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CT-guided 125I brachytherapy in the treatment of distant metastases in the oral cavity and maxillofacial region

PURPOSE: We aimed to evaluate the feasibility and clinical effectiveness of CT-guided 125I brachytherapy for distant oral and maxillofacial metastases. MATERIALS AND METHODS: We retrospectively analyzed 65 patients with 84 distant oral and maxillofacial metastases. Thirty-one patients with 38 lesions received 125I brachytherapy (group A) and 34 with 46 lesions received external beam radiotherapy (EBRT; group B). RESULTS: Median follow-up time was 16 months. The 3-, 6-, 12-, 18-, and 24-month local control rates for group A were 83.9%, 75.9%, 66.7%, 38.4%, and 25.0%, respectively; for group B they were 76.5%, 62.5%, 43.8%, 25.0%, and 0.0%, respectively (P < .05); the median local tumor progression-free survival times were 14 and 9 months, respectively. Group A had a better local tumor progression-free survival (LTPFS) relative to group B (P < .001; HR, 6.961 [95%CI, 2.109, 9.356]). Cox proportional hazards regression analysis indicated that 125I brachytherapy, tumor size, and primary pathological type were the independent factors affecting LTPFS. Additionally, 125I brachytherapy showed better performance in relieving patient clinical symptoms relative to EBRT (P < .05). Group A also had fewer complications than group B, especially regarding grade 3/4 complications according to Radiation Therapy Oncology Group grading criteria. Mean overall survival times in groups A and B were 17.1 and 14.8 months, respectively. CONCLUSION: CT-guided 125I brachytherapy is feasible and safe for distant oral and maxillofacial metastases; it achieved a better local control rate, longer LTPFS and fewer complications without compromising overall survival compared with EBRT.


Introduction
Distant metastasis to the oral and maxillofacial region is rare and represents 1% of all malignancies in this region. The most common primary in males are lung cancer (approximately 33%), followed by kidney cancer and malignant melanoma; in females they are breast cancer tumors (approximately 25%), followed by malignant tumors in the reproductive organs, lung, and kidney [1]. Most patients with oral and maxillofacial metastases usually have end-stage disease; the overall prognosis of such patients is poor, and the overall survival time from the appearance of metastases is 6-52 months [2]. Patient quality of life (QoL) is very poor and often accompanied with obvious clinical symptoms such as local swelling, pain, paresthesia, dysphagia, and trismus [3].
Usually, patients have received a series of previous comprehensive treatments, including surgery, systemic chemotherapy and local radiotherapy, to control the primary tumors and metastasis in other parts of the body [4]. Therefore, the patient's general condition is poor, the effectiveness of radical surgery for improving the prognosis and QoL is limited, perioperative morbidity and mortality are high, and the majority of patients still die from metastasis to another organ in 1-2 years after surgery [5,6]. Most reports consider that improving local control and patient QoL are the main goals at this stage [7]. There is no denying that radiotherapy plays an important role in the treatment of oral and maxillofacial metastases; numerous studies have also confirmed the effectiveness of radiotherapy in the relief of clinical symptoms and improvement in QoL [8]. However, these patients were in the end-stage concerning tumor staging and grading, and were in poor general health condition, especially those with metastasis close to the cardinal organs (such as the pharynx, eyes, and oral cavity); these organs usually have a poor tolerance to high doses of radiation [9]. Curative radiation doses often lead to severe side effects. Even though the latest technology is used, such as sophisticated 3-dimensional computerized planning systems, multileaf beam collimators or altered fractionation schedules, the detrimental side effects of radiotherapy cannot be avoided. This exacerbates the psychological burden of patients, and reduces patient cooperation and treatment efficacy [10]. Some patients may even die of severe complications such as radiation encephalopathy. Consequently, the physician has to reduce the radiation dose because there are too many complications associated with radiotherapy. These palliative radiotherapy regimens lead to a decline in local control and a higher incidence of residual tumors and recurrence; this seriously affects patient QoL [11].
In recent years, a new modality, 125 I brachytherapy, has been accepted as a useful and minimally invasive interventional modality, because it achieves higher local tumor control and fewer complications [12,13]. Many studies have evaluated 125 I brachytherapy have a good curative effect in pancreatic cancer, liver cancer, lung cancer, prostate cancer, and gynecological and brain malignancies [14]. The 125 I seed is a miniature radioactive source; it continuously delivers low doses of x-rays and γ-rays, and the radiation dose decreases rapidly with increasing distance from the source [15]. This characteristic makes it possible for CT-guided 125 I brachytherapy to completely cover the therapeutic target area avoiding damage to the adjacent normal tissues [16,17]. However, to date our study is the first to report on the treatment of distant metastases to the oral and maxillofacial regions using the 125 I brachytherapy modality. The purpose of our study was to evaluate the effectiveness and safety of CT-guided 125 I brachytherapy for distant oral and maxillofacial metastases [18].

