- Email: [email protected]
Image-guided high-dose-rate interstitial brachytherapy boost in the radical radiotherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site
Cancer/Radiothérapie 23 (2019) 426–431
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Case report
Image-guided high-dose-rate interstitial brachytherapy boost in the radical radiotherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site Curiethérapie interstitielle de haut débit de dose guidée par l’image en complément de la radiothérapie radicale pour des adénopathies cervicales métastatiques d’un cancer primitif non retrouvé Minjie Wang 1 , Ning Wu 1 , Dongmei Han 1 , Hongfu Zhao , Guanghui Cheng ∗ Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
a r t i c l e
i n f o
Article history: Received 11 May 2018 Received in revised form 16 January 2019 Accepted 29 January 2019 Keywords: Metastatic carcinoma Unknown primary Interstitial brachytherapy
a b s t r a c t The purpose of this article was to report the treatment effect of image-guided high-dose-rate interstitial brachytherapy boost in the radical radiotherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site. The patient was a 75-year-old male. A diagnostic biopsy showed metastatic squamous cell carcinoma and the tumour size was 7.5 × 6.5 × 11.5 cm3 before treatment (N3; AJCC 7th). After external beam radiotherapy with a dose of 60 Gy in 30 fractions, the residual tumour (6.2 × 4.7 × 6.0 cm3 ) was treated with image-guided high-dose-rate interstitial brachytherapy boost under ultrasound guidance. The brachytherapy dose was 16 Gy in four fractions of 4 Gy each. Removal of the huge metastatic tumour was securely achieved by high dose rate interstitial brachytherapy guided with ultrasound scanning. The refractory tumour in the patients healed uneventfully after image-guided high-dose-rate interstitial brachytherapy without recurrence during the 24 months of follow-up. The image-guided high-dose-rate interstitial brachytherapy boost may be a proposed treatment strategy for metastatic carcinoma of cervical lymph nodes from an unknown primary site with radical radiotherapy, especially for huge residual tumour. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2019 Societ rights reserved.
r é s u m é Mots clés : Carcinome métastatique Primitives inconnues Curiethérapie interstitielle
L’objectif de cette étude était d’analyser l’effet d’une curiethérapie interstitielle de haut débit de dose guidée par image en complément d’une radiothérapie radicale pour les adénopathies cervicales métastatiques d’un carcinome non retrouvé. Le patient était un homme de 75 ans. La biopsie diagnostique a montré un carcinome épidermoïde métastatique, le volume était de 7,5 × 6,5 × 11,5 cm3 , le stade N3 selon la septième édition de la classification de l’American Joint Committee on Cancer. Après une irradiation externe de 60 Gy en 30 fractions, la tumeur résiduelle (6,2 × 4,7 × 6,0 cm3 ) a fait l’objet d’une curiethérapie interstitielle de haut débit de dose guidée par échographie, de 16 Gy en quatre fractions de 4 Gy. Le contrôle tumoral a été obtenu avec 24 mois de suivi. La curiethérapie interstitielle de haut débit de dose guidée par l’image pourrait constituer une stratégie après une radiothérapie radicale pour les adénopathies cervicales métastatiques d’un carcinome non retrouvé, en particulier de grand volume. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2019 Societ ´ ´ droits reserv es.
∗ Corresponding author. E-mail address: chengguanghuifl@163.com (G. Cheng). 1 These three authors contributed equally to this work. https://doi.org/10.1016/j.canrad.2019.01.006 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2019 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
1. Introduction Metastatic carcinoma of cervical lymph nodes from an unknown primary site encompasses a heterogeneous group of tumours for which no primary site can be detected following a thorough history, physical examination, and noninvasive and invasive testing [1]. Metastatic carcinoma of cervical lymph nodes from an unknown primary site reportedly accounts for about 1% to 4% of all cancers in the head and neck [2]. The condition is rare and the optimal treatment remains somewhat controversial. No method is standard for all forms of metastatic carcinoma of cervical lymph nodes from an unknown primary site, but surgery, radiotherapy and chemotherapy may be used alone or in combination to treat patients who have this disease [3]. The therapeutic philosophy has been to identify the therapy that gives the greatest control rates and the best quality of life after treatment. However, the potential side effects of the treatments must be considered along with the potential benefits. Radiotherapy can produce excellent outcomes for patients who present with metastatic carcinoma of cervical lymph nodes from an unknown primary site (especially for N2 and N3) [4]. For tumours with a huge volume, it requires a higher radical dose provided by conventional external beam radiotherapy, and may assume a higher risk of treatment toxicity [5]. Brachytherapy may play a meaningful role in the treatment of metastatic carcinoma of cervical lymph nodes from an unknown primary site because it provides advantages over external beam radiotherapy in that the tumour can be treated with very high dosage of localized radiation, while reducing the probability of unnecessary damage to surrounding healthy tissues [6]. In this paper, we propose a technique using image-guided high-dose-rate interstitial brachytherapy boost to treat residual lesion of metastatic carcinoma of cervical lymph nodes from an unknown primary site after conventional external beam radiotherapy.
