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Proton Beam Therapy for Aged Patients With Hepatocellular Carcinoma
Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 3, pp. 805–812, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2007.04.016
CLINICAL INVESTIGATION
Liver
PROTON BEAM THERAPY FOR AGED PATIENTS WITH HEPATOCELLULAR CARCINOMA MASAHARU HATA, M.D.,*yk KOICHI TOKUUYE, M.D.,*y SHINJI SUGAHARA, M.D.,y ERIKO TOHNO, M.D.,z HIDETSUGU NAKAYAMA, M.D.,*y NOBUYOSHI FUKUMITSU, M.D.,*y MASASHI MIZUMOTO, M.D.,y MASATO ABEI, M.D.,x JUNICHI SHODA, M.D.,x MANABU MINAMI, M.D.,z AND YASUYUKI AKINE, M.D.*y * Proton Medical Research Center, and Departments of yRadiation Oncology, z Radiology, x Gastroenterology and Hepatology, University of Tsukuba, Tsukuba, Ibaraki, Japan; and k Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan Purpose: To investigate the safety and efficacy of proton beam therapy for aged patients with hepatocellular carcinoma (HCC). Methods and Materials: Twenty-one patients aged $80 years with HCC underwent proton beam therapy. At the time of irradiation, patient age ranged from 80 to 85 years (median, 81 years). Hepatic tumors were solitary in 17 patients and multiple in 4. Tumor size ranged from 10 to 135 mm (median, 40 mm) in maximum diameter. Ten, 5, and 6 patients received proton beam irradiation with total doses of 60 Gy in 10 fractions, 66 Gy in 22 fractions, and 70 Gy in 35 fractions, respectively, according to tumor location. Results: All irradiated tumors were controlled during the follow-up period of 6–49 months (median, 16 months). Five patients showed new hepatic tumors outside the irradiated volume, 2–13 months after treatment, and 1 of them also had lung metastasis. The local progression-free and disease-free rates were 100% and 72% at 3 years, respectively. Of 21 patients, 7 died 6–49 months after treatment; 2 patients each died of trauma and old age, and 1 patient each died of HCC, pneumonia, and arrhythmia. The 3-year overall, cause-specific, and disease-free survival rates were 62%, 88%, and 51%, respectively. No therapy-related toxicity of Grade $ 3 but thrombocytopenia in 2 patients was observed. Conclusions: Proton beam therapy seems to be tolerable, effective, and safe for aged patients with HCC. It may contribute to prolonged survival due to tumor control. Ó 2007 Elsevier Inc. Advanced age, Dose-volume analysis, Hepatocellular carcinoma, Proton beam therapy, Radiation therapy.
INTRODUCTION
of HCC, almost 80% of HCC patients are inoperable at the time of diagnosis owing to advanced tumors or coexisting cirrhosis (3–5). These patients are usually treated with the above-mentioned nonsurgical modalities. However, aged HCC patients are frequently excluded as candidates for curative treatment because of risks due to their advanced ages. A less-invasive and effective treatment modality is required for aged patients with HCC because the average life span has increased in many countries. Radiation therapy with photons has been recently attempted for the treatment of HCC with a curative intent. Although advanced radiation techniques with photons, such as threedimensional conformal radiotherapy, allow the delivery of
Primary liver cancer is the fifth most common malignancy worldwide, and the third most common cause of cancer mortality (1). In most countries, more than 75% of primary liver cancers are hepatocellular carcinomas (HCCs), and more than 80% of HCCs occur in countries of Asia and Africa. Currently, advanced treatments for HCC are being developed, and HCC patients are offered various treatment options (e.g., surgical resection, transcatheter arterial chemoembolization [TACE], percutaneous ethanol injection [PEI] and microwave coagulation [PMC], and radiofrequency ablation [RFA]) (2, 3). Although surgical resection remains the most standard and reliable curative modality for the treatment
from the Ministry of Health, Labor and Welfare of the Japanese Government. Conflict of interest: none. Received Feb 22, 2007, and in revised form April 6, 2007. Accepted for publication April 10, 2007.
Reprint requests to: Masaharu Hata, M.D., Department of Radiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. Tel: (+81) 45-787-2696; Fax: (+81) 45-786-0369; E-mail: mhata@ syd.odn.ne.jp Supported in part by a Grant-in-Aid for Cancer Research (15-9) 805
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a higher dose to a target compared with conventional irradiation, it is still difficult to provide a sufficient tumoricidal dose because of the low-dose tolerance of the whole liver. At our institute, in the University of Tsukuba, HCC has been treated with proton beams since 1983 (6–10). Because proton beams theoretically produce excellent dose localization to a target compared with photons, they allow reduction of the irradiated volume and dose given to the normal liver and digestive tract, while increasing the dose to the tumor (11). Therefore, proton beam therapy is expected to result in enhanced efficacy and lower toxicity and may contribute to improved survival of aged patients with HCC. To the best of our knowledge, very few studies on curative treatment for aged patients with HCC, and none on radiation therapy, have been previously reported. Herein we present treatment outcomes of proton beam therapy and determine its roles for aged patients with HCC.
METHODS AND MATERIALS Patients In September 2001, proton beam therapy was started at our new facility using an accelerator with a synchrotron and two treatment rooms with rotational gantries. A total of 312 HCC patients received proton beam therapy there by June 2006. Of these patients, 21 were of advanced aged ($80 years). Exclusion criteria included extrahepatic disease spread, diffusely infiltrated tumor, and a poor general condition (Eastern Cooperative Oncology Group performance status $3) (12). One and 11 patients had hepatitis B virus- and hepatitis C virus-related cirrhosis, respectively; the remaining 9 patients had no hepatitis virus infection. The Child-Pugh classification of liver function was Class A in 15 patients, Class B in 5, and Class C in 1 (13). Of 21 patients, 13 had previously received one or more treatments with surgical resection, TACE, and/or PEI for HCC. In 10 of these 13 patients, the present tumors were local failures after previous treatments; in the other 3 patients, they were new intrahepatic lesions that developed remotely from previously treated tumors. Intervals between the initial treatments and the present proton beam therapy ranged from 1 to 76 months (median, 7 months). For the remaining 8 patients, the present proton beam therapy was the first treatment for HCC. In the current series, surgical resection was considered risky because of advanced age. Transcatheter arterial chemoembolization was unfeasible for 11 patients because the present tumors were local failures after TACE in 9 patients, and 3 patients showed iodine allergy, severe angina pectoris, and Child-Pugh Class C cirrhosis. Furthermore, PEI, PMC, and RFA were unsuitable for 19 patients because of large-sized tumors (>5 cm in diameter) or unfavorable tumor location. Before treatment, abdominal computed tomography (CT) or magnetic resonance imaging (MRI), ultrasonography, and chest X-rays were performed to determine clinical stages. Hepatic tumors were solitary in 17 patients and multiple in 4. No patient showed regional lymph node or distant metastasis. Consequently, 17 patients were diagnosed as clinical Stage I (T1N0M0) and 4 patients as Stage IIIA (T3N0M0), according to the TNM classification of the International Union Against Cancer (14). The 4 patients were diagnosed as Stage IIIA because of multiple tumors >5 cm in maximum diameter without involvement of major vessels. Ten patients were histopathologically diagnosed as having HCC by biopsy, whereas the remaining 11 were clinically diagnosed according to imaging findings
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(tumorous lesions enhanced in the arterial phase and washed out in the delayed phase on multiphase contrast-enhanced CT or MRI) and elevated serum alpha-fetoprotein (AFP) values. Patient and tumor characteristics are summarized in Table 1. Written informed consent was obtained from all patients before treatment.
