A total of 29 patients and 34 tumors were identified (Table 1). Female constituted 52% of the patients. The common symptoms were hearing impairment (52%), tinnitus (52%), hoarseness (42%), and dysphagia (34%). Out of the 15 cases of hearing impairment, four were Gardner-Robertson scale (GR) 1, five were GR 2, two were GR 3, two were GR 5, and the two were unknown (not described in the medical chart). As for the six cases of facial palsy (21%), two were House-Brackmann grade (HB) I, one was HB II, one was HB III, and the other two were HB IV. Previous operation were performed in 15 cases (52%). Among them, 95% or more resections were performed for seven cases. Four operations were done for functional HNPGs. Two were for mass reduction for subsequent CKT. One for immediate abducens nerve decompression for tumor mass effect. And one for open biopsy due to equivocal case. Two patients (7%) had previous history of radiation treatment. One had radiotherapy by linear accelerator knife (24Gy in four fractions) about 12 years before, and the other one had external beam radiation therapy (unknown dose in 23 fractions) about 4.5 years ago. Four cases (14%) were functional in catecholamine production by HNPGs, and all underwent surgical resection before CKT. Most of the tumors were Fish classification[4] D1 or D2 (14 cases, 48%) at the time of CKT. Two cases were not classified according to Fisch classification, as they were neither glomus jugulare or tympanicum. The most common form of CKT was primary treatment (14 cases, 48%), followed by treatment for relapsed tumors (12 cases, 42%) and adjuvant treatment (3 cases, 10%). The median time between the previous surgery and CKT was 25 months and that for relapsed tumors was about 40 months (Table 1). The parameters of CKT is summarized in the Table 2. All therapy were done in multisession and the median target tumor volume was 10 (5.8–21.3) cc. Two patients had more than one tumors, of which only the one symptomatic tumor were treated and the other asymptomatic ones were observed. The asymptomatic ones in the two patients remained the same in size for 31 and 61 months respectively until one of them was treated with CKT as per the patient’s strong wish.
Table 1
Summary of the baseline patient characteristics
Total
|
29
|
Age (mean) (yr)
|
50 ± 16
|
Female
|
15 (52%)
|
Symptoms
Facial palsy
Occasional facial spasm
Dysgeusia
Hearing impairment
Tinnitus
Dizziness
Hoarseness
Dysphagia
Dysarthria
|
6 (21%)
3 (10%)
2 (7%)
15 (52%)
15 (52%)
4 (14%)
12 (42%)
10 (34%)
2 (7%)
|
Right side of radiation
|
16 (55%)
|
Previous operation
Previous radiation
|
15 (52%)
2 (7%)
|
Hormonally functional
Multiple lesions in the head and neck
|
4 (14%)
2 (7%)
|
Fisch classification
B
C
D
Others
|
1 (3%)
12 (42%)
14 (48%)
2 (7%)
|
Form of CKT
Primary Tx
Adjuvant Tx
Tx for relapsed tumor
|
14 (48%)
3 (10%)
12 (42%)
|
Time from the last surgery to relapse (mos) (median) (IQR)
Time from the surgery to CKT (mos) (median) (IQR)
Adjuvant Tx (mos) (median) (IQR)
Tx for relapsed tumor (mos) (median) (IQR)
|
37.0 (8.0–72.5)
25 (8–56)
4 (3.5–8.0)
40.5 (10.0–83.0)
|
Table 2
Summary of CyberKnife therapy
D95 (median) (IQR) (cGy)
Fraction (median) (IQR)
Target (tumor) volume (median) (IQR) (cm3)
|
2500 (2100–2600)
5 (3–5)
10 (5.8–21.3)
|
The outcome of CKT is summarized in the Table 3. Local control (PR + SD) was achieved in 97%. The median time to confirm radiological PR was 12 (IQR 6–17) months. One PD case (3%) deteriorated due to metastasis to a thoracic vertebral body 17 months following the last CKT, which required an emergent surgery. He had a mass reduction surgery for his carotid body paraganglioma, which was found because of neck mass and lower cranial neuropathies. Four months after the operation, CKT was applied for a prescribed dose covering 95% of the planning target volume (D95) of 3000cGy in 10 fractions for target tumor volume of 171cc. The image at the time of PD was not available as he was treated in the other medical facility. He committed suicide 59 months after the last CKT. The death was not directly due to the tumor. As for the symptom control, 45% of patients had some improvement. The most likely symptom to improve was tinnitus (53%) over the mean time of 28 (± 11) months from the CKT. The other improved symptoms and their duration are summarized in the Table 3. As for the hearing impairment, although five patients (33%) improved, all improvement was within the same GR scale. Although all of them experienced subjective improvement in their hearing deficits, we evaluated objectively in only two patients by pure tone average (one patient improved from 40 to 32.5dB, and another one improved from 23.8 to 12.5dB). On the other hand, no one had any subjective improvement in facial palsy, dysgeusia, or dysarthria. As for the ARE, one case (3%) resulted in asymptomatic radiation necrosis in the cerebellar hemisphere near the radiated region (CTCAE grade 1), and another one (3%) resulted in facial nerve disorder (HB II, CTCAE grade 1). The one who had radiation necrosis had had no history of previous radiation treatment. Although ARE occurred in two cases (7%), only one (3%) of them (facial nerve disorder) was clinically significant. It occurred in a 28-year-old male patient with Fisch class B tumor. The D95 was 2100cGy in 3 fraction for 0.7cc target tumor volume. For the four functional HNPGs, where CKT was performed for relapses, serum level of norepinephrine (SNE) was the main laboratory marker to check as well as MRI. Before CKT, the mean level of SNE was 1000 (± 267) pg/ml (normal range: 100–450 pg/ml). After CKT, the mean SNE was 476 pg/ml and under control (post-CKT SNE were unavailable in two cases, whose follow-up were made in the other facilities). The SNE level started to decrease two to three months after CKT.
