SHORT COMMUNICATION

Usefulness of CyberKnife Therapy in Patients withDifferentiated Thyroid Cancer with Distant Metastases
Shigeaki Higashiyama1, Atsushi Yoshida2, Yutaka Katayama3, Takashi Yamanaga4, Joji Kawabe5

A b s t r ac t
Aim and objective: We reported seven cases in which external beam radiotherapy (EBRT) with CyberKnife therapy was effective against distantmetastases from differentiated thyroid carcinoma (DTC).
Materials and methods: The subjects included seven patients (6 males, 1 female; age 53–77 years, average age 65.85 years) who underwent
CyberKnife therapy for metastatic lesions of DTC (pathological diagnosis: differentiated papillary carcinoma). The target lesions included 12
lymph node, 6 bone, and 2 brain metastases. All patients had previously undergone total thyroidectomy, followed by radioactive iodine therapy(RAIT). Since RAIT was not expected to have a therapeutic effect, CyberKnife treatment was selected. CyberKnife irradiation was performed
1–5 times. The radiation doses covering 95% of the planning target volume (D95) ranged from 15 to 26 gray (Gy). To determine the therapeutic
effect, lesion size was evaluated by computed tomography (CT) and magnetic resonance imaging (MRI) before and 6–12 months after treatment.
Results: No increase in size was observed in the brain and bone metastases. Among the lymph node metastatic lesions, a therapeutic effectinvolving internal necrosis without an increase in size was noted in two lymph node metastases in the cervix. Additionally, two lymph nodemetastases in the neck had reduced in size. No increases in size were observed in the other lymph node lesions, reflecting the therapeutic
effect of CyberKnife.
Conclusions: CyberKnife may be useful in treating distant metastatic lesions of papillary thyroid cancer.
Clinical significance: CyberKnife is useful as a multidisciplinary treatment for cases in which radioactive iodine therapy is maladjusted.
Keywords: CyberKnife, Differentiated thyroid carcinoma, Distant metastases, External beam radiotherapy, Papillary adenocarcinoma, Radioactive
iodine therapy.
Otorhinolaryngology Clinics: An International Journal (2020): 10.5005/jp-journals-10003-1352

Introduction
Radioactive iodine therapy (RAIT) is administered for lung andbone metastases from differentiated thyroid carcinomas (DTCs).1,2
DTCs may become malignant in cases involving undifferentiatedcell carcinomas or metastasize to the brain during follow-up.1,2
In these cases, multidisciplinary treatment, including palliative
surgery, external beam radiotherapy (EBRT), 3,4 and moleculartargeted drug treatment, is required.5,6 Among EBRT techniques,
CyberKnife provides accurate irradiation in a small number oftreatment sessions,7,8 and radiation damage to the surrounding
tissues is also limited.9,10
We report 20 distant metastases in seven cases of DTC, against
which CyberKnife treatment showed therapeutic effects.

1,2,5

Department of Nuclear Medicine, Osaka City University, Graduate
School of Medicine, Osaka-City, Osaka-Fu, Japan
3,4
Department of Radiology, Osaka City University Hospital, Osaka-City,
Osaka-Fu, Japan
Corresponding Author: Shigeaki Higashiyama, Department of Nuclear
Medicine, Osaka City University, Graduate School of Medicine, OsakaCity, Osaka-Fu, Japan, Phone: +816-6645-3885, e-mail: higashiya@med.
osaka-cu.ac.jp
How to cite this article: Higashiyama S, Yoshida A, Katayama Y,
et al. Usefulness of CyberKnife Therapy in Patients with DifferentiatedThyroid Cancer with Distant Metastases. Int J Otorhinolaryngol Clin
2020;12(2):38–41.
Source of support: Nil
Conflict of interest: None

M at e r ia l s a n d M e t h o d sPatients
The subjects included seven patients (6 males, 1 female; age 53–77
years, average age 65.85 years) who underwent CyberKnife therapy
for metastatic lesions of thyroid cancer between October 2012 andMarch 2019. All patients had undergone total thyroidectomy forthyroid cancer and were pathologically diagnosed with papillarycancer (Table 1). The target lesions included 12 lymph node lesions,
6 bone metastases, and 2 brain metastases. For metastatic lesions
other than brain metastases, RAIT was performed before CyberKnife
treatment. Scintigraphy performed after RAIT showed no significant
RI accumulation at the treated site. The brain metastases weredetected during the follow-up after RAIT for cervical lymph nodemetastases.

All procedures in this study were performed in accordancewith the ethical standards of our institutional research committee
and in accordance with the principles of the 1964 Declaration of
Helsinki and its later amendments or comparable ethical standards.
At our facility, we obtained written informed consent from all
patients undergoing RAIT to use clinical data from their visits foreducational and research purposes.

