J Neurooncol DOI 10.1007/s11060-014-1463-9
CLINICAL STUDY
Clinical result of stereotactic radiosurgery for spinal metastasis from hepatocellular carcinoma: comparison with conventional radiation therapy Ung-Kyu Chang • Mi-Sook Kim • Chul Ju Han Dong Han Lee
•
Received: 29 November 2013 / Accepted: 24 April 2014 Ó Springer Science+Business Media New York 2014
Abstract We investigated the clinical outcome following stereotactic radiosurgery (SRS) for spinal metastasis from hepatocellular carcinoma (HCC) and compared it with that of conventional radiation therapy (cRT). Thirty-nine metastatic spine tumors from 27 HCC patients were treated with SRS from 2002 to 2011. Their medical records and radiological data were retrospectively analyzed. Median tumor volume was 49.7 cc, and a mean marginal dose of 28.7 Gy was delivered to the tumor mass. We analyzed overall survival (OS), local progression-free survival, and the rate of pain control following SRS. Factors relating to clinical outcomes were also investigated. Clinical results following cRT were obtained from 32 patients. The cRT protocol consisted of 30 Gy in 10 fractions or 39 Gy in 13 fractions. OS and local progression-free survival were compared between SRS and cRT. OS was a median of 7 months following SRS. Significant prognostic factors
U.-K. Chang (&) Department of Neurosurgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Nowon-ro 75, Nowon-ku, Seoul 139-706, Republic of Korea e-mail: [email protected] M.-S. Kim Department of Radiation Oncology, Korean Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea C. J. Han Department of Internal Medicine, Korean Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea D. H. Lee Cyberknife Center, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
relating to OS included Child-Pugh class and Karnofsky performance scale. Tumor recurrence was noted in nine lesions during follow-up. The median local progressionfree survival was 7 months. Previous irradiation was a significant prognostic factor for local recurrence (P = 0.043). The overall pain control rate was 85 % and no factors were found to be significantly correlated with the pain control rate. The median OS was 3 months in the cRT group and 7 months in the SRS group (P = 0.035). The median local progression-free survival was 2.0 months in the cRT group, and 7.0 months in the SRS group, which were significantly different (P = 0.033). SRS showed better local control than cRT in the treatment of HCC spinal metastasis. Keywords Hepatocellular carcinoma spine metastasis Stereotactic radiosurgery Conventional radiation therapy Local control Pain control
Introduction Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer-related death worldwide [1]. It frequently involves people in Asian and African countries, and it ranks as the second most lethal malignancy in Korea. Only 30 % of HCCs are diagnosed in the early stage, while the majority of tumors are diagnosed in systemically progressed state. HCC can frequently metastasize to the lung (34–70 %) and the lymph nodes (16–45 %). Bone metastasis has been reported to develop in 3–20 % of HCC patients. 40 % of bone metastasis is estimated to be spinal metastasis. Spinal involvement was considered to be of poor prognosis in bone metastasis [2]. Spinal metastasis has been increasingly diagnosed as the
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mean survival of HCC has increased from 3 to 4 months in 1986 to 2 years in 2000. Chang et al. reported 102 spinal metastasis out of 5887 HCC patients (1.7 %) in 2001, which is higher than 0.67 % reported by Constans et al. in 1983 [3, 4]. Spinal metastasis from HCC is characterized by osteolytic, expansile soft-tissue masses, which has been treated with conventional radiation therapy (cRT). However, the overall pain control rate after cRT reaches about 50 %, with a high retreatment rate [2, 3]. Convention RT was not as effective as that observed for bone metastasis from other cancers. Technical improvement in radiation delivery enables high dose radiation to be applied to spinal metastasis from HCC in a stereotactic approach. Articles describing the clinical results of SRS for HCC spinal metastasis are not available and no comparative study with cRT has been reported. The purpose of this study is to evaluate the survival, local control rate, and pain control rate after stereotactic radiosurgery (SRS) for spinal metastasis from HCC and compare these data with the results of cRT. We also sought to identify prognostic factors relating to survival, local recurrence, and pain control following SRS.
Materials and methods The study cohort consisted of 39 tumors from 29 patients. They were treated from November 2002 to February 2011 at Korea Cancer Center Hospital. Their medical records and radiological data were retrospectively analyzed. All patients complained of pain and spinal metastases were diagnosed with x-ray, bone scan and Magnetic Resonance Imaging (MRI). The presence of visceral metastasis was examined for by Computed Tomography (CT) of the chest and abdomen. Inclusion criteria were; (1) symptomatic spinal metastasis with the involvement of 1 or 2 vertebral bodies, (2) Child Class A or B, (3) ambulatory state with or without sensory deficit, (4) spinal canal encroachment less than 1/3, and (5) no spinal instability. Exclusion criteria were (1) overt spinal instability, (2) non-ambulatory state, (3) Child-Pugh class C, (4) multiple levels involvement of more than 3 vertebral bodies, and (5) 3-column involvement. SRS was performed as an outpatient procedure in most cases. A CT scan of 2.5 mm slices was done 1 day before treatment. The target lesions and regions of interest such as the esophagus, colon, and spinal cord were contoured on axial CT slices to obtain a 3-dimensional reconstruction using the CyberKnife (Accuray Inc., Sunnyvale, CA, USA) treatment planning software. The most optimal treatment plan was established using an inverse planning algorithm. At first, tumor prescription dose was inserted into the
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algorithm as the maximum and minimum dose. Minimum dose means tumor marginal dose and maximum dose was usually determined to be 1.2 or 1.3 times as much as the minimum dose. Maximum tolerable dose was inserted for visceral structures surrounding the vertebral body, such as the spinal cord, esophagus, and colon. As for the spinal cord, maximum point radiation dose and irradiated spinal cord volume were considered as constraints. The spinal cord volume irradiated more than 10 Gy (single equivalent dose) should be less than 0.4 cc. In previously irradiated cases, a constraint of 70 Gy2/2 (conventional 2 Gy dose, a/ b = 2) was used to point maximum spinal cord radiation dose in all procedures. After all the values for the constraints were inserted, the program was executed and the solution was displayed. The prescribed dose of radiation was determined according to the shape of the tumor and the distance between the tumor margin and the spinal cord. Spinal tumors were prescribed to receive radiation between 41 Gy10 and 90 Gy10 in biological effective dose (BED). In cases where the tumor margin abutted the spinal cord dura, fractionation was determined as 4 or 5. When the tumor margin was more than 3 mm away from the dura, single session radiosurgery was planned. In general, tumor volume which was covered by the prescription dose was more than 90 % (mean, 96 %). The planning tumor volume was defined as the gross tumor volume plus a 2–3 mm margin. A representative treatment plan was shown in Fig. 1. Patients were followed clinically and radiographically with CT, MRI, or positron emission tomography-CT at 3–6 months. In follow-up images, tumors were considered to be controlled when the mass size or hypermetabolic activity were no greater than that before SRS. Local progression was defined as an increase in tumor size or hypermetabolic activity. The change in pain level was evaluated by the visual analogue scale (VAS). Post-SRS pain score was evaluated at 1 month following SRS. When a post-SRS VAS was lower than the pre-SRS VAS and the amount of analgesics was not increased, the pain status was defined as controlled. When the follow-up VAS was found to be higher than that observed at 1 month following SRS or analgesics was increased, the pain status was considered pain relapse. For complications, patients were evaluated with the National Cancer Institute Common Toxicity Criteria, version 2.0. Vertebral compression fracture was defined as a newly developed fracture or progression of an existing fracture at the site of treatment. OS, progression free survival and VAS were investigated. The 14 prognostic factors that were expected to be related to OS and local recurrence included; age (B52 years vs. [53 years), sex (male vs. female), lesion location (cervical and thoracic vs. lumbar and sacral), mode of metastasis presentation (synchronous vs.
