bs_bs_banner
Hepatology Research 2015; 45: 1071–1075
doi: 10.1111/hepr.12457
Original Article
Brain metastasis from hepatocellular carcinoma: The impact of radiotherapy on control of intracranial hemorrhage Yushi Yamakawa,1 Michihisa Moriguchi,1 Takeshi Aramaki,1 Koichi Mitsuya,2 Koiku Asakura,1 Akihiro Sawada,1 Masahiro Endo1 and Yoko Nakasu2 Divisions of 1Diagnostic Radiology and 2Neurosurgery, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan Aim: Brain metastasis from hepatocellular carcinoma (HCC) is rare and causes devastating outcomes with intracranial hemorrhage. We retrospectively analyzed the impact of radiotherapy in preventing hemorrhagic events among patients with brain metastasis from HCC.
intracranial hemorrhage at presentation of brain metastasis. No patients in group R experienced intracranial hemorrhage during follow up, although two patients in group N did. Median overall survival was 22.4 weeks (range, 5.42–69.1) in group R and 2.24 weeks (range, 1.0–15.4) in group N.
Methods: Patients who underwent treatment for brain metastasis from HCC at our cancer center between January 2003 and December 2012 were identified from a prospectively compiled hospital database. Clinical characteristics were analyzed in patients with and without radiotherapy.
Conclusion: For patients with brain metastasis from HCC, radiotherapy appears useful for controlling brain lesions, preventing intracranial hemorrhage and improving survival. Radiotherapy may contribute to control of intracranial tumor and prevention of intracranial hemorrhage for selected patients with brain metastasis from HCC.
Results: Fifteen HCC patients with brain metastasis from HCC were classified into two groups: 11 patients underwent radiotherapy (group R) and four patients received best supportive care without radiotherapy (group N). Six patients (54.5%) in group R and four patients (100%) in group N showed
INTRODUCTION
H
EPATOCELLULAR CARCINOMA (HCC) represents one of the most common causes of cancerrelated death in the world, especially in Asia.1–3 The incidence of HCC seems to be increasing along with the prevalences of hepatitis B and C infections, alcoholism and obesity-related fatty liver disease.4 Recent therapeutic advances in surgical techniques, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), chemotherapeutic agents and molecular-targeted agents have contributed to improved survival for HCC patients, in turn increasing the incidence of extrahepatic metastasis.5,6
Correspondence: Mr Yushi Yamakawa, Division of Diagnostic Radiology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan. Email: [email protected] Received 16 November 2013; revision 26 November 2014; accepted 27 November 2014.
© 2014 The Japan Society of Hepatology
Key words: brain metastasis, hemorrhage, hepatocellular carcinoma, radiotherapy
The most frequent site of extrahepatic metastasis is the lung, followed by the lymph nodes, bones and adrenal glands.7 In contrast, brain metastasis is reported in only 0.6–1.2% of HCC patients.6,8 Brain metastasis from HCC is very rare, because there is little affinity of HCC cells for the brain.9 The prognosis in patients with brain metastasis is extremely poor, with a median survival of 1–3 months.5,10,11 Intracranial hemorrhage is the first manifestation in one-third of patients with brain metastasis from HCC, because HCC is hypervascular and hemorrhagic,5 and this causes devastating outcomes on occurrence and during treatment. The rarity of brain metastasis from HCC means that treatment guidelines have yet to be defined. Several reports have presented the usefulness of surgical removal.6,12,13 We hypothesized that control of intracranial hemorrhage would be a key factor for the survival of patients with brain metastasis from HCC. We therefore undertook this retrospective study to evaluate the efficacy of radiotherapy for preventing intracranial hemorrhage in our patients with brain metastasis from HCC.
1071
1072 Y. Yamakawa et al.
METHODS
P
ATIENTS WITH BRAIN metastasis from HCC who underwent any treatment at our cancer center between January 2004 and December 2012 were identified from a prospectively compiled hospital database. We collected data about patient sex, age, condition of liver lesions, extracranial metastasis, ongoing systemic therapy, size and number of brain metastasis, presence of hemorrhage in brain metastasis, recursive partitioning analysis (RPA) at presentation, treatment modality for brain metastasis, and outcome. RPA was the first prognostic score developed for brain metastasis management. This classification was made after analysis of the relative contributions of pretreatment variables to survival of the patients with brain metastasis by the Radiation Therapy Oncology Group in 1997: (i) class 1 patients are younger than 65 years old, with a Karnofsky Performance Status (KPS) of 70% or more, controlled primary tumor, without extracranial metastasis; (ii) class 2 patients are all not in class 1 or 3; and (iii) class 3 patients have KPS of less than 70%.14 Brain metastasis was confirmed with computed tomography (CT) and/or magnetic resonance imaging (MRI). Decisions regarding treatment for brain metastasis were recommended based on general condition, extent of systemic disease, location of brain lesions and neurological condition by our institute cancer board, as follows. Patients underwent best supportive care (BSC) without radiotherapy when they presented with poor systemic condition or irreversible, rapid and severe neurological deterioration. Patients underwent radiotherapy with or without surgery when they expected to survive more than 3 months if brain lesions could be controlled. Overall survival was defined as the interval between date of diagnosis of brain metastasis and date of death. Overall survival rate was calculated actuarially according to the Kaplan–Meier method and was measured from the date of diagnosis of brain metastasis until the date of last follow up or death. Survival curves were compared using the log–rank test. Statistical analyses were performed using SPSS version 12.0 software (SPSS, Chicago, IL, USA). This retrospective study was approved by the Institutional Review Board for Clinical Investigations at Shizuoka Cancer Center.