Study Population
This retrospective study was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center. All patients in the study were fully informed of the potential risks and voluntarily signed informed consent forms.
From June 2006 to July 2014, we recruited 65 patients diagnosed with oral and maxillofacial metastasis; the site of the primary cancer and pathological type are detailed in Table 1. Most of the patients had already experienced systemic and comprehensive treatment to control local and systemic lesions; all patients were in relatively stable condition but had more prominent clinical symptoms related to the oral and maxillofacial regions. In all patients enrolled, 31 patients could not tolerate or were unwilling to undergo surgery and EBRT because of poor general condition and the location of the metastasis. These 31 patients received 125 I brachytherapy (group A) after they were fully informed of the risks associated with 125 I brachytherapy; 34 patients underwent EBRT (group B). Patient characteristics are detailed in Table 2.  Note: According to the American Joint Committee on Cancer (AJCC), T 1-2, T 3-4 refers to the conditions of the primary tumor, N 0, N 1-3, refers to the regional lymph node involvement.

Inclusion and Exclusion Criteria
Exclusion criteria were: (1) primary or recurrent malignancy in the head and neck; (2) serious skin fester or infection around the lesions; (3) a serious bleeding tendency, and coagulation function disorder; (4) severe liver, kidney, heart, lung, and brain function insufficiency.
Treatment 125 I brachytherapy. The 125 I seed (Atom High Tech, Beijing, China) was formed by outsourcing the shell materials consisting of a titanium pipe with a diameter of 0.8 mm, length of 4.5 mm and wall thickness of 0.05 mm; the 125 I isotope was attached to the inner silver column (diameter, 0.5 mm; length, 3 mm). The main characteristics of 125 I seed were: initial radioactive activity, 0.8 mCi; average energy, 27-32 KeV; half-life, 59.6 days; and effective radiation radius, 1.7 cm.
CT images acquired in b1 week preoperatively were imported into the treatment planning system (TPS; RT-RSI: Beijing Atom and HighTechnique Industries Inc., Beijing, China). As shown in Figure 1, a clinical oncologist and a professional physicist together verified the outline of clinical target volume (CTV) and planning target volume (PTV); PTV refers to the boundary of the CTV scaled out by 1 cm. We calculated the number of 125 I seeds needed, activity and total radioactive dose activity using the TPS, regarding the dose required to reach the prescribed dose, namely the matching peripheral dose. Then we developed a dose-volume histogram, observed dose distribution, and adjusted the guide pin to achieve an optimal dose distribution in the PTV. The dose delivered to the planning target volume should reach 95% of the prescribed dose, namely Vl00 N95%. The prescribed dose in this study was averaged at 120 Gy (100-140 Gy) according to the American Brachytherapy Society for prostate cancer and previous studies from our center.
Patients were usually located in a supine position. We drew the puncture path on the images after the CT scan at a thickness of 5 mm according to the TPS. After local infiltration anesthesia with 5-10 ml of 1% lidocaine, an 18-G spinal needle composed of an inner core needle and a needle cannula forming the outer layer (Yunke Pharmaceutical Limited Liability Company, Chengdu, China) was introduced into the tumor and the direction of the needle adjusted under CT guidance. Eventually, all of the needles reached to the farthest boundary of tumor while ensuring the distance between each seed needle was about 1 cm. The needle core was pulled out and applied using an 125 I seed implantation gun (Yunke Pharmaceuticals Limited Liability Company, Chengdu, China) to transport the 125 I seeds into the tumor through the outer needle cannula. One seed was released with withdrawal every 0.5 cm; a distance of about 1 cm was maintained from the skin and vital organs such as the oral mucosa, throat, nerves and other tissues. A CT scan was performed to confirm the precise release of the 125 I seeds and then the spinal needle was pulled out and the final CT image was imported into TPS to carry out dose verification.
EBRT. Group B were treated by physicians with 10 years' experience in radiotherapy; the radiotherapy modalities used were mainly three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). The radiotherapy physician delineated the gross tumor volume (GTV) and CTV using the Monaco TPS system (version 5.0) according to recent CT or magnetic resonance imaging (MRI) images. The GTV of lesions was visualized on CT or MRI. The CTV was the GTV with an additional 1-to 1.5-cm margin. The PTV was developed by extending the margin by an additional 3 mm relative to the CTV to allow for setup variability and internal motion.
The organs at risk (OAR) included the facial nerve, pharynx, oral mucosa, parotid glands, submandibular gland, temporomandibular joints and mandible. The dose constraints of the OAR were prescribed with a relatively low dose (50-60 Gy). The prescribed doses were 60-70 Gy to the GTV (2 Gy or 1.8 Gy per daily fraction, 5 days per week).