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Fig. 1 A 47-year-old male patient was diagnosed as T12, L1 metastatic tumor from hepatocellular carcinoma. He suffered from back pain and intercostal neuralgia. a MRI axial image taken at T12 level showed large mass involving right side vertebral body, right side diaphragm and spinal canal. b Radiosurgery plan; the volume of
tumor was 200 cc. Tumor margin dose was prescribed as 36 Gy in 4 fractions. The total covered tumor volume was 96 %. Radiation dose in spinal cord was 29.5 Gy in maximum and 18.5 Gy in minimum with 4 fractions. c At post-radiosurgery 6 months, follow-up CT showed mass shrinkage and spinal cord decompression
metachronous), interval between HCC diagnosis and spine metastasis diagnosis (B12 months vs. [12 months), Karnofsky performance scale (KPS) (\70 vs. C70), the presence of extraspinal bone metastasis, the presence of visceral metastasis, Child-Pugh classification (A or B), preSRS irradiation, pre-SRS operation, lesion volume (B63 cc vs. [63 cc), and delivered radiation dose (B21 Gy vs. [21 Gy). Delivered radiation dose to tumor was calculated as a single equivalent dose with the assumption of a/b = 10. Survival curves were produced using Kaplan–Meier life-table analysis. The log-rank test was used to analyze the factors affecting survival rates. The v2 test and Fisher’s exact test were used to compare factors affecting pain control and pain relapse. P-values of 0.05 (2-tailed) were considered significant. Data were analyzed using SPSS, version 16.0 (Chicago, IL, USA). In the cRT group, 32 patients who were treated during the same period as SRS group were enrolled to investigate the treatment result. During that time, 65 patients of HCC spine metastasis were treated. Among them, follow-up data were available in 32 patients. The cRT protocol for the treatment of spinal metastasis was 30 Gy in 10 fractions or 39 Gy in 13 fractions. OS and local progression-free survival were investigated in the cRT group, which were compared with those of the SRS group.
Spinal metastasis was diagnosed simultaneously with HCC in nine lesions and was detected during follow-up in 30 lesions. The time from HCC diagnosis to spinal metastasis detection was a mean of 25 months (±27.6). When the synchronous metastasis cases were excluded, the time was a mean of 32.7 months (±27.2). The lesion sites included seven lesions at the cervical spine, 12 lesions at the thoracic level, 11 lesions at the lumbar level, and nine lesions at the sacral level. The median tumor volume was 49.7 cc (range 3.3–320 cc). Seventeen lesions had previously been exposed to irradiation. Irradiation dose ranged from 30 Gy to 39 Gy (median 33 Gy) and time interval was 2–24 months (median 6 months). Surgery was performed in four lesions before SRS. In 22 lesions, SRS was chosen as the primary treatment, while in 17 lesions SRS was performed for the treatment of progressed lesions. A mean radiation dose of 28.7 Gy (margin dose) was delivered in 1–5 fractions. In 3 lesions, single fraction SRS was applied. When the marginal dose was calculated to single equivalent dose (a/ß = 10), the median value was 20.0 Gy10 (range 16.0–25.4 Gy10). In the BED, it ranged from 41–90 Gy10 (median, 60 Gy10). Mean coverage was 96.4 % and mean isodose line was 78.4 %. The follow-up period ranged from 2 to 49 months (mean 11.0 months). Median survival after the diagnosis of spinal metastasis was 14.0 months (range 3–55 months) and the median OS following SRS was 7.0 months (range 2–49 months) (Table 2). One-year survival after SRS was 30 %. The factors which proved to be significant for overall survival on univariate analysis were age, ChildPugh class and KPS (Table 3). Multi-variate analysis identified Child class and KPS to be significant.
Results The patient cohort was composed of 25 men and 2 women (Table 1). Mean age was 53 years (range 22–73 years).
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J Neurooncol Table 1 Patients characteristics Characteristics
Value
Age
22–73 (mean, 52.9)
Table 2 Treatment result following SRS for spinal metastasis from HCC Factors
Sex Male
37 Lesions
Female
2 Lesions
Time of diagnosis of spinal metastasis Synchronous
9 Lesions
Metachronous
30 Lesions
Interval to diagnosis of spinal metastasis
0–90 Months (mean, 25 mo)
Interval to diagnosis of spinal metastasis
4–90 Months (mean, 32.7 mo)
(excluding synchronous metastasis)
Mean/median (months) (range)
Overall survival From diagnosis of spinal metastasis
16.5/14.0 (3–55)
From SRS treatment Progression free survival
11.0/7.0 (2–49) 8.5/7.0 (1–46)
Ambulatory function maintenance period after diagnosis of spinal metastasis
12.7/10.0 (2–49)
Pain control duration
9.2/6.0 (0–46)
SRS stereotactic radiosurgery, HCC hepatocellular carcinoma
Table 3 Prognostic factors for overall and progression-free survival
Lesion level Cervical
7 Lesions
Thoracic
12 Lesions
Lumbar
11 Lesions
Sacral
9 Lesions
Pre-SRS treatment Irradiation Surgery Purpose of radiosurgery
17 lesions 4 lesions
Initial treatment method
22 lesions
Method for progressed lesions
17 lesions
Factors analyzed
Variables
P value (overall survival)
P value (progressionfree survival)
Age
\52 versus C52
0.005
0.053
Sex
Male versus female
0.182
0.232
Lesion location
Cervical and thoracic versus lumbar and sacral
0.224
0.646
Mode of presentation of spinal metastasis
Synchronous versus metachronous
0.071
0.186
Tumor volume
3.3–320.7 cc (median 49.7 cc)
Extraspinal bone metastasis
21 lesions
B12 mo. versus [12 mo.
0.605
13 lesions
Interval from primary cancer to spinal metastasis
0.261
Visceral metastasis A
28 Lesions
Pre-SRS operation
Yes versus no
0.121
0.108
B
11 Lesions
Pre-SRS irradiation
Yes versus no
0.358
0.043 0.404
28.7 Gy (mean)/1–5
Initial tx versus salvage tx
0.181
Marginal dose/fractions
Purpose of radiosurgery
Single equivalent dose
16–25.4 Gy10 (median, 20.0 Gy10)
Tumor volume
\63 ml versus C63 ml
0.615
0.475
Biological equivalent dose
41–90 Gy10 (median, 60 Gy10)
Radiation dose
\21 Gy versus C21 Gy
0.257
0.576
Child class
A versus B
0.007
0.068
Extraspinal bone metastasis
Yes versus no
0.351
0.876
Child class
Radiation dose
Fractionation Single
3 Lesions
Multiple (2–5)
36 Lesions
SRS stereotactic radiosurgery
During follow-up, 9 lesions showed local progression on imaging analysis (23.1 %). The median progression-free survival was 7 months. Pre-SRS irradiation was determined to be a significant prognostic factor for local recurrence (Table 3). In the re-irradiation group, the median local control was 9 months, whereas in the un-irradiation group, the median value was 6 months (P = 0.043) (Fig. 2). Pain related to lesions was controlled in 33 out of 39 lesions (84.6 %) at 1 month following SRS. The mean of pre-SRS VAS was 6.1 (range 3–9) and the mean of post-
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Visceral metastasis
Yes versus no
0.135
0.884
Karnofsky performance scale
\70 versus C70
0.025
0.177
Bold values indicate statistical significance SRS stereotactic radiosurgery, tx treatment
SRS VAS was 3.7 (range 1–10). The pain control rate was not influenced by any of the factors analyzed (Table 4), though it tended to increase with radiation dose, with 94 % (16/17) of patients’ pain controlled in the high dose group (C21 Gy) and 73 % (17/22) in the low dose group
J Neurooncol Table 5 Comparison between cRT group and SRS group cRT group
SRS group
P value
Age
56.6 (37–84)
52.9 (22–73)
0.99
Time from HCC diagnosis to spine metastasis
14.1 (0–160)
25.3 (0–90)
0.105
Sex Male
0.035 25
37
7
2
A
7
28
B
20
11
C
5
Female Child class
Karnofsky performance scale
0.001
39.2 (20–60)
57.4 (20–90)
0.005
Bold values indicate statistical significance Fig. 2 Local progression-free survival curves of the re-irradiation and un-irradiation groups. In the re-irradiation group, the median local progression-free survival was 9 months, whereas in the unirradiation group, the median value was 6 months (P = 0.043)
HCC hepatocellular carcinoma, cRT conventional radiotherapy, SRS stereotactic radiosurgery
Table 4 Prognostic factors for pain control and pain relapse Factors analyzed
Variables
P value (pain control)
P value (pain relapse)
Age
\52 versus C52
0.412
0.458
Sex
Male versus female
0.536
0.500
Lesion location
Cervical and thoracic versus lumbar and sacral
0.065
0.667
Mode of spinal metastasis
Synchronous versus metachronous
0.685
0.533
Interval from primary cancer to spinal metastasis
B12 mo. versus [12 mo.