RESULTS
B
ETWEEN JANUARY 2003 and December 2011, a total of 1702 patients with HCC were enrolled in the Shizuoka Cancer Center registry. Of these, 15
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 1071–1075
patients (0.9%) were diagnosed with brain metastasis from HCC. Median age at diagnosis of HCC was 64 years (range, 42–78). Hepatitis B virus infection was detected in five patients and hepatitis C infection was identified in eight patients. The majority of patients had undergone surgical resection and RFA and/or TACE to treat the primary HCC. Median age at diagnosis of brain metastasis was 67 years (range, 43–80). The median interval between diagnosis of HCC and diagnosis of metastasis was 71.3 weeks (range, 0–264.2). Most patients had lung metastasis (73.3%). The most frequent symptom was headache, followed by nausea, motor disturbance and disturbance of consciousness. Patient characteristics are summarized in Table 1. Eleven patients underwent radiotherapy (group R) and four patients accepted BSC (group N). In group R, whole-brain radiotherapy (WBRT) had been performed in six patients, gamma knife surgery in three patients and stereotactic radiotherapy (SRT) in four patients. At the time of diagnosis of brain metastasis from HCC, TACE had been performed in seven patients, molecularly targeted therapy in five patients, chemotherapy in one patient and BSC in two patients. Ten of 15 patients (66.7%) showed intracranial hemorrhage at presentation of brain metastasis, including six patients (54.5%) in group R and four patients (100%) in group N. Two patients in group N experienced intracranial hemorrhage during the follow-up period. One of two patients who complained of visual disturbance had brain metastasis in the occipital lobe on T1-weighted gadolinium-enhanced MRI. The next day, that patient suddenly lost consciousness, and CT revealed a large intracerebral hemorrhage (Fig. 1). He died a week later due to neurological deterioration. None of the 11 patients in group R suffered intracranial hemorrhage after treatment for brain metastasis. Seven patients died as a result of progressive hepatic or respiratory failure, without apparent intracranial hemorrhage, and two patients died because of neurological deterioration without hemorrhage. The remaining two patients were still alive at the end of the study period. At the end of follow up, nine patients were dead and two patients were alive in group R, whereas all patients group N were dead. Only one patient underwent TACE for HCC following radiotherapy for brain metastasis. Median overall survival was 3.6 months (95% confidence interval [CI], 0.27–5.53), and survival rates were 73.3%, 26.7% and 20.0% at 1, 6 and 12 months, respectively (Fig. 2). Patients in group R showed significantly
Radiotherapy for brain metastasis from HCC 1073
Hepatology Research 2015; 45: 1071–1075
Table 1 Clinical characteristics and outcomes in 15 patients with brain metastasis from HCC Characteristic Sex Male Female Age, years (median) Etiology HBV HCV NBNC RPA class 1 2 3 PS 0 1 2 3 AFP, ng/mL (median) Platelets, ×104/μL (median) Child–Pugh A B Lung metastasis Yes No Size of BM, mm (median) No. of BM (median) HCC-to-BM interval, weeks (median) Surgical resection for BM Yes No ICH at presentation Yes No ICH after treatment for BM Yes No Survival, months (median) Cause of death Hepatic Neurological
Group R (n = 11)
Group N (n = 4)
6 5 68 (43–80)
4 0 66.5 (60–72)
4 5 2
1 3 0
2 8 1
0 0 4
1 6 1 3 292 (2.2–152 778) 14.5 (4.0–29.6) 9 2 8 3 30 (5–40) 3 (1–17) 107.1 (0–264.2)
0 1 3 0 1199 (196–499 970) 12.1 (9.5–21.2) 2 2 3 1 50 (15–55) 1 (1–7) 49.2 (24.0–146.0)
1 10
0 4
6 5
4 0
0 11 5 (2–16) 7 2
2 2 0.6 (0.2–4) 0 4
AFP, α-fetoprotein; BM, brain metastasis; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICH, intracranial hemorrhage; NBNC, non-B, non-C; PS, performance status; RPA, recursive partitioning analysis.
longer median survival (5.4 months; 95% CI, 2.03– 16.1) than patients in group N (0.55 months; 95% CI, 0.23–3.60; P = 0.012) (Fig. 3).