Proton beam therapy Before the beginning of treatment, metallic fiducial markers were implanted percutaneously into the hepatic parenchyma adjacent to the tumors. The patient’s body was immobilized by an individually shaped body cast (ESFORM; Engineering System, Matsumoto, Japan). Treatment planning for proton beam therapy was based on respiratory-synchronized CT images at 5-mm intervals in the treatment position. Clinical target volume (CTV) was defined as gross tumor volume plus a 5-mm margin. A 5-mm margin was added to the CTV by means of enlarging a multileaf collimator on a plane perpendicular to the beam axis. An additional 5-mm margin in the caudal direction was added for respiratory movements. The CTV was homogeneously encompassed with more than 90% of the prescribed dose using the spread-out Bragg peak of proton beams. Multiple hepatic tumors were entirely included within the target volume. The treatment planning system automatically estimated conditions required for beam delivery, including ridge filter, range shifter, Table 1. Patient and tumor characteristics Total no. of patients Gender Men Women Age (y) Range Median Performance status 0 1 2 Hepatitis virus type HBV HCV None Child-Pugh classification Class A Class B Class C ICGR15 (%) Range Median Number of tumors Solitary Multiple Tumor size in maximum diameter (mm) Range Median Clinical stage T1N0M0, Stage I T3N0M0, Stage IIIA Serum AFP value (ng/mL) Range Median
21 13 8 80–85 81 7 10 4 1 11 9 15 5 1 1–52 21 17 4 10–135 40 17 4 1–15,240 14
Abbreviations: HBV = hepatitis B virus; HCV = hepatitis C virus; ICGR15 = indocyanine green retention rate at 15 min; AFP = alphafetoprotein.
Proton beam therapy for aged patients with HCC d M. HATA et al.
collimator, and bolus (15). The dose of proton beams was verified in an acryl phantom for each patient before initiation of treatment. Proton beams of 155–250 MeV generated by an accelerator with a synchrotron were used for treatment. Beams were synchronized with respiration and were delivered through one to six ports with coplanar angles using a rotational gantry. Respiratory gating was controlled by means of a semiconductor laser irradiated to the abdominal surface of patients, so that proton beams were delivered to the hepatic tumors in the expiratory phase, when the tumor position was considered to be at its most stable and reproducible. This respiratory gating has been previously reported and is briefly described as follows (16). A laser displacement sensor (LDS) (KEYENCE LB-300; KEYENCE, Osaka, Japan) was used for respiratory gating and gave information on the distance from the detector head to the subject. The LDS was placed so that the semiconductor laser could be focused on an area around the patient’s navel. When the distance from the LDS to a point on the abdominal surface changed because of breathing, the LDS detected this displacement as respiratory information. This information was digitized by an analogue-to-digital converter and was then placed into a gate generator in the form of a respiratory waveform. The waveform was expressed through a software program that we developed, and a gating signal was given to enable the accelerator to irradiate when the respiratory waveform dropped to the bottom, which corresponded to the expiratory end. In each treatment session, the positional relationship between the center of radiation fields and implanted fiducial markers was examined, with the patients lying in the treatment position, using the orthogonal fluoroscopy unit attached to the treatment unit. Respiratory gating and positional verification using implanted fiducial markers under fluoroscopy were considered useful for reducing the irradiated volume of the normal liver by enabling a decrease in the field margin for respiratory movements and setup error, respectively. Before treatment all patients were divided into three groups to determine total dose and fraction size according to tumor location, as follows: Group 1: 10 patients with tumors in the peripheral regions of the liver; Group 2: 5 patients with tumors in the central regions of the liver; and Group 3: 6 patients with tumors adjacent to the digestive tract, and the shortest distance between the digestive tract and tumors was <2 cm in these patients. Patients were prospectively treated in accordance with each treatment protocol, namely, total doses of 60 Gy in 10 fractions were delivered to Group 1, 66 Gy in 22 fractions to Group 2, and 70 Gy in 35 fractions to Group 3 (Table 2). Fraction size was decreased to prevent radiationinduced biliary stenosis in Group 2 compared with Group 1 and was further decreased to avoid severe complications of the digestive tract (e.g., ulcer, stenosis, and perforation) in Group 3. Moreover, in Group 3 the digestive tract was completely excluded from the irradiated volume after irradiation with 50 Gy in 25 fractions. All patients received irradiation in daily fractions, 5 days per week, and the overall treatment time was 12–64 days (median, 31 days). A relative biologic effectiveness value of 1.0 was used in accordance with data obtained from a fibrosarcoma NFSa cell line (17). The
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dose of 60 Gy in 10 fractions corresponded to 80 Gy and 108 Gy when 2 Gy per fraction-equivalent doses were given according to the linear quadratic model with a/b ratios of 10 and 3 for earlyand late-responding tissues, respectively, whereas that of 66 Gy in 22 fractions corresponded to 72 Gy and 79 Gy, respectively (18). Dose–volume analyses were performed in all patients to evaluate the irradiated volume and doses given to the liver.
Follow-up and evaluation criteria Patients underwent serum AFP value measurements and abdominal imaging studies (CT or MRI) 1 and 1–4 months after completion of treatment, respectively, and were followed up at 1–3-month intervals. Local responses to treatment were classified according to the modifications of the World Health Organization (WHO) response evaluation criteria, as follows (19). Complete response (CR) was defined as complete disappearance of the irradiated tumor; partial response (PR) corresponded to more than 50% reduction in the tumor volume; progressive disease (PD) was defined as more than 25% increase in the tumor volume; and no change (NC) referred to cases that did not qualify for CR, PR, or PD. Local responses in patients with multiple tumors were assessed on the basis of the worst tumor response among them. Complete response and PR were defined as objective responses. Growth of the irradiated tumor or appearance of a new disease after treatment was regarded as recurrence. When patients showed no growth of the irradiated tumors and no recurrence after treatment, they were considered local progression free and disease free, respectively. Acute and late toxicities associated with treatment were evaluated with the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity scoring criteria and the RTOG/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme, respectively (20).
Statistical analysis Actuarial survival and disease control rates were calculated from the beginning of proton beam therapy according to the KaplanMeier method (21). Differences in survivals were evaluated using the log–rank test (22). A p value of <0.05 was considered statistically significant. All statistical analyses were performed using the statistical software SPSS 11.0J (SPSS, Chicago, IL).
RESULTS Dose–volume analysis The CTV was 3–1295 cm3 (median, 32 cm3), and the total liver volume (TLV) (excluding CTV) was 589–1445 cm3 (median, 916 cm3). When a proportion (percentage) of CTV to TLV was defined as %CTV, it was 0.2–163% (median, 3.4%). The percentages of the volumes to which doses of 0 Gy, $30 Gy, and $50 Gy were irradiated in TLV were termed V0, V30, and V50. The V0, V30, and V50 were 29–96% (median, 65%), 2–38% (median, 14%), and 1–26% (median,
Table 2. Treatment protocols according to tumor location 2 Gy per fraction-equivalent dose (Gy) Group
No. of patients
Tumor location of the liver
Total dose (Gy/fractions)
a/b = 10
a/b = 3
Group 1 Group 2 Group 3
10 5 6
Peripheral Central Adjacent to the digestive tract
60/10 66/22 70/35
80 72 70
108 79 70
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7%), respectively. Mean liver doses (MLDs) were 1.2–21.7 Gy (median, 9.5 Gy). Typical dose-distribution curve and dose–volume histogram in treatment planning for a patient are demonstrated in Fig. 1. Outcomes of dose–volume analyses of livers in all patients are summarized in Table 3. Toxicity Acute reactions were transient, easily manageable, and caused no interruption in the treatment course (Table 4). Regarding adverse events of Grade $3, 2 patients showed thrombocytopenia of Grade 3. However, both patients had thrombocytopenia that corresponded to Grade 2 due to cirrhosis at the beginning of treatment.
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Table 3. Outcomes of dose–volume analyses of livers in 21 patients with hepatocellular carcinoma treated with proton beam therapy Variables
Range (median)
CTV (cm3) TLV (cm3) %CTV (%) V0 (%) V30 (%) V50 (%) MLD (Gy)
3–1295 (32) 589–1445 (916) 0.2–163 (3.4) 29–96 (65) 2–38 (14) 1–26 (7) 1.2–21.7 (9.5)
Abbreviations: CTV = clinical target volume; TLV = total liver volume; V0, V30, and V50 = percentage of the volume to which doses of 0 Gy, $30 Gy, and $50 Gy were irradiated in total liver volume; MLD = mean liver dose.