0.768
0.874
Pre-SRS operation
Yes versus no
0.164
0.216
Pre-SRS irradiation Purpose of radiosurgery
Yes versus no Initial tx versus salvage tx
0.582 0.768
0.874 0.874
Tumor volume
\63 ml versus C63 ml
0.498
0.912
Radiation dose
\21 Gy versus C21 Gy A versus B
0.255
0.289
0.091
0.134
Yes versus no
0.506
0.558
Visceral metastasis
Yes versus no
0.498
0.406
Karnofsky performance scale
\70 versus C70
0.066
0.458
Child class Extraspinal metastasis
SRS stereotactic radiosurgery, tx treatment
Fig. 3 Overall survival was different between the conventional radiation therapy and stereotactic radiosurgery groups (P = 0.035)
(\21 Gy). However, this trend was not statistically significant. During follow-up, pain aggravation due to the treated lesions was detected in 7 cases, with a mean period of pain control of 9.2 (±10.1) months. No factors were found to be correlated with pain relapse. On average, ambulatory function was maintained for a period of 12.7 months (range 2–49 months) following the diagnosis of spinal metastasis. As for complications, the percent of
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Fig. 4 Local progression-free survival was different between the conventional radiation therapy and stereotactic radiosurgery groups (P = 0.033)
patients with 1 or more complications was 37 % (10/27). All morbidities were National Cancer Institute Common Toxicity Criteria grade 1–2. The most common complication was compression fracture. Nausea, esophagitis, enteritis, and cystitis were present in two or three patients, respectively. However, vertebral compression fracture occurred in five patients, among whom vertebroplasty was performed in two patients. In the cRT group, age ranged from 37 to 84 years (mean 56.6 years) and consisted of 25 men and 7 women. The range of KPS was 20–60. When demographic data were compared between the cRT and SRS group, there were no significant difference in age and interval from HCC diagnosis to spinal metastasis. However, a statistical difference was noted in the sex ratio, Child-Pugh class and KPS, which implied that the systemic condition was better in the SRS group than in the cRT group (Table 5). In the cRT group, median OS was 3.0 months (95 % confidence interval [CI], 1.7–4.2), which was different from the 7.0 months observed in the SRS group (95 % CI, 5.7–8.2; P = 0.035; Fig. 3). For the evaluation of local-progression, post-cRT follow-up images were available in 25 patients. The median time to progression was 2.0 months in the cRT group (95 % CI, 0.6–3.3), which was significantly different from the 7.0 months observed in the SRS group (95 % CI, 5.4–8.5; P = 0.033; Fig. 4). Discussion The median survival of HCC patients is estimated as 12 months [5, 6]. In patients with bone metastasis, it is
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shorter: 4–7 months [1, 2, 5, 7] with less than a 20 % 1-year survival rate. The median survival time of HCC patients with spinal metastasis was reported to be 3–6 months [3, 5]. In our study, the mean was 11.0 ± 2.3 months with a median of 7 ± 2.3 months and a 1-year survival of 30 %. The improvement of the OS in our data was thought to be attributed to the good general condition of the patients. In a study evaluating the prognosis of HCC patients with metastatic disease, bone metastases did not significantly influence the survival outcome of patients. In fact, 90 % of patients with bone metastases as the only extrahepatic disease died from hepatic causes and none died from extrahepatic disease [8, 9]. However, in one report, the responsiveness of bone metastases to radiation therapy was shown to affect overall survival [3]. Chang et al. reported that the median survival time was 5 months in the cRTresponsive group and 2 months in the cRT-non responsive group in a study of 102 patients with spinal metastasis from HCC (P = 0.0026). Although local radiotherapy provides only palliative treatment in most cases, responsive radiotherapy for spinal lesions can prolong HCC patients’ survival in selected cases. This may be owing to increased self-care ability, improvement of performance status and a decrease in the complications of being bedridden in cRTresponsive patients. The significance of radiation therapy response in bone metastasis has also been demonstrated in a study of breast cancer patients with spinal metastasis [10]. Conventional RT has been reported to be effective in palliating painful bone metastasis from HCC, including spine metastases, with an overall pain improvement of 58–95 % [1, 2, 5, 7, 11]. He et al. [2] reported that partial pain relief was achieved in 70.2 % of patients and complete pain relief was achieved in 29.3 %. In a report by Kaizu et al. [7], pain relief by radiation therapy was achieved in 83 % of patients. Another article reported an overall pain control rate of 58 % following radiation therapy in 84 patients with HCC bone metastasis; of these 84 patients, 32.1 % showed a complete response, 26.2 % a partial response, and 41.7 % a non-response to the radiotherapy [3]. It appeared that there was no consistent dose– response relationship for the palliation of pain caused by bone metastasis [2, 12]. However, the pain control rate was reported to be statistically significant depending on the delivered radiation dose in another article [5]. Some advocate using higher doses and longer courses of radiation therapy to palliate the pain caused by bone metastasis [13]. Seong et al. [5] reported that pain relief was achieved in 73 % of patients with HCC bone metastasis who received palliative radiation therapy; among them, the pain response rate was 70 % in patients who received radiation dose less than 43 Gy in BED and 96 % in those with radiation dose
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higher than 43 Gy in BED. Our data showed a pain control rate of 84.6 % 1 month after SRS, which was much better than the previously published results with cRT. In our study, pain control depended on delivered radiation dose. The pain control rate was 94 % in patients who had radiation dose greater than 21 Gy in a single equivalent dose and 77.3 % in those with radiation doses less than 21 Gy. However, these values were not statistically significant (P = 0.148). Although in an Radiation Therapy Oncology Group randomized study involving different dose fractionation schedules, no significant difference in pain relief was observed between different schedules, complete pain relief and the elimination of narcotic analgesics occurred more frequently with protracted fractionation [14]. When the SRS result for the treatment of HCC spine metastasis was compared to those for the treatment of spine metastasis from other cancers, the pain control rate was slightly lower. Pain improvement rates reported from early studies on SRS for spinal metastasis ranged from 85 to 100 % [15]. Recent articles reported better pain control rate, which were not different depending on primary tumor histology. Even in radioresistant tumors such as renal cell carcinoma (RCC) and melanoma, pain control rates greater than 90 % have been reported [15]. With regards to local control, it was evident that SRS showed improved results compared to cRT (median 2.0 vs. 7.0 months). This result implies that higher dose radiation can achieve better local control in radioresistant spinal tumor such as HCC spine metastasis. In cRT, radiaton dose was 30 Gy in 10 fractions or 39 Gy in 13 fractions. In SRS, delivered radiation dose was a median of 20 Gy in a single equivalent dose, which corresponds to 50 Gy in conventional daily 2-Gy schedule. The BED for cRT dose was 39 Gy10 to 50.7 Gy10 and the SRS dose was a median of 60 Gy10. In the literatures, the BED in cRT for the treatment of spinal metastasis ranged from 15 Gy10 to 40 Gy10 and the resultant pain control rate and local control rate were unsatisfactory. In contrast, in SRS, the BED was 43–82 Gy10 (20–24 Gy in a single fraction to 24–27 Gy in three fractions), which improved the clinical response rate and local control of the tumor [16]. The finding that higher dose radiation leads to better local control was observed in several reports, which was especially true for radioresistant tumors such as RCC and soft tissue sarcomas [17]. In metastatic RCC treatment, a palliative cRT of 30 Gy in 10 fractions (BED 39 Gy10) resulted in a median duration of pain relief of 3 months (range 1–15 months) [18]. However, stereotactic radiotherapy using 8 Gyx4 (BED 60 Gy10), 10 Gyx4 (BED 80 Gy10), and 15 Gyx3 (BED 115 Gy10) showed 90–98 % local control after a median follow-up of 37 months [17]. In a study of 112 patients with soft tissue sarcoma treated with cRT, Kepka et al. [19] found that patients who received less than 63 Gy achieved
a local control rate of 22 %, whereas those who received more than 63 Gy achieved a local control rate of 60 %. Our previous study of SRS for the treatment of spinal sarcomas revealed that the radiological control rate at 2 years was different depending on the radiation dose [20]. The high radiation group (C22 Gy) showed better local control (6/6) than the low radiation group (B22 Gy; 4/7; P = 0.034). On the basis of these findings, we recommend a higher radiation dose in a subset of HCC patients with bone metastasis and good prognostic factors (young age, high KPS, Child class A). For the safe delivery of a high dose of radiation, advanced technology such as SRS is required. The role of RT in HCC treatment has been limited due to the risk of radiation-induced liver damage. However, recent clinical data have shown the feasibility of stereotactic body radiotherapy (SBRT) for the treatment of HCC and demonstrated high rates of local control and overall survival with a low rate of severe treatment-related toxicity [21–23]. It has been reported in several studies that a radiation dose [45–50 Gy is related to increased survival of patients with HCC [22]. A multi-center retrospective study from Korea, including 398 HCC patients of stage III or IV, in which radiotherapy was chosen after the failure of other treatments, showed that median survival time was 12 months, and the 2-year overall survival rate was 27.9 % [6]. In their study, delivered radiation doses ranged from 4.2 to 124.3 Gy10 in BED with 10 Gy of a/b. Tumour size \ 5 cm, a negative lymph node, Child-Pugh class A and a BED [ 53.1 Gy10 were shown by multivariate analysis to be significant factors for improved survival [6]. In another report by Seo et al. [23], inoperable HCCs were irradiated using the SBRT technique. Lesion volumes ranged from 11 to 464 ml (median 40.5 ml). SBRT dosages of 33–57 Gy in 3 or 4 fractions were delivered according to tumor volumes. Two-year overall survival and local progression-free survival rates were 61.4 and 66.4 %, respectively. Mean time to disease progression was 10 months. This study demonstrated that a high radiation dose could be independently related to survival. Based on SBRT data for primary liver cancer, radiation dose for tumor control of spinal metastasis from HCC should be higher than 55 Gy10 in BED. In single equivalent dose, radiation dose higher than 19 Gy should be applied.
