Jpn J Radiol DOI 10.1007/s11604-014-0300-6
CASE REPORT
First experience of carbon-ion radiotherapy for early breast cancer Hiroko Akamatsu • Kumiko Karasawa Tokuhiko Omatsu • Yoshiharu Isobe • Risa Ogata • Yusuke Koba
•
Received: 23 October 2013 / Accepted: 19 February 2014 Ó Japan Radiological Society 2014
Abstract Breast cancer is increasingly being detected at earlier stages, and partial breast irradiation for patients with low-risk-group tumor has come to be applied in the US and Europe as an alternative to whole-breast irradiation. Based on those experiences, some institutes have tried using particle beams for partial breast irradiation for postoperative or radical intent for early breast cancer, but technical difficulties have hindered its progress. The National Institute of Radiological Sciences has been preparing for carbon-ion radiotherapy (C-ion RT) with radical intent for stage I breast cancer since 2011, and we carried out the first treatment in April 2013. In this case report, we explain our first experience of C-ion RT as a treatment procedure for breast tumor and present the radiation techniques and preliminary treatment results as a reference for other institutes trying to perform the same kind of treatment. Keywords Breast cancer Carbon-ion radiotherapy Accelerated partial breast irradiation
Introduction Breast cancer is the most common cancer in Japanese women, with 59,000 newly diagnosed patients in 2008 [1]. According to the Japan Breast Cancer Society registry, more than 40 % of breast cancer patients were diagnosed as clinical stage I [2]. The standard care for early stage
H. Akamatsu (&) K. Karasawa T. Omatsu Y. Isobe R. Ogata Y. Koba Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan e-mail: [email protected]
breast cancer is breast-conserving therapy consisting of conservative surgery, fractionated whole-breast irradiation and subsequent systemic therapy. Whole-breast irradiation takes more than 5 weeks and sometimes causes adverse skin reactions, breast pain, dysfunction of sweat glands and sebaceous glands, and late breast atrophy. Even though we had recognized the necessity of whole-breast irradiation, several articles reported that 90 % of intra-breast recurrences developed in the same quadrant, especially near the tumor bed [3]. Thus, it must be questioned whether it is really necessary to irradiate the whole breast in all early stage cancer. Sometimes, breast-conserving therapy is an overtreatment for elderly patients with low-risk tumor. In order to reduce the burden, partial breast irradiation has been re-examined and has begun to be used clinically in some patients with low risk of recurrence. In the US and some European countries, accelerated partial breast irradiation (APBI) came into practice as an alternative to whole-breast irradiation in patients with low-risk tumor for postoperative intent, based on 4 randomized trials and more than 40 prospective trials. According to the consensus statement of The American Society of Radiation Oncology (ASTRO) in 2009, patients with age 60 and over, negative BRCA1/2 variation, 2 cm or less tumor (T1), lymph vascular space invasion negative, estrogen receptor (ER) positive, unicentric tumor, invasive ductal or other favorable histology, without extensive intraductal component (EIC) and pN0 are suitable for localized radiotherapy [3]. Some institutes have used proton radiotherapy, which has better dose distribution than photons, for postoperative partial breast irradiation [3–5, 10]. Even though a high cure rate has been reported, breast surgery may give some burden to the patient. We then considered the possibility of partial irradiation without surgery as the next step. If breast cancer can be cured by
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nonsurgical treatment at the same level as surgery, a certain percentage of patients would aspire to that option. Some investigators have performed trials of radical radiotherapy for stage I breast cancer by advanced techniques such as stereotactic radiotherapy or conformal radiotherapy [5]. However, radical radiotherapy has not become an alternative treatment strategy to surgery because of its insufficient result and cosmetic outcome. There are also some technical difficulties such as breast immobilization, optimization of irradiation method, irradiation positioning accuracy, respiratory gating and skin dose constraints [5]. Carbon-ion (C-ion) beams provide superior physical dose distribution because of their finite range in target tissue and their biological advantage due to their high relative biological effectiveness (RBE) in the Bragg peak. At our institute, a dose of carbon ions is expressed in photon equivalent doses (gray equivalent dose: GyE), which is defined as the physical dose multiplied by the RBE of carbon ions. Biological flatness of the spread-out Bragg peak (SOBP) was normalized by the survival fraction of human salivary gland (HSG) tumor cells at the distal region