No late toxicities associated with treatment, especially mucosal toxicities of the digestive tract or radiation-induced liver disease (RILD), were observed. Liver function of all patients was well preserved, and there was no deterioration in Child-Pugh score 6 months after irradiation. Local control and failure patterns Irradiated tumors showed CR in 6 patients, PR in 9, and NC in 6, 1–4 months after completion of treatment. Final tumor responses were CR in 11 patients, PR in 8, and NC in 2 at the last follow-up period of 6–49 months (median, 16 months) after irradiation (Fig. 2). Objective response rate was 90%, and tumor sizes in 2 NC patients were still decreasing at the last follow-up. All irradiated tumors were controlled during the follow-up period, and the local-progression free rate was 100%. Pretreatment AFP values of 8 patients showed abnormally high levels of 23–15,240 ng/mL (median, 305 ng/mL) beyond the upper normal limit (20 ng/mL). These AFP values decreased to 3–6025 ng/mL (median, 31 ng/mL) after irradiation, and they were within the normal limits in 4 patients. On the other hand, 2 of the 4 patients who did not achieve normalization of AFP values showed recurrence. In the remaining 2 patients, AFP values were decreasing at the last follow-up, although they were still over the upper normal limit. Table 4. Therapy-related acute toxicities according to the Radiation Therapy Oncology Group acute radiation morbidity scoring criteria Fig. 1. Treatment planning of proton beam therapy with a total dose of 60 Gy in 10 fractions for a patient with hepatocellular carcinoma. (a) Isodose distribution of proton beams on a CT slice, delivered through two oblique ports. Isodose lines demonstrate 90% of the prescribed dose at the most inside and decreasing by 10% of the dose from inside out. Critical organs, such as the spinal cord and the digestive tract, are located entirely outside the irradiated volume, owing to the sharp distal fall-off of the Bragg peak of proton beams. (b) Dose–volume histograms of the clinical target volume (CTV) and liver. The CTV is entirely irradiated with $90% of the prescribed dose, and V30 and V50 of the liver are 32% and 20%, respectively.
Grade Toxicity Hematologic Leucopenia Anemia Thrombocytopenia Skin Erythema Upper gastrointestinal tract Appetite loss
1
2
3
4
2 1 3
7 0 3
0 0 2
0 0 0
3
2
0
0
1
0
0
0
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Fig. 2. Pretreatment and posttreatment contrast-enhanced computed tomography images of a patient with hepatocellular carcinoma. (a, b) Just before initiation of proton beam therapy, arrowheads represent position of the hepatic tumor, which is slightly and inhomogeneously enhanced in the arterial phase (a) and washed out in the portal venous phase (b). (c, d) Seven months after completion of proton beam therapy, almost complete disappearance of the hepatic tumor in both arterial (c) and portal venous phases (d) can be seen, although the liver parenchyma irradiated with a high dose shows enhancement due to radiation hepatitis.
Of 21 patients, 5 had recurrences 2–13 months after proton beam therapy. All 5 of these patients with recurrence showed new hepatic tumors outside the irradiated volume, and 1 of them also developed lung metastasis. Disease-free rates were 79% at 1 year and 72% at 3 years (Fig. 3). Of the 5 patients with recurrence, 1 received second and third courses of proton beam therapy, leading to control of the recurrent tumors. Of the remaining 4 patients, 2 were followed up with no further treatment because the new lesions were too small, whereas the other 2, including 1 patient with lung metastasis, underwent palliative or supportive care because the new tumors were considered uncontrollable.
Survival Of 21 patients, 7 died 6–49 months after treatment. Causes of death were trauma and old age in 2 patients each, and progressive HCC, pneumonia, and arrhythmia in 1 patient each. The cause-specific and disease-free survival rates were 100% and 70% at 1 year and 88% and 51% at 3 years, respectively (Fig. 4). The overall survival rates were 84% at 1 year and 62% at 3 years. When the expected survival rates were estimated for matching age and gender in the present cases,
according to survival data of the national statistics published by the Ministry of Health, Labor and Welfare of the Japanese Government, they were 94% at 1 year and 82% at 3 years (23). There was no significant difference between the overall survival and the expected survival rates (p = 0.13, Fig. 5). Clinical courses of all patients are shown in Table 5. DISCUSSION Surgical resection remains the most reliable curative treatment for HCC and provides a 5-year survival of 60–70% for patients with small solitary HCC and well-preserved liver function (24). However, only 20% of HCC patients can undergo surgical resection; the remainders are inoperable because of advanced tumors or comorbidities, including cirrhosis. Aged patients frequently are also considered inoperable owing to the intolerable physical burden of surgical procedures. Usually nonsurgical treatments, such as TACE, PEI, PMC, and RFA, are applied to inoperable patients with HCC. Transcatheter arterial chemoembolization is most frequently used as a nonsurgical treatment for HCC, but it is unfeasible for patients with severe cirrhosis owing to the
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Fig. 3. Local progression-free and disease-free rates of 21 patients with hepatocellular carcinoma treated with proton beam therapy.
Fig. 5. Overall and expected survivals of 21 patients with hepatocellular carcinoma treated with proton beam therapy. There was no significant difference between the two survivals (p = 0.13).
risk of liver failure, renal dysfunction, allergy to iodine, or no tumor staining. Furthermore, TACE is still regarded as a noncurative treatment for HCC, although it achieved objective responses in 15–55% of HCC patients, and survival benefits have been recently obtained in several randomized controlled trials (25–27). Percutaneous ethanol injection, PMC, and RFA are less invasive and curative treatments for small HCC and have been reported to result in first CR in approximately 80% of HCCs #3 cm in diameter (24, 28). However, 30–40% of patients with first CR experienced late local failure. Moreover, PEI, PMC, and RFA are unsuitable for patients with a bleeding tendency, unfavorable tumor location, or large-sized tumors; local failure developed in almost 70% of patients with HCCs of 3.1–5 cm in diameter and in all patients with HCCs >5 cm (24, 28). In addition to these treatment constraints, aggressive procedures are frequently difficult for aged patients with decreased physical strength.
Therefore, there are numerous aged patients with HCC who have limited treatment options and are unable to undergo effective treatments. Presently, the average life spans of eight countries, including Japan, are exceeding 80 years (29). The life expectancies for people aged 80 and 85 years in Japan are 8.2 and 5.9 years in men and 11.1 and 8.0 years in women, respectively (23). On the other hand, the median survival for patients with untreated HCC is 1 or 2 years at the most after diagnosis, and the cause of death is progressive HCC in the majority of patients (30, 31). Therefore, even patients aged 85 years should be entitled to an aggressive treatment with curative intent if it is safe and effective. A few previous studies reported nonsurgical treatments using TACE or PEI for HCC patients aged $80 years (32, 33). The overall survival rates were 54.1–75.5% at 1 year and 28.1–32.1% at 3 years, and almost half of the patients died of HCC. These results suggest that prognoses of HCC patients aged $80 years are improved by controlling HCC. Actually, in the present study, all irradiated tumors were controlled, and the overall survival rates of 84% at 1 year and 62% at 3 years were better than those of previous reports, although the follow-up period was still short. Proton beam therapy seemed to contribute to prolonged survival of aged patients with HCC. Recently, radiation therapy with photons has been attempted for the treatment of HCC as advanced radiation techniques have developed. Some investigators demonstrated that a higher dose delivered to the hepatic tumor achieved better local control and survival in HCC patients (34–38). Of note, it was reported that a total dose of $50 Gy in conventional fractions was necessary to significantly reduce tumor volume and to prolong survival of patients with unresectable HCC (34–37). However, it is difficult to safely give HCC patients the sufficient tumoricidal dose because of low-dose tolerance of the whole liver and poorly preserved liver function due to coexisting cirrhosis, even if advanced photon irradiation is used. Therefore, a median total dose
Fig. 4. Cause-specific and disease-free survivals of 21 patients with hepatocellular carcinoma treated with proton beam therapy.
