bs_bs_banner
doi:10.1111/jgh.12843
GASTROENTEROLOGY
Proton beam therapy for unresectable intrahepatic cholangiocarcinoma Ayako Ohkawa,* Masashi Mizumoto,* Hitoshi Ishikawa,* Masato Abei,† Kuniaki Fukuda,† Takayuki Hashimoto,* Takeji Sakae,* Koji Tsuboi,* Toshiyuki Okumura* and Hideyuki Sakurai* Departments of *Radiation Oncology and †Gastroenterology, University of Tsukuba, Tsukuba, Ibaraki, Japan
Key words intrahepatic cholangiocarcinoma, proton beam therapy, radiotherapy, unresectable. Accepted for publication 27 October 2014. Correspondence Dr Hideyuki Sakurai, Department of Radiation Oncology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Email: [email protected] Funding: This work was supported by Grants-in-Aid for Scientific Research (B) (24390286), Challenging Exploratory Research (24659556), Young Scientists (B) (25861064), and Scientific Research (C) (24591832) from the Ministry of Education, Science, Sports and Culture of Japan. Conflict of interest: None.
Abstract Background and Aim: Treatment for unresectable intrahepatic cholangiocarcinoma (ICC) has not been established. The aim of the study was to evaluate the outcome of proton beam therapy (PBT) for patients with unresectable ICC. Methods: Up to 2010, 20 patients (11 males, 9 females, median age 63 years old) with unresectable ICC (two, seven, seven, and four in stages II, IIIA, IIIC, and IV, respectively) were treated with PBT. The largest dimensions of the tumors ranged from 15 to 140 mm (median: 50 mm). The intrahepatic region and lymph nodes received median total proton doses of 72.6 GyE in 22 fractions and 56.1 GyE in 17 fractions, respectively. Four patients received concurrent chemotherapy (tegafur, gimeracil, and oteracil; TS-1) during PBT. Twelve patients were treated curatively, and eight were treated palliatively because tumors were present outside the irradiation field. Results: In the curative group, nine tumors within the irradiated field were controlled in follow-up of 8.6–62.6 months (median: 20.8 months). Median survival rates in the curative and palliative groups were 27.5 and 9.6 months, respectively, and overall 1- and 3-year survival rates were 82% and 38%, and 50% and 0%, respectively. Eight patients survived for > 2 years, and there was no distant metastasis in five of these patients after 2 years. No severe side-effects occurred. Conclusions: The results suggest that long-term survival can be achieved using PBT for patients with unresectable ICC without distant metastasis. Further studies are required to determine the optimal treatment schedule and best combination of PBT and chemotherapy.
Introduction Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the first and second most common cancers of the liver. Japanese data on liver cancer from 2002 and 20031 indicate that 94.2% of malignant neoplasms in the liver were HCC and 4.1% were ICC. In comparison with HCC, rapid local progression and both lymphogenous and hematogenous metastasis often lead to a poor prognosis in ICC cases. Surgery offers the only curative option, but a curative operation is possible in only about 30% of cases of ICC.2 Combined chemotherapy is a treatment option for unresectable ICC, but the prognosis is very poor.3 In these circumstances, it remains unclear if radiation therapy can improve survival in patients with ICC who cannot undergo surgery. Proton beam therapy (PBT) is increasingly used for radiation therapy in medical care. PBT yields excellent dose localization to the target compared with conventional photon irradiation and is able to preserve normal tissue function by avoiding irradiation of surrounding organs. Our previous reports for HCC indicate that PBT can achieve a good local control without severe late toxicity.4–15 PBT is also important as a curative treatment for large
HCC, tumor thrombus, and HCC with poor liver function.10,12,15 In this study, we evaluated the outcome of PBT for patients with unresectable ICC, which is another type of malignant liver tumor.
Methods Patients. Between 1995 and 2009, 20 patients with unresectable ICC were treated with PBT at the Proton Medical Research Center, University of Tsukuba. Eleven were male, nine were female, and the median age was 63 years old (range: 32–82 years old). The Eastern Cooperative Oncology Group PS was 0, 1, and 2 in eight, seven, and five patients, respectively. In the Union for International Cancer Control (UICC) classification ver. 6, there were two patients in stage II (T2N0), seven in stage IIIA (T3N0), seven in stage IIIC (TxN1), and four in stage IV (TxNxM1). Surgery was not performed in stage II patients for various medical reasons. Nine cases were histologically proven to be ICC, and others were diagnosed clinically using diagnostic imaging and tumor markers. The Child–Pugh category for impairment of liver function was class A in 14 patients, class B in 6, and class C in 0.
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
957
Proton beam therapy
Table 1
A Ohkawa et al.
Patient characteristics of 20 patients treated with PBT
Age (median)
Gender Male Female ECOG performance status 0 1 2 TNM (UICC ver. 6) II (T2N0M0) IIIA (T3N0M0) IIIC (TxN1M0) IV (TxNxM1) Maximum diameter of tumor < 50 mm 51–99 mm ≥ 100 mm Number of tumors Solitary Multiple
Curative (n = 12) 55–82 (74)
Palliative (n = 8) 32–81 (63)
Total (n = 20) 32–82 (63)
7 5
4 4
11 9
6 3 3
2 4 2
8 7 5
2 7 3 0
0 0 4 4
2 7 7 4
6 5 1
3 3 2
9 8 3
9 4
4 3
13 7
ECOG, Eastern Cooperative Oncology Group; TNM, TNM classification of malignant tumors; UICC, Union for International Cancer Control.
None of the patients were positive for hepatitis B virus, but three were positive for hepatitis C virus. The tumors ranged in size from 15 to 140 mm (median: 50 mm) in the greatest dimension. Thirteen patients had a solitary tumor and seven had multiple liver tumors. Four patients had a history of cancer treatment before PBT, including chemotherapy, and three patients had a history of liver surgery for previous HCC or ICC. The patient characteristics are summarized in Table 1. The 20 patients were divided into two groups based on receiving curative or palliative treatment. Cases in which the tumors could be irradiated by PBT with curative intent were classified as the curative group.Among the stage IIIC (TxN1) cases, three of seven patients were treated with curative intent, but in the other four cases all the tumors (including lymph node metastases) could not be irradiated sufficiently because the tumor distribution was too wide. Therefore, these four patients were included in the palliative group. Written informed consent was obtained from all patients prior to conduct of PBT.