Follow-up and Evaluation
The sizes of the bone metastases and lymph node lesions on
computed tomography (CT) were compared before and 6–12
months after CyberKnife treatment. The sizes of the brain
metastases, as measured using contrast-enhanced T1-weighted fat© Jaypee Brothers Medical Publishers. 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License(https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons
Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Usefulness of CyberKnife Therapy in Patients with Differentiated Thyroid Cancer
Table 1: Characteristics of the seven patients
Patient
1
2
3
4
5
6
7

Sex
M
M
F
M
M
M
M

Age
71
53
64
62
65
77
69

Table 2: Details of the target lesions and CyberKnife treatment
Pathological subtype
Papillary carcinoma
Papillary carcinoma
Papillary carcinoma
Papillary carcinoma
Papillary carcinoma
Papillary carcinoma
Papillary carcinoma

suppression magnetic resonance imaging (MRI), were compared
before and 6 months after treatment.

Radioiodine and CyberKnife Treatments
All patients received I-131 as RAIT before CyberKnife treatment. The
cumulative dose of I-131 ranged from 80 mCi (2.96 GBq) to 780 mCi(28.86 GBq), with an average dose of 267 mCi (9.88 GBq). Scintigraphy
after RAIT showed no RI accumulation of I-131 in the treated area,
indicating a therapeutic effect. Therefore, we determined that
RAIT could not provide a further therapeutic effect.8 The lymph
node lesions on the cervical surface had developed after multiple
surgical treatments. Conventional EBRT, which uses high doses andirradiates a large area, has a risk of radiation skin damage. Therefore,
we opted for CyberKnife treatment.7,8 CyberKnife was selected toprovide immediate treatment to prevent pathological fractures ofthe vertebral bones due to bone metastases. RAIT requires iodine
restriction before treatment. 8 Moreover, RAIT is performed at
our facility if brain metastases are found, as brain metastases areassociated with a risk of bleeding under iodine-limited conditions.
CyberKnife treatment was performed based on the potential for an
increase in brain metastases.
CyberKnife treatment was performed at Osaka Medical
College Mishima-Minami Hospital CyberKnife Center. Irradiation
planning, including planning regarding the fraction and dosage,
was performed by experienced radiologists based on lesion sizeand location. The gross tumor volume (GTV) was defined basedon the tumors visible on CT or MRI. The GTV was considered to be
the same as the clinical target volume (CTV). The planning target
volume (PTV) included the CTV with a 1.2- to 2.0-mm margin.

Patient Sites
1
Pretracheal LN
Lt submandibular LN
Lt supraclavicular LN
2
Rt side of Cl
Lt side of Cl
Rt side of C3
3
Rt cerebellar hemisphere
Lt corona radiata
Lt nasopharyngeal LN
Rt neck LN
Lt neck LN
Lt lower neck LN
4
Rt submandibular LN
5
Lt petroclival—Cl
Lt side of C4/5
Lt upper neck LN
Lt lower neck LN
6
Lt side of tracheal LN
Rt nasopharyngeal LN
7
C7

Details of
CyberKnife

Lesion size (mm)

Fr
3
1
5
3
4
3
3
3
3
1
1
2
3
4
3
1
1
5
3
5

Pre
18 × 11
9×8
10 × 1115 × 1125 × 1217 × 11
7×6
2×2
19 × 10
9×6
7×6
9×9
8×8
58 × 31
38 × 28
15 × 913 × 7
14 × 1125 × 1719 × 20

D95(Gy)
21.8
22
23
18
16
20
26
25
24
22
18
23
21
15
15
21
21
17
22
21

Post
18 × 118×8
10 × 11
12 × 925 × 1115 × 12
7×6
2×2
15 × 5
9×6
7 × 6*
8 × 6*
7×6
55 × 30
34 × 24
6×3
7×4
12 × 1122 × 1119 × 20

D95, radiation dose covering 95% of planning target volume; Fr, number ofdivided irradiations for CyberKnife treatment; Rt, Right; Lt, Left; LN, lymph
node; С, cervical vertebral body; *Necrotic change

R e s u lts
Table 2 shows the details of the treated lesions and the CyberKnife
treatments. CyberKnife irradiation was performed 1–5 times(average: 3.14). The radiation dose covering 95% of the PTV (D95),
considered the actual dose to the lesion, ranged from 15 to 26 Gy(average: 18.86 Gy). No lesions, including six bone metastasis
lesions, showed an increase in size during follow-up. Figure 1
shows the CyberKnife dose distribution for the brain metastasis in
the right cerebellar hemisphere in Patient 3. The metastatic lesionin the right cerebellar hemisphere before treatment appeared asa 7 × 6-mm2 mass lesion showing a contrast effect on contrastenhanced T1-weighted fat suppression MRI (arrow in the upper
image of Fig. 2). MRI performed 6 months after treatment showedno clear tendency to an increase in size, surrounding edematouschanges, or bleeding (arrowhead in the lower image of Fig. 2). In
two lymph node metastases in the left cervical region (arrow inthe left image of Fig. 3) in Patient 3, a therapeutic effect involving
internal necrosis (arrowhead in the right image of Fig. 3) was seen.