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Table 5. Clinical courses of 21 patients aged $80 years with hepatocellular carcinoma treated with proton beam therapy Patient Age Child-Pugh no. (y)/gender PS class
No. of tumors
Tumor Total dose Tumor size (mm) (Gy/fractions) response
Pattern of failure
Follow-up period (mo) 15 21 49 16 38 35 32 27 15 25 14 23 7 17 17 6 12 11
1 2 3
83/M 81/M 85/M
1 2 1
A B A
Solitary Solitary Solitary
38 40 90
66/22 60/10 60/10
CR CR CR
4 5 6 7 8
80/M 80/M 81/F 82/F 82/F
1 0 1 1 0
A A A A A
Solitary Multiple Multiple Solitary Solitary
13 80 68 30 27
60/10 66/22 60/10 70/35 60/10
CR PR PR CR CR
Liver (OIV) Liver (OIV) Liver (OIV), Lung None None None None Liver (OIV)
9 10 11 12 13 14 15 16 17 18
82/M 81/M 84/F 80/M 80/F 80/F 81/M 80/F 81/M 82/M
2 0 1 0 1 1 0 1 1 2
B A A A A A B C B B
Multiple Solitary Solitary Solitary Solitary Solitary Solitary Solitary Solitary Solitary
135 30 104 28 60 43 10 20 40 45
66/22 60/10 70/35 66/22 70/35 60/10 70/35 60/10 60/10 70/35
PR PR PR PR PR CR CR CR CR PR
None None None None None None None None None Liver (OIV)
19 20 21
84/F 84/M 80/M
0 0 2
A A A
Multiple Solitary Solitary
56 33 19
66/22 60/10 70/35
NC CR NC
None None None
8 8 8
Recent status Dead of trauma Dead of HCC Dead of pneumonia Alive with NED Alive with NED Alive with NED Alive with NED Alive with recurrence Dead of old age Alive with NED Dead of trauma Alive with NED Dead of old age Alive with NED Alive with NED Dead of arrhythmia Alive with NED Alive with recurrence Alive with NED Alive with NED Alive with NED
Abbreviations: PS = performance status; M = male; F = female; CR = complete response; OIV = outside of the irradiated volume; HCC = hepatocellular carcinoma; NED = no evidence of disease; PR = partial response; NC = no change.
of <60 Gy was used to treat HCC in most previous studies using photons, and the objective response rate was <70% (34–39). In all patients in the present series, total doses of $70 Gy in 2 Gy per fraction-equivalent were aggressively delivered to HCCs using proton beams, and an objective response rate of 90% and a local progression-free rate of 100% were achieved, although tumor size was $40 mm in 11 patients and even $80 mm in 4 patients. Conversely, a dose of 60 Gy in 10 fractions, which was maximal in 2 Gy per fraction-equivalent doses among the doses used in the present series, may be excessive to control HCCs, considering that all HCCs treated with doses of 66 Gy in 22 fractions or 70 Gy in 35 fractions showed no local progression. It should be particularly noted that of the 11 patients treated with doses of 66 Gy in 33 fractions or 70 Gy in 35 fractions, 4 had tumors with a maximum diameter $6 cm, and all tumors were locally controlled. Our previous study demonstrated that a total dose of 72 Gy in 16 fractions with a fraction size of 4.5 Gy could be safely delivered to HCCs located in the peripheral regions of the liver (6). Furthermore, an excellent local control rate of 86.9% at 5 years was achieved with doses used previously. This dose corresponded to 87 Gy and 108 Gy in 2 Gy per fraction-equivalent doses, with a/b ratios of 10 and 3, respectively. The present fractionation regimens were decided on the basis of these previous results. Although optimal doses remain unknown for each patient in various conditions, it is possible that a subset of HCCs may be controlled with lower total doses than those assumed necessary in the present study.
The radiation tolerance of the whole normal liver is reported to be approximately 30 Gy in conventional fractions (40). Several studies revealed that the radiation tolerance of the liver was strongly affected by the irradiated volume of the liver; for instance, the doses associated with a 5% risk of RILD for irradiation volumes of one third and two thirds are 90 Gy and 47 Gy, respectively (41, 42). These findings suggest that high-dose irradiation can be delivered safely to a part of the liver including HCC. The V30 and V50 in the present study were far smaller than those assumed to be tolerable. Mean liver dose is also proposed as a reliable predictor of RILD, and MLD associated with 5% risk of RILD is reported to be 28 Gy in conventional fractions (43). Mean liver dose in the current study was also within the above safe limits. Actually, no RILD was observed in the present series, and liver function was well preserved. Furthermore, abundant nonirradiated volume (V0) caused by the Bragg peak of proton beams may allow re-irradiation to newly developed HCC, while preserving liver function. However, the relationship between dose and volume in hypofractionated high-dose irradiation cannot be dealt with in the same way as that in conventional irradiation. There are few previous reports on dose–volume analyses of the liver in hypofractionated high-dose irradiation, so further investigations with a larger number of patients and longer follow-up period are required. In conclusion, proton beam therapy seemed to be tolerable, effective, and safe for aged patients with HCC. The current results suggest that this method contributes to prolonged survival due to tumor control.
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REFERENCES 1. McGlynn KA, London WT. Epidemiology and natural history of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 2005;19:3–23. 2. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol 2005;40:225–235. 3. Hsu C, Cheng JC, Cheng AL. Recent advances in non-surgical treatment for advanced hepatocellular carcinoma. J Formos Med Assoc 2004;103:483–495. 4. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–1917. 5. Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinoma: A retrospective and nationwide survey in Japan. Hepatology 2000;32:1224–1229. 6. Chiba T, Tokuuye K, Matsuzaki Y, et al. Proton beam therapy for hepatocellular carcinoma: A retrospective review of 162 patients. Clin Cancer Res 2005;11:3799–3805. 7. Hata M, Tokuuye K, Sugahara S, et al. Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus. Cancer 2005;104:794–801. 8. Hata M, Tokuuye K, Sugahara S, et al. Proton beam therapy for hepatocellular carcinoma with limited treatment options. Cancer 2006;107:591–598. 9. Hata M, Tokuuye K, Sugahara S, et al. Proton beam therapy for hepatocellular carcinoma patients with severe cirrhosis. Strahlenther Onkol 2006;182:713–720. 10. Hashimoto T, Tokuuye K, Fukumitsu N, et al. Repeated proton beam therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2006;65:196–202. 11. Suit H, Goldberg S, Niemierko A, et al. Proton beams to replace photon beams in radical dose treatments. Acta Oncol 2003;42: 800–808. 12. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649–655. 13. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646–649. 14. Sobin LH, Wittekind C. TNM classification of malignant tumours. 6th ed. New York: Wiley-Liss; 2002. 15. Inada T, Hayakawa Y, Ohara K, et al. Treatment planning system for high energy proton beam. Nippon Acta Radiol 1983; 43:781–793. 16. Tsunashima Y, Sakae T, Shioyama Y, et al. Correlation between the respiratory waveform measured using a respiratory sensor and 3D tumor motion in gated radiotherapy. Int J Radiat Oncol Biol Phys 2004;60:951–958. 17. Ando K, Koike S, Kawachi K, et al. Relative biological effectiveness of the therapeutic proton beam at NIRS and Tsukuba University. Nippon Acta Radiol 1985;45:531–535. 18. Withers HR, Thames HD Jr., Peters LJ. A new isoeffect curve for change in dose per fraction. Radiother Oncol 1983;1:187–191. 19. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer 1981;47:207–214. 20. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346. 21. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 22. Altman DG. Practical statistics for medical research. 2nd ed. London: Chapman and Hall; 2004. 23. Japan Ministry of Health, Labour and Welfare. Statistic and other data. Vital statistics. Available at: http://www.mhlw.go. jp/english/database/db-hw/index.html. Accessed February 22, 2007.