multileaf collimator and adjusting the range shifter. Proton beams from 155 to 250 MeV generated by a linear accelerator and synchrotron were spread out and shaped with ridge filters, doublescattering sheets, multicollimators, and a custom-made bolus to ensure that the beams conformed to the treatment planning data. The intrahepatic region received a median total dose of protons of 72.6 GyE in 22 fractions (range: 55 GyE in 10 fractions to 79.2 GyE in 16 fractions). The schedule was selected depending on the tumor location: a total dose of 60–77.0 GyE in 30–35 fractions for tumors within 2 cm of the gastrointestinal tract (n = 4), 72.6–79.2 GyE in 16–22 fractions for tumors within 2 cm of central structures such as the porta hepatis (n = 14), and 55–66 GyE in 10 fractions for tumors that were not adjacent to the gastrointestinal tract or a hepatic central structure (n = 3). The relative biological effectiveness of the PBT was assumed to be 1.1.18 For treatment of lymph node metastases, the median total dose of proton radiation was 72.6 GyE in 22 fractions (range: 50 GyE in 25 fractions to 72.6 GyE in 22 fractions). Four patients received oral chemotherapy of tegafur, gimeracil, and oteracil (TS-1) during PBT. Adjuvant chemotherapy was performed after PBT in three cases. Follow-up. During treatment, acute treatment-related toxicities were assessed weekly in all patients. After completion of PBT, patients were evaluated by physical examinations, CT or magnetic resonance imaging, and blood tests every 3 months for the first 2 years and every 6 months thereafter. Local progression was defined as tumor regrowth in the radiation field in imaging with or without biopsy. Distant metastases were diagnosed by imaging alone in most cases. Morbidity was scored using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria ver. 4.19 The median follow-up period was 19.3 months (range: 4.4–62.6 months) for all 20 cases. Statistical methods. Statistical tests were performed using the Dr. SPSS II package (SPSS Inc., Chicago, IL, USA). Overall survival was defined as the time interval between the start of PBT and the last follow-up when the patient was alive. Calculation of the local control rate was based on the date on which tumor progression was found. Overall survival and local control were determined from Kaplan–Meier curves.20 A log–rank test and Kaplan–Meier curves were used to compare the curative and palliative groups.
Results PBT. The physical properties of the proton beams we use for irradiation of the liver have been described elsewhere.16,17 Prior to treatment planning, metallic fiduciary markers (iridium seeds of 0.8 mm in diameter and 2 mm in length) for PBT were implanted percutaneously into the hepatic parenchyma adjacent to the tumors to aid in positioning. After making an individual immobilization cradle, computed tomography (CT) images were taken at 5-mm intervals during the expiratory phase under a respiratory gating system (Anzai Medical Co., Tokyo, Japan). The clinical target volume (CTV) encompassed the gross tumor volume with a 5- to 10-mm margin in all directions. An additional margin of 5–10 mm was included on the caudal axes to compensate for uncertainty due to respiration-induced hepatic movement. Another margin of 5–10 mm was added to cover the entire CTV by enlarging the 958
Local control and survival. A Kaplan–Meier curve showing local control in the 12 patients in the curative group is shown in Figure 1a. Nine of the 12 tumors in the irradiated field were controlled at the final follow-up after a follow-up period of 8.6–62.6 months (median: 22.2 months). The 1-, 2-, and 3-year local control rates in the curative group were 88%, 60%, and 60%, respectively. Three patients with poor local control developed intrahepatic and distant metastasis. Of the nine patients with good local control, two developed intrahepatic metastasis, one had regional lymph node metastasis, and two had distant metastases. Four patients were disease-free at the last follow-up. Overall survival curves in the curative and palliative groups are shown in Figure 1b. The curative group had higher 1-, 2-, and
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Ohkawa et al.
(a)
Proton beam therapy
Table 2 ver. 4
1.0
Side-effects in patients treated with PBT based on NCI-CTCAE
Local control rate
0.8 0.6 0.4 0.2 0.0 12
(b)
1.0
24 Time (month)
36
P = 0.048 Curave group (n = 12)
Survival rate
0.8
Grade 2
3
6 1 3 0 3 0
2 4 0 1 1 2
0 0 0 0 1 0
1 0 0
0 1 0
0 0 2
NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events; PBT, proton beam therapy.
distant metastasis was observed in five of these patients at ≥ 2 years. Overall survival curves in patients with and without jaundice at the start of PBT are shown in Figure 1c. Patients with jaundice had lower 1-, 2-, and 3-year survival rates of 17%, 0%, and 0%, respectively, compared with 92%, 60%, and 37%, respectively, in patients without jaundice.
0.6 0.4 0.2
Incurave group (n = 8)
0.0 12
24
36
Time (month) (c)
Acute Dermatitis Anorexia Nausea Gastric ulcer Bone marrow suppression Elevated transaminase Late Dermatitis Gastric ulcer Biliary tract infection
1
1.0
P = 0.002
Side-effects. Acute and chronic side-effects are summarized in Table 2. Grade 3 or higher acute toxicity did not occur, except for bone marrow suppression. One patient developed a grade 2 gastric ulcer, which was close to irradiation field, but the condition resolved with medication with a proton pump inhibitor. Biliary tract infection that required stent insertion occurred in two patients in the late phase.
Without jaundice (n = 14)
0.8 Survival rate
Case presentations 0.6
0.4
0.2
Jaundice (n = 6)
0.0 12
24
36
Time (month) Figure 1 (a) Kaplan–Meier estimate of local control for patients in the curative group (n = 12). (b) Kaplan–Meier estimates of overall survival for patients in the curative and palliative groups. (c) Kaplan–Meier estimates of overall survival for patients with and without jaundice at the start of proton beam therapy.
3-year survival rates of 82%, 61%, and 38%, respectively, compared with 50%, 25%, and 0%, respectively, in the palliative group. The median survival periods were 27.5 and 9.6 months in the respective groups. Eight patients survived for ≥ 2 years, and no
Case 1. The patient was a 78-year-old male in whom a liver tumor was detected during an examination for early gastric cancer. The tumor had a size of 87 × 66 mm and was located in the caudal lobe, with invasion of the medial lobe and regional lymph node metastases. Surgical resection was impossible because of inferior vena cava and hepatic vein invasion. Tumor markers were elevated: carcinoembryonic antigen (CEA) 838.3 ng/mL and carbohydrate antigen (CA19-9) 2172 U/mL. The tumor was in stage IIIC with T3N1M0 (UICC 6th edition). PBT of 72.6 GyE in 22 fractions and oral TS-1 chemotherapy (100 mg/day for 4 weeks followed by withdrawal for 2 weeks) was started. After PBT, the tumor gradually shrunk (Fig. 2). At the last evaluation at 45 months after PBT, disease progression was not detected, and CEA and CA19-9 had decreased to 6.6 ng/mL and 60.0 U/mL, respectively. Gastric ulcer was observed after PBT, but was cured with medical management. Case 2. The patient was a 74-year-old female in whom abnormal liver function and a liver tumor were detected in a routine examination after treatment of breast cancer. She was diagnosed with ICC based on a biopsy. The tumor had invaded from the left lobe
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
959
Proton beam therapy
A Ohkawa et al.
a b
c
d
e
Figure 2 Course of case 1. (a) Computed tomography (CT) image before proton beam therapy (PBT). (b) Dose-distribution chart of administration of a total proton dose of 72.6 GyE in 22 fractions. Isodose curves representing 100–10% of the prescribed dose are shown at 10% intervals. (c, d, e) CT images showing the treatment course at 6, 12, and 41 months after PBT, respectively. Arrowheads shows the tumor in (a), (c), and (d). The tumor gradually decreased in size and had disappeared at 41 months after PBT (e).