2. Case report A 75-year-old male sought medical attention in our institution after being diagnosed with a locally metastatic squamous cell carcinoma involving the left cervical lymph nodes from an unknown primary site. About 2 years before admitting to our clinic, he presented with a lump (less than 1 cm in diameter) which located in the left neck without a history of trauma or familial head and neck cancer. The tumour grew gradually, without complaint about pain, hoarseness, or dyspnoea. The patient did not receive any treatment until he was referred to our clinic. Physical examination showed the tenderness of huge mass that was below the left mandibular ramus with an unclear border and poor mobility. He had an abnormal magnetic resonance imaging (MRI) scan revealing an area of distortion of approximately 7.5 × 6.5 × 11.5 cm3 in size that invaded the left cervical lymph nodes region (levels II–III) (Fig. 1). The fine-needle aspiration of the lymph node confirmed invasion of metastatic squamous cell carcinoma. However, the primary tumour could not be identified according to positron emission tomography-computed tomography (PET-CT) examination. He was diagnosed with metastatic carcinoma of cervical lymph nodes from an unknown primary site (N3 stage according to the 7th classification of the American Joint Committee on Cancer). Because the lesion was directly adjacent to vessels or structures, whose mechanical damage could lead to haemorrhage or organ dysfunction, he was referred to our clinic for treatment by irradiation and rejected the suggestion of chemotherapy. The patient received external beam radiotherapy using intensity-modulated irradiation technique (IMRT) at the beginning of treatment. The gross target volume was defined as all known left
427
neck disease based on clinical examination and CT imaging. Clinical target volume (CTV)-1 included the potential primary mucosal sites, typically the bilateral whole pharynx, larynx, lymph nodes region levels I-V in the ipsilateral neck and II-V in the contralateral neck. CTV-2 was defined as the gross target volume with typical margins of 5 mm. The planning target volume was obtained by adding a 3 mm volumetric expansion to the clinical target volumes (Fig. 2). Organs at risk included the spinal cord, larynx, mandibula, ipsilateral thyroid and parotid glands. Prescription doses were 50 Gy to CTV-1 and 60 Gy to CTV-2 at 2 Gy per fractions, all given in 6 weeks. After external beam radiotherapy with 60 Gy, the tumour size had decreased to 6.2 × 4.7 × 6.0 cm3 according to the CT examination. The doses received by critical organs have approached the maximum tolerated dose of normal tissues (for example the maximum dose of the spinal cord was 29.36 Gy, and 54.47 Gy for the mandibula). Despite recommendation for subsequent external beam boost integrated into the intensity-modulated radiotherapy plan, the patient refused it and requested brachytherapy instead because of the possibility of severe treatment toxicity after radical external irradiation. Before processing each treatment, informed consent was obtained from the patient. Treatments were performed with standard institutional approval. Image-guided high-dose-rate interstitial brachytherapy boost, following external beam radiotherapy within one week, with a total dose of 16 Gy in four fractions over 2 days (4 Gy per fraction, twice a day with a 6 h interval) was administered to the patient. This required a single application procedure and a single treatment planning session. OncoSmart ProGuide needles (Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden) were used and the procedure was conducted under general anaesthesia. Electrocardiogram, arterial oxygen pressure, respiration, and blood pressure monitoring were performed during the procedure. Then, under ultrasound guidance, ten applicator needles (1.1 mm in external diameter and 200 mm in length) were percutaneously inserted into the tumour in a way facilitating irradiation of the whole tumour area, and simultaneously controlling the position of the needle against the adjacent structures. The applicators were inserted in such a way that their layout in the lesion was possibly most parallel, and their distance from one another was 1 cm to ensure adequate dose distribution and target volume coverage. The applicator needles were remained in the lesion from the beginning of the first to the end of the last fraction because of their stabilization (Fig. 3). OncoSmart ProGuide CT-Markers were put inside the catheters in order to facilitate their reconstruction. After implanting the applicators, fine-pitch (2 mm) X-ray CT images were acquired and transferred to the treatment planning computer. The CT-imaging data before interstitial brachytherapy was used to contour gross and clinical target volumes. The clinical target volume was expanded from gross target volume by 5 mm and restricted by the volume of organs at risk. A CT-based treatment plan was created using a graphic optimization tool (Treatment Planning System Oncentra V4.3; Nucletron, Veenendaal, The Netherlands). The normalization and optimization to the target volume was performed, and time and place of ionizing radiation source stopping points were planned. Dosimetry parameters were reported according to the guidelines. The dose–volume histogram parameters are recommended for the evaluation of target volume and organs at risk (Fig. 4). In the external radiotherapy plan, 60 Gy in 2 Gy per fraction was prescribed to the target. In order to compare external radiotherapy and brachytherapy with conventional fractioning of 2 Gy, the doses were converted to dose equivalent 2 Gy (EQD2 model), at ␣/ = 3 (GyEQD2, ␣/ = 3 ) for the organs at risk and ␣/ = 10 (GyEQD2, ␣/ = 10 ) for the target. Dose–volume histogram parameters were analysed taking into account the volume ratio of the target receiving
428
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
Fig. 1. MRI scan showing a huge metastatic tumour in the left neck before radiotherapy.
Fig. 2. Target volumes and radiation fields distribution in external beam radiotherapy with intensity-modulated technique for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site.
Fig. 3. Dose distribution of horizontal, sagittal, and coronal positions in image-guided high-dose-rate interstitial brachytherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site.
90% or 150% of the prescribed dose (V90% and V150% , respectively), the equivalent dose delivered to 98%, 90% and 50% of the target volume (D98% , D90% and D50% , respectively), the critical maximum equivalent dose delivered to spinal cord and mandibula (dose per 2% of the organ located in the maximum dose area: D2%-spinal cord and D2%-mandibula , respectively), the mean equivalent dose delivered to larynx, ipsilateral thyroid and parotid glands (Dmean-larynx, Dmean-left thyroid gland and Dmean-left parotid gland, respectively). The planned doses for brachytherapy were accepted (Table 1). The treatment was conducted using 18 channel iridium-192 (192 Ir) remote afterloader system (Microselectron HDR 192 Ir; Nucletron, Veenendaal, The Netherlands). After completion of
irradiation session, the applicator needles were removed from lesions, CT scan with contrast was performed and the patient was discharged after 2 h under observation in order to rule out potential complications. The patient was required regularly followed up at our affiliated clinics. According to the dose–volume histogram parameters, the actual doses achieved in brachytherapy plan are detailed in Table 1. The total superimposed doses of target volume (D98% was 75.30 Gy, D90% was 80.80 Gy and D50% was 104.33 Gy, respectively) were calculated with combination of internal and external irradiation plans. Due to little respiratory movement of anatomic structures in head and neck region, ultrasound guided insertions of the applicators were precise and relatively safe, despite close vicinity of many
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
429
Fig. 4. Dose–volume histogram parameters in a treatment session of brachytherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site showing high dose distribution of target volume, and low dose distribution of organs at risk: spinal cord, larynx, mandibula, ipsilateral thyroid and parotid glands. Table 1 Image-guided high-dose-rate interstitial brachytherapy boost in the radical radiotherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site in a 75-year old male patient: planned and actual irradiation doses and volumes.