24. Lopez PM, Villanueva A, Llovet JM. Systematic review: Evidence-based management of hepatocellular carcinoma— An updated analysis of randomized controlled trials. Aliment Pharmacol Ther 2006;23:1535–1547. 25. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164–1171. 26. Llovet JM, Real MI, Montan˜a X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomized controlled trial. Lancet 2002;359:1734–1739. 27. Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004;127:S179–S188. 28. Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 2004;40:1352–1360. 29. World Health Organization. The world health report 2006. Available at: http://www.who.int/whr/2006/en/. Accessed February 22, 2007. 30. Llovet JM, Bustamante J, Castells A, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: Rationale for the design and evaluation of therapeutic trials. Hepatology 1999;29:62–67. 31. Nagasue N, Yukaya H, Hamada T, et al. The natural history of hepatocellular carcinoma. A study of 100 untreated cases. Cancer 1984;54:1461–1465. 32. Tsukioka G, Kakizaki S, Sohara N, et al. Hepatocellular carcinoma in extremely elderly patients: An analysis of clinical characteristics, prognosis and patient survival. World J Gastroenterol 2006;12:48–53. 33. Dohmen K, Shirahama M, Shigematsu H, et al. Optimal treatment strategy for elderly patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2004;19:859–865. 34. Park W, Lim do H, Paik SW, et al. Local radiotherapy for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2005;61:1143–1150. 35. Liu MT, Li SH, Chu TC, et al. Three-dimensional conformal radiation therapy for unresectable hepatocellular carcinoma patients who had failed with or were unsuited for transcatheter arterial chemoembolization. Jpn J Clin Oncol 2004;34: 532–539. 36. Seong J, Park HC, Han KH, et al. Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma: A retrospective study of 158 patients. Int J Radiat Oncol Biol Phys 2003;55:329–336. 37. Uno T, Itami J, Shiina T, et al. Radiation therapy in patients with unresectable hepatocellular carcinoma. Cancer Chemother Pharmacol 1992;31(Suppl.):S106–S110. 38. Park HC, Seong J, Han KH, et al. Dose-response relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2002;54:150–155. 39. Cheng SH, Lin YM, Chuang VP, et al. A pilot study of threedimensional conformal radiotherapy in unresectable hepatocellular carcinoma. J Gastroenterol Hepatol 1999;14:1025–1033. 40. Greco C, Catalano G, Di Grazia A, et al. Radiotherapy of liver malignancies. From whole liver irradiation to stereotactic hypofractionated radiotherapy. Tumori 2004;90:73–79. 41. Lawrence TS, Ten Haken RK, Kessler ML, et al. The use of 3-D dose volume analysis to predict radiation hepatitis. Int J Radiat Oncol Biol Phys 1992;23:781–788. 42. Dawson LA, Ten Haken RK, Lawrence TS. Partial irradiation of the liver. Semin Radiat Oncol 2001;11:240–246. 43. Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin Radiat Oncol 2005;15:279–283.
doi:10.1016/j.ijrobp.2007.04.016
CLINICAL INVESTIGATION
Liver
PROTON BEAM THERAPY FOR AGED PATIENTS WITH HEPATOCELLULAR CARCINOMA MASAHARU HATA, M.D.,*yk KOICHI TOKUUYE, M.D.,*y SHINJI SUGAHARA, M.D.,y ERIKO TOHNO, M.D.,z HIDETSUGU NAKAYAMA, M.D.,*y NOBUYOSHI FUKUMITSU, M.D.,*y MASASHI MIZUMOTO, M.D.,y MASATO ABEI, M.D.,x JUNICHI SHODA, M.D.,x MANABU MINAMI, M.D.,z AND YASUYUKI AKINE, M.D.*y * Proton Medical Research Center, and Departments of yRadiation Oncology, z Radiology, x Gastroenterology and Hepatology, University of Tsukuba, Tsukuba, Ibaraki, Japan; and k Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan Purpose: To investigate the safety and efficacy of proton beam therapy for aged patients with hepatocellular carcinoma (HCC). Methods and Materials: Twenty-one patients aged $80 years with HCC underwent proton beam therapy. At the time of irradiation, patient age ranged from 80 to 85 years (median, 81 years). Hepatic tumors were solitary in 17 patients and multiple in 4. Tumor size ranged from 10 to 135 mm (median, 40 mm) in maximum diameter. Ten, 5, and 6 patients received proton beam irradiation with total doses of 60 Gy in 10 fractions, 66 Gy in 22 fractions, and 70 Gy in 35 fractions, respectively, according to tumor location. Results: All irradiated tumors were controlled during the follow-up period of 6–49 months (median, 16 months). Five patients showed new hepatic tumors outside the irradiated volume, 2–13 months after treatment, and 1 of them also had lung metastasis. The local progression-free and disease-free rates were 100% and 72% at 3 years, respectively. Of 21 patients, 7 died 6–49 months after treatment; 2 patients each died of trauma and old age, and 1 patient each died of HCC, pneumonia, and arrhythmia. The 3-year overall, cause-specific, and disease-free survival rates were 62%, 88%, and 51%, respectively. No therapy-related toxicity of Grade $ 3 but thrombocytopenia in 2 patients was observed. Conclusions: Proton beam therapy seems to be tolerable, effective, and safe for aged patients with HCC. It may contribute to prolonged survival due to tumor control. Ó 2007 Elsevier Inc. Advanced age, Dose-volume analysis, Hepatocellular carcinoma, Proton beam therapy, Radiation therapy.
INTRODUCTION
of HCC, almost 80% of HCC patients are inoperable at the time of diagnosis owing to advanced tumors or coexisting cirrhosis (3–5). These patients are usually treated with the above-mentioned nonsurgical modalities. However, aged HCC patients are frequently excluded as candidates for curative treatment because of risks due to their advanced ages. A less-invasive and effective treatment modality is required for aged patients with HCC because the average life span has increased in many countries. Radiation therapy with photons has been recently attempted for the treatment of HCC with a curative intent. Although advanced radiation techniques with photons, such as threedimensional conformal radiotherapy, allow the delivery of
Primary liver cancer is the fifth most common malignancy worldwide, and the third most common cause of cancer mortality (1). In most countries, more than 75% of primary liver cancers are hepatocellular carcinomas (HCCs), and more than 80% of HCCs occur in countries of Asia and Africa. Currently, advanced treatments for HCC are being developed, and HCC patients are offered various treatment options (e.g., surgical resection, transcatheter arterial chemoembolization [TACE], percutaneous ethanol injection [PEI] and microwave coagulation [PMC], and radiofrequency ablation [RFA]) (2, 3). Although surgical resection remains the most standard and reliable curative modality for the treatment
from the Ministry of Health, Labor and Welfare of the Japanese Government. Conflict of interest: none. Received Feb 22, 2007, and in revised form April 6, 2007. Accepted for publication April 10, 2007.
Reprint requests to: Masaharu Hata, M.D., Department of Radiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. Tel: (+81) 45-787-2696; Fax: (+81) 45-786-0369; E-mail: mhata@ syd.odn.ne.jp Supported in part by a Grant-in-Aid for Cancer Research (15-9) 805
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a higher dose to a target compared with conventional irradiation, it is still difficult to provide a sufficient tumoricidal dose because of the low-dose tolerance of the whole liver. At our institute, in the University of Tsukuba, HCC has been treated with proton beams since 1983 (6–10). Because proton beams theoretically produce excellent dose localization to a target compared with photons, they allow reduction of the irradiated volume and dose given to the normal liver and digestive tract, while increasing the dose to the tumor (11). Therefore, proton beam therapy is expected to result in enhanced efficacy and lower toxicity and may contribute to improved survival of aged patients with HCC. To the best of our knowledge, very few studies on curative treatment for aged patients with HCC, and none on radiation therapy, have been previously reported. Herein we present treatment outcomes of proton beam therapy and determine its roles for aged patients with HCC.