Conclusions This study reports that SRS is effective in treating spinal metastasis from HCC, although the pain control rate is slightly lower than that reported for spinal metastasis from other cancers. Compared to results achieved by cRT, SRS showed better local control. In selected patients who have good prognostic factors, SRS could be considered as a
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primary treatment modality for spine metastases from HCC. For better local control, a higher dose of radiation should be applied in SRS planning.
11.
12. Conflict of interest
None to declare.
References 1. Habermehl D, Haase K, Rieken S, Debus J, Combs SE (2011) Defining the role of palliative radiotherapy in bone metastasis from primary liver cancer: an analysis of survival and treatment efficacy. Tumori 97(5):609–613. doi:10.1700/989.10720 2. He J, Zeng ZC, Tang ZY, Fan J, Zhou J, Zeng MS et al (2009) Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma receiving external beam radiotherapy. Cancer 115(12):2710–2720. doi:10.1002/ cncr.24300 3. Chang SS, Luo JC, Chao Y, Chao JY, Chi KH, Wang SS et al (2001) The clinical features and prognostic factors of hepatocellular carcinoma patients with spinal metastasis. Eur J Gastroenterol Hepatol 13(11):1341–1345 4. Constans JP, de Divitiis E, Donzelli R, Spaziante R, Meder JF, Haye C (1983) Spinal metastases with neurological manifestations. Review of 600 cases. J Neurosurg 59(1):111–118. doi:10. 3171/jns.1983.59.1.0111 5. Seong J, Koom WS, Park HC (2005) Radiotherapy for painful bone metastases from hepatocellular carcinoma. Liver Int 25(2):261–265. doi:10.1111/j.1478-3231.2005.01094.x 6. Seong J, Lee IJ, Shim SJ, do Lim H, Kim TH, Kim JH et al (2009) A multicenter retrospective cohort study of practice patterns and clinical outcome on radiotherapy for hepatocellular carcinoma in korea. Liver Int 29(2):147–152. doi:10.1111/j.14783231.2008.01873.x 7. Kaizu T, Karasawa K, Tanaka Y, Matuda T, Kurosaki H, Tanaka S et al (1998) Radiotherapy for osseous metastases from hepatocellular carcinoma: a retrospective study of 57 patients. Am J Gastroenterol 93(11):2167–2171. doi:10.1111/j.1572-0241.1998. 00614.x 8. Montella L, Addeo R, Palmieri G, Caraglia M, Cennamo G, Vincenzi B et al (2010) Zoledronic acid in the treatment of bone metastases by hepatocellular carcinoma: a case series. Cancer Chemother Pharmacol 65(6):1137–1143. doi:10.1007/s00280009-1122-6 9. Okusaka T, Okada S, Ishii H, Nose H, Nagahama H, Nakasuka H et al (1997) Prognosis of hepatocellular carcinoma patients with extrahepatic metastases. Hepatogastroenterology 44(13):251–257 10. Maranzano E, Latini P, Checcaglini F, Perrucci E, Aristei C, Panizza BM et al (1992) Radiation therapy of spinal cord
123
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
compression caused by breast cancer: report of a prospective trial. Int J Radiat Oncol Biol Phys 24(2):301–306 Ratanatharathorn V, Powers WE, Moss WT, Perez CA (1999) Bone metastasis: review and critical analysis of random allocation trials of local field treatment. Int J Radiat Oncol Biol Phys 44(1):1–18 He J, Zeng ZC, Fan J, Zhou J, Sun J, Chen B et al (2011) Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma after liver transplantation. BMC Cancer 11:492. doi:10.1186/1471-2407-11-492 Arcangeli G, Giovinazzo G, Saracino B, D’Angelo L, Giannarelli D, Arcangeli G et al (1998) Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration. Int J Radiat Oncol Biol Phys 42(5):1119–1126 Cole DJ (1989) A randomized trial of a single treatment versus conventional fractionation in the palliative radiotherapy of painful bone metastases. Clin Oncol (R Coll Radiol) 1(2):59–62 Gerszten PC, Mendel E, Yamada Y (2009) Radiotherapy and radiosurgery for metastatic spine disease: what are the options, indications, and outcomes? Spine (Phila Pa 1976) 34(22 Suppl):S78–S92. doi:10.1097/BRS.0b013e3181b8b6f5 Sahgal A, Larson DA, Chang EL (2008) Stereotactic body radiosurgery for spinal metastases: a critical review. Int J Radiat Oncol Biol Phys 71(3):652–665. doi:10.1016/j.ijrobp.2008.02.060 Wersall PJ, Blomgren H, Lax I, Kalkner KM, Linder C, Lundell G et al (2005) Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma. Radiother Oncol 77(1):88–95. doi:10.1016/j.radonc.2005.03.022 Lee J, Hodgson D, Chow E, Bezjak A, Catton P, Tsuji D et al (2005) A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma. Cancer 104(9):1894–1900. doi:10.1002/ cncr.21410 Kepka L, DeLaney TF, Suit HD, Goldberg SI (2005) Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 63(3):852–859. doi:10.1016/j.ijrobp.2005.03.004 Chang UK, Cho WI, Lee DH, Kim MS, Cho CK, Lee SY et al (2012) Stereotactic radiosurgery for primary and metastatic sarcomas involving the spine. J Neurooncol 107(3):551–557. doi:10. 1007/s11060-011-0777-0 Honda Y, Kimura T, Aikata H, Kobayashi T, Fukuhara T, Masaki K et al (2013) Stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma. J Gastroenterol Hepatol 28(3):530–536. doi:10.1111/ jgh.12087 Kang MK, Kim MS, Kim SK, Ye GW, Lee HJ, Kim TN et al (2011) High-dose radiotherapy with intensity-modulated radiation therapy for advanced hepatocellular carcinoma. Tumori 97(6):724–731. doi:10.1700/1018.11088 Seo YS, Kim MS, Yoo SY, Cho CK, Choi CW, Kim JH et al (2010) Preliminary result of stereotactic body radiotherapy as a local salvage treatment for inoperable hepatocellular carcinoma. J Surg Oncol 102(3):209–214. doi:10.1002/jso.21593
CLINICAL STUDY
Clinical result of stereotactic radiosurgery for spinal metastasis from hepatocellular carcinoma: comparison with conventional radiation therapy Ung-Kyu Chang • Mi-Sook Kim • Chul Ju Han Dong Han Lee
•
Received: 29 November 2013 / Accepted: 24 April 2014 Ó Springer Science+Business Media New York 2014
Abstract We investigated the clinical outcome following stereotactic radiosurgery (SRS) for spinal metastasis from hepatocellular carcinoma (HCC) and compared it with that of conventional radiation therapy (cRT). Thirty-nine metastatic spine tumors from 27 HCC patients were treated with SRS from 2002 to 2011. Their medical records and radiological data were retrospectively analyzed. Median tumor volume was 49.7 cc, and a mean marginal dose of 28.7 Gy was delivered to the tumor mass. We analyzed overall survival (OS), local progression-free survival, and the rate of pain control following SRS. Factors relating to clinical outcomes were also investigated. Clinical results following cRT were obtained from 32 patients. The cRT protocol consisted of 30 Gy in 10 fractions or 39 Gy in 13 fractions. OS and local progression-free survival were compared between SRS and cRT. OS was a median of 7 months following SRS. Significant prognostic factors
U.-K. Chang (&) Department of Neurosurgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Nowon-ro 75, Nowon-ku, Seoul 139-706, Republic of Korea e-mail: [email protected] M.-S. Kim Department of Radiation Oncology, Korean Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea C. J. Han Department of Internal Medicine, Korean Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea D. H. Lee Cyberknife Center, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea
relating to OS included Child-Pugh class and Karnofsky performance scale. Tumor recurrence was noted in nine lesions during follow-up. The median local progressionfree survival was 7 months. Previous irradiation was a significant prognostic factor for local recurrence (P = 0.043). The overall pain control rate was 85 % and no factors were found to be significantly correlated with the pain control rate. The median OS was 3 months in the cRT group and 7 months in the SRS group (P = 0.035). The median local progression-free survival was 2.0 months in the cRT group, and 7.0 months in the SRS group, which were significantly different (P = 0.033). SRS showed better local control than cRT in the treatment of HCC spinal metastasis. Keywords Hepatocellular carcinoma spine metastasis Stereotactic radiosurgery Conventional radiation therapy Local control Pain control
Introduction Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer-related death worldwide [1]. It frequently involves people in Asian and African countries, and it ranks as the second most lethal malignancy in Korea. Only 30 % of HCCs are diagnosed in the early stage, while the majority of tumors are diagnosed in systemically progressed state. HCC can frequently metastasize to the lung (34–70 %) and the lymph nodes (16–45 %). Bone metastasis has been reported to develop in 3–20 % of HCC patients. 40 % of bone metastasis is estimated to be spinal metastasis. Spinal involvement was considered to be of poor prognosis in bone metastasis [2]. Spinal metastasis has been increasingly diagnosed as the
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mean survival of HCC has increased from 3 to 4 months in 1986 to 2 years in 2000. Chang et al. reported 102 spinal metastasis out of 5887 HCC patients (1.7 %) in 2001, which is higher than 0.67 % reported by Constans et al. in 1983 [3, 4]. Spinal metastasis from HCC is characterized by osteolytic, expansile soft-tissue masses, which has been treated with conventional radiation therapy (cRT). However, the overall pain control rate after cRT reaches about 50 %, with a high retreatment rate [2, 3]. Convention RT was not as effective as that observed for bone metastasis from other cancers. Technical improvement in radiation delivery enables high dose radiation to be applied to spinal metastasis from HCC in a stereotactic approach. Articles describing the clinical results of SRS for HCC spinal metastasis are not available and no comparative study with cRT has been reported. The purpose of this study is to evaluate the survival, local control rate, and pain control rate after stereotactic radiosurgery (SRS) for spinal metastasis from HCC and compare these data with the results of cRT. We also sought to identify prognostic factors relating to survival, local recurrence, and pain control following SRS.
Materials and methods The study cohort consisted of 39 tumors from 29 patients. They were treated from November 2002 to February 2011 at Korea Cancer Center Hospital. Their medical records and radiological data were retrospectively analyzed. All patients complained of pain and spinal metastases were diagnosed with x-ray, bone scan and Magnetic Resonance Imaging (MRI). The presence of visceral metastasis was examined for by Computed Tomography (CT) of the chest and abdomen. Inclusion criteria were; (1) symptomatic spinal metastasis with the involvement of 1 or 2 vertebral bodies, (2) Child Class A or B, (3) ambulatory state with or without sensory deficit, (4) spinal canal encroachment less than 1/3, and (5) no spinal instability. Exclusion criteria were (1) overt spinal instability, (2) non-ambulatory state, (3) Child-Pugh class C, (4) multiple levels involvement of more than 3 vertebral bodies, and (5) 3-column involvement. SRS was performed as an outpatient procedure in most cases. A CT scan of 2.5 mm slices was done 1 day before treatment. The target lesions and regions of interest such as the esophagus, colon, and spinal cord were contoured on axial CT slices to obtain a 3-dimensional reconstruction using the CyberKnife (Accuray Inc., Sunnyvale, CA, USA) treatment planning software. The most optimal treatment plan was established using an inverse planning algorithm. At first, tumor prescription dose was inserted into the
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algorithm as the maximum and minimum dose. Minimum dose means tumor marginal dose and maximum dose was usually determined to be 1.2 or 1.3 times as much as the minimum dose. Maximum tolerable dose was inserted for visceral structures surrounding the vertebral body, such as the spinal cord, esophagus, and colon. As for the spinal cord, maximum point radiation dose and irradiated spinal cord volume were considered as constraints. The spinal cord volume irradiated more than 10 Gy (single equivalent dose) should be less than 0.4 cc. In previously irradiated cases, a constraint of 70 Gy2/2 (conventional 2 Gy dose, a/ b = 2) was used to point maximum spinal cord radiation dose in all procedures. After all the values for the constraints were inserted, the program was executed and the solution was displayed. The prescribed dose of radiation was determined according to the shape of the tumor and the distance between the tumor margin and the spinal cord. Spinal tumors were prescribed to receive radiation between 41 Gy10 and 90 Gy10 in biological effective dose (BED). In cases where the tumor margin abutted the spinal cord dura, fractionation was determined as 4 or 5. When the tumor margin was more than 3 mm away from the dura, single session radiosurgery was planned. In general, tumor volume which was covered by the prescription dose was more than 90 % (mean, 96 %). The planning tumor volume was defined as the gross tumor volume plus a 2–3 mm margin. A representative treatment plan was shown in Fig. 1. Patients were followed clinically and radiographically with CT, MRI, or positron emission tomography-CT at 3–6 months. In follow-up images, tumors were considered to be controlled when the mass size or hypermetabolic activity were no greater than that before SRS. Local progression was defined as an increase in tumor size or hypermetabolic activity. The change in pain level was evaluated by the visual analogue scale (VAS). Post-SRS pain score was evaluated at 1 month following SRS. When a post-SRS VAS was lower than the pre-SRS VAS and the amount of analgesics was not increased, the pain status was defined as controlled. When the follow-up VAS was found to be higher than that observed at 1 month following SRS or analgesics was increased, the pain status was considered pain relapse. For complications, patients were evaluated with the National Cancer Institute Common Toxicity Criteria, version 2.0. Vertebral compression fracture was defined as a newly developed fracture or progression of an existing fracture at the site of treatment. OS, progression free survival and VAS were investigated. The 14 prognostic factors that were expected to be related to OS and local recurrence included; age (B52 years vs. [53 years), sex (male vs. female), lesion location (cervical and thoracic vs. lumbar and sacral), mode of metastasis presentation (synchronous vs.
