Clinical application of computed tomography-guided ¹²⁵I seed interstitial implantation for head and neck cancer patients with unmanageable cervical lymph node metastases

This study was approved by The People’s Hospital of Liaoning Province Ethics Committee, and informed consent was obtained from all the enrolled patients. Between February 2010 and December 2013, 31 consecutive patients with unmanageable cervical lymph node metastases in HNC, including 19 men and 12 women, aged 48–75 years (mean 67 years), who received CT-guided ¹²⁵I seed interstitial implantation in our hospital were included in this study. The source of the metastatic tumor included nine cases of nasopharyngeal carcinoma, eight cases of tongue cancer, five cases of laryngeal carcinoma, three cases of maxillary sinus carcinoma, and six cases of thyroid carcinoma. The previous surgeries performed on the patients included 18 cases of radical neck dissection (RND) and 13 cases of selective or modified neck dissection (MND). The primary tumor stage was all stage IV for all patients. The tumor-node-metastasis (TNM) staging included three cases of T3N3M1, 11 cases of T2N3M1, four cases of T2N2M1, six cases of T2N1M1, two cases of T3N1M1, one case of T1N1M1, one case of T1N3M1, one case of T4N3M1, one case of T1N2M1, and one case of T3N2M1. Among the 31 patients, 25 patients underwent one surgery, while six patients underwent surgery twice. All patients had undergone prior adjuvant external-beam radiation therapy (EBRT). Of these patients, 25 patients underwent EBRT once, and six patients underwent EBRT twice. The cumulative radiotherapy dose was 28-90 GY (mean 66 ± 13.34 GY). In addition, six patients received chemotherapy for four cycles and eight patients accepted chemotherapy for three cycles (Table 1).

The indication for CT-guided ¹²⁵I seed implantation was as follows: (1) clinically diagnosed as cervical lymph node metastasis, with HNC being confirmed by pathology; (2) Karnofsky performance score (KPS) ≥ 60; (3) normal function in liver, kidneys, and heart; (4) persistent pain of cervical tumors and treatment of medication, physical therapy, or other conservative therapy made no significant improvement; (5) expected lifetime was more than 3 months; (6) the trachea, esophagus or other vital organs were compressed by cervical metastatic tumor, which had seriously affected the quality of the patient’s life; and (7) patients were not suitable for reoperation, chemotherapy, or radiotherapy, or the patients were not willing to receive any chemotherapy or radiotherapy.

Before the operation, the history and physical condition, hematological and chemical profiles of all the patients were evaluated. Additionally, each patient underwent a detailed tumor volume study using contrast-enhanced CT scanning (GE Lightspeed 64, General Electric Company, Fairfield, CT, USA, thickness = 5 mm) of the neck 1 week before seed implantation (Fig. 1a). The planning target volume (PTV) was extended beyond the clinical target volume (CTV) by a 1-cm margin, which was outlined by the radiation oncologist on each transverse image. Treatment Planning System (TPS, Prowess 3D, SSGI, Chico, CA, USA) was performed to calculate the dose distribution, which was based on the American Association of Physicists in Medicine TG43 brachytherapy formalism [19]. The ¹²⁵I seed sources were purchased from ZhiBo Carve Out Development Ltd. Beijing, China. It releases rays with a nominal activity of 0.4–0.8 mCi/seed, a half-life of 60.2 days, and a size of 0.8 × 0.45 mm. The 18-G implantation needles and turntable implantation gun (ZhiBo Carve out Development Ltd. Beijing, China) were utilized for seed implantation. The depth and angle of implantation needles were guided under CT supervision, avoiding important vessels and nerves. Patients were allowed a clear liquid diet for 24 h before the implantation. This procedure was carried out in a standard CT room under local anesthesia by using 0.5 % lidocaine. The distance between the two adjacent implantation needles was about 1 cm (Fig. 1b). Repeated CT was performed within 24 h after the implantation to confirm the distribution of seeds, and then the images were collected and put into the TPS (Fig. 1c). Re-implantation was performed if necessary. After the implantation, all patients were kept under observation, and then returned toward only if there was no sign or symptom of complications, such as bleeding. Then, anti-inflammatory and hemostasis were given to all the subjects after implantation.

Tumor response was evaluated according to the World Health Organization (WHO) standard criteria [20]. Tumor size was estimated from bidimensional measurements (product of the longest diameter and its longest perpendicular diameter for each tumor). CT examination was conducted at 3 and 6 months after the implantation and classified as follows: a complete response (CR) indicated the disappearance of all tumoral lesions lasting for more than 4 weeks; partial response (PR) indicated that total tumor size decreased at least a 50 %; stable disease (SD) indicated that total tumor size decreased by less than 50 % or increased by less than 25 %; and progressive disease (PD) indicated an exacerbation of tumor size at least a 25 % or lager.