Follow-up and Evaluation Criteria
In accordance with our follow-up protocol, enhanced CT or MRI images were obtained for the evaluation of curative effect at the first month after treatment and then every 3 months.
Local control (LC) was defined as the proportion of patients with a complete response and partial response. The European Organization for Research and Treatment of Cancer-Quality of Life-Head and Neck Questionnaire (EORTC QLQ H&N35) was used to evaluate patient QoL; we statistically analyzed every patient's score and converted it into a standardized score ranging from 0 to 100. The two groups of patients were required to complete the EORTC QLQH&N35 before treatment and at 0, 3, 6, and 12 months after treatment. Complications in the two groups were evaluated according to the Radiation Therapy Oncology Group (RTOG) grading criterion.

Statistical Analysis
Statistical analysis was performed using statistical software (SPSS 20.0). All statistical tests were bilateral; there was considered to be a significant difference when the P b .05. Kaplan-Meier analysis and the log-rank test were used to compare OS and LTPFS in the two groups. We also built stratified Cox proportional hazard models and used the forward stepwise procedure to investigate the potential factors related to LTPFS and OS. Cox proportional hazards regression analysis was used to calculate the covariate entered into the model, hazard ratios and the confidence intervals (CI).

Results
A total of 31 patients with 38 lesions received 125 I brachytherapy procedures under CT guidance by radiologists with 10 years' experience. All patients underwent postoperative dose verification using the TPS. The median number of 125 I seeds used was 31 (range, . In group B, the median radiotherapy dose was 55 Gy (range, 45-70) Gy, the median radiotherapy treatment time was 30 (range, 25-35) days, and the median follow-up time in the two groups was 18 (range, 3-44) months.
The median LTPFS times in groups A and group B were 14 and 9 months, respectively. Kaplan-Meier curves for LTPFS are presented in Figure 2. Cox proportional hazards regression analysis revealed that  .356]) and 125 I brachytherapy was an independent factor related to LTPFS. As shown in Table 4, tumor sizes and primary pathological type were also independent factors affecting the LTPFS.

Relief of Clinical Symptoms
In this study, the major clinical symptoms in the oral and maxillofacial regions were pain (84.6%), swelling (100%), paresthesia (55.4%), bleeding (18.5%), trismus (30.8%) and dysphagia (16.9%). As summarized in Table 5, the remission rate of clinical symptoms in group A was significantly superior to that in group B.

QoL
As summarized in Table 6, before treatment, the QoL scores were 71.34 ± 21.13 and 69.87 ± 23.98 (P = .681). At 3, 6 and 12 months after treatment, the scores for group A had significantly improved 9.21, 15.20, and 18.55, respectively and reached 62.13, 56.14, and 52.79, respectively. However, in group B the scores had not obviously improved relative to group A and had even deteriorated; at 0, 3, and 6 months after treatment they degenerated 6.02, 6.28, and 1.48, respectively and reached 75.89, 76.15, and 71.35, respectively. Only at 12 months after treatment had the QoL scores for group B mildly improved 5.66 to 64.21. Statistical analysis also indicated that group A had better performance regarding the improvement in QoL score than group B (P b .001).

Complications in Groups A and B
No serious complications occurred during the process of 125 I brachytherapy. Major complications in the two groups during the follow-up period are detailed in Table

OS
The mean OS in groups A and B was 17.1 months and 14.8 months, respectively. The 1-, 2-, and 3-year OS rates were 54.8%, 25.8%, and 6.5%, respectively in group A and 47.6%, 14.7%, and 2.9%, respectively in group B. Kaplan-Meier survival curves are presented in Figure 3. The  log-rank (Mantel-Cox) test suggested no statistical difference (χ-3.190; P = .074) in the survival curves. Cox proportional hazards regression analysis revealed that the number of other invaded organs was the only independent factor affecting OS. (See Fig. 4.)

