Radiotherapy and Oncology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland Nobutaka Mizoguchi a,b,⇑, Hiroshi Tsuji a, Shingo Toyama a, Tadashi Kamada a, Hirohiko Tsujii a, Yuko Nakayama b, Atsushi Mizota c, Yoshitaka Ohnishi d, On behalf the Working Group for Ophthalmologic Tumors a c
Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba; b Department of Radiation Oncology, Kanagawa Cancer Center; Department of Ophthalmology, Teikyo University School of Medicine, Tokyo; and d Department of Ophthalmology, Wakayama Medical University, Japan
a r t i c l e
i n f o
Article history: Received 26 January 2014 Received in revised form 18 January 2015 Accepted 18 January 2015 Available online xxxx Keywords: Carbon ion radiotherapy Charged particle therapy Carcinoma of the lacrimal gland
a b s t r a c t Purpose: To evaluate the applicability of carbon ion beams for the treatment of carcinoma of the lacrimal gland with regard to normal tissue morbidity and local tumor control. Methods and materials: Between April 2002 and January 2011, 21 patients with locally advanced primary epithelial carcinoma of the lacrimal gland were enrolled in a Phase I/II clinical trial of carbon-ion radiotherapy (CIRT) at the National Institute of Radiological Sciences. Acute radiation toxicity was the primary endpoint of this dose-escalation study and the late toxicity, local control, and overall survival were additionally evaluated as secondary endpoints. Of the 21 subjects enrolled, all patients were followed for more than 6 months and analyzed. Results: The radiation dose was increased from the initial dose of 48.0 Gy equivalents (GyE)/12 fractions at 10% increments up to 52.8 GyE. Of the 21 patients, five received a total dose of 48.0 GyE, and 16 received a total dose of 52.8 GyE. No patient developed grade 3 or higher skin toxicity. As late ocular/ visual toxicity, three patients had grade 3 retinopathy and seven patients lost their vision. Among the 10 patients treated until May 2005, five patients had local recurrence, three of whom had marginal recurrence. Therefore, the margin for the CTV (clinical target volume) was set to a range according to the orbital exenteration since June 2005. After the application of the extended margin, no local recurrence has been observed. The three-year overall survival and local control rates were 82.2% and 79.0%, respectively. Conclusion: CIRT can be applied for primary epithelial carcinoma of the lacrimal gland, with a borderline acceptable morbidity and sufficient antitumor effect when an extended margin is adopted. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2015) xxx–xxx
An epithelial tumor of the lacrimal gland is a very rare orbital tumor. The incidence of this disease is estimated to be 0.072 per 100,000 people [1]. In the field of ophthalmology, these tumors are associated with a poor prognosis, frequently leading to death. Adenoid cystic carcinoma histology occurs most frequently, and accounts for 20–30% of all malignant tumors of the lacrimal gland [2]. There is no current standard therapy due to the low incidence of the disease; however, surgical resection (orbital exenteration or eye-sparing surgery) and postoperative radiotherapy are generally selected. A five-year local control rate of about 50% has been reported in previous studies, and the outcomes are not satisfactory for patients with carcinoma of the lacrimal gland [3–9]. Moreover, orbital exenteration is a highly invasive treatment for patients, resulting in significant impairment of the QOL (quality of life) both physically and cosmetically. Consequently, it is hoped that a ⇑ Corresponding author.
treatment allowing both preservation of the eyeball and improved tumor control rates can be established. In the present study, we evaluated the safety and efficacy of carbon-ion radiotherapy (CIRT) for locally advanced or postoperative recurrent epithelial carcinoma of the lacrimal gland. Methods and materials Protocol The purpose of the present study was to establish a treatment method that can control primary epithelial malignant tumors of the lacrimal gland using carbon ion beams, and possibly to preserve the eyeball. A Phase I/II study was conducted beginning in April 2002 using the medical heavy particle accelerator (HIMAC: Heavy ion medical accelerator in Chiba) installed in the National Institute of Radiological Sciences. Regarding the CIRT, a dose escalation trial was conducted from a starting radiation dose of
http://dx.doi.org/10.1016/j.radonc.2015.01.009 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
2
Carbon-ion radiotherapy for carcinoma of the lacrimal gland
48.0 Gray equivalent (GyE)/12 fractions. A follow-up of 3 months or more was conducted in at least three of the patients that were treated with the same radiation dose, and if a reaction of Grade 3 or more was not observed in the acute normal tissue reaction score of the NCI-CTC (National Cancer Institute Common Toxicity Criteria) version 2.0 [10] regarding all cases, the radiation dose was increased by 10%. However, if a normal tissue reaction of Grade 3 or more was observed, the subsequent irradiation method and radiation dosage in these cases were investigated upon consultation with the protocol management committee. Patient eligibility Patients were eligible if they had pathologically diagnosed epithelial carcinoma of the lacrimal gland that was untreated or was remaining or recurring following conservative surgery, and in whom there was no lymph node or distant metastasis. The staging was performed according to the American Joint Committee on Cancer (AJCC) system, fifth edition (1997) [11]. All patients signed an informed consent form approved by the local institutional review board prior to their participation. Carbon-ion radiotherapy (CIRT) Carbon ion beams were generated by the HIMAC and were delivered to the target such that the target could be covered with a homogeneous biological effect by the spread-out Bragg peak (SOBP). The clinical radiation dose obtained by applying the relative biological effectiveness (RBE) of the carbon ion beam to the physical radiation dose was defined as the photon equivalent dose, and using units of GyE, the RBE was normalized so that it was 3.0 where the mean LET (Linear Energy Transfer) was 80 keV/lm. To immobilize the patient, a head rest (Moldcare; Alcare, Tokyo, Japan) and a low-temperature thermoplastic shell (Shellfitter; Kuraray, Osaka, Japan) were used. A set of 2.5-mm-thick computed tomography (CT) images was taken for treatment planning with the patient in the immobilization devices. Three-dimensional treatment planning was performed with the Heavy Ion Plan software program [12]. The gross tumor volume (GTV) was determined
Pre CIRT
with reference to contrast-enhanced CT, contrast-enhanced MRI (magnetic resonance imaging) and methionine PET-CT (positron emission tomography-CT). The clinical target volume (CTV) was defined by adding regions in which potential tumor was considered. Until May 2005, the CTV was generally determined to be in the range of 0–5 mm of the GTV border to spare adjacent critical organs, such as the optic nerve or retina (MM: minimal margin). Thereafter, a margin according to the orbital exenteration was set as the CTV, where the inner edge contained the lacrimal sac, the outer edge was the frontal bone configuring the outer orbit, the upper edge of the outer malar bone was the outer frontal bone containing the lacrimal gland, the lower edge was the upper maxillary bone configuring the outer orbit, and the outside (as well as the posterior edge) of the malar bone was the distal optic nerve of the affected side not containing the optic chiasm (EM: extended margin). The planning target volume (PTV) was set as the set-up margin by adding about 3 mm to the CTV. Typical dose distributions with a minimal margin and extended margins are shown in Fig. 1.