DISCUSSION
H
EPATOCELLULAR CARCINOMA PATIENTS with brain metastasis generally show poor prognosis,
with a median survival of 1–3 months.4 Tumor hemorrhage is one of the noticeable causes of mortality with brain metastasis from HCC. Brain metastasis from HCC is frequently associated with hemorrhage, because HCC itself is hypervascular and most patients also have coagulopathy due to liver cirrhosis. Chang et al. reported that 18 of 45 patients with brain metastasis from HCC-associated intracranial hemorrhage as their
© 2014 The Japan Society of Hepatology
1074 Y. Yamakawa et al.
a
Hepatology Research 2015; 45: 1071–1075
1.0
b
Survival probability
0.8 p=0.012
0.6 0.4 0.2
Figure 1 (a) T1-weighted gadolinium-enhanced magnetic resonance imaging in a patient with visual disturbance caused by a mass lesion in the occipital lobe. (b) Computed tomography showing a large intracranial hemorrhage in the same patient with sudden disturbance of consciousness the next day.
first manifestation.5 Most patients who received BSC died within several days to 1 month. Ten of their 45 patients died of intracranial hemorrhage and/or increased intracranial pressure with or without brain herniation. In addition, Han et al.4 reported that almost half of patients with intracranial hemorrhage from HCC experienced recurrent bleeding from tumors after treatment, so recurrent bleeding from tumor after treatment was a most problematic event during the management of patients with brain metastasis from HCC. In our study, six of 10 patients who had intracranial hemorrhage were treated with radiotherapy, and none suffered from intracranial hemorrhage until death or the end of the study.
1.0
Survival probability
0.8 0.6 0.4 0.2 0.0 0
8
16 24 32 40 Survival time (weeks)
48
56
Figure 2 Kaplan–Meier estimates of overall survival in the whole series (n = 15). The median survival time was 14.4 weeks (95% confidence interval, 1.1–22.1), and the actuarial survival rates were 73.3%, 26.7% and 20.0% at 4, 24 and 48 months.
© 2014 The Japan Society of Hepatology
0.0 0
8
16 24 32 40 Survival time (weeks)
48
56
Figure 3 Kaplan–Meier estimates to test for differences in overall survival between group R and group N using a log–rank test. Group R showed a significantly longer median survival time than group N (22.4 weeks; 95% confidence interval [CI], 8.1–64.4) versus 2.2 weeks (95% CI, 0.92–14.4) (P = 0.012). , group R; , group N.
Surgery and/or radiotherapy have positive effects on survival.8 Surgical resection is recommended for patients with a large single brain metastasis in an anatomically accessible location, and for those who require emergency decompression of life-threatening masses.15 Radiotherapy seems promising for patients with brain metastasis from HCC. The addition of WBRT to surgical resection of brain metastasis has been shown to decrease the risks of local relapse and death from neurological causes.12 Other studies have reported that SRT combined with WBRT may prolong the survival of patients with controlled extracranial lesions or multiple intracranial lesions.13 Intracranial hemorrhage will become an important issue in the near future, because the incidence of brain metastasis from HCC is increasing as more patients survive longer thanks to advances in both medical and surgical treatments for primary lesions and systemic control in HCC patients. A review of Japanese HCC autopsy cases showed a 2.2% incidence of brain metastasis in 1996.16 Kim et al. reported clinically detected brain metastasis in 0.6% of 3100 HCC patients in 1998,6 while Choi et al.8 also reported identifying brain metastasis in 0.9% of 6919 patients diagnosed between 1995 and 2006. In a recent series of HCC metastasis, Shao et al.17 reported brain metastasis in 7% of 158 advanced HCC patients in 2011. In our study, the incidence of brain metastasis from HCC was 0.9%. At our institute, four of 915 HCC patients developed brain metastasis in 4 years from 2003, and 11 of 787 in 3 years
Hepatology Research 2015; 45: 1071–1075
from 2008. That means 0.1% patients per year in the former years, and 0.43% per year in the recent years. Including the results from our study, these figures probably underestimate the true frequency. Patients in most studies did not undergo brain imaging as part of routine evaluation. The real incidence of brain metastasis from HCC should be estimated in community-based screening imaging studies. Guidelines on the diagnosis and treatment of patients with brain metastasis from HCC have yet to be established. No routine brain screening is recommended for HCC patients. According to the published work, the median time from diagnosis to brain metastasis is 10.5– 18.2 months,5,8,18 comparable with the 16.6 months in our series. We may have to include screening of the brain using whole-body screening CT. An appropriate timing for screening may be 10–18 months after initial diagnosis of HCC. Although few studies have reported systemic therapy following radiotherapy for brain metastasis,19 radiotherapy for brain metastasis and continuing systemic treatment of HCC may further prolong survival in HCC patients. Several limitations must be considered when interpreting the present results. Clinical features were reviewed retrospectively from the medical records in a single institution, and selection bias may be present, as patients with better condition received radiotherapy. Even so, our results indicate that radiotherapy may contribute to control of intracranial tumor and prevention of intracranial hemorrhage for selected patients with brain metastasis from HCC. Randomized control trials are not feasible given the rarity of the disease. A multiinstitutional prospective study is therefore needed to explore risk and prognostic factors for brain metastasis from HCC.