of the SOBP, where RBE of carbon ions was assumed to be 3.0 [7, 8]. Clinical trials with C-ion RT have two major scopes, one being the treatment of advanced tumors that are hard to cure with conventional treatment and the other the treatment of common cancers with the aim of improving survival and quality of life of patients. At the National Institute of Radiological Sciences (NIRS), we have treated more than 7,500 patients in over 50 clinical trials, although a breast cancer protocol has not been performed until this year. The reasons for not performing this treatment sooner were technical difficulties, candidate selection and the fact that breast cancer already had other treatment strategies offering sufficient local control. Based on the usefulness of APBI for low-grade tumor, we planned to start radical radiotherapy using C-ion beams for low-grade stage I breast cancer. The breast cancer C-ion project was begun in 2011. Members of the project in our institute include radiation oncologists, diagnostic radiologists, medical physicists and radiological technicians. After we solved all technical difficulties, a clinical trial of radical C-ion RT for patients with low-risk early breast cancer was started in April 2013. Enrollment criteria for candidates for phase I/II clinical trials of C-ion RT for breast tumor are age [60 years, Union for International Cancer Control (UICC) clinical stage T1N0M0, ER positive, human epidermal growth factor related 2 (HER2) negative, invasive ductal carcinoma or other favorable histology, absence of EIC, no lymph vascular space invasion, performance status 0–2 and tumor location [5 mm from the skin. Patients desiring to receive C-ion RT but ineligible to enroll in the clinical trial because of minor variance were treated by a ‘‘C-ion RT general treatment
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protocol for localized solid tumors’’ with the patient’s and NIRS’s agreement. The candidates for this ‘‘general protocol’’ of C-ion RT for breast tumor have low-grade tumor not completely fitting the clinical trial criteria, although there are certain reasons that make them unsuitable for standard treatment. In this report, we present our first experience of C-ion RT for breast tumor in terms of treatment procedure, irradiation techniques and preliminary treatment results as a reference for other institutes planning to perform similar partial breast treatment.
Case report A 50-year-old female without clinical symptoms presented with an abnormality on screening mammography. A mass in the upper inner quadrant of the left breast, diameter about 2 cm, was detected by palpation at a workup at her regional hospital. Medical examination revealed no axillary lymph node swelling. There was no skin or nipple retraction or adhesion to the skin. A core needle biopsy was performed on the low-echoic lesion in the left breast, and the diagnosis was ductal carcinoma with micro invasion foci, ER-positive, 34bE12-positive and progesterone receptor (PgR) positive. The sample with micro foci was not sufficient to allow determination of HER2 and Ki-67. On whole-body CT, only a 2-cm mass in the left breast was detected without other abnormal lesions. Because of an iodine allergy, CT was performed without contrast medium. The patient was diagnosed as having breast cancer T1N0M0. A breast surgeon recommended breast-conserving surgery with sentinel lymph node biopsy followed by wholebreast irradiation. However, the patient refused any type of surgery because of adverse effects from previous surgery for Cushing syndrome, expressing a desire to have nonsurgical low-invasive radical treatment. Upon her request, she was referred to our hospital for C-ion RT. In her first visit to our hospital, because she was younger than the selection criteria for our study, we explained that breast-conserving therapy is standard treatment with the highest cure rate, and radiofrequency wave ablation was also suggested as another nonsurgical treatment. We also explained that our treatment was experimental and that there was no previous case treated with C-ion RT. Nonetheless, she refused all other alternative treatments and strongly desired to be treated with C-ion RT. After some discussions, we finally decided to treat her as the first patient. Before treatment, a confirmation diagnostic workup was conducted by enhanced magnetic resonance (MR) imaging and 18F-fluorodeoxyglucose positron emission tomography
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Fig. 1 MR imaging of the left breast revealed that the mass was isointense on transverse T1-weighted images (a) and transverse T2weighted images (b); the boundary with the surrounding breast tissue was unclear, but showed a high signal on transverse diffusionweighted images (c) (b 1,000 s/mm2). Contrast-enhanced threedimensional gradient-echo T1-weighted MR images showed an inhomogeneous enhancement mass with an irregular and spiculated