960
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Ohkawa et al.
a
Proton beam therapy
b
PBT :74GyE /37 fx
Cranial field
Caudal field
c
d
Figure 3 Course of case 2. (a) Computed tomography (CT) image before proton beam therapy (PBT). (b) Dose-distribution chart of administration of a total proton dose of 74 GyE in 37 fractions. The tumor was large and extended beyond the available PBT field size. Therefore, two different fields were used to cover the tumor. The dose to the alimentary tract was restricted to 50 GyE in this case. (c, d) CT images showing the treatment course at 12 and 36 months after PBT, respectively. Arrowheads shows the tumor in (a), (c), and (d). The tumor gradually decreased in size and was well controlled at 36 months after PBT (d).
to the right lobe and had a size of 14 × 10 cm. The left portal vein was obstructed by the tumor, and the intrahepatic biliary duct was dilated. Tumor markers had normal values. The tumor was in stage IIIA with T3N0M0 (UICC 6th edition). Surgical resection was impossible. Gemcitabine was administered, but the tumor size was unchanged. Therefore, PBT of 74 GyE in 37 fractions with oral TS-1 (50 mg/day for 4 weeks followed by withdrawal for 2 weeks) was started. The tumor was too large to irradiate in a single field; therefore, two fields were used. After PBT, the tumor decreased in size (Fig. 3), but single liver and lung metastases were detected 18 months later. Secondary PBT of 66 GyE in 33 fractions and stereotactic photon radiotherapy of 66 Gy in 10 fractions were conducted for the respective metastases and these disappeared completely. At 38 months after the start of PBT, the patient is alive and disease-free.
Discussion Patients with unresectable advanced cholangiocarcinoma generally have a very poor prognosis. In a review of the natural history
and prognostic factors in 203 patients with ICC and 127 with hilar cholangiocarcinoma, with no history of surgery, chemotherapy, or radiotherapy, Park et al.3 found a median overall survival time of 3.9 months for the entire cohort. The patients with ICC had more aggressive tumors and median survival of only 3.0 months, compared with 5.9 months for those with hilar cholangiocarcinoma. Surgery is considered to be the only curative method for ICC. Sulpice et al. found a median survival time of 33 months, and 1-, 3-, and 5-year overall survival rates of 79%, 47%, and 31% in 87 patients with ICC after partial liver resection with curative intent.21 In 367 patients who underwent partial hepatectomy for ICC, Wang et al. found a median survival period of 21.0 months, and 1-, 3-, and 5-year overall survival rates of 61.9%, 40.8%, and 35.2%, respectively.22 In this cohort, factors with an independent association with survival included serum CEA, CA 19-9, tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extrahepatic metastasis. Tumor location is an important factor in deciding whether a surgical procedure can be performed. In 250 surgical cases with perihilar cholangiocarcinoma, Ebata et al. found that 3-year
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
961
Proton beam therapy
A Ohkawa et al.
survival was marginally better for 167 patients with extrahepatic cholangiocarcinoma and compared with 83 patients with ICC (43.4% vs 29.0%).23 More aggressive surgery, such as extended hepatic resection, may help with long-term survival in ICC. Ohtsuka et al. found that hemi- or more extensive hepatectomy was performed in 40 of 50 patients (80%) who underwent surgical resection with macroscopic curative objectives. The 1-, 3-, and 5-year overall survival rates in these 50 patients were 61%, 38%, and 23%, respectively, with a median survival time of 25.5 months.24 These reports suggest that surgery is worthwhile as a curative treatment for ICC, but the prognosis after hepatectomy is still unsatisfactory, with a high incidence of locoregional and distant metastasis. Combined chemotherapy is the standard therapy for unresectable biliary duct cancer. Gemcitabine is a key agent, and cisplatin, oxaliplatin, and capecitabine have also been used in combination therapy. Recent clinical studies have shown median overall survival of 8.8–12.7 months using combined chemotherapy regimens, including gemcitabine.25–27 S-1, an oral fluoropyrimidine regimen containing tegafur, gimeracil, and oteracil potassium, may be a good candidate for treatment of advanced biliary duct cancer due of its cytotoxicity. However, combined chemotherapy using S-1 did not give a marked survival benefit, with median overall survival found to be 8.7–11.6 months.28,29 Patients with unresectable ICC have a limited benefit from systemic standard chemotherapy, with a meta-analysis showing a survival benefit of only a few months using chemotherapy-based transarterial therapy.30 Several studies have described palliative radiation therapy for unresectable ICC. Shinohara conducted a retrospective analysis of 3839 patients with ICC in their Surveillance, Epidemiology, and End Results (SEER) database. The cure rate remained low, with median overall survival of 11, 6, 7, and 3 months for surgery and adjuvant radiation therapy, surgery alone, radiation alone, and no treatment, respectively.31 However, there was a significant difference in overall survival for surgery versus surgery plus radiation (P = 0.014), and for radiation versus no treatment (P < 0.0001). More recently, Chen found that conventional radiation therapy at 50 Gy gave prolonged survival in ICC, with median survival times of 5.1 and 9.5 months without and with radiation therapy, respectively (P = 0.003). These studies show that radiation therapy can improve the prognosis and relieve symptoms in patients with unresectable ICC, even if given with palliative intent. Treatment of ICC with more intensive radiation therapy, such as stereotactic body radiation therapy (SBRT) or particle therapy, has not been reported, and the current study is the first report of treatment of ICC with high dose PBT. The 3-year control rate was about 60% and median survival was 27.5 months in the curative group. The number of patients in the study was small, but the survival time is close to that for surgery, which has been thought of as the sole curative method for ICC.21,24 We previously showed that PBT for HCC gave a 5-year local control rate of 80–90%.7,8 We used three treatment protocols depending on tumor location—74 GyE in 37 fractions (close to the gastrointestinal tract), 72.6 GyE in 22 fractions (close to the porta hepatis), and 66 GyE in 10 fractions—and found no significant difference in the local control rates of these protocols.7 In the current study, the optimal treatment protocol for ICC was uncertain, and so we selected a protocol similar to that for HCC. The 962
median dose for ICC was 72.6 GyE in 22 fractions. A tumor response similar to that of HCC should give a 5-year local control rate of 80–90%. However, the 3-year local control rate of ICC was only 60%, which suggests a lower tumor response compared with that of HCC. Hence, we recommend treatment for ICC using at least the same dose as that used for HCC. Dose escalation and/or concurrent chemotherapy may also be needed to achieve better local control. Patients with jaundice (a relatively small number in the study) had a significantly poorer prognosis compared with those who did not have jaundice, and a short course treatment protocol may be better in cases of jaundice. Radiofrequency ablation (RFA) is another intense treatment for a liver tumor. In 12 patients with ICC treated with RFA, Fu et al. obtained a median survival time of 30 months.32 However, RFA with curative intent is applicable only to small tumors of < 3 cm, while PBT was used to treat larger tumors ranging in size from 15 to 140 mm (median: 50 mm) in the current study. Intensive local therapy for liver tumors can result in severe side-effects, especially in the digestive tract. In 27 patients with unresectable hilar cholangiocarcinoma treated with Linac-based SBRT at 45 Gy in 3 fractions, Kopek et al.33 found median progression-free and overall survival of 6.7 and 10.6 months, respectively. However, six patients developed severe duodenal/ pyloric ulceration and three had duodenal stenosis, which may have been due to the SBRT being performed using an abdominal compression device attached to the stereotactic body frame. More recently, Polistina et al. found no higher than grade 3 toxicity in SBRT for ICC using the cyberknife system, which allows for respiratory motion-tracking during irradiation.34 In our study using a respiratory gating system with metallic fiduciary markers, no higher than grade 3 toxicity in the digestive tract was found. These results show the importance of exact control of respiratory motion during intense radiation therapy. In conclusion, long-term survival can be achieved using PBT for patients with ICC without distant metastasis. We found that PBT is a safe treatment that resulted in a median survival time of 27.5 months for patients with unresectable ICC. Further studies are required to determine the optimal total dose, fractionation schedules, and the best combination of PBT and chemotherapy, and to compare the outcome of PBT with that of surgery as a curative treatment for ICC.