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Fig. 1 A 47-year-old male patient was diagnosed as T12, L1 metastatic tumor from hepatocellular carcinoma. He suffered from back pain and intercostal neuralgia. a MRI axial image taken at T12 level showed large mass involving right side vertebral body, right side diaphragm and spinal canal. b Radiosurgery plan; the volume of
tumor was 200 cc. Tumor margin dose was prescribed as 36 Gy in 4 fractions. The total covered tumor volume was 96 %. Radiation dose in spinal cord was 29.5 Gy in maximum and 18.5 Gy in minimum with 4 fractions. c At post-radiosurgery 6 months, follow-up CT showed mass shrinkage and spinal cord decompression
metachronous), interval between HCC diagnosis and spine metastasis diagnosis (B12 months vs. [12 months), Karnofsky performance scale (KPS) (\70 vs. C70), the presence of extraspinal bone metastasis, the presence of visceral metastasis, Child-Pugh classification (A or B), preSRS irradiation, pre-SRS operation, lesion volume (B63 cc vs. [63 cc), and delivered radiation dose (B21 Gy vs. [21 Gy). Delivered radiation dose to tumor was calculated as a single equivalent dose with the assumption of a/b = 10. Survival curves were produced using Kaplan–Meier life-table analysis. The log-rank test was used to analyze the factors affecting survival rates. The v2 test and Fisher’s exact test were used to compare factors affecting pain control and pain relapse. P-values of 0.05 (2-tailed) were considered significant. Data were analyzed using SPSS, version 16.0 (Chicago, IL, USA). In the cRT group, 32 patients who were treated during the same period as SRS group were enrolled to investigate the treatment result. During that time, 65 patients of HCC spine metastasis were treated. Among them, follow-up data were available in 32 patients. The cRT protocol for the treatment of spinal metastasis was 30 Gy in 10 fractions or 39 Gy in 13 fractions. OS and local progression-free survival were investigated in the cRT group, which were compared with those of the SRS group.
Spinal metastasis was diagnosed simultaneously with HCC in nine lesions and was detected during follow-up in 30 lesions. The time from HCC diagnosis to spinal metastasis detection was a mean of 25 months (±27.6). When the synchronous metastasis cases were excluded, the time was a mean of 32.7 months (±27.2). The lesion sites included seven lesions at the cervical spine, 12 lesions at the thoracic level, 11 lesions at the lumbar level, and nine lesions at the sacral level. The median tumor volume was 49.7 cc (range 3.3–320 cc). Seventeen lesions had previously been exposed to irradiation. Irradiation dose ranged from 30 Gy to 39 Gy (median 33 Gy) and time interval was 2–24 months (median 6 months). Surgery was performed in four lesions before SRS. In 22 lesions, SRS was chosen as the primary treatment, while in 17 lesions SRS was performed for the treatment of progressed lesions. A mean radiation dose of 28.7 Gy (margin dose) was delivered in 1–5 fractions. In 3 lesions, single fraction SRS was applied. When the marginal dose was calculated to single equivalent dose (a/ß = 10), the median value was 20.0 Gy10 (range 16.0–25.4 Gy10). In the BED, it ranged from 41–90 Gy10 (median, 60 Gy10). Mean coverage was 96.4 % and mean isodose line was 78.4 %. The follow-up period ranged from 2 to 49 months (mean 11.0 months). Median survival after the diagnosis of spinal metastasis was 14.0 months (range 3–55 months) and the median OS following SRS was 7.0 months (range 2–49 months) (Table 2). One-year survival after SRS was 30 %. The factors which proved to be significant for overall survival on univariate analysis were age, ChildPugh class and KPS (Table 3). Multi-variate analysis identified Child class and KPS to be significant.
Results The patient cohort was composed of 25 men and 2 women (Table 1). Mean age was 53 years (range 22–73 years).
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J Neurooncol Table 1 Patients characteristics Characteristics
Value
Age
22–73 (mean, 52.9)
Table 2 Treatment result following SRS for spinal metastasis from HCC Factors
Sex Male
37 Lesions
Female
2 Lesions
Time of diagnosis of spinal metastasis Synchronous
9 Lesions
Metachronous
30 Lesions
Interval to diagnosis of spinal metastasis
0–90 Months (mean, 25 mo)
Interval to diagnosis of spinal metastasis
4–90 Months (mean, 32.7 mo)
(excluding synchronous metastasis)
Mean/median (months) (range)
Overall survival From diagnosis of spinal metastasis
16.5/14.0 (3–55)
From SRS treatment Progression free survival
11.0/7.0 (2–49) 8.5/7.0 (1–46)
Ambulatory function maintenance period after diagnosis of spinal metastasis
12.7/10.0 (2–49)
Pain control duration
9.2/6.0 (0–46)
SRS stereotactic radiosurgery, HCC hepatocellular carcinoma
Table 3 Prognostic factors for overall and progression-free survival
Lesion level Cervical
7 Lesions
Thoracic
12 Lesions
Lumbar
11 Lesions
Sacral
9 Lesions
Pre-SRS treatment Irradiation Surgery Purpose of radiosurgery
17 lesions 4 lesions
Initial treatment method
22 lesions
Method for progressed lesions
17 lesions
Factors analyzed
Variables
P value (overall survival)
P value (progressionfree survival)
Age
\52 versus C52
0.005
0.053
Sex
Male versus female
0.182
0.232
Lesion location
Cervical and thoracic versus lumbar and sacral
0.224
0.646
Mode of presentation of spinal metastasis
Synchronous versus metachronous
0.071
0.186
Tumor volume
3.3–320.7 cc (median 49.7 cc)
Extraspinal bone metastasis
21 lesions
B12 mo. versus [12 mo.
0.605
13 lesions
Interval from primary cancer to spinal metastasis
0.261
Visceral metastasis A
28 Lesions
Pre-SRS operation
Yes versus no
0.121
0.108
B
11 Lesions
Pre-SRS irradiation
Yes versus no
0.358
0.043 0.404
28.7 Gy (mean)/1–5
Initial tx versus salvage tx
0.181
Marginal dose/fractions
Purpose of radiosurgery
Single equivalent dose
16–25.4 Gy10 (median, 20.0 Gy10)
Tumor volume
\63 ml versus C63 ml
0.615
0.475
Biological equivalent dose
41–90 Gy10 (median, 60 Gy10)
Radiation dose
\21 Gy versus C21 Gy
0.257
0.576
Child class
A versus B
0.007
0.068
Extraspinal bone metastasis
Yes versus no
0.351
0.876
Child class
Radiation dose
Fractionation Single
3 Lesions
Multiple (2–5)
36 Lesions
SRS stereotactic radiosurgery
During follow-up, 9 lesions showed local progression on imaging analysis (23.1 %). The median progression-free survival was 7 months. Pre-SRS irradiation was determined to be a significant prognostic factor for local recurrence (Table 3). In the re-irradiation group, the median local control was 9 months, whereas in the un-irradiation group, the median value was 6 months (P = 0.043) (Fig. 2). Pain related to lesions was controlled in 33 out of 39 lesions (84.6 %) at 1 month following SRS. The mean of pre-SRS VAS was 6.1 (range 3–9) and the mean of post-
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Visceral metastasis
Yes versus no
0.135
0.884
Karnofsky performance scale
\70 versus C70
0.025
0.177
Bold values indicate statistical significance SRS stereotactic radiosurgery, tx treatment
SRS VAS was 3.7 (range 1–10). The pain control rate was not influenced by any of the factors analyzed (Table 4), though it tended to increase with radiation dose, with 94 % (16/17) of patients’ pain controlled in the high dose group (C21 Gy) and 73 % (17/22) in the low dose group
J Neurooncol Table 5 Comparison between cRT group and SRS group cRT group
SRS group
P value
Age
56.6 (37–84)
52.9 (22–73)
0.99
Time from HCC diagnosis to spine metastasis
14.1 (0–160)
25.3 (0–90)
0.105
Sex Male
0.035 25
37
7
2
A
7
28
B
20
11
C
5
Female Child class
Karnofsky performance scale
0.001
39.2 (20–60)
57.4 (20–90)
0.005
Bold values indicate statistical significance Fig. 2 Local progression-free survival curves of the re-irradiation and un-irradiation groups. In the re-irradiation group, the median local progression-free survival was 9 months, whereas in the unirradiation group, the median value was 6 months (P = 0.043)
HCC hepatocellular carcinoma, cRT conventional radiotherapy, SRS stereotactic radiosurgery
Table 4 Prognostic factors for pain control and pain relapse Factors analyzed
Variables
P value (pain control)
P value (pain relapse)
Age
\52 versus C52
0.412
0.458
Sex
Male versus female
0.536
0.500
Lesion location
Cervical and thoracic versus lumbar and sacral
0.065
0.667
Mode of spinal metastasis
Synchronous versus metachronous
0.685
0.533
Interval from primary cancer to spinal metastasis
B12 mo. versus [12 mo.
