Japanese Journal of Clinical Oncology Advance Access originally published online on December 1, 2006
Japanese Journal of Clinical Oncology 2007 37(1):38-43; doi:10.1093/jjco/hyl128
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 Foundation for Promotion of Cancer Research
A Retrospective Study of Radiotherapy for Spinal Bone Metastases from Hepatocellular Carcinoma (HCC)
1 Department of Radiology
2 Department of Gastroenterology
3 Department of Hepato-Biliary-Pancreatic Surgery, Tokyo University Hospital, Tokyo, Japan
For reprints and all correspondence: Naoki Nakamura, Department of Radiology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: nnakamur-tky{at}umin.ac.jp
Received July 31, 2006; accepted August 21, 2006
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSConflict of interest statementReferences |
|---|
OBJECTIVE: To evaluate the therapeutic effects of radiotherapy on spinal bone metastases from hepatocellular carcinoma (HCC).
METHODS: A retrospective review was conducted on 24 ambulatory patients with spinal bone metastases from HCC treated by radiotherapy from 1995 to 2004. Ambulatory rate and local progression-free rate after radiotherapy were analyzed. Eight (33%) of 24 patients had radiographic spinal cord compression from the spinal bone metastases before the treatment. Two (8.3%) of the 24 patients had some spinal deficits before the treatment. Biological equivalent dose (BED) with 
/ß ratios of 10 ranged from 39 to 50.7 Gy (median 44.8 Gy).
RESULTS: The median observation period was 5.1 months ranging from 0.9 to 36.0 months. Among the 24 patients, five (21%) underwent salvage therapies, while of the remaining 19 patients four (21%) became nonambulatory by the last follow-up. The ambulatory rates at 3 months and 6 months were 85 and 63%, respectively. The local progression-free rates at 3 months and 6 months were 53 and 47%, respectively.
CONCLUSIONS: Radiotherapy with a BED of 39–50.7 Gy (median 44.8 Gy) is not sufficiently effective for the patients with spinal bone metastases from HCC to prevent paralysis. Dose escalation with a highly precise radiation technique will need to be evaluated.
Key Words: HCC • spinal bone metastases • radiotherapy • gait function
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSConflict of interest statementReferences |
|---|
Hepatocellular carcinoma (HCC) is a common malignancy in Asia. In Japan, it ranks as the fourth highest cause of cancer death. However, because of a better control of the primary tumor with recent advances in treatment and prolonged survivals of the patients, extrahepatic spread from HCC is increasing (1–3). It is estimated that 30–78% of HCC showed metastases at autopsy. The most frequent sites of metastases from HCC are the lungs and lymph nodes, followed by the skeletal system. HCC is accompanied by bone metastases in 6–20% of patients (1,2). Bone metastases from HCC commonly occur as expansive soft tissue masses with bony destruction (3) (Fig. 1). In spinal bone metastases from HCC, extra-osseous soft tissue masses often compress the spinal cord, causing paralysis to patients. Therefore, in such cases the role of radiotherapy is very important to preserve the quality of life of patients.
|
Although radiotherapy with about 30 Gy in 10 fractions is considered effective for ambulatory patients who have spinal bone metastases with spinal cord compression from miscellaneous primary sites (4–14), there are no reports of radiotherapy on such metastases from HCC.
The purpose of this study was to conduct a retrospective evaluation of the therapeutic effects of radiotherapy on spinal bone metastases from HCC. Analyses of ambulatory rate and local progression-free rate after radiotherapy were performed.
|
PATIENTS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSConflict of interest statementReferences |
|---|
From January 1995 to December 2004, 32 patients with spinal bone metastases (between the first cervical spine and second lumbar spine) were treated by radiotherapy without surgery. Twenty-four of the 32 patients received radiotherapy either to prevent or to improve paralysis after they had not been diagnosed as the indication of decompressive surgery by orthopedists. Eight patients received radiotherapy to provide pain relief. Eight of the 32 patients were excluded from the analysis: one patient discontinued the treatment because of his poor condition, six patients had lost ambulatory abilities before the treatment started and one had been irradiated previously for his spinal bone metastasis at another institution. The remaining 24 patients were reviewed with regard to ambulatory function and local progression.