In the present study, local control rate (LCR) was defined as the absence of tumor progression in CT (SD + PR + CR), while overall survival rate (OSR) was defined as the percentage of patients who are alive after a specified number of years of follow-up from the start point of post-implication to the end of follow-up or death.

The numerical rating scale (NRS) was used to measure of pain intensity before and after operation [21]. The NRS is an 11-point scale, which consists of integers from 0 through 10 where 0 represents no pain; 1–3, mild pain without affecting sleep; 4–6, moderate pain; 7–9, severe pain (affect sleep or wake up from the pain); and 10 represents the worst imaginable pain. Patients were inquired for the pain degree and were required to select a single number during 0–11 that could best reveal their pain intensity and this selected number was the NRS.

Furthermore, a Radiation Therapy Oncology Group (RTOG) was utilized to assess the acute radiation morbidity, and the RTOG/European Organization for Research and Treatment of Cancer (RTOG/EORTC) was employed to assess the latest radiation morbidity [22].

All patients received follow-up phase immediately after the implantation. The follow-up period was 6–38 months, with first visits at the third month after intervention, and then subsequent follow-ups occurred at the 6 months, 1, and 2 years. The tumor volume was recorded at 3- and 6-month post-implantation using CT images. The LCR and OSR at 3, 6 months, 1 and 2 years were assessed. All patients successfully completed the follow-up.

All data were expressed as mean ± SD, and the statistical analysis was performed by using the SPSS software version 19.0 (SPSS, Chicago, IL, USA). The median survival time of survival analysis was assessed by Kaplan–Meier methods. The difference of pain relief before and after treatment was analyzed by paired t test. P < 0.05 was considered statistically significant.

The seed implantation procedure was successfully conducted in all patients. The implanted number of ¹²⁵I seeds was 16–84 (mean 46.13 ± 16.28) for each patient. The mean activity of each seed was 0.4–0.8 mCi (mean 0.65 ± 0.15). The D90 of ¹²⁵I seeds ranged from 90–125 Gy (mean 101.03 ± 8.54 Gy).

After ¹²⁵I seed interstitial implantation, the tumor volume was significantly reduced from 21.23 ± 8.83 cm² pre-implantation to 9.19 ± 7.52 and 6.42 ± 9.79 cm² at 3 months and 6 months after implantation (P < 0.05) (Table 2; Fig. 2). Repeated CT conducted at 3-month post-implantation showed that there were three cases (9.68 %) in CR, 25 cases (80.65 %) in PR, two cases (6.45 %) in SD, and one case (3.22 %) in PD, respectively. The NRS scores for pre-implantation, and 3- and 6-month post-implantation were 7.77 ± 0.92, 3.06 ± 1.06, and 2.39 ± 1.15, respectively. Symptoms of pain were significantly reduced postoperatively at 3 and 6 months (P < 0.05). Furthermore, KPS significantly improved at 3- and 6-month post-implantation compared with pre-implantation (83.18 ± 5.97 versus 73.60 ± 7.90; 82.86 ± 5.43 versus 73.60 ± 7.90; P < 0.05), respectively. As shown in Fig. 3, the LCR at 3, 6 months, 1 and 2-years was 96.30, 83.87, 64.51, and 45.16 %, respectively. The OSR was 100, 100, 67.74, and 45.16 %, respectively. Four patients died of local recurrence; 11 patients died of lung metastasis; 13 patients died of recurrent tumor and distant metastases; and 3 patients had severe heart disease and died of heart disease, which was unrelated to the tumor.

Of all the patients, three patients suffered from fever post-implantation, but the fever did not exceeded 38.5 °C, and body temperature returned to normal in 3–5 days. Additionally, 3 and 2 patients developed grade I and grade II acute radiation toxicity on the skin (for example, faint or dull erythema/epilation/dry desquamation/moderate edema) and mucous membrane (for example, mild/moderate pain, patchy mucositis), respectively. Moreover, 1, 2, and 1 patients experienced grade I, grade II, and late radiation toxicity on the skin (pigmentation change), subcutaneous tissue (for example, slight in duration and loss of subcutaneous fat) and mucous membrane (dryness), respectively. Other tissues, such as the eyes, spinal cord, and lung, were not involved. No patients developed grade III, IV, or V acute/late radiation toxicity, or other serious complications (for example, massive hemorrhage, acute pulmonary embolism, or fistula).