REFERENCES 1 El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med [Research Support, U.S. Gov’t, Non-P.H.S.] 2003; 139: 817–23. 2 Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D. Global cancer statistics. Ca 2011; 61: 69–90. 3 Jiang X-B, Ke C, Zhang G-H et al. Brain metastases from hepatocellular carcinoma: clinical features and prognostic factors. BMC Cancer 2012; 12: 49. 4 Han JH, Kim DG, Park JC, Chung HT, Paek SH, Chung YS. Little response of cerebral metastasis from hepatocellular carcinoma to any treatments. J Korean Neurosurg Soc 2010; 47: 325–31.
Radiotherapy for brain metastasis from HCC 1075
5 Chang L, Chen YL, Kao MC. Intracranial metastasis of hepatocellular carcinoma: review of 45 cases. Surg Neurol [Case Reports Review] 2004; 62: 172–7. 6 Kim M, Na DL, Park SH, Jeon BS, Roh JK. Nervous system involvement by metastatic hepatocellular carcinoma. J Neurooncol 1998; 36 (1): 85–90. 7 Uka K, Aikata H, Takaki S et al. Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol 2007; 13: 414–20. 8 Choi HJ, Cho BC, Sohn JH et al. Brain metastases from hepatocellular carcinoma: prognostic factors and outcome: brain metastasis from HCC. J Neurooncol [Clinical Trial] 2009; 91: 307–13. 9 Kawaguchi T, Endo M, Yokoya S, Nakamura K. Difference in proliferation-kinetics between tumor cells arrested in the brain and liver. Experientia 1982; 38: 1236–7. 10 Asahara T, Yano M, Fukuda S et al. Brain metastasis from hepatocellular carcinoma after radical hepatectomy. Hiroshima J Med Sci [Case Reports] 1999; 48: 91–4. 11 Tanabe H, Kondo A, Kinuta Y et al. Unusual presentation of brain metastasis from hepatocellular carcinoma – two case reports. Neurol Med Chir (Tokyo) [Case Reports Review] 1994; 34: 748–53. 12 Patchell RA, Tibbs PA, Regine WF et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA [Clinical Trial Multicenter Study Randomized Controlled Trial] 1998; 280: 1485–9. 13 Khuntia D, Brown P, Li J, Mehta MP. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol [Review] 2006; 24: 1295–304. 14 Gaspar L, Scott C, Rotman M et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745–51. 15 Lang FF. Surgical management and techniques. In: Sawaya R, ed. Intracranial Metastases. Malden, Massachusetts, Blackwell, 2004; 106–25. 16 Murakami K, Nawano S, Moriyama N et al. Intracranial metastases of hepatocellular carcinoma: CT and MRI. Neuroradiology 1996; 38 (Suppl 1): S31–35. 17 Shao YY, Lu LC, Cheng AL, Hsu CH. Increasing incidence of brain metastasis in patients with advanced hepatocellular carcinoma in the era of antiangiogenic targeted therapy. Oncologist [Research Support, Non-U.S. Gov’t] 2011; 16 (1): 82–6. 18 Hsieh M-J, Lu C-H, Tsai N-W et al. Prediction, clinical characteristics and prognosis of intracerebral hemorrhage in hepatocellular carcinoma patients with intracerebral metastasis. J Clin Neurosci 2009; 16: 394–8. 19 Kagawa K, Kawakami Y, Honda Y et al. [A case of advanced hepatocellular carcinoma with lung, brain and lymph node metastases recurred 8 years after hepatectomy successfully treated by operation, radiation and systemic chemotherapy using S-1/CDDP]. Jpn J Gastroenterol 2012; 109: 1401–8.