Endpoints and statistical analyses The primary endpoint was the acute adverse reaction of the normal tissue configuring the eyelid, orbit and eyeball, while the secondary endpoints were the late adverse reactions, survival rate and local control rate. The acute adverse reactions until 3 months following treatment were evaluated based on the NCI-CTC Version 2.0, and scoring of the late adverse reactions was conducted according to the RTOG/EORTC (Radiation Therapy Oncology Group/ European Organization for Research and Treatment of Cancer) Late Radiation Morbidity Scoring Schema [13], with the highest grade determined for the early and late reactions, respectively. Patients were followed by the referring ophthalmologist and radiation oncologist at three-month intervals during the first three years after CIRT and at intervals of 6 months thereafter. An MRI of the head and neck, whole body CT and methionine PET scans were taken every 6 months. The visual acuity, intraocular pressure and visual field were evaluated at each ophthalmological examination with special focus on the development of blindness or neovascular
Dose distribuon
(a) minimal margin
(b) extended margin
Fig. 1. (a) This MRI was obtained before carbon ion radiotherapy (CIRT) (left). The dose distribution of CIRT with minimal margin is illustrated for patients with carcinoma of the lacrimal gland (the red line indicates 96% isodose of the prescribed dose) (right). (b) The dose distribution of CIRT with extended margin is illustrated.
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
Carbon-ion radiotherapy for carcinoma of the lacrimal gland
(a) Local Control
(b) Overall Survival
extended margin, n=11
extended margin, n=11
minimal margin, n=10 minimal margin, n=10 p=0.0367
p=0.0889
Number at risk
Number at risk
extended margin
11
10
8
6
3
3
2
0
0
0
0
extended margin
11
10
8
6
3
3
2
0
0
0
0
minimal margin
10
9
5
5
5
5
5
4
4
2
0
minimal margin
10
10
9
8
7
6
6
5
5
2
0
Fig. 2. (a) Local control and (b) overall survival curves shown for 10 patients treated with minimal margin and for 11 patients treated with extended margin.
glaucoma. The overall survival rate (OS), disease free survival rate (DFS) and local control rate (LC) were calculated by the Kaplan– Meier method using the Prism 5 software program for Mac OS X (version 5.0; GraphPad Software, Inc.). The time to recurrence was determined from the day of the commencement of CIRT. A value of p < 0.05 was considered to be statistically significant. Furthermore, the evaluation of the therapeutic effect was performed using the RECIST guideline (version 1.1) as the standard [14]. Results Patient characteristics From April 2002 through February 2011, 21 patients were enrolled in the study and received CIRT as planned. Patient characteristics are described in Supplementary Table 1. All patients had been followed up for more than 6 months at the date of analysis. The median duration of follow-up was 42 months (range: 7–109 months) for all patients, and 43 months (range: 7–109 months) for surviving patients. Concerning the histology of the treated tumors, sixteen patients (76%) had adenoid cystic carcinoma, three had adenocarcinoma, and the other two had a malignant mixed tumor and undifferentiated carcinoma. Regarding the treatment prior to the CIRT, fifteen patients had residual or recurrent disease after eye-sparing surgery, and the remaining six were previously untreated and diagnosed by biopsy. All patients were divided into three groups: a low-dose group (LD), in which five patients were irradiated with a total dose of 48.0 GyE/12 fr with minimal margin, a high-dose minimal-margin group (HDMM), in which five patients were irradiated with a total dose of 52.8 GyE/12 fr with minimal margin, and an extended margin group (HDEM), in which 11 patients were treated with 52.8 GyE/12 fr with extended margin.