METHODS AND MATERIALS Patients In September 2001, proton beam therapy was started at our new facility using an accelerator with a synchrotron and two treatment rooms with rotational gantries. A total of 312 HCC patients received proton beam therapy there by June 2006. Of these patients, 21 were of advanced aged ($80 years). Exclusion criteria included extrahepatic disease spread, diffusely infiltrated tumor, and a poor general condition (Eastern Cooperative Oncology Group performance status $3) (12). One and 11 patients had hepatitis B virus- and hepatitis C virus-related cirrhosis, respectively; the remaining 9 patients had no hepatitis virus infection. The Child-Pugh classification of liver function was Class A in 15 patients, Class B in 5, and Class C in 1 (13). Of 21 patients, 13 had previously received one or more treatments with surgical resection, TACE, and/or PEI for HCC. In 10 of these 13 patients, the present tumors were local failures after previous treatments; in the other 3 patients, they were new intrahepatic lesions that developed remotely from previously treated tumors. Intervals between the initial treatments and the present proton beam therapy ranged from 1 to 76 months (median, 7 months). For the remaining 8 patients, the present proton beam therapy was the first treatment for HCC. In the current series, surgical resection was considered risky because of advanced age. Transcatheter arterial chemoembolization was unfeasible for 11 patients because the present tumors were local failures after TACE in 9 patients, and 3 patients showed iodine allergy, severe angina pectoris, and Child-Pugh Class C cirrhosis. Furthermore, PEI, PMC, and RFA were unsuitable for 19 patients because of large-sized tumors (>5 cm in diameter) or unfavorable tumor location. Before treatment, abdominal computed tomography (CT) or magnetic resonance imaging (MRI), ultrasonography, and chest X-rays were performed to determine clinical stages. Hepatic tumors were solitary in 17 patients and multiple in 4. No patient showed regional lymph node or distant metastasis. Consequently, 17 patients were diagnosed as clinical Stage I (T1N0M0) and 4 patients as Stage IIIA (T3N0M0), according to the TNM classification of the International Union Against Cancer (14). The 4 patients were diagnosed as Stage IIIA because of multiple tumors >5 cm in maximum diameter without involvement of major vessels. Ten patients were histopathologically diagnosed as having HCC by biopsy, whereas the remaining 11 were clinically diagnosed according to imaging findings
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(tumorous lesions enhanced in the arterial phase and washed out in the delayed phase on multiphase contrast-enhanced CT or MRI) and elevated serum alpha-fetoprotein (AFP) values. Patient and tumor characteristics are summarized in Table 1. Written informed consent was obtained from all patients before treatment.
Proton beam therapy Before the beginning of treatment, metallic fiducial markers were implanted percutaneously into the hepatic parenchyma adjacent to the tumors. The patient’s body was immobilized by an individually shaped body cast (ESFORM; Engineering System, Matsumoto, Japan). Treatment planning for proton beam therapy was based on respiratory-synchronized CT images at 5-mm intervals in the treatment position. Clinical target volume (CTV) was defined as gross tumor volume plus a 5-mm margin. A 5-mm margin was added to the CTV by means of enlarging a multileaf collimator on a plane perpendicular to the beam axis. An additional 5-mm margin in the caudal direction was added for respiratory movements. The CTV was homogeneously encompassed with more than 90% of the prescribed dose using the spread-out Bragg peak of proton beams. Multiple hepatic tumors were entirely included within the target volume. The treatment planning system automatically estimated conditions required for beam delivery, including ridge filter, range shifter, Table 1. Patient and tumor characteristics Total no. of patients Gender Men Women Age (y) Range Median Performance status 0 1 2 Hepatitis virus type HBV HCV None Child-Pugh classification Class A Class B Class C ICGR15 (%) Range Median Number of tumors Solitary Multiple Tumor size in maximum diameter (mm) Range Median Clinical stage T1N0M0, Stage I T3N0M0, Stage IIIA Serum AFP value (ng/mL) Range Median
21 13 8 80–85 81 7 10 4 1 11 9 15 5 1 1–52 21 17 4 10–135 40 17 4 1–15,240 14
Abbreviations: HBV = hepatitis B virus; HCV = hepatitis C virus; ICGR15 = indocyanine green retention rate at 15 min; AFP = alphafetoprotein.
Proton beam therapy for aged patients with HCC d M. HATA et al.
collimator, and bolus (15). The dose of proton beams was verified in an acryl phantom for each patient before initiation of treatment. Proton beams of 155–250 MeV generated by an accelerator with a synchrotron were used for treatment. Beams were synchronized with respiration and were delivered through one to six ports with coplanar angles using a rotational gantry. Respiratory gating was controlled by means of a semiconductor laser irradiated to the abdominal surface of patients, so that proton beams were delivered to the hepatic tumors in the expiratory phase, when the tumor position was considered to be at its most stable and reproducible. This respiratory gating has been previously reported and is briefly described as follows (16). A laser displacement sensor (LDS) (KEYENCE LB-300; KEYENCE, Osaka, Japan) was used for respiratory gating and gave information on the distance from the detector head to the subject. The LDS was placed so that the semiconductor laser could be focused on an area around the patient’s navel. When the distance from the LDS to a point on the abdominal surface changed because of breathing, the LDS detected this displacement as respiratory information. This information was digitized by an analogue-to-digital converter and was then placed into a gate generator in the form of a respiratory waveform. The waveform was expressed through a software program that we developed, and a gating signal was given to enable the accelerator to irradiate when the respiratory waveform dropped to the bottom, which corresponded to the expiratory end. In each treatment session, the positional relationship between the center of radiation fields and implanted fiducial markers was examined, with the patients lying in the treatment position, using the orthogonal fluoroscopy unit attached to the treatment unit. Respiratory gating and positional verification using implanted fiducial markers under fluoroscopy were considered useful for reducing the irradiated volume of the normal liver by enabling a decrease in the field margin for respiratory movements and setup error, respectively. Before treatment all patients were divided into three groups to determine total dose and fraction size according to tumor location, as follows: Group 1: 10 patients with tumors in the peripheral regions of the liver; Group 2: 5 patients with tumors in the central regions of the liver; and Group 3: 6 patients with tumors adjacent to the digestive tract, and the shortest distance between the digestive tract and tumors was <2 cm in these patients. Patients were prospectively treated in accordance with each treatment protocol, namely, total doses of 60 Gy in 10 fractions were delivered to Group 1, 66 Gy in 22 fractions to Group 2, and 70 Gy in 35 fractions to Group 3 (Table 2). Fraction size was decreased to prevent radiationinduced biliary stenosis in Group 2 compared with Group 1 and was further decreased to avoid severe complications of the digestive tract (e.g., ulcer, stenosis, and perforation) in Group 3. Moreover, in Group 3 the digestive tract was completely excluded from the irradiated volume after irradiation with 50 Gy in 25 fractions. All patients received irradiation in daily fractions, 5 days per week, and the overall treatment time was 12–64 days (median, 31 days). A relative biologic effectiveness value of 1.0 was used in accordance with data obtained from a fibrosarcoma NFSa cell line (17). The
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dose of 60 Gy in 10 fractions corresponded to 80 Gy and 108 Gy when 2 Gy per fraction-equivalent doses were given according to the linear quadratic model with a/b ratios of 10 and 3 for earlyand late-responding tissues, respectively, whereas that of 66 Gy in 22 fractions corresponded to 72 Gy and 79 Gy, respectively (18). Dose–volume analyses were performed in all patients to evaluate the irradiated volume and doses given to the liver.
Follow-up and evaluation criteria Patients underwent serum AFP value measurements and abdominal imaging studies (CT or MRI) 1 and 1–4 months after completion of treatment, respectively, and were followed up at 1–3-month intervals. Local responses to treatment were classified according to the modifications of the World Health Organization (WHO) response evaluation criteria, as follows (19). Complete response (CR) was defined as complete disappearance of the irradiated tumor; partial response (PR) corresponded to more than 50% reduction in the tumor volume; progressive disease (PD) was defined as more than 25% increase in the tumor volume; and no change (NC) referred to cases that did not qualify for CR, PR, or PD. Local responses in patients with multiple tumors were assessed on the basis of the worst tumor response among them. Complete response and PR were defined as objective responses. Growth of the irradiated tumor or appearance of a new disease after treatment was regarded as recurrence. When patients showed no growth of the irradiated tumors and no recurrence after treatment, they were considered local progression free and disease free, respectively. Acute and late toxicities associated with treatment were evaluated with the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity scoring criteria and the RTOG/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme, respectively (20).