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 1071–1075
doi: 10.1111/hepr.12457
Original Article
Brain metastasis from hepatocellular carcinoma: The impact of radiotherapy on control of intracranial hemorrhage Yushi Yamakawa,1 Michihisa Moriguchi,1 Takeshi Aramaki,1 Koichi Mitsuya,2 Koiku Asakura,1 Akihiro Sawada,1 Masahiro Endo1 and Yoko Nakasu2 Divisions of 1Diagnostic Radiology and 2Neurosurgery, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan Aim: Brain metastasis from hepatocellular carcinoma (HCC) is rare and causes devastating outcomes with intracranial hemorrhage. We retrospectively analyzed the impact of radiotherapy in preventing hemorrhagic events among patients with brain metastasis from HCC.
intracranial hemorrhage at presentation of brain metastasis. No patients in group R experienced intracranial hemorrhage during follow up, although two patients in group N did. Median overall survival was 22.4 weeks (range, 5.42–69.1) in group R and 2.24 weeks (range, 1.0–15.4) in group N.
Methods: Patients who underwent treatment for brain metastasis from HCC at our cancer center between January 2003 and December 2012 were identified from a prospectively compiled hospital database. Clinical characteristics were analyzed in patients with and without radiotherapy.
Conclusion: For patients with brain metastasis from HCC, radiotherapy appears useful for controlling brain lesions, preventing intracranial hemorrhage and improving survival. Radiotherapy may contribute to control of intracranial tumor and prevention of intracranial hemorrhage for selected patients with brain metastasis from HCC.
Results: Fifteen HCC patients with brain metastasis from HCC were classified into two groups: 11 patients underwent radiotherapy (group R) and four patients received best supportive care without radiotherapy (group N). Six patients (54.5%) in group R and four patients (100%) in group N showed
INTRODUCTION
H
EPATOCELLULAR CARCINOMA (HCC) represents one of the most common causes of cancerrelated death in the world, especially in Asia.1–3 The incidence of HCC seems to be increasing along with the prevalences of hepatitis B and C infections, alcoholism and obesity-related fatty liver disease.4 Recent therapeutic advances in surgical techniques, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), chemotherapeutic agents and molecular-targeted agents have contributed to improved survival for HCC patients, in turn increasing the incidence of extrahepatic metastasis.5,6
Correspondence: Mr Yushi Yamakawa, Division of Diagnostic Radiology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan. Email: [email protected] Received 16 November 2013; revision 26 November 2014; accepted 27 November 2014.
© 2014 The Japan Society of Hepatology
Key words: brain metastasis, hemorrhage, hepatocellular carcinoma, radiotherapy
The most frequent site of extrahepatic metastasis is the lung, followed by the lymph nodes, bones and adrenal glands.7 In contrast, brain metastasis is reported in only 0.6–1.2% of HCC patients.6,8 Brain metastasis from HCC is very rare, because there is little affinity of HCC cells for the brain.9 The prognosis in patients with brain metastasis is extremely poor, with a median survival of 1–3 months.5,10,11 Intracranial hemorrhage is the first manifestation in one-third of patients with brain metastasis from HCC, because HCC is hypervascular and hemorrhagic,5 and this causes devastating outcomes on occurrence and during treatment. The rarity of brain metastasis from HCC means that treatment guidelines have yet to be defined. Several reports have presented the usefulness of surgical removal.6,12,13 We hypothesized that control of intracranial hemorrhage would be a key factor for the survival of patients with brain metastasis from HCC. We therefore undertook this retrospective study to evaluate the efficacy of radiotherapy for preventing intracranial hemorrhage in our patients with brain metastasis from HCC.
1071
1072 Y. Yamakawa et al.
METHODS
P
ATIENTS WITH BRAIN metastasis from HCC who underwent any treatment at our cancer center between January 2004 and December 2012 were identified from a prospectively compiled hospital database. We collected data about patient sex, age, condition of liver lesions, extracranial metastasis, ongoing systemic therapy, size and number of brain metastasis, presence of hemorrhage in brain metastasis, recursive partitioning analysis (RPA) at presentation, treatment modality for brain metastasis, and outcome. RPA was the first prognostic score developed for brain metastasis management. This classification was made after analysis of the relative contributions of pretreatment variables to survival of the patients with brain metastasis by the Radiation Therapy Oncology Group in 1997: (i) class 1 patients are younger than 65 years old, with a Karnofsky Performance Status (KPS) of 70% or more, controlled primary tumor, without extracranial metastasis; (ii) class 2 patients are all not in class 1 or 3; and (iii) class 3 patients have KPS of less than 70%.14 Brain metastasis was confirmed with computed tomography (CT) and/or magnetic resonance imaging (MRI). Decisions regarding treatment for brain metastasis were recommended based on general condition, extent of systemic disease, location of brain lesions and neurological condition by our institute cancer board, as follows. Patients underwent best supportive care (BSC) without radiotherapy when they presented with poor systemic condition or irreversible, rapid and severe neurological deterioration. Patients underwent radiotherapy with or without surgery when they expected to survive more than 3 months if brain lesions could be controlled. Overall survival was defined as the interval between date of diagnosis of brain metastasis and date of death. Overall survival rate was calculated actuarially according to the Kaplan–Meier method and was measured from the date of diagnosis of brain metastasis until the date of last follow up or death. Survival curves were compared using the log–rank test. Statistical analyses were performed using SPSS version 12.0 software (SPSS, Chicago, IL, USA). This retrospective study was approved by the Institutional Review Board for Clinical Investigations at Shizuoka Cancer Center.