Local control The three-year local control rate of the entire group was 79.0%, and two out of five local failures occurred within the CTV, and the remaining three recurrences occurred at the marginal area of the CTV, so that the in-field recurrence free rate was 93.3% (Supplementary Fig. 1a). The in-field recurrences occurred at 15 months and 77 months, and the marginal recurrences occurred at 6 months, 8 months and 12 months after CIRT. Of the five patients in the LD group, four had a partial response (PR) and one achieved stable disease (SD) at 3 months. Of the five patients in the HDMM group, two had a PR and three had SD, and of the 11 patients in the HDEM group, four had a PR and seven achieved SD. Local recurrence was observed in five patients, two in the LD group and three in the HDMM group, and none of the
patients in the HDEM group has developed local recurrence as of the date of this analysis. Therefore, the three-year local control rate in the HDEM group was 100%, while that in the LD and HDMM groups (10 patients) was 60%, and a statistically significant difference was observed among the groups (p = 0.0367, Fig. 2a). The tumor-related factors such as the tumor size, histology and surgical status were not significant predictors of the local recurrence. Orbital exenteration has been carried out as salvage therapy for two patients with local recurrence. The rate of preservation of the eyeball was therefore 90.4%. Cervical lymph node metastasis occurred in two patients, while lung metastasis occurred in three patients as the first recurrent lesion. Reactions of normal tissues Acute skin reactions were mild. Of the five patients irradiated with a total dose of 48.0 GyE/12 fr, a Grade 2 reaction occurred in only one patient, and a Grade 1 reaction occurred in the remaining four patients. Of the 16 patients irradiated with 52.8 Gy/12 fr, only one patient had a Grade 2 reaction, and the other 15 patients had Grade 1 or 0 reactions. Late skin reactions were also mild: a Grade 1 or lower reaction was recorded in all patients (Table 1a). No apparent dose-response relationship was observed in the skin reactions. Regarding acute ocular/visual reactions, none of the patients in the LD and HDMM groups had remarkable acute reactions. On the other hand, of the 11 patients in the HDEM group, eight had Grade 1 conjunctivitis or dry eye (Table 1b). Regarding late ocular/visual reactions, one patient had vision loss due to the tumor invasion before the CIRT and 10 out of the remaining 20 patients had a decrease in the decimal visual acuity by 0.3 or more due to optic neuritis compared to before treatment. Blindness was observed in seven patients, two in the LD group, two in the HDMM group and three in the HDEM group. The time to occurrence of blindness varied from 11 to 26 months after the CIRT. No apparent correlation between the carbon ion dose or size of the margin and the post-treatment visual acuity was observed. Glaucoma was observed in four of the HDEM patients; however, no patients required ophthalmectomy. Survival Five out of the 21 patients died, including four patients who died from the lacrimal gland cancer and one patient who died from esophageal cancer. The three-year overall survival rate of all patients was 82.2% (Supplementary Fig. 1b). The three-year survival rates of patients in the HDEM group and those in the LD or HDMM group were 100% and 70%, respectively. With regard to the CTV margin, a favorable trend was observed in the treatment
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
4
Carbon-ion radiotherapy for carcinoma of the lacrimal gland
Table 1 Radiation associated acute and late reactions. Acute radiation morbidity
*
Late radiation morbidity
Gr 0
Gr 1
Gr 2
Gr 3
Gr 4
Gr 0
Gr 1
Gr 2
Gr 3
Gr 4
(a) Skin 48.0 GyE 52.8 GyE 52.8 GyE* Total
0 0 1 1
4 5 9 18
1 0 1 2
0 0 0 0
0 0 0 0
0 2 2 4
5 3 9 17
0 0 0 0
0 0 0 0
0 0 0 0
(b) Ocular/visual 48.0 GyE 52.8 GyE 52.8 GyE* Total
5 5 3 13
0 0 8 8
0 0 0 0
0 0 0 0
0 0 0 0
0 2 4 6
1 0 0 1
1 1 2 4
1 0 2 3
2 2 3 7
Extended margin.
using the extended margin (p = 0.0889, Fig. 2b). Tumor-related factors such as the tumor size and histology were not significant predictors of the overall survival. The three-year disease-free survival rate of all patients was 48.0% (Supplementary Fig. 1c). The rates of patients in the HDEM group and those in the LD or HDMM groups were 62.5% and 30.0%, respectively, and a statistically significant difference was observed among the groups (p = 0.0253, data not shown). Moreover, there was a correlation between the tumor size and the disease-free survival rate, with significantly lower survival observed when the tumor exceeded 3.5 cm in size (p = 0.029). Discussion Carbon ion beams, which are one of the heavy particle beams, provide superior physical dose distribution and possess a high antitumor effect, making them suitable for cancer treatment. We have already demonstrated CIRT to be a safe and useful treatment method for various malignant tumors [15–18]. It is also believed to be suitable for orbital tumors, such as choroidal malignant melanoma [19]. In the present study, we evaluated the safety and efficacy of CIRT for locally advanced or postoperative recurrent epithelial carcinoma of the lacrimal gland. Regarding normal tissue toxicity, skin reactions of Grade 3 or more did not occur as either acute or late toxicity, even after expansion of the irradiation field. In addition, acute ocular/visual reactions of grade 2 or more did not occur in these patients. However, with regard to the late toxicity of ocular/visual reactions, three patients had grade 3 retinopathy and seven patients (two irradiated with 48.0 GyE/12 fr (LD), two irradiated with 52.8 GyE/12 fr with a minimal margin (HDMM) and three with extended margins (HDEM)), lost their vision. No apparent difference among the three groups was found, however, the occurrence of these toxicities strongly depended upon the area of the CTV that was determined individually in the LD and HDMM groups, and was extended in the HDEM group. For example, most of the patients with a tumor adjacent to the optic nerve lost their vision because the nerve could not be spared from the high dose area. This had been predicted at the beginning of the clinical trial, therefore, the loss of eyesight was not treated as a dose-limiting toxicity in this study. Neovascular glaucoma developed in four patients in the HDEM group, although none of them required ophthalmectomy, whereas no patient in the LD or HDMM group developed glaucoma. It was thought that the use of a high dose on a wide area of the retina likely caused severe retinopathy and subsequent neovascularization, resulting in an elevation of the intraocular pressure. Losing vision and neovascular glaucoma are undoubtedly severe adverse events, however, they are still less burdensome to patients