References 1 Ikai I, Arii S, Okazaki M et al. Report of the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan. Hepatol. Res. 2007; 37: 676–91. 2 Kuhlmann JB, Blum HE. Locoregional therapy for cholangiocarcinoma. Curr. Opin. Gastroenterol. 2013; 29: 324–8. 3 Park J, Kim MH, Kim KP et al. Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study. Gut Liver 2009; 3: 298–305. 4 Fukumitsu N, Sugahara S, Nakayama H et al. A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2009; 74: 831–6. 5 Mizumoto M, Tokuuye K, Sugahara S et al. Proton beam therapy for hepatocellular carcinoma adjacent to the porta hepatis. Int. J. Radiat. Oncol. Biol. Phys. 2008; 71: 462–7.
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Ohkawa et al.
6 Nakayama H, Sugahara S, Fukuda K et al. Proton beam therapy for hepatocellular carcinoma located adjacent to the alimentary tract. Int. J. Radiat. Oncol. Biol. Phys. 2011; 80: 992–5. 7 Mizumoto M, Okumura T, Hashimoto T et al. Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols. Int. J. Radiat. Oncol. Biol. Phys. 2011; 81: 1039–45. 8 Nakayama H, Sugahara S, Tokita M et al. Proton beam therapy for hepatocellular carcinoma: the University of Tsukuba experience. Cancer 2009; 115: 5499–506. 9 Sugahara S, Oshiro Y, Nakayama H et al. Proton beam therapy for large hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2010; 76: 460–6. 10 Sugahara S, Nakayama H, Fukuda K et al. Proton-beam therapy for hepatocellular carcinoma associated with portal vein tumor thrombosis. Strahlenther. Onkol. 2009; 185: 782–8. 11 Hata M, Tokuuye K, Kagei K et al. Hypofractionated high-dose proton beam therapy for stage I non-small-cell lung cancer: preliminary results of a phase I/II clinical study. Int. J. Radiat. Oncol. Biol. Phys. 2007; 68: 786–93. 12 Hata M, Tokuuye K, Sugahara S et al. Proton beam therapy for hepatocellular carcinoma with limited treatment options. Cancer 2006; 107: 591–8. 13 Hata M, Tokuuye K, Sugahara S et al. Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus. Cancer 2005; 104: 794–801. 14 Hata M, Tokuuye K, Sugahara S et al. Proton beam therapy for aged patients with hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2007; 69: 805–12. 15 Mizumoto M, Tokuuye K, Sugahara S et al. Proton beam therapy for hepatocellular carcinoma with inferior vena cava tumor thrombus: report of three cases. Jpn J. Clin. Oncol. 2007; 37: 459–62. 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: 951–8. 17 Oshiro Y, Okumura T, Ishida M et al. Displacement of hepatic tumor at time to exposure in end-expiratory-triggered-pulse proton therapy. Radiother. Oncol. 2011; 99: 124–30. 18 Paganetti H, Niemierko A, Ancukiewicz M et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int. J. Radiat. Oncol. Biol. Phys. 2002; 53: 407–21. 19 Common Terminology Criteria for Adverse Events (CTCAE) V.4.0. 2013. Bethesda, MD, USA: National Institute of Health, National Cancer Institute, 2009. 20 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 1958; 31: 457–81.
Proton beam therapy
21 Sulpice L, Rayar M, Boucher E et al. Treatment of recurrent intrahepatic cholangiocarcinoma. Br. J. Surg. 2013; 99: 1711–7. 22 Wang Y, Li J, Xia Y et al. Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. J. Clin. Oncol. 2013; 31: 1188–95. 23 Ebata T, Kamiya J, Nishio H et al. The concept of perihilar cholangiocarcinoma is valid. Br. J. Surg. 2009; 96: 926–34. 24 Ohtsuka M, Ito H, Kimura F et al. Extended hepatic resection and outcomes in intrahepatic cholangiocarcinoma. J. Hepatobiliary Pancreat. Surg. 2003; 10: 259–64. 25 Valle J, Wasan H, Palmer DH et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 2010; 362: 1273–81. 26 Andre T, Reyes-Vidal JM, Fartoux L et al. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br. J. Cancer 2008; 99: 862–7. 27 Riechelmann RP, Townsley CA, Chin SN et al. Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer 2007; 110: 1307–12. 28 Sasaki T, Isayama H, Nakai Y et al. Multicenter, phase II study of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer. Cancer Chemother. Pharmacol. 2010; 65: 1101–7. 29 Kim YJ, Im SA, Kim HG et al. A phase II trial of S-1 and cisplatin in patients with metastatic or relapsed biliary tract cancer. Ann. Oncol. 2008; 19: 99–103. 30 Ray CE Jr, Edwards A, Smith MT et al. Metaanalysis of survival, complications, and imaging response following chemotherapy-based transarterial therapy in patients with unresectable intrahepatic cholangiocarcinoma. J. Vasc. Interv. Radiol. 2013; 24: 1218–26. 31 Shinohara ET, Mitra N, Guo M et al. Radiation therapy is associated with improved survival in the adjuvant and definitive treatment of intrahepatic cholangiocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2008; 72: 1495–501. 32 Fu Y, Yang W, Wu W et al. Radiofrequency ablation for postoperative recurrences of intrahepatic cholangiocarcinoma. Chin. J. Cancer Res. 2011; 23: 295–300. 33 Kopek N, Holt MI, Hansen AT et al. Stereotactic body radiotherapy for unresectable cholangiocarcinoma. Radiother. Oncol. 2010; 94: 47–52. 34 Polistina FA, Guglielmi R, Baiocchi C et al. Chemoradiation treatment with gemcitabine plus stereotactic body radiotherapy for unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma. Results of a five year experience. Radiother. Oncol. 2011; 99: 120–3.