Table 1 shows the patients' characteristics. Their ages ranged from 43 to 75 yr (mean, 62 yr), and the male:female ratio was 23:1. ECOG performance status was grade 0–1 in 16 patients and grade 2 in 8 patients. Two (8.3%) of 24 patients had some neurological symptoms caused by spinal cord compression, but all patients were able to walk at the beginning of treatment.
|
Bone metastases were diagnosed by computerized tomography (CT) and/or magnetic resonance imaging (MRI). In two (8.3%) of 24 patients, the bone metastases were confirmed pathologically. Table 2 shows characteristics of the spinal bone metastases. Ten (42%) of 24 patients received radiotherapy for multiple spinal bone metastases and 14 (58%) patients received radiotherapy for a single metastatic lesion. The maximal diameter of tumors ranged from 1.0 to 5.9 cm (mean 3.4 cm). Eight (33%) of 24 patients had radiological SCC from the spinal bone metastases before the treatment.
|
Radiotherapy
Five (21%) of 24 patients took moderate doses of steroids simultaneously with radiotherapy. Twenty-three (96%) of 24 patients were treated by a 6 or 10 MV X-ray beam. Only one (4.2%) patient was treated by a 12 MeV electron beam to his tumor originating from the spur. All irradiation fields were formed to contain the whole target tumors. Treatment plans for 18 (75%) of 24 patients were made with a 2D simulator, and six (25%) were made with a 3D simulator (Fig. 2). Five (50%) of 10 patients who had multiple metastases were treated with single fields, and the other five (50%) were treated with separate fields. Nineteen (66%) of 29 fields used PA single port (the distances from the skin to the reference point ranged from 4 to 7 cm); nine (31%) used AP-PA or RL-LR opposed ports (three of them did not have the same dose contributions in the two opposed ports); and one (3.4%) used three ports (RL, LR and PA). Table 3 shows the dose fractionations. Total irradiation dose ranged from 30 to 39 Gy (mean 34.3 Gy). Biological equivalent dose (BED) = (total dose) x [1 + daily dose/(
/ß)] using a linear quadratic model with /ß ratios of 10 ranging from 39 to 50.7 Gy (median 44.8 Gy).
|
|
Evaluation
Ambulatory rate was defined as the rate for the status of maintaining ambulatory abilities without any salvage treatments. Local progression-free rate was defined as the rate of the situation in which an irradiated tumor showed no sign of recurrence in CT or MRI examinations.
Statistical Methods
Ambulatory rate, local progression-free rate and overall survival rate were calculated from the start of radiation therapy using the Kaplan–Meier method.
|
RESULTS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSConflict of interest statementReferences |
|---|
All patients were followed up until death or 31 December 2005. The median observation period for survival for all patients was 5.1 months ranging from 0.9 to 36.0 months. Of the 24 patients, one (4.2%) was alive at the last follow-up. The overall 3-month and 6-month survival rates were 75 and 38% (Fig. 3).
|
Ambulatory Rate
Among the 24 patients, salvage therapies were performed for five (30%) after radiotherapy by the last follow-up, because the tumors had grown again toward the spinal cords in spite of the irradiation. Decompressive surgery was performed on two (40%) of five patients and three (60%) were re-irradiated. Of the remaining 19 patients, four (21%) became nonambulatory by the last follow-up because the irradiated tumors had increased, causing SCC. The ambulatory rates at 3 months and 6 months were 85 and 63%, respectively (Fig. 4). Table 4 shows the subgroup outcomes as the pretreatment spinal states with or without SCC. In both groups, 38% of patients took salvage therapy or became nonambulatory by the last follow-up.
|
|
Local Progression-free Rate
Among the 24 patients, recurrence of the irradiated tumors was found in 11 (46%) patients in CT or MRI examinations by the last follow up. The local progression-free rates at 3 months and 6 months were 53 and 47%, respectively (Fig. 5).