Statistical analysis Actuarial survival and disease control rates were calculated from the beginning of proton beam therapy according to the KaplanMeier method (21). Differences in survivals were evaluated using the log–rank test (22). A p value of <0.05 was considered statistically significant. All statistical analyses were performed using the statistical software SPSS 11.0J (SPSS, Chicago, IL).
RESULTS Dose–volume analysis The CTV was 3–1295 cm3 (median, 32 cm3), and the total liver volume (TLV) (excluding CTV) was 589–1445 cm3 (median, 916 cm3). When a proportion (percentage) of CTV to TLV was defined as %CTV, it was 0.2–163% (median, 3.4%). The percentages of the volumes to which doses of 0 Gy, $30 Gy, and $50 Gy were irradiated in TLV were termed V0, V30, and V50. The V0, V30, and V50 were 29–96% (median, 65%), 2–38% (median, 14%), and 1–26% (median,
Table 2. Treatment protocols according to tumor location 2 Gy per fraction-equivalent dose (Gy) Group
No. of patients
Tumor location of the liver
Total dose (Gy/fractions)
a/b = 10
a/b = 3
Group 1 Group 2 Group 3
10 5 6
Peripheral Central Adjacent to the digestive tract
60/10 66/22 70/35
80 72 70
108 79 70
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7%), respectively. Mean liver doses (MLDs) were 1.2–21.7 Gy (median, 9.5 Gy). Typical dose-distribution curve and dose–volume histogram in treatment planning for a patient are demonstrated in Fig. 1. Outcomes of dose–volume analyses of livers in all patients are summarized in Table 3. Toxicity Acute reactions were transient, easily manageable, and caused no interruption in the treatment course (Table 4). Regarding adverse events of Grade $3, 2 patients showed thrombocytopenia of Grade 3. However, both patients had thrombocytopenia that corresponded to Grade 2 due to cirrhosis at the beginning of treatment.
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Table 3. Outcomes of dose–volume analyses of livers in 21 patients with hepatocellular carcinoma treated with proton beam therapy Variables
Range (median)
CTV (cm3) TLV (cm3) %CTV (%) V0 (%) V30 (%) V50 (%) MLD (Gy)
3–1295 (32) 589–1445 (916) 0.2–163 (3.4) 29–96 (65) 2–38 (14) 1–26 (7) 1.2–21.7 (9.5)
Abbreviations: CTV = clinical target volume; TLV = total liver volume; V0, V30, and V50 = percentage of the volume to which doses of 0 Gy, $30 Gy, and $50 Gy were irradiated in total liver volume; MLD = mean liver dose.
No late toxicities associated with treatment, especially mucosal toxicities of the digestive tract or radiation-induced liver disease (RILD), were observed. Liver function of all patients was well preserved, and there was no deterioration in Child-Pugh score 6 months after irradiation. Local control and failure patterns Irradiated tumors showed CR in 6 patients, PR in 9, and NC in 6, 1–4 months after completion of treatment. Final tumor responses were CR in 11 patients, PR in 8, and NC in 2 at the last follow-up period of 6–49 months (median, 16 months) after irradiation (Fig. 2). Objective response rate was 90%, and tumor sizes in 2 NC patients were still decreasing at the last follow-up. All irradiated tumors were controlled during the follow-up period, and the local-progression free rate was 100%. Pretreatment AFP values of 8 patients showed abnormally high levels of 23–15,240 ng/mL (median, 305 ng/mL) beyond the upper normal limit (20 ng/mL). These AFP values decreased to 3–6025 ng/mL (median, 31 ng/mL) after irradiation, and they were within the normal limits in 4 patients. On the other hand, 2 of the 4 patients who did not achieve normalization of AFP values showed recurrence. In the remaining 2 patients, AFP values were decreasing at the last follow-up, although they were still over the upper normal limit. Table 4. Therapy-related acute toxicities according to the Radiation Therapy Oncology Group acute radiation morbidity scoring criteria Fig. 1. Treatment planning of proton beam therapy with a total dose of 60 Gy in 10 fractions for a patient with hepatocellular carcinoma. (a) Isodose distribution of proton beams on a CT slice, delivered through two oblique ports. Isodose lines demonstrate 90% of the prescribed dose at the most inside and decreasing by 10% of the dose from inside out. Critical organs, such as the spinal cord and the digestive tract, are located entirely outside the irradiated volume, owing to the sharp distal fall-off of the Bragg peak of proton beams. (b) Dose–volume histograms of the clinical target volume (CTV) and liver. The CTV is entirely irradiated with $90% of the prescribed dose, and V30 and V50 of the liver are 32% and 20%, respectively.
Grade Toxicity Hematologic Leucopenia Anemia Thrombocytopenia Skin Erythema Upper gastrointestinal tract Appetite loss
1
2
3
4
2 1 3
7 0 3
0 0 2
0 0 0
3
2
0
0
1
0
0
0
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Fig. 2. Pretreatment and posttreatment contrast-enhanced computed tomography images of a patient with hepatocellular carcinoma. (a, b) Just before initiation of proton beam therapy, arrowheads represent position of the hepatic tumor, which is slightly and inhomogeneously enhanced in the arterial phase (a) and washed out in the portal venous phase (b). (c, d) Seven months after completion of proton beam therapy, almost complete disappearance of the hepatic tumor in both arterial (c) and portal venous phases (d) can be seen, although the liver parenchyma irradiated with a high dose shows enhancement due to radiation hepatitis.
Of 21 patients, 5 had recurrences 2–13 months after proton beam therapy. All 5 of these patients with recurrence showed new hepatic tumors outside the irradiated volume, and 1 of them also developed lung metastasis. Disease-free rates were 79% at 1 year and 72% at 3 years (Fig. 3). Of the 5 patients with recurrence, 1 received second and third courses of proton beam therapy, leading to control of the recurrent tumors. Of the remaining 4 patients, 2 were followed up with no further treatment because the new lesions were too small, whereas the other 2, including 1 patient with lung metastasis, underwent palliative or supportive care because the new tumors were considered uncontrollable.
Survival Of 21 patients, 7 died 6–49 months after treatment. Causes of death were trauma and old age in 2 patients each, and progressive HCC, pneumonia, and arrhythmia in 1 patient each. The cause-specific and disease-free survival rates were 100% and 70% at 1 year and 88% and 51% at 3 years, respectively (Fig. 4). The overall survival rates were 84% at 1 year and 62% at 3 years. When the expected survival rates were estimated for matching age and gender in the present cases,
according to survival data of the national statistics published by the Ministry of Health, Labor and Welfare of the Japanese Government, they were 94% at 1 year and 82% at 3 years (23). There was no significant difference between the overall survival and the expected survival rates (p = 0.13, Fig. 5). Clinical courses of all patients are shown in Table 5. DISCUSSION Surgical resection remains the most reliable curative treatment for HCC and provides a 5-year survival of 60–70% for patients with small solitary HCC and well-preserved liver function (24). However, only 20% of HCC patients can undergo surgical resection; the remainders are inoperable because of advanced tumors or comorbidities, including cirrhosis. Aged patients frequently are also considered inoperable owing to the intolerable physical burden of surgical procedures. Usually nonsurgical treatments, such as TACE, PEI, PMC, and RFA, are applied to inoperable patients with HCC. Transcatheter arterial chemoembolization is most frequently used as a nonsurgical treatment for HCC, but it is unfeasible for patients with severe cirrhosis owing to the
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Fig. 3. Local progression-free and disease-free rates of 21 patients with hepatocellular carcinoma treated with proton beam therapy.