Discussion
Although 125 I brachytherapy has been successfully applied in many solid tumors, our study is the first to use this modality in the treatment of oral and maxillofacial metastases [19]. It is significant because patients with oral and maxillofacial metastases can often feel the presence of these lesions and have obvious clinical symptoms in these regions [20,21]. Palliative radiotherapy can alleviate the clinical symptoms to some extent, but its side effects and complications are significant [22,23]. 125 I seeds emit continuous low doses of γ-rays, this can efficiently inhibit tumor cell proliferation, promote apoptosis and maximize the destruction of the tumor without damaging the normal surrounding tissue; this is because the energy of the γ-rays rapidly decays with increased distance [24]. Therefore, 125 I brachytherapy with a higher LC rate and fewer complications is a good choice for patients with distant oral and maxillofacial metastasis.
A major finding of this study was that 125 I brachytherapy can achieve better LC (P b .05) and longer LTPFS (HR, 6.961 [95% CI, 2.109, 9.356]). In comparing LC over different time periods, it was  H&N35) is a questionnaire specific to head and neck cancer patients consisting of 35 items designed to assess health-related QoL. Given that all the scales assess symptoms, higher scores correspond to lower quality of life.
Calculated every patient's score in each items and converted into standardized score ranged 0 to 100, adding score of 35 items and then using the sum score of 35 items divided 35.    125 I brachytherapy was an independent factor related to LTPFS. This is because 125 I seeds can deliver locally higher radiation doses; the prescribed dose for group A reached 100-140 Gy, while in group B it only reached 60-70 Gy. Additionally, in group B, most of the patients had to reduce their total radiation dose because they could not tolerate the acute radiotherapy-induced complications; thus, the total radiation dose in group B merely reached 45-70 Gy although the prescribed dose was 60-70 Gy. This resulted in a reduction in LC and LTPFS rates for patients in group B. Another finding in our study was that 125 I brachytherapy had a huge advantage concerning the improvement of clinical symptoms and QoL. Higher clinical remission rates can significantly improve the clinical symptoms and QoL. There was no significant difference in the EORTC QLQH&N35 score before treatment, but this score significantly improved to 9.21, 15.20, and 18.55 at 3, 6, and 12 months, respectively after treatment in group A, while in group B there was unobviously improvement and the score even deteriorated; it was deteriorated 6.02, 6.28, and 1.48 at 0, 3, and 6 months, respectively after treatment. QoL has a close relationship with radiotherapy-induced acute complications; the late radiation-induced complications reduced the positive role of EBRT in improving clinical symptoms to some extent and resulted in a worse QoL. Even though the QoL score for group B improved mildly 5.66 at 12 months after treatment, treatment effectiveness was far lower than 125 I brachytherapy at 12 months after treatment.
Complications associated with radiotherapy are often more significant because of the unique oral and maxillofacial anatomy [25]. Schoot et al. reported that 70% of patients who undergo radiotherapy for head and neck cancer may experience RTOG complications of grade 3/4 [26]. In our study, 61.8% (21/34) of patients in group B experienced complications of grade 3/4, while only 12.9% (4/31) experienced these complications in group A. Although in group A 3/31 (9.7%) patients had seed migration, this did not cause severe complications. This was because the radiation dose of 125 I seeds decayed rapidly with increased distance; This had a significant effect regarding tumor cell killing while minimizing damage to the surrounding normal tissue [27]. Thiele et al. reported that in a study of metastases in the head and neck that the mean OS from manifestation of the metastasis was 14 months [28]; in our study the findings were similar where the mean OS in groups A and B were 17.1 and 14.8 months, respectively. Although Cox proportional hazards regression analysis suggested that 125 I brachytherapy is not an independent factor affecting OS, the aim of our study was to improve patient QoL and maxillofacial symptoms; Indeed, the therapeutic effectiveness of 125 I brachytherapy was comparable with EBRT regarding OS.
Our study had several limitations. First, it was a single-center retrospective study; as a result of low morbidity, only 65 patients could be enrolled. Second, although we strictly followed the TPS during 125 I implantation, there was still some deviation in the actual seed implantation as a result of patient positioning and movement, which will have affected the treatment effect to some extent.

Ethics Approval and Consent to Participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of Sun Yat-sen University Cancer Center and met the basic standards of the Declaration of Helsinki. All patients in the study were fully informed the potential risks and voluntarily signed informed consent.

Consent for Publication
All authors read and approved the final manuscript.