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
963
doi:10.1111/jgh.12843
GASTROENTEROLOGY
Proton beam therapy for unresectable intrahepatic cholangiocarcinoma Ayako Ohkawa,* Masashi Mizumoto,* Hitoshi Ishikawa,* Masato Abei,† Kuniaki Fukuda,† Takayuki Hashimoto,* Takeji Sakae,* Koji Tsuboi,* Toshiyuki Okumura* and Hideyuki Sakurai* Departments of *Radiation Oncology and †Gastroenterology, University of Tsukuba, Tsukuba, Ibaraki, Japan
Key words intrahepatic cholangiocarcinoma, proton beam therapy, radiotherapy, unresectable. Accepted for publication 27 October 2014. Correspondence Dr Hideyuki Sakurai, Department of Radiation Oncology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Email: [email protected] Funding: This work was supported by Grants-in-Aid for Scientific Research (B) (24390286), Challenging Exploratory Research (24659556), Young Scientists (B) (25861064), and Scientific Research (C) (24591832) from the Ministry of Education, Science, Sports and Culture of Japan. Conflict of interest: None.
Abstract Background and Aim: Treatment for unresectable intrahepatic cholangiocarcinoma (ICC) has not been established. The aim of the study was to evaluate the outcome of proton beam therapy (PBT) for patients with unresectable ICC. Methods: Up to 2010, 20 patients (11 males, 9 females, median age 63 years old) with unresectable ICC (two, seven, seven, and four in stages II, IIIA, IIIC, and IV, respectively) were treated with PBT. The largest dimensions of the tumors ranged from 15 to 140 mm (median: 50 mm). The intrahepatic region and lymph nodes received median total proton doses of 72.6 GyE in 22 fractions and 56.1 GyE in 17 fractions, respectively. Four patients received concurrent chemotherapy (tegafur, gimeracil, and oteracil; TS-1) during PBT. Twelve patients were treated curatively, and eight were treated palliatively because tumors were present outside the irradiation field. Results: In the curative group, nine tumors within the irradiated field were controlled in follow-up of 8.6–62.6 months (median: 20.8 months). Median survival rates in the curative and palliative groups were 27.5 and 9.6 months, respectively, and overall 1- and 3-year survival rates were 82% and 38%, and 50% and 0%, respectively. Eight patients survived for > 2 years, and there was no distant metastasis in five of these patients after 2 years. No severe side-effects occurred. Conclusions: The results suggest that long-term survival can be achieved using PBT for patients with unresectable ICC without distant metastasis. Further studies are required to determine the optimal treatment schedule and best combination of PBT and chemotherapy.
Introduction Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the first and second most common cancers of the liver. Japanese data on liver cancer from 2002 and 20031 indicate that 94.2% of malignant neoplasms in the liver were HCC and 4.1% were ICC. In comparison with HCC, rapid local progression and both lymphogenous and hematogenous metastasis often lead to a poor prognosis in ICC cases. Surgery offers the only curative option, but a curative operation is possible in only about 30% of cases of ICC.2 Combined chemotherapy is a treatment option for unresectable ICC, but the prognosis is very poor.3 In these circumstances, it remains unclear if radiation therapy can improve survival in patients with ICC who cannot undergo surgery. Proton beam therapy (PBT) is increasingly used for radiation therapy in medical care. PBT yields excellent dose localization to the target compared with conventional photon irradiation and is able to preserve normal tissue function by avoiding irradiation of surrounding organs. Our previous reports for HCC indicate that PBT can achieve a good local control without severe late toxicity.4–15 PBT is also important as a curative treatment for large
HCC, tumor thrombus, and HCC with poor liver function.10,12,15 In this study, we evaluated the outcome of PBT for patients with unresectable ICC, which is another type of malignant liver tumor.
Methods Patients. Between 1995 and 2009, 20 patients with unresectable ICC were treated with PBT at the Proton Medical Research Center, University of Tsukuba. Eleven were male, nine were female, and the median age was 63 years old (range: 32–82 years old). The Eastern Cooperative Oncology Group PS was 0, 1, and 2 in eight, seven, and five patients, respectively. In the Union for International Cancer Control (UICC) classification ver. 6, there were two patients in stage II (T2N0), seven in stage IIIA (T3N0), seven in stage IIIC (TxN1), and four in stage IV (TxNxM1). Surgery was not performed in stage II patients for various medical reasons. Nine cases were histologically proven to be ICC, and others were diagnosed clinically using diagnostic imaging and tumor markers. The Child–Pugh category for impairment of liver function was class A in 14 patients, class B in 6, and class C in 0.
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
957
Proton beam therapy
Table 1
A Ohkawa et al.
Patient characteristics of 20 patients treated with PBT
Age (median)
Gender Male Female ECOG performance status 0 1 2 TNM (UICC ver. 6) II (T2N0M0) IIIA (T3N0M0) IIIC (TxN1M0) IV (TxNxM1) Maximum diameter of tumor < 50 mm 51–99 mm ≥ 100 mm Number of tumors Solitary Multiple
Curative (n = 12) 55–82 (74)
Palliative (n = 8) 32–81 (63)
Total (n = 20) 32–82 (63)
7 5
4 4
11 9
6 3 3
2 4 2
8 7 5
2 7 3 0
0 0 4 4
2 7 7 4
6 5 1
3 3 2
9 8 3
9 4
4 3
13 7
ECOG, Eastern Cooperative Oncology Group; TNM, TNM classification of malignant tumors; UICC, Union for International Cancer Control.
None of the patients were positive for hepatitis B virus, but three were positive for hepatitis C virus. The tumors ranged in size from 15 to 140 mm (median: 50 mm) in the greatest dimension. Thirteen patients had a solitary tumor and seven had multiple liver tumors. Four patients had a history of cancer treatment before PBT, including chemotherapy, and three patients had a history of liver surgery for previous HCC or ICC. The patient characteristics are summarized in Table 1. The 20 patients were divided into two groups based on receiving curative or palliative treatment. Cases in which the tumors could be irradiated by PBT with curative intent were classified as the curative group.Among the stage IIIC (TxN1) cases, three of seven patients were treated with curative intent, but in the other four cases all the tumors (including lymph node metastases) could not be irradiated sufficiently because the tumor distribution was too wide. Therefore, these four patients were included in the palliative group. Written informed consent was obtained from all patients prior to conduct of PBT.