RESULTS
B
ETWEEN JANUARY 2003 and December 2011, a total of 1702 patients with HCC were enrolled in the Shizuoka Cancer Center registry. Of these, 15
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 1071–1075
patients (0.9%) were diagnosed with brain metastasis from HCC. Median age at diagnosis of HCC was 64 years (range, 42–78). Hepatitis B virus infection was detected in five patients and hepatitis C infection was identified in eight patients. The majority of patients had undergone surgical resection and RFA and/or TACE to treat the primary HCC. Median age at diagnosis of brain metastasis was 67 years (range, 43–80). The median interval between diagnosis of HCC and diagnosis of metastasis was 71.3 weeks (range, 0–264.2). Most patients had lung metastasis (73.3%). The most frequent symptom was headache, followed by nausea, motor disturbance and disturbance of consciousness. Patient characteristics are summarized in Table 1. Eleven patients underwent radiotherapy (group R) and four patients accepted BSC (group N). In group R, whole-brain radiotherapy (WBRT) had been performed in six patients, gamma knife surgery in three patients and stereotactic radiotherapy (SRT) in four patients. At the time of diagnosis of brain metastasis from HCC, TACE had been performed in seven patients, molecularly targeted therapy in five patients, chemotherapy in one patient and BSC in two patients. Ten of 15 patients (66.7%) showed intracranial hemorrhage at presentation of brain metastasis, including six patients (54.5%) in group R and four patients (100%) in group N. Two patients in group N experienced intracranial hemorrhage during the follow-up period. One of two patients who complained of visual disturbance had brain metastasis in the occipital lobe on T1-weighted gadolinium-enhanced MRI. The next day, that patient suddenly lost consciousness, and CT revealed a large intracerebral hemorrhage (Fig. 1). He died a week later due to neurological deterioration. None of the 11 patients in group R suffered intracranial hemorrhage after treatment for brain metastasis. Seven patients died as a result of progressive hepatic or respiratory failure, without apparent intracranial hemorrhage, and two patients died because of neurological deterioration without hemorrhage. The remaining two patients were still alive at the end of the study period. At the end of follow up, nine patients were dead and two patients were alive in group R, whereas all patients group N were dead. Only one patient underwent TACE for HCC following radiotherapy for brain metastasis. Median overall survival was 3.6 months (95% confidence interval [CI], 0.27–5.53), and survival rates were 73.3%, 26.7% and 20.0% at 1, 6 and 12 months, respectively (Fig. 2). Patients in group R showed significantly
Radiotherapy for brain metastasis from HCC 1073
Hepatology Research 2015; 45: 1071–1075
Table 1 Clinical characteristics and outcomes in 15 patients with brain metastasis from HCC Characteristic Sex Male Female Age, years (median) Etiology HBV HCV NBNC RPA class 1 2 3 PS 0 1 2 3 AFP, ng/mL (median) Platelets, ×104/μL (median) Child–Pugh A B Lung metastasis Yes No Size of BM, mm (median) No. of BM (median) HCC-to-BM interval, weeks (median) Surgical resection for BM Yes No ICH at presentation Yes No ICH after treatment for BM Yes No Survival, months (median) Cause of death Hepatic Neurological
Group R (n = 11)
Group N (n = 4)
6 5 68 (43–80)
4 0 66.5 (60–72)
4 5 2
1 3 0
2 8 1
0 0 4
1 6 1 3 292 (2.2–152 778) 14.5 (4.0–29.6) 9 2 8 3 30 (5–40) 3 (1–17) 107.1 (0–264.2)
0 1 3 0 1199 (196–499 970) 12.1 (9.5–21.2) 2 2 3 1 50 (15–55) 1 (1–7) 49.2 (24.0–146.0)
1 10
0 4
6 5
4 0
0 11 5 (2–16) 7 2
2 2 0.6 (0.2–4) 0 4
AFP, α-fetoprotein; BM, brain metastasis; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICH, intracranial hemorrhage; NBNC, non-B, non-C; PS, performance status; RPA, recursive partitioning analysis.
longer median survival (5.4 months; 95% CI, 2.03– 16.1) than patients in group N (0.55 months; 95% CI, 0.23–3.60; P = 0.012) (Fig. 3).