|
|
DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSConflict of interest statementReferences |
|---|
Spinal cord compression from bone metastases is one of the most dreaded complications of metastatic cancers. Although it has not yet been established that radiotherapy is superior to surgery for its initial treatment (15,16), many studies have reported the effectiveness of radiotherapy for asymptomatic or ambulatory patients with spinal cord compression by spinal bone metastases from miscellaneous primary sites (4–14). Helweg-Larsen et al. (9) reported that 9% (7/79) of patients who were ambulatory at the beginning of radiotherapy and who were dosed with 28 Gy in seven fractions progressed into a nonambulatory state because of the treatment failure until death or encountered a new episode of cord compression. Maranzano et al. (10) showed that 107 of 109 patients alive at 6 months after radiotherapy were able to walk, although 48% (100/209) of their patients were in a nonwalking state at the start of radiotherapy with the dose of 30 Gy over 2 weeks. They also reported the median duration of improvement on motor capacity according to each primary site. For spinal bone metastases from the liver, the median duration of improvement was 1 month, which was worse than those from other primary sites (Table 5). Sorensen et al. (11) demonstrated that 94% (34/36) of pretreatment ambulatory patients remained ambulatory at 3 months after radiotherapy with a dose of 28 Gy in seven fractions. Although using similar doses, our outcomes, in which 38% (9/24) of patients became nonambulatory or took salvage therapy, are far from satisfactory, considering that all patients were ambulatory at the start of radiotherapy and 67% (16/24) of patients were without spinal cord compression.
|
Our outcomes suggest that the effectiveness of radiotherapy for spinal bone metastases from HCC is inferior to that for spinal bone metastases from other primary sites. The dose around 30 Gy in 10 fractions may not be enough to control spinal bone metastases from HCC. The poor local control rate of irradiated tumors leads to the poor preservation of the ability to walk.
This retrospective study is perhaps the first report focusing on spinal bone metastases from HCC. There are only a few reports concerning the efforts of radiotherapy on general bone metastasis from HCC (17–20). As for HCC metastases to other sites, excellent local control rate by radiotherapy has been reported on lymph node metastasis. Zeng et al. (21) showed a response rate of 96.8% with a dose of 50 Gy in 25 fractions for lymph node metastases from HCC.
On the other hand, a dose–response relationship was recently demonstrated in local control for primary HCC (22–24) (Table 6). BED with /ß ratios of 10 was supposed to be a important prognosis factor in these reports. It was shown that the total irradiated dose with the BED > 50–58 Gy10 had improved the control rates in radiotherapy for primary HCC. This supports the hypothesis that the dose of around 30 Gy in 10 fractions is below the necessary dose to control spinal bone metastases from HCC. The BED used in our study ranged from 39 to 50.7 Gy10 (median 44.8 Gy10). We believe a dose escalation in radiotherapy to spinal bone metastases from HCC will improve the local control rate and lead to improving the preservation of gait function.
|
However, a dose escalation to spinal bone metastases with the conventional technique of irradiation cannot be recommended because the dose to the spinal cord may exceed its tolerance. The ideal approach would be to use a high quality 3D conformal technique (for example stereotactic radiotherapy, intensity modulated radiotherapy, etc.) to spare the spinal cord from the risk of radiation-induced myelitis.
|
CONCLUSIONS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSConflict of interest statementReferences |
|---|
The results of this retrospective analysis suggest that radiotherapy with a BED ranging from 39 to 50.7 Gy (median 44.8 Gy) is not sufficiently effective for the patients with spinal bone metastases from HCC to prevent paralysis. Dose escalation with a highly precise radiation technique needs to be evaluated.
|
Conflict of interest statement |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSConflict of interest statementReferences |
|---|
None declared.
|
References |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSConflict of interest statementReferences |
|---|
1 The Liver Cancer Study Group of Japan. (1984) Primary liver cancer in Japan. Cancer 54 1747–55.[CrossRef][Web of Science][Medline]
2 Nakashima T, Okuda K, Kojiro M, Jimi A, Yamaguchi R, Sakamoto K, et al. (1983) Pathology of hepatocellular carcinoma in Japan. Cancer 51 863–77.[CrossRef][Web of Science][Medline]
3 Liaw CC, Ng KT, Chen TJ, Liaw YF. (1989) Hepatocellular carcinoma presenting as bone metastasis. Cancer 64 1753–7.[CrossRef][Web of Science][Medline]
4 Loblaw DA and Laperriere NJ. (1998) Emergency treatment of treatment of malignant extradural spinal cord compression: an evidence-based guideline. J Clin Oncol 16 1613–24.