Fig. 1: CyberKnife dose distribution in the cerebellar hemisphere ofPatient 3. The planning target volume is indicated by the thin orange line

Otorhinolaryngology Clinics: An International Journal, Volume 12 Issue 2 (May–August 2020)39

Usefulness of CyberKnife Therapy in Patients with Differentiated Thyroid Cancer

Fig. 2: Metastatic brain lesion in the left cerebellar hemisphere before
treatment in Patient 3. The white arrow in the contrast-enhanced, T1weighted, fat suppression magnetic resonance on the upper image
indicates metastatic lesions. Contrast-enhanced, T1-weighted, fat
suppression magnetic resonance image taken 6 months after treatment.
The metastatic lesions (white arrowhead) show no increase in size

In Patient 5, two lymph nodes in the left cervical region showed
size reduction (Table 2).

Discussion
We reported on the cases of seven patients who underwent
CyberKnife treatment for distant metastatic lesions of papillary
thyroid cancer. We observed no bone metastases and no increasein brain metastases within the follow-up period. Two lymph nodemetastases were reduced in size, and a therapeutic effect involving
internal necrosis was seen in two other lymph node metastases.
Distant metastatic lesions of DTC are less sensitive to EBRT.1
In particular, RAIT and EBRT are reported to have low therapeutic
effects on bone metastases.4 In contrast, high doses of EBRT for
distant metastatic lesions are reportedly useful in controlling
locoregional thyroid cancer.11,12
Among the modalities used for high-dose radiation therapy,
CyberKnife treatment is reportedly useful for spinal metastases andrecurrent lesions of DTC.13,14 With CyberKnife treatment, the reduced
irradiation frequency, compared to that for normal EBRT, decreases
the burden of going to the hospital. 8 In addition, CyberKnife
treatment minimizes the irradiation of surrounding tissues byenabling stereotactic, accurate, and high-dose irradiation of thetarget lesion.9,10 This is useful in avoiding side effects such as skindamage due to long-term irradiation with conventional EBRT.9,10 Our
patients showed no symptoms of radiation damage, such as acuteskin damage, after CyberKnife treatment. It was possible to treat
multiple lesions such as brain and cervical lymph node metastasesin the same patient, suggesting that CyberKnife treatment may be
useful for local control.
40

Fig. 3: Cervical-enhanced computed tomography scans of Patient 3.
On the left image, white arrows indicate two lymph node metastatic
lesions in the left neck before CyberKnife treatment. Contrast-enhanced
computed tomography scans after treatment showing a therapeutic
effect involving internal necrosis in the cervical lymph node metastases(white arrowheads on the right image)

Treatment of DTC with molecular-targeted drugs is premised
on total thyroidectomy and RAIT.15,16 In addition, starting theadministration of molecular-targeted drugs is recommended
when the tumor becomes refractory to RAIT or when the thyroid
cancer is undifferentiated and the disease progresses rapidly.17
Our institution selects the best treatment method for patientsas a part of multimodal treatment comprising surgical treatment,
RAIT, and EBRT for thyroid cancer, in anticipation of the initiationof treatment with molecular-targeted drugs as the final treatment
method.
Although many studies have demonstrated the usefulnessof molecular-targeted drugs for the treatment of DTC lesions,various side effects can cause the deterioration of patients’Otorhinolaryngology Clinics: An International Journal, Volume 12 Issue 2 (May–August 2020)

Usefulness of CyberKnife Therapy in Patients with Differentiated Thyroid Cancer
quality of life.18 Additionally, once targeted therapy is started, it isdifficult to discontinue medication or change to another treatment
method.19 Therefore, for the control of locally recurrent lesions
and the treatment of multiple metastatic lesions, we believe that
it is important to use treatments other than molecular-targeteddrugs as much as possible and to delay the introduction ofmolecular-targeted drugs. The results of this study demonstrated
the usefulness of CyberKnife treatment for local control of multiple
metastatic lesions including brain metastases.
In patients with thyroid cancer, lymph node metastatic
lesions in the deep cervical region and mediastinum may invade
the blood vessels and bronchi if they increase in size. The safest
treatment is surgical removal; however, additional surgicaltreatment is often difficult due to reasons such as total thyroid
cancer removal. 20 A risk of bleeding has been reported withthe use of molecular-targeted drugs for the treatment of lymph
node lesions adjacent to major blood vessels. 21 The accurate
irradiation provided by CyberKnife treatment may be useful insuch instances.

C o n c lu s i o n sCyberKnife may be useful in treating distant metastatic lesions ofpapillary thyroid cancer.

Clinical Significance
CyberKnife is useful as a multidisciplinary treatment for cases inwhich radioactive iodine therapy is maladjusted.

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