V90% V150% D98% D50% D90% D2%-spinal cord D2%-mandibula Dmean-larynx Dmean-thyroid gland Dmean-parotid gland
Planned irradiation doses
Actual irradiation volume or doses
> 20 GyEQD2, ␣/ = 10 < 5 GyEQD2, ␣/ = 3 < 15 GyEQD2, ␣/ = 3 < 5 GyEQD2, ␣/ = 3 < 5 GyEQD2, ␣/ = 3 < 10 GyEQD2, ␣/ = 3
97.00% 68.20% 3.42 Gy × 4 (15.30 GyEQD2, ␣/ = 10 ) 7.57 Gy × 4 (44.33 GyEQD2, ␣/ = 10 ) 4.35 Gy × 4 (20.80 GyEQD2, ␣/ = 10 ) 1.34 Gy × 4 (4.65 GyEQD2, ␣/ = 3 ) 3.02 Gy × 4 (14.54 GyEQD2, ␣/ = 3 ) 0.47 Gy × 4 (1.30 GyEQD2, ␣/ = 3 ) 0.51 Gy × 4 (1.43 GyEQD2, ␣/ = 3 )a 2.23 Gy × 4 (9.33 GyEQD2, ␣/ = 3 )a
Vx%: volume ratio of the target receiving x% of the prescribed dose; Dx%: equivalent dose delivered to x% of the target volume; EQD2: 2 Gy equivalent dose; D2% : dose per 2% of the organ located in the maximum dose area; Dmean : mean dose delivered to the organ. a Left side.
organs at risk. No complications were reported during the treatment and the brachytherapy was well tolerated by the patient. The radiotherapy related toxicity was measured using Radiation Therapy Oncology Group (RTOG) scale. Nearly 2 months after completion of brachytherapy, it could be observed that the huge tumour in left neck shrank obviously with radiation-induced skin reaction (RTOG scale grade 2) which was characterized by skin oedema, red patch and wet peeling. The patient chose to go to a vicinity clinic for re-examination every three months after treatment, with no tumor recurrence of left neck and metastases of critical organs. During the follow-up examination in the 24th month after brachytherapy, it was showed that the mass disappeared without locoregional recurrence according to the CT results. RTOG scale grade 1 of radiotherapy related morbidity could be observed with slight skin atrophy and subcutaneous tissue fibrosis (Fig. 5).
3. Discussion Metastatic carcinoma of cervical lymph nodes from an unknown primary site carries a poor prognosis in most (80% to 85%) of those circumstances. The other 15% to 20% of patients, however, have a relatively long survival with appropriate treatment [7].
The treatment of metastatic carcinoma of cervical lymph nodes from an unknown primary site remains an important challenge, with a combination of neck dissection and adjuvant radiotherapy or definitive radiotherapy both commonly used [8–10]. Some studies have published the investigation that neck dissection or radiotherapy alone provide similar locoregional control in patients with metastatic carcinoma of cervical lymph nodes from an unknown primary site with N1 and selected N2a nodal classification without extracapsular extension but, if possible, surgery should be favoured because it consents a more precise staging [11,12]. Davidson et al. found that 34% of patients with metastatic carcinoma of cervical lymph nodes from an unknown primary site initially staged as N1 or N2a had multiple nodes found on dissection of the ipsilateral side of the neck [11]. Moreover, surgery can help deciding the indication for postoperative radiotherapy because it can provide pN stage, histologic grade, extracapsular extension, lymphovascular invasion and perineural invasion [12]. However, patients with more advanced conditions require combined treatment in the form of either resection followed by adjuvant irradiation (with or without chemotherapy) or primary radiotherapy (with or without chemotherapy and post-therapy neck dissection) [3]. A potential advantage of radiotherapy over surgery is that it allows for treatment of at-risk mucosal sites with a subclinical dose of radiation [13]. Although IMRT technique with dose modulation can
430
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
Fig. 5. 24 months follow-up of a patient with a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site treated by image-guided high-dose-rate interstitial brachytherapy; a: computed tomography; b: skin surface on left neck.