than morbidity due to orbital exenteration. In fact, adverse events occurring only within the CTV, and the surrounding normal tissues, such as the contralateral orbit or frontal lobe of the brain, could be spared from the high dose area by the well-localized dose distribution associated with the unique physical properties of the carbonion beam. In addition, the main advantage of CIRT over radical surgery is that the eyeball can be preserved and the features are not deteriorated in most cases (described below). Therefore, the current outcomes with regard to normal tissue toxicity in this clinical trial could be judged as borderline acceptable for this particular disease if the tumor control rate is comparable to that of radical surgery. Concerning the patient survival and the local tumor control, the three-year overall survival rate was 82.2%, and the three-year local control rate was 79.0%. These outcomes were comparable to similar past reports by various authors [3-9] in terms of both the survival rate and local control rate (Supplementary Fig. 1). In this study, the setting of the CTV margin was strongly correlated with the local control and survival rates. Local recurrence occurred in the LD and HDMM groups, both of which used the minimal margin. On the other hand, none of the patients in the HDEM group has developed local failure so far. The three-year local control rate of the HDEM and other groups (LD and HDMM) was 100% and 60%, respectively, with a statistically significant difference being observed between them (p = 0.0367). Concerning the dose-response of the CIRT, the rate of recurrence within the CTV in the low dose group (LD; 1/5) was higher than that in the high dose group (HDMM + HDEM; 1/16). However, the number of cases with local recurrence within the CTV was too small to obtain a clear dose–response relationship, and therefore, the CIRT of the low dose treatment with an extended margin should be evaluated. At present, it appears that 52.8 GyE in 12 fractions with an extended margin is appropriate for treatment in terms of the tumor control. Orbital exenteration refers to the surgical removal of the eyeball and the surrounding tissues, these included eyelids, muscles, nerves and fatty tissue adjacent to the eye. As a result, physical appearance undergoes a profound change. Orbital exenteration was performed as salvage therapy for two patients with local recurrence; however, the rate of preservation of the eyeball was 90.5%, so CIRT can be considered to be effective for maintaining the QOL of individuals with regard to their physical appearance. Based on this study, it appears that HDEM is appropriate for the treatment of epithelial carcinoma of the lacrimal gland in terms of tumor control. However, neovascular glaucoma developed in some of the HDEM patients, whereas no patients in the LD or HDMM group developed glaucoma. Therefore, to decrease the risk of adverse events, using 48.0 GyE/12 fr with extended margins (i.e., LDEM) should be considered in selected patients.
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
Carbon-ion radiotherapy for carcinoma of the lacrimal gland
In conclusion, CIRT for epithelial carcinoma of the lacrimal gland appears to be effective, with acceptable toxicities, and has favorable outcomes regarding the preservation of the eyeball. By adopting 52.8 GyE in 12 fractions, the local tumor control was satisfactory and the toxicity was still acceptable in consideration of the expected role of this treatment. Although further investigation is needed to optimize the dose with extended margins, this is a promising treatment method that may replace surgical resection and postoperative irradiation. Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2015.01. 009. References [1] Lacrimal Gland Tumor Study Group. An epidemiological survey of lacrimal fossa lesions in Japan: number of patients and their sex ratio by pathological diagnosis. Jpn J Ophthalmol 2005;49:343–8. [2] Weis E, Rootman J, Joly TJ, et al. Epithelial lacrimal gland tumors: pathologic classification and current understanding. Arch Ophthalmol 2009;127: 1016–28.
[3] Skinner HD, Garden AS, Rosenthal DI, et al. Outcomes of malignant tumors of the lacrimal apparatus: The University of Texas MD Anderson Cancer Center experience. Cancer 2011;117:2801–10. [4] Ahmad SM, Esmaeli B, Williams M, et al. American Joint Committee on Cancer classification predicts outcome of patients with lacrimal gland adenoid cystic carcinoma. Ophthalmology 2009;116:1210–5. [5] Font RL, Smith SL, Bryan RG. Malignant epithelial tumors of the lacrimal gland: a clinicopathologic study of 21 cases. Arch Ophthalmol 1998;116:613–6. [6] Wright JE, Rose GE, Garner A. Primary malignant neoplasms of the lacrimal gland. Br J Ophthalmol 1992;76:401–7. [7] Tse DT, Benedetto P, Dubovy S, et al. Clinical analysis of the effect of intraarterial cytoreductive chemotherapy in the treatment of lacrimal gland adenoid cystic carcinoma. Am J Ophthalmol 2006;141:44–53. [8] Brada M, Henk JM. Radiotherapy for lacrimal gland tumours. Radiother Oncol 1987;9:175–83. [9] Meldrum ML, Tse DT, Benedetto P. Neoadjuvant intracarotid chemotherapy for treatment of advanced adenocystic carcinoma of the lacrimal gland. Arch Ophthalmol 1998;116:315–21. [10] Common Toxicity Criteria v2.0. National Cancer Institute, 1999. [11] Fleming ID, Cooper JS, Henson DE, et al. Carcinoma of the Lacrimal Gland. AJCC Cancer Staging Manual. 5th ed. Lippincott Raven; 1997. p. 273–5. [12] Endo M, Koyama-Ito H, Minohara S, et al. HIPLAN-A heavy ion treatment planning system at HIMAC. J Jpn Soc Ther Radiol Oncol 1996;8:231–8. [13] RTOG/EORTC Late Radiation Morbidity Scoring Schema. Radiation Therapy Oncology Group website: http://www.rtog.org. [14] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. [15] Kamada T, Tsujii H, Tsuji H, et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin Oncol 2002;20:4466–71. [16] Tsuji H, Yanagi T, Ishikawa H, et al. Hypofractionated radiotherapy with carbon ion beams for prostate cancer. Int J Radiat Oncol Biol Phys 2005;63:1153–60. [17] Tsujii H, Mizoe J, et al. Overview of clinical experiences on carbon ion radiotherapy at NIRS. Radiother Oncol 2004;73:S41–9. [18] Mizoe J, Hasegawa A, et al. Results of carbon ion radiotherapy for head and neck cancer. Radiother Oncol 2012;103:32–7. [19] Tsuji H, Ishikawa H, Yanagi T, et al. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: a Phase I/II doseescalation study. Int J Radiat Oncol Biol Phys 2007;67:857–62.