multileaf collimator and adjusting the range shifter. Proton beams from 155 to 250 MeV generated by a linear accelerator and synchrotron were spread out and shaped with ridge filters, doublescattering sheets, multicollimators, and a custom-made bolus to ensure that the beams conformed to the treatment planning data. The intrahepatic region received a median total dose of protons of 72.6 GyE in 22 fractions (range: 55 GyE in 10 fractions to 79.2 GyE in 16 fractions). The schedule was selected depending on the tumor location: a total dose of 60–77.0 GyE in 30–35 fractions for tumors within 2 cm of the gastrointestinal tract (n = 4), 72.6–79.2 GyE in 16–22 fractions for tumors within 2 cm of central structures such as the porta hepatis (n = 14), and 55–66 GyE in 10 fractions for tumors that were not adjacent to the gastrointestinal tract or a hepatic central structure (n = 3). The relative biological effectiveness of the PBT was assumed to be 1.1.18 For treatment of lymph node metastases, the median total dose of proton radiation was 72.6 GyE in 22 fractions (range: 50 GyE in 25 fractions to 72.6 GyE in 22 fractions). Four patients received oral chemotherapy of tegafur, gimeracil, and oteracil (TS-1) during PBT. Adjuvant chemotherapy was performed after PBT in three cases. Follow-up. During treatment, acute treatment-related toxicities were assessed weekly in all patients. After completion of PBT, patients were evaluated by physical examinations, CT or magnetic resonance imaging, and blood tests every 3 months for the first 2 years and every 6 months thereafter. Local progression was defined as tumor regrowth in the radiation field in imaging with or without biopsy. Distant metastases were diagnosed by imaging alone in most cases. Morbidity was scored using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria ver. 4.19 The median follow-up period was 19.3 months (range: 4.4–62.6 months) for all 20 cases. Statistical methods. Statistical tests were performed using the Dr. SPSS II package (SPSS Inc., Chicago, IL, USA). Overall survival was defined as the time interval between the start of PBT and the last follow-up when the patient was alive. Calculation of the local control rate was based on the date on which tumor progression was found. Overall survival and local control were determined from Kaplan–Meier curves.20 A log–rank test and Kaplan–Meier curves were used to compare the curative and palliative groups.
Results PBT. The physical properties of the proton beams we use for irradiation of the liver have been described elsewhere.16,17 Prior to treatment planning, metallic fiduciary markers (iridium seeds of 0.8 mm in diameter and 2 mm in length) for PBT were implanted percutaneously into the hepatic parenchyma adjacent to the tumors to aid in positioning. After making an individual immobilization cradle, computed tomography (CT) images were taken at 5-mm intervals during the expiratory phase under a respiratory gating system (Anzai Medical Co., Tokyo, Japan). The clinical target volume (CTV) encompassed the gross tumor volume with a 5- to 10-mm margin in all directions. An additional margin of 5–10 mm was included on the caudal axes to compensate for uncertainty due to respiration-induced hepatic movement. Another margin of 5–10 mm was added to cover the entire CTV by enlarging the 958
Local control and survival. A Kaplan–Meier curve showing local control in the 12 patients in the curative group is shown in Figure 1a. Nine of the 12 tumors in the irradiated field were controlled at the final follow-up after a follow-up period of 8.6–62.6 months (median: 22.2 months). The 1-, 2-, and 3-year local control rates in the curative group were 88%, 60%, and 60%, respectively. Three patients with poor local control developed intrahepatic and distant metastasis. Of the nine patients with good local control, two developed intrahepatic metastasis, one had regional lymph node metastasis, and two had distant metastases. Four patients were disease-free at the last follow-up. Overall survival curves in the curative and palliative groups are shown in Figure 1b. The curative group had higher 1-, 2-, and
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Ohkawa et al.
(a)
Proton beam therapy
Table 2 ver. 4
1.0
Side-effects in patients treated with PBT based on NCI-CTCAE
Local control rate
0.8 0.6 0.4 0.2 0.0 12
(b)
1.0
24 Time (month)
36
P = 0.048 Curave group (n = 12)
Survival rate
0.8
Grade 2
3
6 1 3 0 3 0
2 4 0 1 1 2
0 0 0 0 1 0
1 0 0
0 1 0
0 0 2
NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events; PBT, proton beam therapy.
distant metastasis was observed in five of these patients at ≥ 2 years. Overall survival curves in patients with and without jaundice at the start of PBT are shown in Figure 1c. Patients with jaundice had lower 1-, 2-, and 3-year survival rates of 17%, 0%, and 0%, respectively, compared with 92%, 60%, and 37%, respectively, in patients without jaundice.
0.6 0.4 0.2
Incurave group (n = 8)
0.0 12
24
36
Time (month) (c)
Acute Dermatitis Anorexia Nausea Gastric ulcer Bone marrow suppression Elevated transaminase Late Dermatitis Gastric ulcer Biliary tract infection
1
1.0
P = 0.002
Side-effects. Acute and chronic side-effects are summarized in Table 2. Grade 3 or higher acute toxicity did not occur, except for bone marrow suppression. One patient developed a grade 2 gastric ulcer, which was close to irradiation field, but the condition resolved with medication with a proton pump inhibitor. Biliary tract infection that required stent insertion occurred in two patients in the late phase.
Without jaundice (n = 14)
0.8 Survival rate
Case presentations 0.6
0.4
0.2
Jaundice (n = 6)
0.0 12
24
36
Time (month) Figure 1 (a) Kaplan–Meier estimate of local control for patients in the curative group (n = 12). (b) Kaplan–Meier estimates of overall survival for patients in the curative and palliative groups. (c) Kaplan–Meier estimates of overall survival for patients with and without jaundice at the start of proton beam therapy.
3-year survival rates of 82%, 61%, and 38%, respectively, compared with 50%, 25%, and 0%, respectively, in the palliative group. The median survival periods were 27.5 and 9.6 months in the respective groups. Eight patients survived for ≥ 2 years, and no
Case 1. The patient was a 78-year-old male in whom a liver tumor was detected during an examination for early gastric cancer. The tumor had a size of 87 × 66 mm and was located in the caudal lobe, with invasion of the medial lobe and regional lymph node metastases. Surgical resection was impossible because of inferior vena cava and hepatic vein invasion. Tumor markers were elevated: carcinoembryonic antigen (CEA) 838.3 ng/mL and carbohydrate antigen (CA19-9) 2172 U/mL. The tumor was in stage IIIC with T3N1M0 (UICC 6th edition). PBT of 72.6 GyE in 22 fractions and oral TS-1 chemotherapy (100 mg/day for 4 weeks followed by withdrawal for 2 weeks) was started. After PBT, the tumor gradually shrunk (Fig. 2). At the last evaluation at 45 months after PBT, disease progression was not detected, and CEA and CA19-9 had decreased to 6.6 ng/mL and 60.0 U/mL, respectively. Gastric ulcer was observed after PBT, but was cured with medical management. Case 2. The patient was a 74-year-old female in whom abnormal liver function and a liver tumor were detected in a routine examination after treatment of breast cancer. She was diagnosed with ICC based on a biopsy. The tumor had invaded from the left lobe
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
959
Proton beam therapy
A Ohkawa et al.
a b
c
d
e
Figure 2 Course of case 1. (a) Computed tomography (CT) image before proton beam therapy (PBT). (b) Dose-distribution chart of administration of a total proton dose of 72.6 GyE in 22 fractions. Isodose curves representing 100–10% of the prescribed dose are shown at 10% intervals. (c, d, e) CT images showing the treatment course at 6, 12, and 41 months after PBT, respectively. Arrowheads shows the tumor in (a), (c), and (d). The tumor gradually decreased in size and had disappeared at 41 months after PBT (e).