border (d, e). Transverse Gd-enhanced maximum intensity projection (MIP) images (f) demonstrated a mass in the upper inner quadrant of the left breast with a diameter of about 2 cm, as well as other multiple small nodules. The small nodules were diagnosed as mastopexy. On FDG-PET/CT, the left breast tumor showed a maximum standardized uptake value (SUV) of 2.4 in early stage (a) and 2.5 in delay stage before treatment (g)
CT (FDG-PET/CT) in our institution. All breast MR imaging was performed by 3.0-T MR scanner (Magnetom Skyra; Siemens, Erlangen, Germany). Two breast MR imaging examinations, one for diagnosis and the other for therapy planning, were performed before C-ion RT. The diagnostic MR imaging was performed with a breast fourchannel phased-array coil in the prone position for diagnosis of the spread of the breast cancer, judgement of C-ion RT and negation of multiple breast cancer. The diagnostic breast MR imaging protocol includes pre-contrast T1weighted imaging, T2-weighted imaging with fat saturation, diffusion-weighted imaging, dynamic contrast enhanced (DCE) imaging and post-contrast high spatial resolution T1-weighted imaging with fat saturation. DCE imaging and post-contrast high spatial resolution imaging were performed using T1-weighted three-dimensional gradient echo sequence (FLASH; Siemens) with parallel imaging; 0.1 mmol/kg of body weight of gadoterate meglumine (Gd) (Magnescope; Terumo, Tokyo, Japan) was injected at 2 ml/s by using a programmable power injector, followed by a saline flush. DCE imaging acquisition consisted of eight continuous image volume sets with a temporal resolution of 40 s. High spatial resolution imaging was performed immediately after DCE imaging and was obtained with 0.8-mm isotropic spatial resolution.
Apparent diffusion coefficient (ADC) maps were calculated using diffusion-weighted images with b values of 0 and 1,000 s/mm2. DCE images were analyzed by the shape of the time-signal intensity curves using software integrated in the MR scanner. Transverse, coronal and sagittal sections of the single breast were reconstructed, and coronal and transverse maximum intensity projection (MIP) images were generated from high spatial resolution images. Follow-up MR examinations after C-ion RT were performed by the same protocol to determine the therapeutic effect. By the MR examination before C-ion RT, an iso-intense mass was revealed on transverse T1-weighted images (Fig. 1a) and transverse T2-weighted images with fat saturation (Fig. 1b). The boundary with the surrounding breast tissue was unclear, but a high signal on transverse diffusion-weighted images was observed (Fig. 1c). Contrast-enhanced three-dimensional gradient-echo T1weighted MR images showed a heterogeneous enhancement mass with an irregular and spiculated border (Fig. 1d, e). Transverse Gd-enhanced MIP images demonstrated the mass in the upper inner quadrant of the left breast with a diameter of about 2 cm and other multiple small nodules (Fig. 1f). In DCE images, the mass showed significant rapid wash-in and wash-out. This enhancement kinetic was
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Fig. 2 Immobilization cast fitting/placement. The patient’s shoulders were back, with a chest-out posture in supine position and puffing of chest when the fixation body shell and cast were placed. The contralateral breast was pressed with the shell to be lower than the affected breast
compatible with patterns of invasive breast cancers. Other multiple small nodules were diagnosed as mastopathy by time-signal intensity-curve analysis. Two radiologists evaluated the enhanced MR images of tumor extension including ductal spread. FDG-PET images showed increased metabolism in the tumor, with a maximal standardized uptake value (SUV) of 2.4 in early stage and 2.5 in delay stage (Fig. 1g). Since October 2003, our institute has been approved for carrying out advanced medical care under the name ‘‘heavy particle beam treatment for solid tumors’’ by the Ministry of Health, Labour and Welfare. This advanced medical care corresponds to the diversification of needs for health care and new medical technology, and it has been allowed in certain medical institutions. Advanced medical review boards are in place in our institutions to evaluate the eligibility of patients and treatment. Further, we perform medical judgment of the eligibility of the patient in the ‘‘heavy particle beam therapy adaptation study group.’’ We informed the patient about the risk of acute adverse events including skin reaction, chest pain and radiation pneumonitis after C-ion irradiation. We also explained about the risk of late adverse effects to the skin, sub-cutaneous tissue, breast, bone, lung, heart and induced cancer after C-ion RT using a similar document of informed consent as that for the clinical trial of breast cancer. The patient was allowed to receive C-ion RT by ‘‘advanced medical treatment protocol of localized solid tumor’’ in our institute, and written informed consent for the treatment was obtained. Treatment For C-ion RT, the treatment-positioning setup with the immobilization device is very important. The basic position of the treatment was 0° supine, and the best beam direction was decided using a maximum rotation of 20°. Body shape varies slightly because of the rotation of the