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland Nobutaka Mizoguchi a,b,⇑, Hiroshi Tsuji a, Shingo Toyama a, Tadashi Kamada a, Hirohiko Tsujii a, Yuko Nakayama b, Atsushi Mizota c, Yoshitaka Ohnishi d, On behalf the Working Group for Ophthalmologic Tumors a c
Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba; b Department of Radiation Oncology, Kanagawa Cancer Center; Department of Ophthalmology, Teikyo University School of Medicine, Tokyo; and d Department of Ophthalmology, Wakayama Medical University, Japan
a r t i c l e
i n f o
Article history: Received 26 January 2014 Received in revised form 18 January 2015 Accepted 18 January 2015 Available online xxxx Keywords: Carbon ion radiotherapy Charged particle therapy Carcinoma of the lacrimal gland
a b s t r a c t Purpose: To evaluate the applicability of carbon ion beams for the treatment of carcinoma of the lacrimal gland with regard to normal tissue morbidity and local tumor control. Methods and materials: Between April 2002 and January 2011, 21 patients with locally advanced primary epithelial carcinoma of the lacrimal gland were enrolled in a Phase I/II clinical trial of carbon-ion radiotherapy (CIRT) at the National Institute of Radiological Sciences. Acute radiation toxicity was the primary endpoint of this dose-escalation study and the late toxicity, local control, and overall survival were additionally evaluated as secondary endpoints. Of the 21 subjects enrolled, all patients were followed for more than 6 months and analyzed. Results: The radiation dose was increased from the initial dose of 48.0 Gy equivalents (GyE)/12 fractions at 10% increments up to 52.8 GyE. Of the 21 patients, five received a total dose of 48.0 GyE, and 16 received a total dose of 52.8 GyE. No patient developed grade 3 or higher skin toxicity. As late ocular/ visual toxicity, three patients had grade 3 retinopathy and seven patients lost their vision. Among the 10 patients treated until May 2005, five patients had local recurrence, three of whom had marginal recurrence. Therefore, the margin for the CTV (clinical target volume) was set to a range according to the orbital exenteration since June 2005. After the application of the extended margin, no local recurrence has been observed. The three-year overall survival and local control rates were 82.2% and 79.0%, respectively. Conclusion: CIRT can be applied for primary epithelial carcinoma of the lacrimal gland, with a borderline acceptable morbidity and sufficient antitumor effect when an extended margin is adopted. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2015) xxx–xxx
An epithelial tumor of the lacrimal gland is a very rare orbital tumor. The incidence of this disease is estimated to be 0.072 per 100,000 people [1]. In the field of ophthalmology, these tumors are associated with a poor prognosis, frequently leading to death. Adenoid cystic carcinoma histology occurs most frequently, and accounts for 20–30% of all malignant tumors of the lacrimal gland [2]. There is no current standard therapy due to the low incidence of the disease; however, surgical resection (orbital exenteration or eye-sparing surgery) and postoperative radiotherapy are generally selected. A five-year local control rate of about 50% has been reported in previous studies, and the outcomes are not satisfactory for patients with carcinoma of the lacrimal gland [3–9]. Moreover, orbital exenteration is a highly invasive treatment for patients, resulting in significant impairment of the QOL (quality of life) both physically and cosmetically. Consequently, it is hoped that a ⇑ Corresponding author.
treatment allowing both preservation of the eyeball and improved tumor control rates can be established. In the present study, we evaluated the safety and efficacy of carbon-ion radiotherapy (CIRT) for locally advanced or postoperative recurrent epithelial carcinoma of the lacrimal gland. Methods and materials Protocol The purpose of the present study was to establish a treatment method that can control primary epithelial malignant tumors of the lacrimal gland using carbon ion beams, and possibly to preserve the eyeball. A Phase I/II study was conducted beginning in April 2002 using the medical heavy particle accelerator (HIMAC: Heavy ion medical accelerator in Chiba) installed in the National Institute of Radiological Sciences. Regarding the CIRT, a dose escalation trial was conducted from a starting radiation dose of
http://dx.doi.org/10.1016/j.radonc.2015.01.009 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
2
Carbon-ion radiotherapy for carcinoma of the lacrimal gland
48.0 Gray equivalent (GyE)/12 fractions. A follow-up of 3 months or more was conducted in at least three of the patients that were treated with the same radiation dose, and if a reaction of Grade 3 or more was not observed in the acute normal tissue reaction score of the NCI-CTC (National Cancer Institute Common Toxicity Criteria) version 2.0 [10] regarding all cases, the radiation dose was increased by 10%. However, if a normal tissue reaction of Grade 3 or more was observed, the subsequent irradiation method and radiation dosage in these cases were investigated upon consultation with the protocol management committee. Patient eligibility Patients were eligible if they had pathologically diagnosed epithelial carcinoma of the lacrimal gland that was untreated or was remaining or recurring following conservative surgery, and in whom there was no lymph node or distant metastasis. The staging was performed according to the American Joint Committee on Cancer (AJCC) system, fifth edition (1997) [11]. All patients signed an informed consent form approved by the local institutional review board prior to their participation. Carbon-ion radiotherapy (CIRT) Carbon ion beams were generated by the HIMAC and were delivered to the target such that the target could be covered with a homogeneous biological effect by the spread-out Bragg peak (SOBP). The clinical radiation dose obtained by applying the relative biological effectiveness (RBE) of the carbon ion beam to the physical radiation dose was defined as the photon equivalent dose, and using units of GyE, the RBE was normalized so that it was 3.0 where the mean LET (Linear Energy Transfer) was 80 keV/lm. To immobilize the patient, a head rest (Moldcare; Alcare, Tokyo, Japan) and a low-temperature thermoplastic shell (Shellfitter; Kuraray, Osaka, Japan) were used. A set of 2.5-mm-thick computed tomography (CT) images was taken for treatment planning with the patient in the immobilization devices. Three-dimensional treatment planning was performed with the Heavy Ion Plan software program [12]. The gross tumor volume (GTV) was determined
Pre CIRT
with reference to contrast-enhanced CT, contrast-enhanced MRI (magnetic resonance imaging) and methionine PET-CT (positron emission tomography-CT). The clinical target volume (CTV) was defined by adding regions in which potential tumor was considered. Until May 2005, the CTV was generally determined to be in the range of 0–5 mm of the GTV border to spare adjacent critical organs, such as the optic nerve or retina (MM: minimal margin). Thereafter, a margin according to the orbital exenteration was set as the CTV, where the inner edge contained the lacrimal sac, the outer edge was the frontal bone configuring the outer orbit, the upper edge of the outer malar bone was the outer frontal bone containing the lacrimal gland, the lower edge was the upper maxillary bone configuring the outer orbit, and the outside (as well as the posterior edge) of the malar bone was the distal optic nerve of the affected side not containing the optic chiasm (EM: extended margin). The planning target volume (PTV) was set as the set-up margin by adding about 3 mm to the CTV. Typical dose distributions with a minimal margin and extended margins are shown in Fig. 1.