960
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Ohkawa et al.
a
Proton beam therapy
b
PBT :74GyE /37 fx
Cranial field
Caudal field
c
d
Figure 3 Course of case 2. (a) Computed tomography (CT) image before proton beam therapy (PBT). (b) Dose-distribution chart of administration of a total proton dose of 74 GyE in 37 fractions. The tumor was large and extended beyond the available PBT field size. Therefore, two different fields were used to cover the tumor. The dose to the alimentary tract was restricted to 50 GyE in this case. (c, d) CT images showing the treatment course at 12 and 36 months after PBT, respectively. Arrowheads shows the tumor in (a), (c), and (d). The tumor gradually decreased in size and was well controlled at 36 months after PBT (d).
to the right lobe and had a size of 14 × 10 cm. The left portal vein was obstructed by the tumor, and the intrahepatic biliary duct was dilated. Tumor markers had normal values. The tumor was in stage IIIA with T3N0M0 (UICC 6th edition). Surgical resection was impossible. Gemcitabine was administered, but the tumor size was unchanged. Therefore, PBT of 74 GyE in 37 fractions with oral TS-1 (50 mg/day for 4 weeks followed by withdrawal for 2 weeks) was started. The tumor was too large to irradiate in a single field; therefore, two fields were used. After PBT, the tumor decreased in size (Fig. 3), but single liver and lung metastases were detected 18 months later. Secondary PBT of 66 GyE in 33 fractions and stereotactic photon radiotherapy of 66 Gy in 10 fractions were conducted for the respective metastases and these disappeared completely. At 38 months after the start of PBT, the patient is alive and disease-free.
Discussion Patients with unresectable advanced cholangiocarcinoma generally have a very poor prognosis. In a review of the natural history
and prognostic factors in 203 patients with ICC and 127 with hilar cholangiocarcinoma, with no history of surgery, chemotherapy, or radiotherapy, Park et al.3 found a median overall survival time of 3.9 months for the entire cohort. The patients with ICC had more aggressive tumors and median survival of only 3.0 months, compared with 5.9 months for those with hilar cholangiocarcinoma. Surgery is considered to be the only curative method for ICC. Sulpice et al. found a median survival time of 33 months, and 1-, 3-, and 5-year overall survival rates of 79%, 47%, and 31% in 87 patients with ICC after partial liver resection with curative intent.21 In 367 patients who underwent partial hepatectomy for ICC, Wang et al. found a median survival period of 21.0 months, and 1-, 3-, and 5-year overall survival rates of 61.9%, 40.8%, and 35.2%, respectively.22 In this cohort, factors with an independent association with survival included serum CEA, CA 19-9, tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extrahepatic metastasis. Tumor location is an important factor in deciding whether a surgical procedure can be performed. In 250 surgical cases with perihilar cholangiocarcinoma, Ebata et al. found that 3-year
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
961
Proton beam therapy
A Ohkawa et al.
survival was marginally better for 167 patients with extrahepatic cholangiocarcinoma and compared with 83 patients with ICC (43.4% vs 29.0%).23 More aggressive surgery, such as extended hepatic resection, may help with long-term survival in ICC. Ohtsuka et al. found that hemi- or more extensive hepatectomy was performed in 40 of 50 patients (80%) who underwent surgical resection with macroscopic curative objectives. The 1-, 3-, and 5-year overall survival rates in these 50 patients were 61%, 38%, and 23%, respectively, with a median survival time of 25.5 months.24 These reports suggest that surgery is worthwhile as a curative treatment for ICC, but the prognosis after hepatectomy is still unsatisfactory, with a high incidence of locoregional and distant metastasis. Combined chemotherapy is the standard therapy for unresectable biliary duct cancer. Gemcitabine is a key agent, and cisplatin, oxaliplatin, and capecitabine have also been used in combination therapy. Recent clinical studies have shown median overall survival of 8.8–12.7 months using combined chemotherapy regimens, including gemcitabine.25–27 S-1, an oral fluoropyrimidine regimen containing tegafur, gimeracil, and oteracil potassium, may be a good candidate for treatment of advanced biliary duct cancer due of its cytotoxicity. However, combined chemotherapy using S-1 did not give a marked survival benefit, with median overall survival found to be 8.7–11.6 months.28,29 Patients with unresectable ICC have a limited benefit from systemic standard chemotherapy, with a meta-analysis showing a survival benefit of only a few months using chemotherapy-based transarterial therapy.30 Several studies have described palliative radiation therapy for unresectable ICC. Shinohara conducted a retrospective analysis of 3839 patients with ICC in their Surveillance, Epidemiology, and End Results (SEER) database. The cure rate remained low, with median overall survival of 11, 6, 7, and 3 months for surgery and adjuvant radiation therapy, surgery alone, radiation alone, and no treatment, respectively.31 However, there was a significant difference in overall survival for surgery versus surgery plus radiation (P = 0.014), and for radiation versus no treatment (P < 0.0001). More recently, Chen found that conventional radiation therapy at 50 Gy gave prolonged survival in ICC, with median survival times of 5.1 and 9.5 months without and with radiation therapy, respectively (P = 0.003). These studies show that radiation therapy can improve the prognosis and relieve symptoms in patients with unresectable ICC, even if given with palliative intent. Treatment of ICC with more intensive radiation therapy, such as stereotactic body radiation therapy (SBRT) or particle therapy, has not been reported, and the current study is the first report of treatment of ICC with high dose PBT. The 3-year control rate was about 60% and median survival was 27.5 months in the curative group. The number of patients in the study was small, but the survival time is close to that for surgery, which has been thought of as the sole curative method for ICC.21,24 We previously showed that PBT for HCC gave a 5-year local control rate of 80–90%.7,8 We used three treatment protocols depending on tumor location—74 GyE in 37 fractions (close to the gastrointestinal tract), 72.6 GyE in 22 fractions (close to the porta hepatis), and 66 GyE in 10 fractions—and found no significant difference in the local control rates of these protocols.7 In the current study, the optimal treatment protocol for ICC was uncertain, and so we selected a protocol similar to that for HCC. The 962
median dose for ICC was 72.6 GyE in 22 fractions. A tumor response similar to that of HCC should give a 5-year local control rate of 80–90%. However, the 3-year local control rate of ICC was only 60%, which suggests a lower tumor response compared with that of HCC. Hence, we recommend treatment for ICC using at least the same dose as that used for HCC. Dose escalation and/or concurrent chemotherapy may also be needed to achieve better local control. Patients with jaundice (a relatively small number in the study) had a significantly poorer prognosis compared with those who did not have jaundice, and a short course treatment protocol may be better in cases of jaundice. Radiofrequency ablation (RFA) is another intense treatment for a liver tumor. In 12 patients with ICC treated with RFA, Fu et al. obtained a median survival time of 30 months.32 However, RFA with curative intent is applicable only to small tumors of < 3 cm, while PBT was used to treat larger tumors ranging in size from 15 to 140 mm (median: 50 mm) in the current study. Intensive local therapy for liver tumors can result in severe side-effects, especially in the digestive tract. In 27 patients with unresectable hilar cholangiocarcinoma treated with Linac-based SBRT at 45 Gy in 3 fractions, Kopek et al.33 found median progression-free and overall survival of 6.7 and 10.6 months, respectively. However, six patients developed severe duodenal/ pyloric ulceration and three had duodenal stenosis, which may have been due to the SBRT being performed using an abdominal compression device attached to the stereotactic body frame. More recently, Polistina et al. found no higher than grade 3 toxicity in SBRT for ICC using the cyberknife system, which allows for respiratory motion-tracking during irradiation.34 In our study using a respiratory gating system with metallic fiduciary markers, no higher than grade 3 toxicity in the digestive tract was found. These results show the importance of exact control of respiratory motion during intense radiation therapy. In conclusion, long-term survival can be achieved using PBT for patients with ICC without distant metastasis. We found that PBT is a safe treatment that resulted in a median survival time of 27.5 months for patients with unresectable ICC. Further studies are required to determine the optimal total dose, fractionation schedules, and the best combination of PBT and chemotherapy, and to compare the outcome of PBT with that of surgery as a curative treatment for ICC.