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bed, and treatment planning CT at all beam angles was performed and used for the target input, then synthesized. Both a cast and fixation body shell are used for each C-ion RT session. The cast (Mold care; Alcare, Tokyo, Japan) was made for the supine position, slightly head up to the lower area of both upper limbs. The fixation body shell (Shellfitter; Kerary Co., Ltd., Osaka, Japan) was made of three parts: neck, breast and abdomen (Fig. 2). The contralateral breast was placed lower than the affected breast by pressing with the shell. As for the breast shell, a hole was opened for the circumference of the nipple of the affected breast. Tumor positioning at the same placement for every treatment is extremely important, and thus the nipple was guided through the hole and fixed. Tumor positioning at every treatment was guided with inserted fiducial markers. With confirmation of the tumor by ultrasound, two fiducial markers (VisicoilTM; IBA, Schwarzenbruck, Germany) were implanted 5 mm apart from the upper and lower border of the ductal spread (Fig. 3). The upper and lower markers were 20 and 50 mm apart from the skin, respectively. Planning CT was performed using the immobilization device, 2.5-mm thickness per slice. Four-dimensional (4D) CT according to the respiratory phase was applied. Breast MR imaging for treatment planning was performed with a body 18-channel phased-array coil put on with the immobilization device in the supine position in the same position as for C-ion RT, for identifying the location of the markers inserted for C-ion RT and for fusion of MR images with CT images for treatment planning. MR imaging for the planning protocol includes the three-dimensional fast imaging with steady-state precession (FISP) and postcontrast high spatial resolution T1-weighted imaging with fat saturation using 0.1 mmol/kg of body weight of gadoterate meglumine (Magnescope). Both images were at 1.2mm isotropic spatial resolution. This was applied for treatment planning by dynamic MR image fusion (Fig. 3). Following the image acquisitions, XiO-N (Elekta, Stockholm, Sweden) was used for radiation treatment planning. The gross tumor volume (GTV) was defined as the gross tumor and intraductal component detected by MR images. The clinical target volume (CTV) includes GTV and the region suspected to contain the tumor by MR images. The planning target volume (PTV) was created by adding 5 mm to CTV, and an anterior margin of 5 mm was also added (Fig. 4). Radiation dose and fractionation were decided based on our experience with other T1 adenocarcinomas. We have treated stage IA lung cancer with 52.8 GyE and stage IB lung cancer with 60.0 GyE in 4 fractions/1 week. In breast cancer treatment, similar to lung cancer irradiation, adjacent organs of the skin, ribs, lungs and heart must be taken into account, and as tumor size is also similar to stage I
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Fig. 3 Insult fiducial markers in the affected breast. Two fiducial markers were implanted 5 mm apart from the upper and lower border of ductal spread on MR images by guiding ultrasound. On axial
planning CT and MRI, the two fiducial markers were used for treatment planning and position collation
lung cancer, we decided on the same dose description as for stage I lung cancer. We decided to treat her tumor with four fractions of 13.2 GyE, amounting to a total dose of 52.8 GyE [8]. Treatment was given daily from Tuesday to Friday, within 1 week. Irradiation was performed using respiratory gating. The C-ion beam is on around exhalation in the treatment. By the respiratory gating system, intrafraction motion does not have much influence on the accuracy of the treatment. We could immobilize the treatment field with less than 2-mm positioning error using these tools. For positioning collation, not only the sites of the Visicoils, but also the skin border and location of the ribs were considered. From five to seven fiducial points were collated in three dimensions of each beam field. The mean shift length of fiducial points was -1.3 mm in right– left (range -1.3 to 0.7), -0.4 mm in superior–inferior (range -1.0 to 0.5) and 0.0 mm in anterior–posterior (range -0.4 to 1.3) directions, respectively. Figure 4 shows the mean shift length of fiducial points in 4 treatment days. Figure 5 shows the dose distribution of the breast, and D95 of CTV was 50.8 GyE. Maximum dose to normal tissue was 21 GyE in skin, 33.7 GyE in the left lung and 48.4