DISCUSSION
H
EPATOCELLULAR CARCINOMA PATIENTS with brain metastasis generally show poor prognosis,
with a median survival of 1–3 months.4 Tumor hemorrhage is one of the noticeable causes of mortality with brain metastasis from HCC. Brain metastasis from HCC is frequently associated with hemorrhage, because HCC itself is hypervascular and most patients also have coagulopathy due to liver cirrhosis. Chang et al. reported that 18 of 45 patients with brain metastasis from HCC-associated intracranial hemorrhage as their
© 2014 The Japan Society of Hepatology
1074 Y. Yamakawa et al.
a
Hepatology Research 2015; 45: 1071–1075
1.0
b
Survival probability
0.8 p=0.012
0.6 0.4 0.2
Figure 1 (a) T1-weighted gadolinium-enhanced magnetic resonance imaging in a patient with visual disturbance caused by a mass lesion in the occipital lobe. (b) Computed tomography showing a large intracranial hemorrhage in the same patient with sudden disturbance of consciousness the next day.
first manifestation.5 Most patients who received BSC died within several days to 1 month. Ten of their 45 patients died of intracranial hemorrhage and/or increased intracranial pressure with or without brain herniation. In addition, Han et al.4 reported that almost half of patients with intracranial hemorrhage from HCC experienced recurrent bleeding from tumors after treatment, so recurrent bleeding from tumor after treatment was a most problematic event during the management of patients with brain metastasis from HCC. In our study, six of 10 patients who had intracranial hemorrhage were treated with radiotherapy, and none suffered from intracranial hemorrhage until death or the end of the study.
1.0
Survival probability
0.8 0.6 0.4 0.2 0.0 0
8
16 24 32 40 Survival time (weeks)
48
56
Figure 2 Kaplan–Meier estimates of overall survival in the whole series (n = 15). The median survival time was 14.4 weeks (95% confidence interval, 1.1–22.1), and the actuarial survival rates were 73.3%, 26.7% and 20.0% at 4, 24 and 48 months.
© 2014 The Japan Society of Hepatology
0.0 0
8
16 24 32 40 Survival time (weeks)
48
56
Figure 3 Kaplan–Meier estimates to test for differences in overall survival between group R and group N using a log–rank test. Group R showed a significantly longer median survival time than group N (22.4 weeks; 95% confidence interval [CI], 8.1–64.4) versus 2.2 weeks (95% CI, 0.92–14.4) (P = 0.012). , group R; , group N.
Surgery and/or radiotherapy have positive effects on survival.8 Surgical resection is recommended for patients with a large single brain metastasis in an anatomically accessible location, and for those who require emergency decompression of life-threatening masses.15 Radiotherapy seems promising for patients with brain metastasis from HCC. The addition of WBRT to surgical resection of brain metastasis has been shown to decrease the risks of local relapse and death from neurological causes.12 Other studies have reported that SRT combined with WBRT may prolong the survival of patients with controlled extracranial lesions or multiple intracranial lesions.13 Intracranial hemorrhage will become an important issue in the near future, because the incidence of brain metastasis from HCC is increasing as more patients survive longer thanks to advances in both medical and surgical treatments for primary lesions and systemic control in HCC patients. A review of Japanese HCC autopsy cases showed a 2.2% incidence of brain metastasis in 1996.16 Kim et al. reported clinically detected brain metastasis in 0.6% of 3100 HCC patients in 1998,6 while Choi et al.8 also reported identifying brain metastasis in 0.9% of 6919 patients diagnosed between 1995 and 2006. In a recent series of HCC metastasis, Shao et al.17 reported brain metastasis in 7% of 158 advanced HCC patients in 2011. In our study, the incidence of brain metastasis from HCC was 0.9%. At our institute, four of 915 HCC patients developed brain metastasis in 4 years from 2003, and 11 of 787 in 3 years
Hepatology Research 2015; 45: 1071–1075
from 2008. That means 0.1% patients per year in the former years, and 0.43% per year in the recent years. Including the results from our study, these figures probably underestimate the true frequency. Patients in most studies did not undergo brain imaging as part of routine evaluation. The real incidence of brain metastasis from HCC should be estimated in community-based screening imaging studies. Guidelines on the diagnosis and treatment of patients with brain metastasis from HCC have yet to be established. No routine brain screening is recommended for HCC patients. According to the published work, the median time from diagnosis to brain metastasis is 10.5– 18.2 months,5,8,18 comparable with the 16.6 months in our series. We may have to include screening of the brain using whole-body screening CT. An appropriate timing for screening may be 10–18 months after initial diagnosis of HCC. Although few studies have reported systemic therapy following radiotherapy for brain metastasis,19 radiotherapy for brain metastasis and continuing systemic treatment of HCC may further prolong survival in HCC patients. Several limitations must be considered when interpreting the present results. Clinical features were reviewed retrospectively from the medical records in a single institution, and selection bias may be present, as patients with better condition received radiotherapy. Even so, our results indicate that radiotherapy may contribute to control of intracranial tumor and prevention of intracranial hemorrhage for selected patients with brain metastasis from HCC. Randomized control trials are not feasible given the rarity of the disease. A multiinstitutional prospective study is therefore needed to explore risk and prognostic factors for brain metastasis from HCC.