0.768
0.874
Pre-SRS operation
Yes versus no
0.164
0.216
Pre-SRS irradiation Purpose of radiosurgery
Yes versus no Initial tx versus salvage tx
0.582 0.768
0.874 0.874
Tumor volume
\63 ml versus C63 ml
0.498
0.912
Radiation dose
\21 Gy versus C21 Gy A versus B
0.255
0.289
0.091
0.134
Yes versus no
0.506
0.558
Visceral metastasis
Yes versus no
0.498
0.406
Karnofsky performance scale
\70 versus C70
0.066
0.458
Child class Extraspinal metastasis
SRS stereotactic radiosurgery, tx treatment
Fig. 3 Overall survival was different between the conventional radiation therapy and stereotactic radiosurgery groups (P = 0.035)
(\21 Gy). However, this trend was not statistically significant. During follow-up, pain aggravation due to the treated lesions was detected in 7 cases, with a mean period of pain control of 9.2 (±10.1) months. No factors were found to be correlated with pain relapse. On average, ambulatory function was maintained for a period of 12.7 months (range 2–49 months) following the diagnosis of spinal metastasis. As for complications, the percent of
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Fig. 4 Local progression-free survival was different between the conventional radiation therapy and stereotactic radiosurgery groups (P = 0.033)
patients with 1 or more complications was 37 % (10/27). All morbidities were National Cancer Institute Common Toxicity Criteria grade 1–2. The most common complication was compression fracture. Nausea, esophagitis, enteritis, and cystitis were present in two or three patients, respectively. However, vertebral compression fracture occurred in five patients, among whom vertebroplasty was performed in two patients. In the cRT group, age ranged from 37 to 84 years (mean 56.6 years) and consisted of 25 men and 7 women. The range of KPS was 20–60. When demographic data were compared between the cRT and SRS group, there were no significant difference in age and interval from HCC diagnosis to spinal metastasis. However, a statistical difference was noted in the sex ratio, Child-Pugh class and KPS, which implied that the systemic condition was better in the SRS group than in the cRT group (Table 5). In the cRT group, median OS was 3.0 months (95 % confidence interval [CI], 1.7–4.2), which was different from the 7.0 months observed in the SRS group (95 % CI, 5.7–8.2; P = 0.035; Fig. 3). For the evaluation of local-progression, post-cRT follow-up images were available in 25 patients. The median time to progression was 2.0 months in the cRT group (95 % CI, 0.6–3.3), which was significantly different from the 7.0 months observed in the SRS group (95 % CI, 5.4–8.5; P = 0.033; Fig. 4). Discussion The median survival of HCC patients is estimated as 12 months [5, 6]. In patients with bone metastasis, it is
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shorter: 4–7 months [1, 2, 5, 7] with less than a 20 % 1-year survival rate. The median survival time of HCC patients with spinal metastasis was reported to be 3–6 months [3, 5]. In our study, the mean was 11.0 ± 2.3 months with a median of 7 ± 2.3 months and a 1-year survival of 30 %. The improvement of the OS in our data was thought to be attributed to the good general condition of the patients. In a study evaluating the prognosis of HCC patients with metastatic disease, bone metastases did not significantly influence the survival outcome of patients. In fact, 90 % of patients with bone metastases as the only extrahepatic disease died from hepatic causes and none died from extrahepatic disease [8, 9]. However, in one report, the responsiveness of bone metastases to radiation therapy was shown to affect overall survival [3]. Chang et al. reported that the median survival time was 5 months in the cRTresponsive group and 2 months in the cRT-non responsive group in a study of 102 patients with spinal metastasis from HCC (P = 0.0026). Although local radiotherapy provides only palliative treatment in most cases, responsive radiotherapy for spinal lesions can prolong HCC patients’ survival in selected cases. This may be owing to increased self-care ability, improvement of performance status and a decrease in the complications of being bedridden in cRTresponsive patients. The significance of radiation therapy response in bone metastasis has also been demonstrated in a study of breast cancer patients with spinal metastasis [10]. Conventional RT has been reported to be effective in palliating painful bone metastasis from HCC, including spine metastases, with an overall pain improvement of 58–95 % [1, 2, 5, 7, 11]. He et al. [2] reported that partial pain relief was achieved in 70.2 % of patients and complete pain relief was achieved in 29.3 %. In a report by Kaizu et al. [7], pain relief by radiation therapy was achieved in 83 % of patients. Another article reported an overall pain control rate of 58 % following radiation therapy in 84 patients with HCC bone metastasis; of these 84 patients, 32.1 % showed a complete response, 26.2 % a partial response, and 41.7 % a non-response to the radiotherapy [3]. It appeared that there was no consistent dose– response relationship for the palliation of pain caused by bone metastasis [2, 12]. However, the pain control rate was reported to be statistically significant depending on the delivered radiation dose in another article [5]. Some advocate using higher doses and longer courses of radiation therapy to palliate the pain caused by bone metastasis [13]. Seong et al. [5] reported that pain relief was achieved in 73 % of patients with HCC bone metastasis who received palliative radiation therapy; among them, the pain response rate was 70 % in patients who received radiation dose less than 43 Gy in BED and 96 % in those with radiation dose
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higher than 43 Gy in BED. Our data showed a pain control rate of 84.6 % 1 month after SRS, which was much better than the previously published results with cRT. In our study, pain control depended on delivered radiation dose. The pain control rate was 94 % in patients who had radiation dose greater than 21 Gy in a single equivalent dose and 77.3 % in those with radiation doses less than 21 Gy. However, these values were not statistically significant (P = 0.148). Although in an Radiation Therapy Oncology Group randomized study involving different dose fractionation schedules, no significant difference in pain relief was observed between different schedules, complete pain relief and the elimination of narcotic analgesics occurred more frequently with protracted fractionation [14]. When the SRS result for the treatment of HCC spine metastasis was compared to those for the treatment of spine metastasis from other cancers, the pain control rate was slightly lower. Pain improvement rates reported from early studies on SRS for spinal metastasis ranged from 85 to 100 % [15]. Recent articles reported better pain control rate, which were not different depending on primary tumor histology. Even in radioresistant tumors such as renal cell carcinoma (RCC) and melanoma, pain control rates greater than 90 % have been reported [15]. With regards to local control, it was evident that SRS showed improved results compared to cRT (median 2.0 vs. 7.0 months). This result implies that higher dose radiation can achieve better local control in radioresistant spinal tumor such as HCC spine metastasis. In cRT, radiaton dose was 30 Gy in 10 fractions or 39 Gy in 13 fractions. In SRS, delivered radiation dose was a median of 20 Gy in a single equivalent dose, which corresponds to 50 Gy in conventional daily 2-Gy schedule. The BED for cRT dose was 39 Gy10 to 50.7 Gy10 and the SRS dose was a median of 60 Gy10. In the literatures, the BED in cRT for the treatment of spinal metastasis ranged from 15 Gy10 to 40 Gy10 and the resultant pain control rate and local control rate were unsatisfactory. In contrast, in SRS, the BED was 43–82 Gy10 (20–24 Gy in a single fraction to 24–27 Gy in three fractions), which improved the clinical response rate and local control of the tumor [16]. The finding that higher dose radiation leads to better local control was observed in several reports, which was especially true for radioresistant tumors such as RCC and soft tissue sarcomas [17]. In metastatic RCC treatment, a palliative cRT of 30 Gy in 10 fractions (BED 39 Gy10) resulted in a median duration of pain relief of 3 months (range 1–15 months) [18]. However, stereotactic radiotherapy using 8 Gyx4 (BED 60 Gy10), 10 Gyx4 (BED 80 Gy10), and 15 Gyx3 (BED 115 Gy10) showed 90–98 % local control after a median follow-up of 37 months [17]. In a study of 112 patients with soft tissue sarcoma treated with cRT, Kepka et al. [19] found that patients who received less than 63 Gy achieved
a local control rate of 22 %, whereas those who received more than 63 Gy achieved a local control rate of 60 %. Our previous study of SRS for the treatment of spinal sarcomas revealed that the radiological control rate at 2 years was different depending on the radiation dose [20]. The high radiation group (C22 Gy) showed better local control (6/6) than the low radiation group (B22 Gy; 4/7; P = 0.034). On the basis of these findings, we recommend a higher radiation dose in a subset of HCC patients with bone metastasis and good prognostic factors (young age, high KPS, Child class A). For the safe delivery of a high dose of radiation, advanced technology such as SRS is required. The role of RT in HCC treatment has been limited due to the risk of radiation-induced liver damage. However, recent clinical data have shown the feasibility of stereotactic body radiotherapy (SBRT) for the treatment of HCC and demonstrated high rates of local control and overall survival with a low rate of severe treatment-related toxicity [21–23]. It has been reported in several studies that a radiation dose [45–50 Gy is related to increased survival of patients with HCC [22]. A multi-center retrospective study from Korea, including 398 HCC patients of stage III or IV, in which radiotherapy was chosen after the failure of other treatments, showed that median survival time was 12 months, and the 2-year overall survival rate was 27.9 % [6]. In their study, delivered radiation doses ranged from 4.2 to 124.3 Gy10 in BED with 10 Gy of a/b. Tumour size \ 5 cm, a negative lymph node, Child-Pugh class A and a BED [ 53.1 Gy10 were shown by multivariate analysis to be significant factors for improved survival [6]. In another report by Seo et al. [23], inoperable HCCs were irradiated using the SBRT technique. Lesion volumes ranged from 11 to 464 ml (median 40.5 ml). SBRT dosages of 33–57 Gy in 3 or 4 fractions were delivered according to tumor volumes. Two-year overall survival and local progression-free survival rates were 61.4 and 66.4 %, respectively. Mean time to disease progression was 10 months. This study demonstrated that a high radiation dose could be independently related to survival. Based on SBRT data for primary liver cancer, radiation dose for tumor control of spinal metastasis from HCC should be higher than 55 Gy10 in BED. In single equivalent dose, radiation dose higher than 19 Gy should be applied.