Endpoints and statistical analyses The primary endpoint was the acute adverse reaction of the normal tissue configuring the eyelid, orbit and eyeball, while the secondary endpoints were the late adverse reactions, survival rate and local control rate. The acute adverse reactions until 3 months following treatment were evaluated based on the NCI-CTC Version 2.0, and scoring of the late adverse reactions was conducted according to the RTOG/EORTC (Radiation Therapy Oncology Group/ European Organization for Research and Treatment of Cancer) Late Radiation Morbidity Scoring Schema [13], with the highest grade determined for the early and late reactions, respectively. Patients were followed by the referring ophthalmologist and radiation oncologist at three-month intervals during the first three years after CIRT and at intervals of 6 months thereafter. An MRI of the head and neck, whole body CT and methionine PET scans were taken every 6 months. The visual acuity, intraocular pressure and visual field were evaluated at each ophthalmological examination with special focus on the development of blindness or neovascular
Dose distribuon
(a) minimal margin
(b) extended margin
Fig. 1. (a) This MRI was obtained before carbon ion radiotherapy (CIRT) (left). The dose distribution of CIRT with minimal margin is illustrated for patients with carcinoma of the lacrimal gland (the red line indicates 96% isodose of the prescribed dose) (right). (b) The dose distribution of CIRT with extended margin is illustrated.
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
Carbon-ion radiotherapy for carcinoma of the lacrimal gland
(a) Local Control
(b) Overall Survival
extended margin, n=11
extended margin, n=11
minimal margin, n=10 minimal margin, n=10 p=0.0367
p=0.0889
Number at risk
Number at risk
extended margin
11
10
8
6
3
3
2
0
0
0
0
extended margin
11
10
8
6
3
3
2
0
0
0
0
minimal margin
10
9
5
5
5
5
5
4
4
2
0
minimal margin
10
10
9
8
7
6
6
5
5
2
0
Fig. 2. (a) Local control and (b) overall survival curves shown for 10 patients treated with minimal margin and for 11 patients treated with extended margin.
glaucoma. The overall survival rate (OS), disease free survival rate (DFS) and local control rate (LC) were calculated by the Kaplan– Meier method using the Prism 5 software program for Mac OS X (version 5.0; GraphPad Software, Inc.). The time to recurrence was determined from the day of the commencement of CIRT. A value of p < 0.05 was considered to be statistically significant. Furthermore, the evaluation of the therapeutic effect was performed using the RECIST guideline (version 1.1) as the standard [14]. Results Patient characteristics From April 2002 through February 2011, 21 patients were enrolled in the study and received CIRT as planned. Patient characteristics are described in Supplementary Table 1. All patients had been followed up for more than 6 months at the date of analysis. The median duration of follow-up was 42 months (range: 7–109 months) for all patients, and 43 months (range: 7–109 months) for surviving patients. Concerning the histology of the treated tumors, sixteen patients (76%) had adenoid cystic carcinoma, three had adenocarcinoma, and the other two had a malignant mixed tumor and undifferentiated carcinoma. Regarding the treatment prior to the CIRT, fifteen patients had residual or recurrent disease after eye-sparing surgery, and the remaining six were previously untreated and diagnosed by biopsy. All patients were divided into three groups: a low-dose group (LD), in which five patients were irradiated with a total dose of 48.0 GyE/12 fr with minimal margin, a high-dose minimal-margin group (HDMM), in which five patients were irradiated with a total dose of 52.8 GyE/12 fr with minimal margin, and an extended margin group (HDEM), in which 11 patients were treated with 52.8 GyE/12 fr with extended margin.