GyE in the left ribs, respectively. Figure 6 shows the dose volume histogram of this treatment. No acute toxicity was observed at the time of completion of C-ion RT. Follow-up study was performed monthly for 3 months after the completion of C-ion RT. One and 3 months after treatment, MR imaging and ultrasound (US) were performed. On MR imaging, the tumor had slightly shrunk after 1 month and had shrunk even more at 3 months (Fig. 7a–c). Reduction of tumor size was observed, but the tumor did not completely disappear. However, in diffusionweighted images, abnormal high signal of the tumor was decreased, and in DCE images the early intensely enhanced area was decreased. By enhancement kinetic analysis, the time to peak enhancement of the tumor was prolonged, and wash-out from the tumor was obscured. These findings suggested that the viability of the tumor was decreased. The surrounding normal mammary gland had shrunk, but obvious signal change and strong enhancement were not observed. At 2 months after C-ion RT, FDG-PET/CT showed the disappearance of the pre-treatment increased metabolism of the left breast tumor (Fig. 7g). For the time being, the tumor was under control. A grade 1 adverse skin
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Jpn J Radiol Fig. 4 Dose distribution of the breast. Three-field C-ion beam used the anterior oblique angle and posterior oblique angle and a maximum rotation of 20°. This dose distribution showed the dose to skin as \50 %, and doses to lung, heart and contralateral breast as minimal or not measurable
Fig. 6 Dose volume histogram of the C-ion RT of the breast in this patient. D95 of CTV was 50.8 GyE. The dose to the breast skin and left lung were reduced to \50 % of the prescribed dose Fig. 5 This chart shows the mean shift length of fiducial points in 4 treatment days. From five to seven fiducial points were collated in three dimensions of each beam field with \2 mm
Discussion
reaction (pigmentation) was observed at the irradiated site from 2 to 6 weeks after the treatment (Fig. 8). No other adverse reactions were observed. Tamoxifen was started from 1 month after C-ion RT.
This report presents the world’s first case of breast irradiation with C-ions. The purpose of this preliminary report is to provide our experience as a reference for other institutes that may be planning to perform the same kind of
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Fig. 7 Pre-treatment (a), 1 month after start of C-ion RT (b), 3 months later (c); transverse maximum intensity projection (MIP) images of the left breast. Enhancement of the tumor (arrow) in the upper inner region of the breast shrank gradually after the start of C-ion RT. Pre-treatment (d), 1 month after the start of C-ion RT (e), 3 months later (f); transverse early phase images subtracted from
DCE images of the left breast. The area of early intense enhancement in the center of the tumor was gradually reduced in size. Reduction of early enhancement was faster than reduction of tumor observed in MIP images. Two months after C-ion RT, the increased metabolism in the left breast had successfully disappeared (g)
Fig. 8 Early adverse skin reaction after radiotherapy. Along the radiation field, grade 1 subcutaneous toxicity appeared at 1 month after radiotherapy. The pigmentation disappeared at 1.5 months after radiotherapy
irradiation. For this reason, we would like to add our investigation results to the information leading to treatment decisions. After we decided to treat breast cancer, we first investigated the treatment position and immobilization method. We initially discussed the possibility of the prone breastdrooping position, but taking advantage of our extensive experience with treatment techniques, we finally decided to treat the patient in a supine position with an immobilization cast and shell. Cast and shell are normally used in our facilities. The shell was made to correspond to the beams
from left and right by heaping up at the therapeutic side of the breast while compressing the breast on the opposite side. Of course, immobilization methods depend on each facility’s circumstances. The prone breast-drooping position has often been reported, but we could perform precise treatment in the supine position with a fixation body shell. Within a few years, we expect to be able to use a rotation gantry in our facility, and then we will re-consider the prone breast-drooping position. The treatment position is matched by the position X-ray image in our institution, and the insertion of markers must