5 Greenberg HS, Kim J-H, Posner JB. (1980) Epidural spinal cord compression from metastatic tumor: results with a new treatment protocol. Ann Neurol 8 361–6.[CrossRef][Web of Science][Medline]
6 Young R, Post E, King G. (1980) Treatment of spinal epidural metastases. A randomized prospective comparison of laminectomy and radiotherapy. J Neurosurg 53 741–8.[Web of Science][Medline]
7 Findlay GF. (1984) Adverse effects of the management of malignant spinal cord compression. J Neurol Neurosurg Psych 47 761–8.
8 Leviov M, Dale J, Stein M, Ben-shahar M, Ben-Arush M, Milstein D, et al. (1993) The management of metastatic spinal cord compression: a radiotherapeutic success ceiling. Int J Radiat Oncol Biol Phys 27 231–4.[Web of Science][Medline]
9 Hewled-Larsens D. (1996) Clinical outcome in metastatic spinal cord compression. A prospective study of 153 patients. Acta Neurol Scand 94 269–75.[Web of Science][Medline]
10 Maranzano E and Latini P. (1995) Effectiveness of radiation therapy without surgery in metastatic spinal cord compression: final results from a prospective trial. Int J Radiat Oncol Biol Phys 32 959–67.[CrossRef][Web of Science][Medline]
11 Sorensen S, Helweg-Larsen S, Mouridsen H, Hansen HH. (1994) Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression with radiotherapy: a randomized trial. Eur J Cancer 1 22–7.[Medline]
12 Maranzano E, Latini P, Perrucci E, Beneventi S, Lupattelli M, Corgna E. (1997) Short-course radiotherapy (8 Gy x 2) in metastatic spinal cord compression: an effective and feasible treatment. Int J Radiat Oncol Biol Phys 38 1037–44.[CrossRef][Web of Science][Medline]
13 Maranzano E, Bellavita R, Rossi R, De Angelis V, Frattegiani A, Baqnoli R, et al. (2005) Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III randomized, multicenter trial. J Clin Oncol 23 3358–65.
14 Rades D, Stalpers LJA, Veninga T, Scheulte R, Hoskin PJ, Obralic N, et al. (2005) Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 23 3366–75.
15 Landomann C, Hunig R, Gratzl O. (1992) The role of laminectomy in the combined treatment of metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 24 627–31.[Web of Science][Medline]
16 Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, et al. (2005) Direct compressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomized trial. Lancet 366 643–8.[CrossRef][Web of Science][Medline]
17 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 2167–71.[CrossRef][Web of Science][Medline]
18 Roca EL, Okazaki N, Okada S, Nose H, Aoki K, Akine Y, et al. (1992) Radiotherapy for bone metastases of hepatocellular carcinoma. Jpn J Clin Oncol 22 113–6.
19 Murakami R, Baba Y, Furusawa M, Yokoyama T, Nishimura R, Uozumi H, et al. (1996) The value of embolization therapy in painful osseous metastases from hepatocellular carcinomas: comparative study with radiation therapy. Br J Radiol 69 1042–4.
20 Taki Y, Yamaoka Y, Takayasu T, Ino K, Shimahara Y, Mori K, et al. (1992) Bone metastases of hepatocellular carcinoma after liver resection. J Surg Oncol 50 12–8.[Web of Science][Medline]
21 Zeng ZC, Tang ZY, Fan J, Qin LX, Ye SL, Zhou J, et al. (2005) Consideration of role of radiotherapy for lymph node metastases in patients with HCC: retrospective analysis for prognostic factors from 125 patients. Int J Radiat Oncol Biol Phys 63 1067–76.[CrossRef][Web of Science][Medline]
22 Park HC, Seong J, Han KH, Chou CY, Moon YM, Suh CO, et al. (2002) Dose–response relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 54 150–5.[Web of Science][Medline]
23 Park W, Lim DH, Paik SW, Koh KC, Choi MS, Park CK, et al. (2005) Local radiotherapy for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 61 1143–50.[CrossRef][Web of Science][Medline]
24 Kim DY, Park W, Lim DH, Lee JH, Yoo BC, Paik SW, et al. (2005) Three-dimensional conformal radiotherapy for portal vein thrombosis of hepatocellular carcinoma. Cancer 103 2419–26.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||