Local control The three-year local control rate of the entire group was 79.0%, and two out of five local failures occurred within the CTV, and the remaining three recurrences occurred at the marginal area of the CTV, so that the in-field recurrence free rate was 93.3% (Supplementary Fig. 1a). The in-field recurrences occurred at 15 months and 77 months, and the marginal recurrences occurred at 6 months, 8 months and 12 months after CIRT. Of the five patients in the LD group, four had a partial response (PR) and one achieved stable disease (SD) at 3 months. Of the five patients in the HDMM group, two had a PR and three had SD, and of the 11 patients in the HDEM group, four had a PR and seven achieved SD. Local recurrence was observed in five patients, two in the LD group and three in the HDMM group, and none of the
patients in the HDEM group has developed local recurrence as of the date of this analysis. Therefore, the three-year local control rate in the HDEM group was 100%, while that in the LD and HDMM groups (10 patients) was 60%, and a statistically significant difference was observed among the groups (p = 0.0367, Fig. 2a). The tumor-related factors such as the tumor size, histology and surgical status were not significant predictors of the local recurrence. Orbital exenteration has been carried out as salvage therapy for two patients with local recurrence. The rate of preservation of the eyeball was therefore 90.4%. Cervical lymph node metastasis occurred in two patients, while lung metastasis occurred in three patients as the first recurrent lesion. Reactions of normal tissues Acute skin reactions were mild. Of the five patients irradiated with a total dose of 48.0 GyE/12 fr, a Grade 2 reaction occurred in only one patient, and a Grade 1 reaction occurred in the remaining four patients. Of the 16 patients irradiated with 52.8 Gy/12 fr, only one patient had a Grade 2 reaction, and the other 15 patients had Grade 1 or 0 reactions. Late skin reactions were also mild: a Grade 1 or lower reaction was recorded in all patients (Table 1a). No apparent dose-response relationship was observed in the skin reactions. Regarding acute ocular/visual reactions, none of the patients in the LD and HDMM groups had remarkable acute reactions. On the other hand, of the 11 patients in the HDEM group, eight had Grade 1 conjunctivitis or dry eye (Table 1b). Regarding late ocular/visual reactions, one patient had vision loss due to the tumor invasion before the CIRT and 10 out of the remaining 20 patients had a decrease in the decimal visual acuity by 0.3 or more due to optic neuritis compared to before treatment. Blindness was observed in seven patients, two in the LD group, two in the HDMM group and three in the HDEM group. The time to occurrence of blindness varied from 11 to 26 months after the CIRT. No apparent correlation between the carbon ion dose or size of the margin and the post-treatment visual acuity was observed. Glaucoma was observed in four of the HDEM patients; however, no patients required ophthalmectomy. Survival Five out of the 21 patients died, including four patients who died from the lacrimal gland cancer and one patient who died from esophageal cancer. The three-year overall survival rate of all patients was 82.2% (Supplementary Fig. 1b). The three-year survival rates of patients in the HDEM group and those in the LD or HDMM group were 100% and 70%, respectively. With regard to the CTV margin, a favorable trend was observed in the treatment
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
4
Carbon-ion radiotherapy for carcinoma of the lacrimal gland
Table 1 Radiation associated acute and late reactions. Acute radiation morbidity
*
Late radiation morbidity
Gr 0
Gr 1
Gr 2
Gr 3
Gr 4
Gr 0
Gr 1
Gr 2
Gr 3
Gr 4
(a) Skin 48.0 GyE 52.8 GyE 52.8 GyE* Total
0 0 1 1
4 5 9 18
1 0 1 2
0 0 0 0
0 0 0 0
0 2 2 4
5 3 9 17
0 0 0 0
0 0 0 0
0 0 0 0
(b) Ocular/visual 48.0 GyE 52.8 GyE 52.8 GyE* Total
5 5 3 13
0 0 8 8
0 0 0 0
0 0 0 0
0 0 0 0
0 2 4 6
1 0 0 1
1 1 2 4
1 0 2 3
2 2 3 7
Extended margin.
using the extended margin (p = 0.0889, Fig. 2b). Tumor-related factors such as the tumor size and histology were not significant predictors of the overall survival. The three-year disease-free survival rate of all patients was 48.0% (Supplementary Fig. 1c). The rates of patients in the HDEM group and those in the LD or HDMM groups were 62.5% and 30.0%, respectively, and a statistically significant difference was observed among the groups (p = 0.0253, data not shown). Moreover, there was a correlation between the tumor size and the disease-free survival rate, with significantly lower survival observed when the tumor exceeded 3.5 cm in size (p = 0.029). Discussion Carbon ion beams, which are one of the heavy particle beams, provide superior physical dose distribution and possess a high antitumor effect, making them suitable for cancer treatment. We have already demonstrated CIRT to be a safe and useful treatment method for various malignant tumors [15–18]. It is also believed to be suitable for orbital tumors, such as choroidal malignant melanoma [19]. In the present study, we evaluated the safety and efficacy of CIRT for locally advanced or postoperative recurrent epithelial carcinoma of the lacrimal gland. Regarding normal tissue toxicity, skin reactions of Grade 3 or more did not occur as either acute or late toxicity, even after expansion of the irradiation field. In addition, acute ocular/visual reactions of grade 2 or more did not occur in these patients. However, with regard to the late toxicity of ocular/visual reactions, three patients had grade 3 retinopathy and seven patients (two irradiated with 48.0 GyE/12 fr (LD), two irradiated with 52.8 GyE/12 fr with a minimal margin (HDMM) and three with extended margins (HDEM)), lost their vision. No apparent difference among the three groups was found, however, the occurrence of these toxicities strongly depended upon the area of the CTV that was determined individually in the LD and HDMM groups, and was extended in the HDEM group. For example, most of the patients with a tumor adjacent to the optic nerve lost their vision because the nerve could not be spared from the high dose area. This had been predicted at the beginning of the clinical trial, therefore, the loss of eyesight was not treated as a dose-limiting toxicity in this study. Neovascular glaucoma developed in four patients in the HDEM group, although none of them required ophthalmectomy, whereas no patient in the LD or HDMM group developed glaucoma. It was thought that the use of a high dose on a wide area of the retina likely caused severe retinopathy and subsequent neovascularization, resulting in an elevation of the intraocular pressure. Losing vision and neovascular glaucoma are undoubtedly severe adverse events, however, they are still less burdensome to patients
than morbidity due to orbital exenteration. In fact, adverse events occurring only within the CTV, and the surrounding normal tissues, such as the contralateral orbit or frontal lobe of the brain, could be spared from the high dose area by the well-localized dose distribution associated with the unique physical properties of the carbonion beam. In addition, the main advantage of CIRT over radical surgery is that the eyeball can be preserved and the features are not deteriorated in most cases (described below). Therefore, the current outcomes with regard to normal tissue toxicity in this clinical trial could be judged as borderline acceptable for this particular disease if the tumor control rate is comparable to that of radical surgery. Concerning the patient survival and the local tumor control, the three-year overall survival rate was 82.2%, and the three-year local control rate was 79.0%. These outcomes were comparable to similar past reports by various authors [3-9] in terms of both the survival rate and local control rate (Supplementary Fig. 1). In this study, the setting of the CTV margin was strongly correlated with the local control and survival rates. Local recurrence occurred in the LD and HDMM groups, both of which used the minimal margin. On the other hand, none of the patients in the HDEM group has developed local failure so far. The three-year local control rate of the HDEM and other groups (LD and HDMM) was 100% and 60%, respectively, with a statistically significant difference being observed between them (p = 0.0367). Concerning the dose-response of the CIRT, the rate of recurrence within the CTV in the low dose group (LD; 1/5) was higher than that in the high dose group (HDMM + HDEM; 1/16). However, the number of cases with local recurrence within the CTV was too small to obtain a clear dose–response relationship, and therefore, the CIRT of the low dose treatment with an extended margin should be evaluated. At present, it appears that 52.8 GyE in 12 fractions with an extended margin is appropriate for treatment in terms of the tumor control. Orbital exenteration refers to the surgical removal of the eyeball and the surrounding tissues, these included eyelids, muscles, nerves and fatty tissue adjacent to the eye. As a result, physical appearance undergoes a profound change. Orbital exenteration was performed as salvage therapy for two patients with local recurrence; however, the rate of preservation of the eyeball was 90.5%, so CIRT can be considered to be effective for maintaining the QOL of individuals with regard to their physical appearance. Based on this study, it appears that HDEM is appropriate for the treatment of epithelial carcinoma of the lacrimal gland in terms of tumor control. However, neovascular glaucoma developed in some of the HDEM patients, whereas no patients in the LD or HDMM group developed glaucoma. Therefore, to decrease the risk of adverse events, using 48.0 GyE/12 fr with extended margins (i.e., LDEM) should be considered in selected patients.