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be verified by X-ray image. We took images of each type of Visicoil inserted in the phantom to ensure visibility and its artifact to confirm the effect of dose distribution when entering the beam pass. We decided to use a 5-mm length with a 0.5-mm diameter. The distances between tumor and nipple and between tumor and skin were measured by MIP image, deciding the puncture site of insertion of the metal markers. The fixation body shell for inserting Visicoils was made, and the breast shape was set as closely as possible to the taken MR images. A balanced field echo (BFE) after insertion of the Visicoils was not useful for the inflammatory change by the insertion. MR imaging post-insertion was better at least 1 day later. The team radiologist had inserted two Visicoils under US imaging with reference to MR imaging. The appropriate position of the Visicoils was considered as up and down, about 5 mm apart from CTV, where it can be easily set up without affecting the beam. MR imaging was more useful than other imaging modalities for determining the irradiation field. Tumor extension was determined by the contrast effect of dynamic MR, and enhanced spiculated margins were included in CTV. Other nodules were distinguished from the tumor by the time–intensity curve pattern by making the lesion the region of interest (ROI). In this case, the shape and relationship between the two Visicoils were kept constant during the treatment. The usefulness of the two Visicoils for position collation was obvious. Tumor positioning was checked for every treatment at four points of head to tail of the two fiducial markers. For positioning collation, not only the sites of the Visicoils, but also the skin border and location of ribs were considered. It took from 5 min minimum to 34 min maximum for treatment positioning after putting on the body shell in the correct position. Total treatment time each day was approximately 1 h. Some techniques for putting on the shell accurately within a shorter time are thought to be necessary, so we made a window in the breast shell and marked three points on the shell and skin of the breast for the next case. As early adverse events after treatment, only a grade 1 skin reaction between 2 and 6 weeks was observed. The first C-ion RT for breast cancer was performed without problems. Tumor reduction after C-ion RT could not be detected by US. MR imaging was most useful for determining the treatment result. Tumor shrinkage was slower than we expected. The dose to breast skin was reduced to \50 % of the prescribed dose, and doses to the lung, heart and contralateral breast were minimal or not measurable. In comparison, the reported dose to breast skin was more than 50 % of the prescribed dose by APBI using the threedimensional conformal radiotherapy (3D-CRT) technique
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or proton beam [9]. It was also reported that 3D-CRT for APBI had a high rate of moderate-to-severe late toxicity in 10 % of the patients [10]. Sung et al. reported that nonPTV breast volume receiving 50 % of the prescribed dose by APBI using a proton beam was a mean of 16.5 % [6]. C-ion RT showed superior dose distribution to proton RT, IMRT and 3D-CRT [6]. The final result of treatment outcome will need a longer follow-up period, but the initial therapeutic effect was good, with minimal acute adverse effects. If the biological effects of carbon radiotherapy on breast cancer are as good as on other cancers, we might be able to treat breast cancer without surgery. We think our experience can be used as a reference by other institutes trying to perform radical partial breast irradiation. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. National Cancer Center for Cancer Control and Information Service. http://ganjoho.jp/public/statistics/pub/statistics01.html. 2. The japanese breast cancer society. http://www.jbcs.gr.jp/people/ nenjihoukoku/2011nenji.pdf. 3. Smith BD, Arthur DW, Buchholz TA, Haffty BG, Hahn CA, Hardenbergh PH, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74(4):987–1001. 4. Wang X, Amos RA, Zhang X, Taddei PJ, Woodward WA, Hoffman KE, et al. External-beam accelerated partial breast irradiation using multiple proton beam configurations. Int J Radiat Oncol Biol Phys. 2011;80(5):1464–72. 5. Sato K, Uematsu M, Saito T, Tsuda H, Takeuchi H, Shigekawa T, et al. Efficacy of accelerated partial breast irradiation as a neoadjuvant treatment for patients with breast cancer: a pilot study. Surgery. 2006;139(5):617–23. 6. Moon SH, Shin KH, Kim TH, Yoon M, Park S, Lee DH, et al. Dosimetric comparison of four different external beam partial breast irradiation techniques: three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, helical tomotherapy, and proton beam therapy. Radiother Oncol. 2009;90(1):66–73. 7. Kanai T, Endo M, Minohara S, Miyahara N, Koyama-Ito H, Tomura H, et al. Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy. Int J Radiat Oncol Biol Phys. 1999;44(1):201–10. 8. Okada T, Kamada T, Tsuji H, Mizoe JE, Baba M, Kato S, et al. Carbon ion radiotherapy: clinical experiences at National Institute of Radiological Science (NIRS). J Radiat Res. 2010;51(4):355–64. 9. Wang X, Zhang X, Li X, Amos RA, Shaitelman SF, Hoffman K, et al. Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits? Br J Radiol. 2013;86(1029):20130176. 10. Hepel JT, Tokita M, MacAusland SG, Evans SB, Hiatt JR, Price LL, et al. Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2009;75(5):1290–6.
