rank test was performed to compare the changes of nodules volume before implantation and at each follow-up point as well as the serum Tg levels before implantation and at the last follow-up visit. P < 0.05 indicated that the difference was statistically significant.