References 1 Ikai I, Arii S, Okazaki M et al. Report of the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan. Hepatol. Res. 2007; 37: 676–91. 2 Kuhlmann JB, Blum HE. Locoregional therapy for cholangiocarcinoma. Curr. Opin. Gastroenterol. 2013; 29: 324–8. 3 Park J, Kim MH, Kim KP et al. Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study. Gut Liver 2009; 3: 298–305. 4 Fukumitsu N, Sugahara S, Nakayama H et al. A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2009; 74: 831–6. 5 Mizumoto M, Tokuuye K, Sugahara S et al. Proton beam therapy for hepatocellular carcinoma adjacent to the porta hepatis. Int. J. Radiat. Oncol. Biol. Phys. 2008; 71: 462–7.
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
A Ohkawa et al.
6 Nakayama H, Sugahara S, Fukuda K et al. Proton beam therapy for hepatocellular carcinoma located adjacent to the alimentary tract. Int. J. Radiat. Oncol. Biol. Phys. 2011; 80: 992–5. 7 Mizumoto M, Okumura T, Hashimoto T et al. Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols. Int. J. Radiat. Oncol. Biol. Phys. 2011; 81: 1039–45. 8 Nakayama H, Sugahara S, Tokita M et al. Proton beam therapy for hepatocellular carcinoma: the University of Tsukuba experience. Cancer 2009; 115: 5499–506. 9 Sugahara S, Oshiro Y, Nakayama H et al. Proton beam therapy for large hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2010; 76: 460–6. 10 Sugahara S, Nakayama H, Fukuda K et al. Proton-beam therapy for hepatocellular carcinoma associated with portal vein tumor thrombosis. Strahlenther. Onkol. 2009; 185: 782–8. 11 Hata M, Tokuuye K, Kagei K et al. Hypofractionated high-dose proton beam therapy for stage I non-small-cell lung cancer: preliminary results of a phase I/II clinical study. Int. J. Radiat. Oncol. Biol. Phys. 2007; 68: 786–93. 12 Hata M, Tokuuye K, Sugahara S et al. Proton beam therapy for hepatocellular carcinoma with limited treatment options. Cancer 2006; 107: 591–8. 13 Hata M, Tokuuye K, Sugahara S et al. Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus. Cancer 2005; 104: 794–801. 14 Hata M, Tokuuye K, Sugahara S et al. Proton beam therapy for aged patients with hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2007; 69: 805–12. 15 Mizumoto M, Tokuuye K, Sugahara S et al. Proton beam therapy for hepatocellular carcinoma with inferior vena cava tumor thrombus: report of three cases. Jpn J. Clin. Oncol. 2007; 37: 459–62. 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: 951–8. 17 Oshiro Y, Okumura T, Ishida M et al. Displacement of hepatic tumor at time to exposure in end-expiratory-triggered-pulse proton therapy. Radiother. Oncol. 2011; 99: 124–30. 18 Paganetti H, Niemierko A, Ancukiewicz M et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int. J. Radiat. Oncol. Biol. Phys. 2002; 53: 407–21. 19 Common Terminology Criteria for Adverse Events (CTCAE) V.4.0. 2013. Bethesda, MD, USA: National Institute of Health, National Cancer Institute, 2009. 20 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 1958; 31: 457–81.
Proton beam therapy
21 Sulpice L, Rayar M, Boucher E et al. Treatment of recurrent intrahepatic cholangiocarcinoma. Br. J. Surg. 2013; 99: 1711–7. 22 Wang Y, Li J, Xia Y et al. Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. J. Clin. Oncol. 2013; 31: 1188–95. 23 Ebata T, Kamiya J, Nishio H et al. The concept of perihilar cholangiocarcinoma is valid. Br. J. Surg. 2009; 96: 926–34. 24 Ohtsuka M, Ito H, Kimura F et al. Extended hepatic resection and outcomes in intrahepatic cholangiocarcinoma. J. Hepatobiliary Pancreat. Surg. 2003; 10: 259–64. 25 Valle J, Wasan H, Palmer DH et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 2010; 362: 1273–81. 26 Andre T, Reyes-Vidal JM, Fartoux L et al. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study. Br. J. Cancer 2008; 99: 862–7. 27 Riechelmann RP, Townsley CA, Chin SN et al. Expanded phase II trial of gemcitabine and capecitabine for advanced biliary cancer. Cancer 2007; 110: 1307–12. 28 Sasaki T, Isayama H, Nakai Y et al. Multicenter, phase II study of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer. Cancer Chemother. Pharmacol. 2010; 65: 1101–7. 29 Kim YJ, Im SA, Kim HG et al. A phase II trial of S-1 and cisplatin in patients with metastatic or relapsed biliary tract cancer. Ann. Oncol. 2008; 19: 99–103. 30 Ray CE Jr, Edwards A, Smith MT et al. Metaanalysis of survival, complications, and imaging response following chemotherapy-based transarterial therapy in patients with unresectable intrahepatic cholangiocarcinoma. J. Vasc. Interv. Radiol. 2013; 24: 1218–26. 31 Shinohara ET, Mitra N, Guo M et al. Radiation therapy is associated with improved survival in the adjuvant and definitive treatment of intrahepatic cholangiocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2008; 72: 1495–501. 32 Fu Y, Yang W, Wu W et al. Radiofrequency ablation for postoperative recurrences of intrahepatic cholangiocarcinoma. Chin. J. Cancer Res. 2011; 23: 295–300. 33 Kopek N, Holt MI, Hansen AT et al. Stereotactic body radiotherapy for unresectable cholangiocarcinoma. Radiother. Oncol. 2010; 94: 47–52. 34 Polistina FA, Guglielmi R, Baiocchi C et al. Chemoradiation treatment with gemcitabine plus stereotactic body radiotherapy for unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma. Results of a five year experience. Radiother. Oncol. 2011; 99: 120–3.
Journal of Gastroenterology and Hepatology 30 (2015) 957–963 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
963