permit accelerated fractionation to sites of gross disease and minimize the excess radiation to normal structures, the tumour cannot completely regress even with a radical dose of 70 Gy to 80 Gy administered by external irradiation for a giant cervical lymph node metastasis [4]. And the incidence of severe side effects and complications may increase significantly and affect the course of treatment and quality of life [5]. There is little reported in the medical literature concerning the interstitial brachytherapy for metastatic carcinoma of cervical lymph nodes from an unknown primary site, but some exploratory studies have focused on the application of brachytherapy in the treatment of head and neck cancers [14,15]. Bhalavat et al. evaluated the treatment outcomes with implementation of high-dose-rate interstitial brachytherapy used alone or as boost in head and neck cancers [16]. The disease-free survival probability at year 1 was 82.7%, and 68% at year 7. The overall survival probability was 91.3% at year 1 and 85.8% at year 7. The local control rate was 70%. Wu et al. reported their experience with high-dose-rate interstitial brachytherapy for refractory recurrence of papillary thyroid cancer [17]. The refractory tumour in the patients healed uneventfully after treatment without recurrence during the 14 months of follow-up. The authors considered that the role of high-dose-rate interstitial brachytherapy in head and neck cancers is a proven, effective, and safe treatment method with excellent long term outcome as seen in their study. In the present case, the image-guided high-dose-rate interstitial brachytherapy boost with good adherence was used for this patient in order to control the huge tumour of metastatic carcinoma of cervical lymph nodes from an unknown primary site. And the dose–volume histograms showed that target volume was covered with high dose irradiation, but the dosage of organs at risk were relative low. The patient with metastatic carcinoma of cervical lymph nodes from an unknown primary site obtained good locoregional control by high-dose-rate interstitial radiotherapy with ultrasound guidance. The tumour shrank obviously 2 months later, and no serious complications were found in follow-up over 2 years. And positive effects were achieved in case of both treatment efficiency and quality of life. Although there is ongoing discussion regarding the optimal management procedure for metastatic carcinoma of cervical lymph nodes from an unknown primary site (especially with high-volume neck disease), the combination treatment using boost with image-guided high-dose-rate interstitial brachytherapy
is effective and seems a viable alternative to radical external beam radiotherapy with tolerable toxicity. 4. Conclusion Image-guided high-dose-rate interstitial brachytherapy may be a safe and practicable method for patients with metastatic carcinoma of cervical lymph nodes from an unknown primary site as boost. Image-guided high-dose-rate interstitial brachytherapy boost should be attempted and integrated with external beam radiotherapy whenever possible, depending on the clinical response after moderate dose external beam radiotherapy and availability of expertise. The main benefit of image-guided highdose-rate interstitial brachytherapy is that a high dose of radiation can be precisely applied to the tumour while sparing radiation to healthy tissues simultaneously. In select patients, the image-guided high-dose-rate interstitial brachytherapy boost may be a valuable treatment approach for metastatic carcinoma of cervical lymph nodes from an unknown primary site. Funding This work was partially supported by grants from the National Natural Science Foundation of China [81201737], Youth Science and Technology Training Program in Health Commission of Jilin Province [2018Q014], Project of Science and Technology Department of Jilin Province [20090458], Project of Health and Family Planning Commission of Jilin Province [2014ZC054], Bethune Special Research of Science and Technology Department of Jilin Province [20160101079JC], Jilin University Technical Services Research Foundation [2015YX154], Jilin University Network Experiment Project [VE2015081], Jilin University Undergraduate Education Reform Research Project [2017XYB080] and Excellent Talents Training Program of China-Japanese Union Hospital of Jilin University [YXQ1-201801] and Youth Science and Technology Training Program in Health Commission of Jilin Province [2018Q014]. Disclosure of interest The authors declare that they have no competing interest.
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
References [1] Smith KA, Dort JC, Hall SF, Rudmik L. Cost-effectiveness of positron emission tomography-CT in the evaluation of cancer of unknown primary of the head and neck. Head Neck 2014;37:1781–7. [2] Richards TM, Bhide SA, Miah AB, Del Rosario L, Bodla S, Thway K, et al. Total mucosal irradiation with intensity-modulated radiotherapy in patients with head and neck carcinoma of unknown primary: a pooled analysis of two prospective studies. Clin Oncol 2016;28:e77–84. [3] Pfister DG, Spencer S, Brizel DM, Burtness B, Busse PM, Caudell JJ, et al. Head and neck cancers version 2.2014. Clinical practice guidelines in oncology. J Natl Compr Cancer Netw 2014;12:1454–87. [4] Frank SJ, Rosenthal DI, Petsuksiri J, Ang KK, Morrison WH, Weber RS, et al. Intensity-modulated radiotherapy for cervical node squamous cell carcinoma metastases from unknown head-and-neck primary site: M.D. Anderson Cancer Center outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 2010;78:1005–10. [5] Al Kadah B, Papaspyrou G, Linxweiler M, Schick B, Rübe C, Büchler BS, et al. Cancer of unknown primary (CUP) of the head and neck: retrospective analysis of 81 patients. Eur Arch Otorhinolaryngol 2017;274:2557–66. [6] Lukens JN, Gamez M, Hu K, Harrison LB. Modern brachytherapy. Semin Oncol 2014;41:831–47. [7] Stella GM, Senetta R, Cassenti A, Ronco M, Cassoni P. Cancers of unknown primary origin: current perspectives and future therapeutic strategies. J Transl Med 2012;10:12. [8] Demiroz C, Vainshtein JM, Koukourakis GV, Gutfeld O, Prince ME, Bradford CR, et al. Head and neck squamous cell carcinoma of unknown primary: neck dissection and radiotherapy or definitive radiotherapy. Head Neck 2014;36:1589–95.
431
[9] Arosio AD, Pignataro L, Gaini RM, Garavello W. Neck lymph node metastases from unknown primary. Cancer Treat Rev 2017;53:1–9. [10] Arrangoiz R, Galloway TJ, Papavasiliou P, Ridge JA, Lango MN. Metastatic cervical carcinoma from an unknown primary: literature review. Ear Nose Throat J 2014;93:E1–10. [11] Davidson BJ, Spiro RH, Patel S, Patel K, Shah JP. Cervical metastases of occult origin: the impact of combined modality therapy. Am J Surg 1994;168: 395–9. [12] Wang RC, Goepfert H, Barber AE, Wolf P. Unknown primary squamous cell carcinoma metastatic to the neck. Arch Otolaryngol Head Neck Surg 1990;116:1388–93. [13] Cianchetti M, Mancuso AA, Amdur RJ, Werning JW, Kirwan J, Morris CG, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope 2009;119:2348–54. [14] Lapeyre M, Coche-Dequéant B, Moreira JF, Le Bourhis J, Peiffert D. Brachytherapy for head and neck cancers. Cancer Radiother 2013;17:130–5. [15] Nag S, Cano ER, Demanes DJ, Puthawala AA, Vikram B. American Brachytherapy Society. The American Brachytherapy Society recommendations for high-doserate brachytherapy for head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2001;50:1190–8. [16] Bhalavat R, Chandra M, Pareek V, Nellore L, George K, Nandakumar P, et al. Highdose-rate interstitial brachytherapy in head and neck cancer: do we need a look back into a forgotten art–a single institute experience. J Contemp Brachyther 2017;9:124–31. [17] Wu N, Zhao H, Han D, Cheng G, Zhao Z, Ge Y. Image-guided high-dose-rate interstitial brachytherapy – a valuable salvage treatment approach for locoregional recurrence of papillary thyroid cancer. J Contemp Brachyther 2016;8: 150–5.