Fig. 5. Overall and expected survivals of 21 patients with hepatocellular carcinoma treated with proton beam therapy. There was no significant difference between the two survivals (p = 0.13).
risk of liver failure, renal dysfunction, allergy to iodine, or no tumor staining. Furthermore, TACE is still regarded as a noncurative treatment for HCC, although it achieved objective responses in 15–55% of HCC patients, and survival benefits have been recently obtained in several randomized controlled trials (25–27). Percutaneous ethanol injection, PMC, and RFA are less invasive and curative treatments for small HCC and have been reported to result in first CR in approximately 80% of HCCs #3 cm in diameter (24, 28). However, 30–40% of patients with first CR experienced late local failure. Moreover, PEI, PMC, and RFA are unsuitable for patients with a bleeding tendency, unfavorable tumor location, or large-sized tumors; local failure developed in almost 70% of patients with HCCs of 3.1–5 cm in diameter and in all patients with HCCs >5 cm (24, 28). In addition to these treatment constraints, aggressive procedures are frequently difficult for aged patients with decreased physical strength.
Therefore, there are numerous aged patients with HCC who have limited treatment options and are unable to undergo effective treatments. Presently, the average life spans of eight countries, including Japan, are exceeding 80 years (29). The life expectancies for people aged 80 and 85 years in Japan are 8.2 and 5.9 years in men and 11.1 and 8.0 years in women, respectively (23). On the other hand, the median survival for patients with untreated HCC is 1 or 2 years at the most after diagnosis, and the cause of death is progressive HCC in the majority of patients (30, 31). Therefore, even patients aged 85 years should be entitled to an aggressive treatment with curative intent if it is safe and effective. A few previous studies reported nonsurgical treatments using TACE or PEI for HCC patients aged $80 years (32, 33). The overall survival rates were 54.1–75.5% at 1 year and 28.1–32.1% at 3 years, and almost half of the patients died of HCC. These results suggest that prognoses of HCC patients aged $80 years are improved by controlling HCC. Actually, in the present study, all irradiated tumors were controlled, and the overall survival rates of 84% at 1 year and 62% at 3 years were better than those of previous reports, although the follow-up period was still short. Proton beam therapy seemed to contribute to prolonged survival of aged patients with HCC. Recently, radiation therapy with photons has been attempted for the treatment of HCC as advanced radiation techniques have developed. Some investigators demonstrated that a higher dose delivered to the hepatic tumor achieved better local control and survival in HCC patients (34–38). Of note, it was reported that a total dose of $50 Gy in conventional fractions was necessary to significantly reduce tumor volume and to prolong survival of patients with unresectable HCC (34–37). However, it is difficult to safely give HCC patients the sufficient tumoricidal dose because of low-dose tolerance of the whole liver and poorly preserved liver function due to coexisting cirrhosis, even if advanced photon irradiation is used. Therefore, a median total dose
Fig. 4. Cause-specific and disease-free survivals of 21 patients with hepatocellular carcinoma treated with proton beam therapy.
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Table 5. Clinical courses of 21 patients aged $80 years with hepatocellular carcinoma treated with proton beam therapy Patient Age Child-Pugh no. (y)/gender PS class
No. of tumors
Tumor Total dose Tumor size (mm) (Gy/fractions) response
Pattern of failure
Follow-up period (mo) 15 21 49 16 38 35 32 27 15 25 14 23 7 17 17 6 12 11
1 2 3
83/M 81/M 85/M
1 2 1
A B A
Solitary Solitary Solitary
38 40 90
66/22 60/10 60/10
CR CR CR
4 5 6 7 8
80/M 80/M 81/F 82/F 82/F
1 0 1 1 0
A A A A A
Solitary Multiple Multiple Solitary Solitary
13 80 68 30 27
60/10 66/22 60/10 70/35 60/10
CR PR PR CR CR
Liver (OIV) Liver (OIV) Liver (OIV), Lung None None None None Liver (OIV)
9 10 11 12 13 14 15 16 17 18
82/M 81/M 84/F 80/M 80/F 80/F 81/M 80/F 81/M 82/M
2 0 1 0 1 1 0 1 1 2
B A A A A A B C B B
Multiple Solitary Solitary Solitary Solitary Solitary Solitary Solitary Solitary Solitary
135 30 104 28 60 43 10 20 40 45
66/22 60/10 70/35 66/22 70/35 60/10 70/35 60/10 60/10 70/35
PR PR PR PR PR CR CR CR CR PR
None None None None None None None None None Liver (OIV)
19 20 21
84/F 84/M 80/M
0 0 2
A A A
Multiple Solitary Solitary
56 33 19
66/22 60/10 70/35
NC CR NC
None None None
8 8 8
Recent status Dead of trauma Dead of HCC Dead of pneumonia Alive with NED Alive with NED Alive with NED Alive with NED Alive with recurrence Dead of old age Alive with NED Dead of trauma Alive with NED Dead of old age Alive with NED Alive with NED Dead of arrhythmia Alive with NED Alive with recurrence Alive with NED Alive with NED Alive with NED
Abbreviations: PS = performance status; M = male; F = female; CR = complete response; OIV = outside of the irradiated volume; HCC = hepatocellular carcinoma; NED = no evidence of disease; PR = partial response; NC = no change.
of <60 Gy was used to treat HCC in most previous studies using photons, and the objective response rate was <70% (34–39). In all patients in the present series, total doses of $70 Gy in 2 Gy per fraction-equivalent were aggressively delivered to HCCs using proton beams, and an objective response rate of 90% and a local progression-free rate of 100% were achieved, although tumor size was $40 mm in 11 patients and even $80 mm in 4 patients. Conversely, a dose of 60 Gy in 10 fractions, which was maximal in 2 Gy per fraction-equivalent doses among the doses used in the present series, may be excessive to control HCCs, considering that all HCCs treated with doses of 66 Gy in 22 fractions or 70 Gy in 35 fractions showed no local progression. It should be particularly noted that of the 11 patients treated with doses of 66 Gy in 33 fractions or 70 Gy in 35 fractions, 4 had tumors with a maximum diameter $6 cm, and all tumors were locally controlled. Our previous study demonstrated that a total dose of 72 Gy in 16 fractions with a fraction size of 4.5 Gy could be safely delivered to HCCs located in the peripheral regions of the liver (6). Furthermore, an excellent local control rate of 86.9% at 5 years was achieved with doses used previously. This dose corresponded to 87 Gy and 108 Gy in 2 Gy per fraction-equivalent doses, with a/b ratios of 10 and 3, respectively. The present fractionation regimens were decided on the basis of these previous results. Although optimal doses remain unknown for each patient in various conditions, it is possible that a subset of HCCs may be controlled with lower total doses than those assumed necessary in the present study.
The radiation tolerance of the whole normal liver is reported to be approximately 30 Gy in conventional fractions (40). Several studies revealed that the radiation tolerance of the liver was strongly affected by the irradiated volume of the liver; for instance, the doses associated with a 5% risk of RILD for irradiation volumes of one third and two thirds are 90 Gy and 47 Gy, respectively (41, 42). These findings suggest that high-dose irradiation can be delivered safely to a part of the liver including HCC. The V30 and V50 in the present study were far smaller than those assumed to be tolerable. Mean liver dose is also proposed as a reliable predictor of RILD, and MLD associated with 5% risk of RILD is reported to be 28 Gy in conventional fractions (43). Mean liver dose in the current study was also within the above safe limits. Actually, no RILD was observed in the present series, and liver function was well preserved. Furthermore, abundant nonirradiated volume (V0) caused by the Bragg peak of proton beams may allow re-irradiation to newly developed HCC, while preserving liver function. However, the relationship between dose and volume in hypofractionated high-dose irradiation cannot be dealt with in the same way as that in conventional irradiation. There are few previous reports on dose–volume analyses of the liver in hypofractionated high-dose irradiation, so further investigations with a larger number of patients and longer follow-up period are required. In conclusion, proton beam therapy seemed to be tolerable, effective, and safe for aged patients with HCC. The current results suggest that this method contributes to prolonged survival due to tumor control.
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I. J. Radiation Oncology d Biology d Physics
Volume 69, Number 3, 2007
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