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
Carbon-ion radiotherapy for carcinoma of the lacrimal gland
In conclusion, CIRT for epithelial carcinoma of the lacrimal gland appears to be effective, with acceptable toxicities, and has favorable outcomes regarding the preservation of the eyeball. By adopting 52.8 GyE in 12 fractions, the local tumor control was satisfactory and the toxicity was still acceptable in consideration of the expected role of this treatment. Although further investigation is needed to optimize the dose with extended margins, this is a promising treatment method that may replace surgical resection and postoperative irradiation. Conflict of interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2015.01. 009. References [1] Lacrimal Gland Tumor Study Group. An epidemiological survey of lacrimal fossa lesions in Japan: number of patients and their sex ratio by pathological diagnosis. Jpn J Ophthalmol 2005;49:343–8. [2] Weis E, Rootman J, Joly TJ, et al. Epithelial lacrimal gland tumors: pathologic classification and current understanding. Arch Ophthalmol 2009;127: 1016–28.
[3] Skinner HD, Garden AS, Rosenthal DI, et al. Outcomes of malignant tumors of the lacrimal apparatus: The University of Texas MD Anderson Cancer Center experience. Cancer 2011;117:2801–10. [4] Ahmad SM, Esmaeli B, Williams M, et al. American Joint Committee on Cancer classification predicts outcome of patients with lacrimal gland adenoid cystic carcinoma. Ophthalmology 2009;116:1210–5. [5] Font RL, Smith SL, Bryan RG. Malignant epithelial tumors of the lacrimal gland: a clinicopathologic study of 21 cases. Arch Ophthalmol 1998;116:613–6. [6] Wright JE, Rose GE, Garner A. Primary malignant neoplasms of the lacrimal gland. Br J Ophthalmol 1992;76:401–7. [7] Tse DT, Benedetto P, Dubovy S, et al. Clinical analysis of the effect of intraarterial cytoreductive chemotherapy in the treatment of lacrimal gland adenoid cystic carcinoma. Am J Ophthalmol 2006;141:44–53. [8] Brada M, Henk JM. Radiotherapy for lacrimal gland tumours. Radiother Oncol 1987;9:175–83. [9] Meldrum ML, Tse DT, Benedetto P. Neoadjuvant intracarotid chemotherapy for treatment of advanced adenocystic carcinoma of the lacrimal gland. Arch Ophthalmol 1998;116:315–21. [10] Common Toxicity Criteria v2.0. National Cancer Institute, 1999. [11] Fleming ID, Cooper JS, Henson DE, et al. Carcinoma of the Lacrimal Gland. AJCC Cancer Staging Manual. 5th ed. Lippincott Raven; 1997. p. 273–5. [12] Endo M, Koyama-Ito H, Minohara S, et al. HIPLAN-A heavy ion treatment planning system at HIMAC. J Jpn Soc Ther Radiol Oncol 1996;8:231–8. [13] RTOG/EORTC Late Radiation Morbidity Scoring Schema. Radiation Therapy Oncology Group website: http://www.rtog.org. [14] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. [15] Kamada T, Tsujii H, Tsuji H, et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin Oncol 2002;20:4466–71. [16] Tsuji H, Yanagi T, Ishikawa H, et al. Hypofractionated radiotherapy with carbon ion beams for prostate cancer. Int J Radiat Oncol Biol Phys 2005;63:1153–60. [17] Tsujii H, Mizoe J, et al. Overview of clinical experiences on carbon ion radiotherapy at NIRS. Radiother Oncol 2004;73:S41–9. [18] Mizoe J, Hasegawa A, et al. Results of carbon ion radiotherapy for head and neck cancer. Radiother Oncol 2012;103:32–7. [19] Tsuji H, Ishikawa H, Yanagi T, et al. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: a Phase I/II doseescalation study. Int J Radiat Oncol Biol Phys 2007;67:857–62.
Please cite this article in press as: Mizoguchi N et al. Carbon-ion radiotherapy for locally advanced primary or postoperative recurrent epithelial carcinoma of the lacrimal gland. Radiother Oncol (2015), http://dx.doi.org/10.1016/j.radonc.2015.01.009