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Case report
Image-guided high-dose-rate interstitial brachytherapy boost in the radical radiotherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site Curiethérapie interstitielle de haut débit de dose guidée par l’image en complément de la radiothérapie radicale pour des adénopathies cervicales métastatiques d’un cancer primitif non retrouvé Minjie Wang 1 , Ning Wu 1 , Dongmei Han 1 , Hongfu Zhao , Guanghui Cheng ∗ Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
a r t i c l e
i n f o
Article history: Received 11 May 2018 Received in revised form 16 January 2019 Accepted 29 January 2019 Keywords: Metastatic carcinoma Unknown primary Interstitial brachytherapy
a b s t r a c t The purpose of this article was to report the treatment effect of image-guided high-dose-rate interstitial brachytherapy boost in the radical radiotherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site. The patient was a 75-year-old male. A diagnostic biopsy showed metastatic squamous cell carcinoma and the tumour size was 7.5 × 6.5 × 11.5 cm3 before treatment (N3; AJCC 7th). After external beam radiotherapy with a dose of 60 Gy in 30 fractions, the residual tumour (6.2 × 4.7 × 6.0 cm3 ) was treated with image-guided high-dose-rate interstitial brachytherapy boost under ultrasound guidance. The brachytherapy dose was 16 Gy in four fractions of 4 Gy each. Removal of the huge metastatic tumour was securely achieved by high dose rate interstitial brachytherapy guided with ultrasound scanning. The refractory tumour in the patients healed uneventfully after image-guided high-dose-rate interstitial brachytherapy without recurrence during the 24 months of follow-up. The image-guided high-dose-rate interstitial brachytherapy boost may be a proposed treatment strategy for metastatic carcinoma of cervical lymph nodes from an unknown primary site with radical radiotherapy, especially for huge residual tumour. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2019 Societ rights reserved.
r é s u m é Mots clés : Carcinome métastatique Primitives inconnues Curiethérapie interstitielle
L’objectif de cette étude était d’analyser l’effet d’une curiethérapie interstitielle de haut débit de dose guidée par image en complément d’une radiothérapie radicale pour les adénopathies cervicales métastatiques d’un carcinome non retrouvé. Le patient était un homme de 75 ans. La biopsie diagnostique a montré un carcinome épidermoïde métastatique, le volume était de 7,5 × 6,5 × 11,5 cm3 , le stade N3 selon la septième édition de la classification de l’American Joint Committee on Cancer. Après une irradiation externe de 60 Gy en 30 fractions, la tumeur résiduelle (6,2 × 4,7 × 6,0 cm3 ) a fait l’objet d’une curiethérapie interstitielle de haut débit de dose guidée par échographie, de 16 Gy en quatre fractions de 4 Gy. Le contrôle tumoral a été obtenu avec 24 mois de suivi. La curiethérapie interstitielle de haut débit de dose guidée par l’image pourrait constituer une stratégie après une radiothérapie radicale pour les adénopathies cervicales métastatiques d’un carcinome non retrouvé, en particulier de grand volume. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2019 Societ ´ ´ droits reserv es.
∗ Corresponding author. E-mail address: chengguanghuifl@163.com (G. Cheng). 1 These three authors contributed equally to this work. https://doi.org/10.1016/j.canrad.2019.01.006 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2019 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
1. Introduction Metastatic carcinoma of cervical lymph nodes from an unknown primary site encompasses a heterogeneous group of tumours for which no primary site can be detected following a thorough history, physical examination, and noninvasive and invasive testing [1]. Metastatic carcinoma of cervical lymph nodes from an unknown primary site reportedly accounts for about 1% to 4% of all cancers in the head and neck [2]. The condition is rare and the optimal treatment remains somewhat controversial. No method is standard for all forms of metastatic carcinoma of cervical lymph nodes from an unknown primary site, but surgery, radiotherapy and chemotherapy may be used alone or in combination to treat patients who have this disease [3]. The therapeutic philosophy has been to identify the therapy that gives the greatest control rates and the best quality of life after treatment. However, the potential side effects of the treatments must be considered along with the potential benefits. Radiotherapy can produce excellent outcomes for patients who present with metastatic carcinoma of cervical lymph nodes from an unknown primary site (especially for N2 and N3) [4]. For tumours with a huge volume, it requires a higher radical dose provided by conventional external beam radiotherapy, and may assume a higher risk of treatment toxicity [5]. Brachytherapy may play a meaningful role in the treatment of metastatic carcinoma of cervical lymph nodes from an unknown primary site because it provides advantages over external beam radiotherapy in that the tumour can be treated with very high dosage of localized radiation, while reducing the probability of unnecessary damage to surrounding healthy tissues [6]. In this paper, we propose a technique using image-guided high-dose-rate interstitial brachytherapy boost to treat residual lesion of metastatic carcinoma of cervical lymph nodes from an unknown primary site after conventional external beam radiotherapy.