CASE REPORT
First experience of carbon-ion radiotherapy for early breast cancer Hiroko Akamatsu • Kumiko Karasawa Tokuhiko Omatsu • Yoshiharu Isobe • Risa Ogata • Yusuke Koba
•
Received: 23 October 2013 / Accepted: 19 February 2014 Ó Japan Radiological Society 2014
Abstract Breast cancer is increasingly being detected at earlier stages, and partial breast irradiation for patients with low-risk-group tumor has come to be applied in the US and Europe as an alternative to whole-breast irradiation. Based on those experiences, some institutes have tried using particle beams for partial breast irradiation for postoperative or radical intent for early breast cancer, but technical difficulties have hindered its progress. The National Institute of Radiological Sciences has been preparing for carbon-ion radiotherapy (C-ion RT) with radical intent for stage I breast cancer since 2011, and we carried out the first treatment in April 2013. In this case report, we explain our first experience of C-ion RT as a treatment procedure for breast tumor and present the radiation techniques and preliminary treatment results as a reference for other institutes trying to perform the same kind of treatment. Keywords Breast cancer Carbon-ion radiotherapy Accelerated partial breast irradiation
Introduction Breast cancer is the most common cancer in Japanese women, with 59,000 newly diagnosed patients in 2008 [1]. According to the Japan Breast Cancer Society registry, more than 40 % of breast cancer patients were diagnosed as clinical stage I [2]. The standard care for early stage
H. Akamatsu (&) K. Karasawa T. Omatsu Y. Isobe R. Ogata Y. Koba Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan e-mail: [email protected]
breast cancer is breast-conserving therapy consisting of conservative surgery, fractionated whole-breast irradiation and subsequent systemic therapy. Whole-breast irradiation takes more than 5 weeks and sometimes causes adverse skin reactions, breast pain, dysfunction of sweat glands and sebaceous glands, and late breast atrophy. Even though we had recognized the necessity of whole-breast irradiation, several articles reported that 90 % of intra-breast recurrences developed in the same quadrant, especially near the tumor bed [3]. Thus, it must be questioned whether it is really necessary to irradiate the whole breast in all early stage cancer. Sometimes, breast-conserving therapy is an overtreatment for elderly patients with low-risk tumor. In order to reduce the burden, partial breast irradiation has been re-examined and has begun to be used clinically in some patients with low risk of recurrence. In the US and some European countries, accelerated partial breast irradiation (APBI) came into practice as an alternative to whole-breast irradiation in patients with low-risk tumor for postoperative intent, based on 4 randomized trials and more than 40 prospective trials. According to the consensus statement of The American Society of Radiation Oncology (ASTRO) in 2009, patients with age 60 and over, negative BRCA1/2 variation, 2 cm or less tumor (T1), lymph vascular space invasion negative, estrogen receptor (ER) positive, unicentric tumor, invasive ductal or other favorable histology, without extensive intraductal component (EIC) and pN0 are suitable for localized radiotherapy [3]. Some institutes have used proton radiotherapy, which has better dose distribution than photons, for postoperative partial breast irradiation [3–5, 10]. Even though a high cure rate has been reported, breast surgery may give some burden to the patient. We then considered the possibility of partial irradiation without surgery as the next step. If breast cancer can be cured by