REFERENCES 1 El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med [Research Support, U.S. Gov’t, Non-P.H.S.] 2003; 139: 817–23. 2 Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D. Global cancer statistics. Ca 2011; 61: 69–90. 3 Jiang X-B, Ke C, Zhang G-H et al. Brain metastases from hepatocellular carcinoma: clinical features and prognostic factors. BMC Cancer 2012; 12: 49. 4 Han JH, Kim DG, Park JC, Chung HT, Paek SH, Chung YS. Little response of cerebral metastasis from hepatocellular carcinoma to any treatments. J Korean Neurosurg Soc 2010; 47: 325–31.
Radiotherapy for brain metastasis from HCC 1075
5 Chang L, Chen YL, Kao MC. Intracranial metastasis of hepatocellular carcinoma: review of 45 cases. Surg Neurol [Case Reports Review] 2004; 62: 172–7. 6 Kim M, Na DL, Park SH, Jeon BS, Roh JK. Nervous system involvement by metastatic hepatocellular carcinoma. J Neurooncol 1998; 36 (1): 85–90. 7 Uka K, Aikata H, Takaki S et al. Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol 2007; 13: 414–20. 8 Choi HJ, Cho BC, Sohn JH et al. Brain metastases from hepatocellular carcinoma: prognostic factors and outcome: brain metastasis from HCC. J Neurooncol [Clinical Trial] 2009; 91: 307–13. 9 Kawaguchi T, Endo M, Yokoya S, Nakamura K. Difference in proliferation-kinetics between tumor cells arrested in the brain and liver. Experientia 1982; 38: 1236–7. 10 Asahara T, Yano M, Fukuda S et al. Brain metastasis from hepatocellular carcinoma after radical hepatectomy. Hiroshima J Med Sci [Case Reports] 1999; 48: 91–4. 11 Tanabe H, Kondo A, Kinuta Y et al. Unusual presentation of brain metastasis from hepatocellular carcinoma – two case reports. Neurol Med Chir (Tokyo) [Case Reports Review] 1994; 34: 748–53. 12 Patchell RA, Tibbs PA, Regine WF et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA [Clinical Trial Multicenter Study Randomized Controlled Trial] 1998; 280: 1485–9. 13 Khuntia D, Brown P, Li J, Mehta MP. Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol [Review] 2006; 24: 1295–304. 14 Gaspar L, Scott C, Rotman M et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745–51. 15 Lang FF. Surgical management and techniques. In: Sawaya R, ed. Intracranial Metastases. Malden, Massachusetts, Blackwell, 2004; 106–25. 16 Murakami K, Nawano S, Moriyama N et al. Intracranial metastases of hepatocellular carcinoma: CT and MRI. Neuroradiology 1996; 38 (Suppl 1): S31–35. 17 Shao YY, Lu LC, Cheng AL, Hsu CH. Increasing incidence of brain metastasis in patients with advanced hepatocellular carcinoma in the era of antiangiogenic targeted therapy. Oncologist [Research Support, Non-U.S. Gov’t] 2011; 16 (1): 82–6. 18 Hsieh M-J, Lu C-H, Tsai N-W et al. Prediction, clinical characteristics and prognosis of intracerebral hemorrhage in hepatocellular carcinoma patients with intracerebral metastasis. J Clin Neurosci 2009; 16: 394–8. 19 Kagawa K, Kawakami Y, Honda Y et al. [A case of advanced hepatocellular carcinoma with lung, brain and lymph node metastases recurred 8 years after hepatectomy successfully treated by operation, radiation and systemic chemotherapy using S-1/CDDP]. Jpn J Gastroenterol 2012; 109: 1401–8.
© 2014 The Japan Society of Hepatology