2. Case report A 75-year-old male sought medical attention in our institution after being diagnosed with a locally metastatic squamous cell carcinoma involving the left cervical lymph nodes from an unknown primary site. About 2 years before admitting to our clinic, he presented with a lump (less than 1 cm in diameter) which located in the left neck without a history of trauma or familial head and neck cancer. The tumour grew gradually, without complaint about pain, hoarseness, or dyspnoea. The patient did not receive any treatment until he was referred to our clinic. Physical examination showed the tenderness of huge mass that was below the left mandibular ramus with an unclear border and poor mobility. He had an abnormal magnetic resonance imaging (MRI) scan revealing an area of distortion of approximately 7.5 × 6.5 × 11.5 cm3 in size that invaded the left cervical lymph nodes region (levels II–III) (Fig. 1). The fine-needle aspiration of the lymph node confirmed invasion of metastatic squamous cell carcinoma. However, the primary tumour could not be identified according to positron emission tomography-computed tomography (PET-CT) examination. He was diagnosed with metastatic carcinoma of cervical lymph nodes from an unknown primary site (N3 stage according to the 7th classification of the American Joint Committee on Cancer). Because the lesion was directly adjacent to vessels or structures, whose mechanical damage could lead to haemorrhage or organ dysfunction, he was referred to our clinic for treatment by irradiation and rejected the suggestion of chemotherapy. The patient received external beam radiotherapy using intensity-modulated irradiation technique (IMRT) at the beginning of treatment. The gross target volume was defined as all known left
427
neck disease based on clinical examination and CT imaging. Clinical target volume (CTV)-1 included the potential primary mucosal sites, typically the bilateral whole pharynx, larynx, lymph nodes region levels I-V in the ipsilateral neck and II-V in the contralateral neck. CTV-2 was defined as the gross target volume with typical margins of 5 mm. The planning target volume was obtained by adding a 3 mm volumetric expansion to the clinical target volumes (Fig. 2). Organs at risk included the spinal cord, larynx, mandibula, ipsilateral thyroid and parotid glands. Prescription doses were 50 Gy to CTV-1 and 60 Gy to CTV-2 at 2 Gy per fractions, all given in 6 weeks. After external beam radiotherapy with 60 Gy, the tumour size had decreased to 6.2 × 4.7 × 6.0 cm3 according to the CT examination. The doses received by critical organs have approached the maximum tolerated dose of normal tissues (for example the maximum dose of the spinal cord was 29.36 Gy, and 54.47 Gy for the mandibula). Despite recommendation for subsequent external beam boost integrated into the intensity-modulated radiotherapy plan, the patient refused it and requested brachytherapy instead because of the possibility of severe treatment toxicity after radical external irradiation. Before processing each treatment, informed consent was obtained from the patient. Treatments were performed with standard institutional approval. Image-guided high-dose-rate interstitial brachytherapy boost, following external beam radiotherapy within one week, with a total dose of 16 Gy in four fractions over 2 days (4 Gy per fraction, twice a day with a 6 h interval) was administered to the patient. This required a single application procedure and a single treatment planning session. OncoSmart ProGuide needles (Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden) were used and the procedure was conducted under general anaesthesia. Electrocardiogram, arterial oxygen pressure, respiration, and blood pressure monitoring were performed during the procedure. Then, under ultrasound guidance, ten applicator needles (1.1 mm in external diameter and 200 mm in length) were percutaneously inserted into the tumour in a way facilitating irradiation of the whole tumour area, and simultaneously controlling the position of the needle against the adjacent structures. The applicators were inserted in such a way that their layout in the lesion was possibly most parallel, and their distance from one another was 1 cm to ensure adequate dose distribution and target volume coverage. The applicator needles were remained in the lesion from the beginning of the first to the end of the last fraction because of their stabilization (Fig. 3). OncoSmart ProGuide CT-Markers were put inside the catheters in order to facilitate their reconstruction. After implanting the applicators, fine-pitch (2 mm) X-ray CT images were acquired and transferred to the treatment planning computer. The CT-imaging data before interstitial brachytherapy was used to contour gross and clinical target volumes. The clinical target volume was expanded from gross target volume by 5 mm and restricted by the volume of organs at risk. A CT-based treatment plan was created using a graphic optimization tool (Treatment Planning System Oncentra V4.3; Nucletron, Veenendaal, The Netherlands). The normalization and optimization to the target volume was performed, and time and place of ionizing radiation source stopping points were planned. Dosimetry parameters were reported according to the guidelines. The dose–volume histogram parameters are recommended for the evaluation of target volume and organs at risk (Fig. 4). In the external radiotherapy plan, 60 Gy in 2 Gy per fraction was prescribed to the target. In order to compare external radiotherapy and brachytherapy with conventional fractioning of 2 Gy, the doses were converted to dose equivalent 2 Gy (EQD2 model), at ␣/ = 3 (GyEQD2, ␣/ = 3 ) for the organs at risk and ␣/ = 10 (GyEQD2, ␣/ = 10 ) for the target. Dose–volume histogram parameters were analysed taking into account the volume ratio of the target receiving
428
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
Fig. 1. MRI scan showing a huge metastatic tumour in the left neck before radiotherapy.
Fig. 2. Target volumes and radiation fields distribution in external beam radiotherapy with intensity-modulated technique for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site.
Fig. 3. Dose distribution of horizontal, sagittal, and coronal positions in image-guided high-dose-rate interstitial brachytherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site.
90% or 150% of the prescribed dose (V90% and V150% , respectively), the equivalent dose delivered to 98%, 90% and 50% of the target volume (D98% , D90% and D50% , respectively), the critical maximum equivalent dose delivered to spinal cord and mandibula (dose per 2% of the organ located in the maximum dose area: D2%-spinal cord and D2%-mandibula , respectively), the mean equivalent dose delivered to larynx, ipsilateral thyroid and parotid glands (Dmean-larynx, Dmean-left thyroid gland and Dmean-left parotid gland, respectively). The planned doses for brachytherapy were accepted (Table 1). The treatment was conducted using 18 channel iridium-192 (192 Ir) remote afterloader system (Microselectron HDR 192 Ir; Nucletron, Veenendaal, The Netherlands). After completion of
irradiation session, the applicator needles were removed from lesions, CT scan with contrast was performed and the patient was discharged after 2 h under observation in order to rule out potential complications. The patient was required regularly followed up at our affiliated clinics. According to the dose–volume histogram parameters, the actual doses achieved in brachytherapy plan are detailed in Table 1. The total superimposed doses of target volume (D98% was 75.30 Gy, D90% was 80.80 Gy and D50% was 104.33 Gy, respectively) were calculated with combination of internal and external irradiation plans. Due to little respiratory movement of anatomic structures in head and neck region, ultrasound guided insertions of the applicators were precise and relatively safe, despite close vicinity of many
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
429
Fig. 4. Dose–volume histogram parameters in a treatment session of brachytherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site showing high dose distribution of target volume, and low dose distribution of organs at risk: spinal cord, larynx, mandibula, ipsilateral thyroid and parotid glands. Table 1 Image-guided high-dose-rate interstitial brachytherapy boost in the radical radiotherapy for a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site in a 75-year old male patient: planned and actual irradiation doses and volumes.