Table 3
Outcome after CyberKnife therapy (CKT). Value written in italic were parametric data and represented in the mean value (± standard deviation), whereas nonparametric data were represented in the median value (interquartile range).
Radiological outcome
PR
SD
PD
|
n (%)
17 (59%)
11 (38%)
1 (3%)
|
The time from the last CKT (months)
12 (6–17)
-
17
|
The number of patients whose symptoms improved
Occasional facial spasm
Hearing impairment
Tinnitus
Dizziness
Hoarseness
Dysphagia
Adverse radiation effect
Facial nerve disorder*
Asymptomatic cerebellar necrosis**
Dead***
|
13 (45%)
1 (33%)
5 (33%)
8 (53%)
2 (50%)
4 (33%)
1 (10%)
1 (3%)
1 (3%)
1 (3%)
|
25 (± 15) for PR + SD
27 (± 17) for PR
29
23 (± 11)
27.5 (± 10.7)
37.5 (± 31.8)
30.7 (± 23.0)
5
85*
40
59
|
PFS
OS
|
-
-
|
66.0 (28.0–95.0)
66.0 (28.5–95.0)
|
*House-Brackmann grade II (CTCAE grade 1), which was diagnosed when he presented for a follow-up for the first time in eight years after. It was unclear when he developed the facial palsy. |
**Small radiation necrosis in the right cerebellar hemisphere near the radiated region |
***Due to suicide |
The medians of radiological (PFS) and clinical follow-up period (OS) were both 66 months. PFS and OS curves were drawn in the Fig. 1. PFS at 3, 5, and 7 years were 94.1%, 93.8%, and 91.7% respectively. We illustrate two PR cases as examples (Fig. 2).
Analysis for prognostic factors
Univariate analysis for the symptoms improvement showed that age, and having no history of previous surgery were statistically significant factors for recovery of symptoms (Table 4). Age, sex and the status of having no previous operation (p < = 0.1) were included in the multivariate analysis, the result of which is summarized in the Table 4. The status of no history of surgery remained still significant (p = 0.03). The same kind of analysis was performed exclusively in the nonfunctional group (no hormone production by the tumor). The two factors (female sex, and no history of previous operation) were significant (p = 0.05) for symptom improvement. Univariate analysis for the PD (local control failure) resulted in no variables (age, sex, previous operation, time to CKT, target volume, and firm of CKT) to be statistically significant (not shown).
Table 4
Univariate and multivariate analyses on the improvement of overall symptoms.
|
Overall improvement
|
Overall improvement
(nonfunctional group)
|
|
Univariate (p value)
|
Multivariate
(OR, 95% CI, p value)
|
Univariate (p value)
|
Multivariate
(OR, 95% CI, p value)
|
Age
|
0.05
|
1.06, 1.0–1.1, 0.07
|
0.12
|
|
Sex (female)
|
0.10
|
2.61, 0.4–16.7, 0.31
|
0.03
|
6.7, 0.9–47.3, 0.05
|
Side of CKT
|
0.11
|
|
0.32
|
|
No previous operation
|
0.02
|
8.58, 1.2–59.7, 0.03
|
0.03
|
6.7, 0.9–47.3, 0.05
|
Previous radiation
|
0.88
|
|
0.95
|
|
Functional
|
0.41
|
|
-
|
|
Fisch classification
|
0.32
|
|
0.33
|
|
Form of CKT
|
0.14
|
|
0.20
|
|
Time to CKT
|
0.82
|
|
0.76
|
|
Target tumor volume
|
0.77
|
|
0.98
|
|
Radiological outcome
|
0.81
|
|
0.46
|
|