Conclusions This study reports that SRS is effective in treating spinal metastasis from HCC, although the pain control rate is slightly lower than that reported for spinal metastasis from other cancers. Compared to results achieved by cRT, SRS showed better local control. In selected patients who have good prognostic factors, SRS could be considered as a
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primary treatment modality for spine metastases from HCC. For better local control, a higher dose of radiation should be applied in SRS planning.
11.
12. Conflict of interest
None to declare.
References 1. Habermehl D, Haase K, Rieken S, Debus J, Combs SE (2011) Defining the role of palliative radiotherapy in bone metastasis from primary liver cancer: an analysis of survival and treatment efficacy. Tumori 97(5):609–613. doi:10.1700/989.10720 2. He J, Zeng ZC, Tang ZY, Fan J, Zhou J, Zeng MS et al (2009) Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma receiving external beam radiotherapy. Cancer 115(12):2710–2720. doi:10.1002/ cncr.24300 3. Chang SS, Luo JC, Chao Y, Chao JY, Chi KH, Wang SS et al (2001) The clinical features and prognostic factors of hepatocellular carcinoma patients with spinal metastasis. Eur J Gastroenterol Hepatol 13(11):1341–1345 4. Constans JP, de Divitiis E, Donzelli R, Spaziante R, Meder JF, Haye C (1983) Spinal metastases with neurological manifestations. Review of 600 cases. J Neurosurg 59(1):111–118. doi:10. 3171/jns.1983.59.1.0111 5. Seong J, Koom WS, Park HC (2005) Radiotherapy for painful bone metastases from hepatocellular carcinoma. Liver Int 25(2):261–265. doi:10.1111/j.1478-3231.2005.01094.x 6. Seong J, Lee IJ, Shim SJ, do Lim H, Kim TH, Kim JH et al (2009) A multicenter retrospective cohort study of practice patterns and clinical outcome on radiotherapy for hepatocellular carcinoma in korea. Liver Int 29(2):147–152. doi:10.1111/j.14783231.2008.01873.x 7. Kaizu T, Karasawa K, Tanaka Y, Matuda T, Kurosaki H, Tanaka S et al (1998) Radiotherapy for osseous metastases from hepatocellular carcinoma: a retrospective study of 57 patients. Am J Gastroenterol 93(11):2167–2171. doi:10.1111/j.1572-0241.1998. 00614.x 8. Montella L, Addeo R, Palmieri G, Caraglia M, Cennamo G, Vincenzi B et al (2010) Zoledronic acid in the treatment of bone metastases by hepatocellular carcinoma: a case series. Cancer Chemother Pharmacol 65(6):1137–1143. doi:10.1007/s00280009-1122-6 9. Okusaka T, Okada S, Ishii H, Nose H, Nagahama H, Nakasuka H et al (1997) Prognosis of hepatocellular carcinoma patients with extrahepatic metastases. Hepatogastroenterology 44(13):251–257 10. Maranzano E, Latini P, Checcaglini F, Perrucci E, Aristei C, Panizza BM et al (1992) Radiation therapy of spinal cord
123
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
compression caused by breast cancer: report of a prospective trial. Int J Radiat Oncol Biol Phys 24(2):301–306 Ratanatharathorn V, Powers WE, Moss WT, Perez CA (1999) Bone metastasis: review and critical analysis of random allocation trials of local field treatment. Int J Radiat Oncol Biol Phys 44(1):1–18 He J, Zeng ZC, Fan J, Zhou J, Sun J, Chen B et al (2011) Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma after liver transplantation. BMC Cancer 11:492. doi:10.1186/1471-2407-11-492 Arcangeli G, Giovinazzo G, Saracino B, D’Angelo L, Giannarelli D, Arcangeli G et al (1998) Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration. Int J Radiat Oncol Biol Phys 42(5):1119–1126 Cole DJ (1989) A randomized trial of a single treatment versus conventional fractionation in the palliative radiotherapy of painful bone metastases. Clin Oncol (R Coll Radiol) 1(2):59–62 Gerszten PC, Mendel E, Yamada Y (2009) Radiotherapy and radiosurgery for metastatic spine disease: what are the options, indications, and outcomes? Spine (Phila Pa 1976) 34(22 Suppl):S78–S92. doi:10.1097/BRS.0b013e3181b8b6f5 Sahgal A, Larson DA, Chang EL (2008) Stereotactic body radiosurgery for spinal metastases: a critical review. Int J Radiat Oncol Biol Phys 71(3):652–665. doi:10.1016/j.ijrobp.2008.02.060 Wersall PJ, Blomgren H, Lax I, Kalkner KM, Linder C, Lundell G et al (2005) Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma. Radiother Oncol 77(1):88–95. doi:10.1016/j.radonc.2005.03.022 Lee J, Hodgson D, Chow E, Bezjak A, Catton P, Tsuji D et al (2005) A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma. Cancer 104(9):1894–1900. doi:10.1002/ cncr.21410 Kepka L, DeLaney TF, Suit HD, Goldberg SI (2005) Results of radiation therapy for unresected soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 63(3):852–859. doi:10.1016/j.ijrobp.2005.03.004 Chang UK, Cho WI, Lee DH, Kim MS, Cho CK, Lee SY et al (2012) Stereotactic radiosurgery for primary and metastatic sarcomas involving the spine. J Neurooncol 107(3):551–557. doi:10. 1007/s11060-011-0777-0 Honda Y, Kimura T, Aikata H, Kobayashi T, Fukuhara T, Masaki K et al (2013) Stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma. J Gastroenterol Hepatol 28(3):530–536. doi:10.1111/ jgh.12087 Kang MK, Kim MS, Kim SK, Ye GW, Lee HJ, Kim TN et al (2011) High-dose radiotherapy with intensity-modulated radiation therapy for advanced hepatocellular carcinoma. Tumori 97(6):724–731. doi:10.1700/1018.11088 Seo YS, Kim MS, Yoo SY, Cho CK, Choi CW, Kim JH et al (2010) Preliminary result of stereotactic body radiotherapy as a local salvage treatment for inoperable hepatocellular carcinoma. J Surg Oncol 102(3):209–214. doi:10.1002/jso.21593