V90% V150% D98% D50% D90% D2%-spinal cord D2%-mandibula Dmean-larynx Dmean-thyroid gland Dmean-parotid gland
Planned irradiation doses
Actual irradiation volume or doses
> 20 GyEQD2, ␣/ = 10 < 5 GyEQD2, ␣/ = 3 < 15 GyEQD2, ␣/ = 3 < 5 GyEQD2, ␣/ = 3 < 5 GyEQD2, ␣/ = 3 < 10 GyEQD2, ␣/ = 3
97.00% 68.20% 3.42 Gy × 4 (15.30 GyEQD2, ␣/ = 10 ) 7.57 Gy × 4 (44.33 GyEQD2, ␣/ = 10 ) 4.35 Gy × 4 (20.80 GyEQD2, ␣/ = 10 ) 1.34 Gy × 4 (4.65 GyEQD2, ␣/ = 3 ) 3.02 Gy × 4 (14.54 GyEQD2, ␣/ = 3 ) 0.47 Gy × 4 (1.30 GyEQD2, ␣/ = 3 ) 0.51 Gy × 4 (1.43 GyEQD2, ␣/ = 3 )a 2.23 Gy × 4 (9.33 GyEQD2, ␣/ = 3 )a
Vx%: volume ratio of the target receiving x% of the prescribed dose; Dx%: equivalent dose delivered to x% of the target volume; EQD2: 2 Gy equivalent dose; D2% : dose per 2% of the organ located in the maximum dose area; Dmean : mean dose delivered to the organ. a Left side.
organs at risk. No complications were reported during the treatment and the brachytherapy was well tolerated by the patient. The radiotherapy related toxicity was measured using Radiation Therapy Oncology Group (RTOG) scale. Nearly 2 months after completion of brachytherapy, it could be observed that the huge tumour in left neck shrank obviously with radiation-induced skin reaction (RTOG scale grade 2) which was characterized by skin oedema, red patch and wet peeling. The patient chose to go to a vicinity clinic for re-examination every three months after treatment, with no tumor recurrence of left neck and metastases of critical organs. During the follow-up examination in the 24th month after brachytherapy, it was showed that the mass disappeared without locoregional recurrence according to the CT results. RTOG scale grade 1 of radiotherapy related morbidity could be observed with slight skin atrophy and subcutaneous tissue fibrosis (Fig. 5).
3. Discussion Metastatic carcinoma of cervical lymph nodes from an unknown primary site carries a poor prognosis in most (80% to 85%) of those circumstances. The other 15% to 20% of patients, however, have a relatively long survival with appropriate treatment [7].
The treatment of metastatic carcinoma of cervical lymph nodes from an unknown primary site remains an important challenge, with a combination of neck dissection and adjuvant radiotherapy or definitive radiotherapy both commonly used [8–10]. Some studies have published the investigation that neck dissection or radiotherapy alone provide similar locoregional control in patients with metastatic carcinoma of cervical lymph nodes from an unknown primary site with N1 and selected N2a nodal classification without extracapsular extension but, if possible, surgery should be favoured because it consents a more precise staging [11,12]. Davidson et al. found that 34% of patients with metastatic carcinoma of cervical lymph nodes from an unknown primary site initially staged as N1 or N2a had multiple nodes found on dissection of the ipsilateral side of the neck [11]. Moreover, surgery can help deciding the indication for postoperative radiotherapy because it can provide pN stage, histologic grade, extracapsular extension, lymphovascular invasion and perineural invasion [12]. However, patients with more advanced conditions require combined treatment in the form of either resection followed by adjuvant irradiation (with or without chemotherapy) or primary radiotherapy (with or without chemotherapy and post-therapy neck dissection) [3]. A potential advantage of radiotherapy over surgery is that it allows for treatment of at-risk mucosal sites with a subclinical dose of radiation [13]. Although IMRT technique with dose modulation can
430
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
Fig. 5. 24 months follow-up of a patient with a huge metastatic carcinoma of cervical lymph nodes from an unknown primary site treated by image-guided high-dose-rate interstitial brachytherapy; a: computed tomography; b: skin surface on left neck.
permit accelerated fractionation to sites of gross disease and minimize the excess radiation to normal structures, the tumour cannot completely regress even with a radical dose of 70 Gy to 80 Gy administered by external irradiation for a giant cervical lymph node metastasis [4]. And the incidence of severe side effects and complications may increase significantly and affect the course of treatment and quality of life [5]. There is little reported in the medical literature concerning the interstitial brachytherapy for metastatic carcinoma of cervical lymph nodes from an unknown primary site, but some exploratory studies have focused on the application of brachytherapy in the treatment of head and neck cancers [14,15]. Bhalavat et al. evaluated the treatment outcomes with implementation of high-dose-rate interstitial brachytherapy used alone or as boost in head and neck cancers [16]. The disease-free survival probability at year 1 was 82.7%, and 68% at year 7. The overall survival probability was 91.3% at year 1 and 85.8% at year 7. The local control rate was 70%. Wu et al. reported their experience with high-dose-rate interstitial brachytherapy for refractory recurrence of papillary thyroid cancer [17]. The refractory tumour in the patients healed uneventfully after treatment without recurrence during the 14 months of follow-up. The authors considered that the role of high-dose-rate interstitial brachytherapy in head and neck cancers is a proven, effective, and safe treatment method with excellent long term outcome as seen in their study. In the present case, the image-guided high-dose-rate interstitial brachytherapy boost with good adherence was used for this patient in order to control the huge tumour of metastatic carcinoma of cervical lymph nodes from an unknown primary site. And the dose–volume histograms showed that target volume was covered with high dose irradiation, but the dosage of organs at risk were relative low. The patient with metastatic carcinoma of cervical lymph nodes from an unknown primary site obtained good locoregional control by high-dose-rate interstitial radiotherapy with ultrasound guidance. The tumour shrank obviously 2 months later, and no serious complications were found in follow-up over 2 years. And positive effects were achieved in case of both treatment efficiency and quality of life. Although there is ongoing discussion regarding the optimal management procedure for metastatic carcinoma of cervical lymph nodes from an unknown primary site (especially with high-volume neck disease), the combination treatment using boost with image-guided high-dose-rate interstitial brachytherapy
is effective and seems a viable alternative to radical external beam radiotherapy with tolerable toxicity. 4. Conclusion Image-guided high-dose-rate interstitial brachytherapy may be a safe and practicable method for patients with metastatic carcinoma of cervical lymph nodes from an unknown primary site as boost. Image-guided high-dose-rate interstitial brachytherapy boost should be attempted and integrated with external beam radiotherapy whenever possible, depending on the clinical response after moderate dose external beam radiotherapy and availability of expertise. The main benefit of image-guided highdose-rate interstitial brachytherapy is that a high dose of radiation can be precisely applied to the tumour while sparing radiation to healthy tissues simultaneously. In select patients, the image-guided high-dose-rate interstitial brachytherapy boost may be a valuable treatment approach for metastatic carcinoma of cervical lymph nodes from an unknown primary site. Funding This work was partially supported by grants from the National Natural Science Foundation of China [81201737], Youth Science and Technology Training Program in Health Commission of Jilin Province [2018Q014], Project of Science and Technology Department of Jilin Province [20090458], Project of Health and Family Planning Commission of Jilin Province [2014ZC054], Bethune Special Research of Science and Technology Department of Jilin Province [20160101079JC], Jilin University Technical Services Research Foundation [2015YX154], Jilin University Network Experiment Project [VE2015081], Jilin University Undergraduate Education Reform Research Project [2017XYB080] and Excellent Talents Training Program of China-Japanese Union Hospital of Jilin University [YXQ1-201801] and Youth Science and Technology Training Program in Health Commission of Jilin Province [2018Q014]. Disclosure of interest The authors declare that they have no competing interest.
M. Wang et al. / Cancer/Radiothérapie 23 (2019) 426–431
References [1] Smith KA, Dort JC, Hall SF, Rudmik L. Cost-effectiveness of positron emission tomography-CT in the evaluation of cancer of unknown primary of the head and neck. Head Neck 2014;37:1781–7. [2] Richards TM, Bhide SA, Miah AB, Del Rosario L, Bodla S, Thway K, et al. Total mucosal irradiation with intensity-modulated radiotherapy in patients with head and neck carcinoma of unknown primary: a pooled analysis of two prospective studies. Clin Oncol 2016;28:e77–84. [3] Pfister DG, Spencer S, Brizel DM, Burtness B, Busse PM, Caudell JJ, et al. Head and neck cancers version 2.2014. Clinical practice guidelines in oncology. J Natl Compr Cancer Netw 2014;12:1454–87. [4] Frank SJ, Rosenthal DI, Petsuksiri J, Ang KK, Morrison WH, Weber RS, et al. Intensity-modulated radiotherapy for cervical node squamous cell carcinoma metastases from unknown head-and-neck primary site: M.D. Anderson Cancer Center outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 2010;78:1005–10. [5] Al Kadah B, Papaspyrou G, Linxweiler M, Schick B, Rübe C, Büchler BS, et al. Cancer of unknown primary (CUP) of the head and neck: retrospective analysis of 81 patients. Eur Arch Otorhinolaryngol 2017;274:2557–66. [6] Lukens JN, Gamez M, Hu K, Harrison LB. Modern brachytherapy. Semin Oncol 2014;41:831–47. [7] Stella GM, Senetta R, Cassenti A, Ronco M, Cassoni P. Cancers of unknown primary origin: current perspectives and future therapeutic strategies. J Transl Med 2012;10:12. [8] Demiroz C, Vainshtein JM, Koukourakis GV, Gutfeld O, Prince ME, Bradford CR, et al. Head and neck squamous cell carcinoma of unknown primary: neck dissection and radiotherapy or definitive radiotherapy. Head Neck 2014;36:1589–95.
431
[9] Arosio AD, Pignataro L, Gaini RM, Garavello W. Neck lymph node metastases from unknown primary. Cancer Treat Rev 2017;53:1–9. [10] Arrangoiz R, Galloway TJ, Papavasiliou P, Ridge JA, Lango MN. Metastatic cervical carcinoma from an unknown primary: literature review. Ear Nose Throat J 2014;93:E1–10. [11] Davidson BJ, Spiro RH, Patel S, Patel K, Shah JP. Cervical metastases of occult origin: the impact of combined modality therapy. Am J Surg 1994;168: 395–9. [12] Wang RC, Goepfert H, Barber AE, Wolf P. Unknown primary squamous cell carcinoma metastatic to the neck. Arch Otolaryngol Head Neck Surg 1990;116:1388–93. [13] Cianchetti M, Mancuso AA, Amdur RJ, Werning JW, Kirwan J, Morris CG, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope 2009;119:2348–54. [14] Lapeyre M, Coche-Dequéant B, Moreira JF, Le Bourhis J, Peiffert D. Brachytherapy for head and neck cancers. Cancer Radiother 2013;17:130–5. [15] Nag S, Cano ER, Demanes DJ, Puthawala AA, Vikram B. American Brachytherapy Society. The American Brachytherapy Society recommendations for high-doserate brachytherapy for head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2001;50:1190–8. [16] Bhalavat R, Chandra M, Pareek V, Nellore L, George K, Nandakumar P, et al. Highdose-rate interstitial brachytherapy in head and neck cancer: do we need a look back into a forgotten art–a single institute experience. J Contemp Brachyther 2017;9:124–31. [17] Wu N, Zhao H, Han D, Cheng G, Zhao Z, Ge Y. Image-guided high-dose-rate interstitial brachytherapy – a valuable salvage treatment approach for locoregional recurrence of papillary thyroid cancer. J Contemp Brachyther 2016;8: 150–5.