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nonsurgical treatment at the same level as surgery, a certain percentage of patients would aspire to that option. Some investigators have performed trials of radical radiotherapy for stage I breast cancer by advanced techniques such as stereotactic radiotherapy or conformal radiotherapy [5]. However, radical radiotherapy has not become an alternative treatment strategy to surgery because of its insufficient result and cosmetic outcome. There are also some technical difficulties such as breast immobilization, optimization of irradiation method, irradiation positioning accuracy, respiratory gating and skin dose constraints [5]. Carbon-ion (C-ion) beams provide superior physical dose distribution because of their finite range in target tissue and their biological advantage due to their high relative biological effectiveness (RBE) in the Bragg peak. At our institute, a dose of carbon ions is expressed in photon equivalent doses (gray equivalent dose: GyE), which is defined as the physical dose multiplied by the RBE of carbon ions. Biological flatness of the spread-out Bragg peak (SOBP) was normalized by the survival fraction of human salivary gland (HSG) tumor cells at the distal region of the SOBP, where RBE of carbon ions was assumed to be 3.0 [7, 8]. Clinical trials with C-ion RT have two major scopes, one being the treatment of advanced tumors that are hard to cure with conventional treatment and the other the treatment of common cancers with the aim of improving survival and quality of life of patients. At the National Institute of Radiological Sciences (NIRS), we have treated more than 7,500 patients in over 50 clinical trials, although a breast cancer protocol has not been performed until this year. The reasons for not performing this treatment sooner were technical difficulties, candidate selection and the fact that breast cancer already had other treatment strategies offering sufficient local control. Based on the usefulness of APBI for low-grade tumor, we planned to start radical radiotherapy using C-ion beams for low-grade stage I breast cancer. The breast cancer C-ion project was begun in 2011. Members of the project in our institute include radiation oncologists, diagnostic radiologists, medical physicists and radiological technicians. After we solved all technical difficulties, a clinical trial of radical C-ion RT for patients with low-risk early breast cancer was started in April 2013. Enrollment criteria for candidates for phase I/II clinical trials of C-ion RT for breast tumor are age [60 years, Union for International Cancer Control (UICC) clinical stage T1N0M0, ER positive, human epidermal growth factor related 2 (HER2) negative, invasive ductal carcinoma or other favorable histology, absence of EIC, no lymph vascular space invasion, performance status 0–2 and tumor location [5 mm from the skin. Patients desiring to receive C-ion RT but ineligible to enroll in the clinical trial because of minor variance were treated by a ‘‘C-ion RT general treatment
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protocol for localized solid tumors’’ with the patient’s and NIRS’s agreement. The candidates for this ‘‘general protocol’’ of C-ion RT for breast tumor have low-grade tumor not completely fitting the clinical trial criteria, although there are certain reasons that make them unsuitable for standard treatment. In this report, we present our first experience of C-ion RT for breast tumor in terms of treatment procedure, irradiation techniques and preliminary treatment results as a reference for other institutes planning to perform similar partial breast treatment.
Case report A 50-year-old female without clinical symptoms presented with an abnormality on screening mammography. A mass in the upper inner quadrant of the left breast, diameter about 2 cm, was detected by palpation at a workup at her regional hospital. Medical examination revealed no axillary lymph node swelling. There was no skin or nipple retraction or adhesion to the skin. A core needle biopsy was performed on the low-echoic lesion in the left breast, and the diagnosis was ductal carcinoma with micro invasion foci, ER-positive, 34bE12-positive and progesterone receptor (PgR) positive. The sample with micro foci was not sufficient to allow determination of HER2 and Ki-67. On whole-body CT, only a 2-cm mass in the left breast was detected without other abnormal lesions. Because of an iodine allergy, CT was performed without contrast medium. The patient was diagnosed as having breast cancer T1N0M0. A breast surgeon recommended breast-conserving surgery with sentinel lymph node biopsy followed by wholebreast irradiation. However, the patient refused any type of surgery because of adverse effects from previous surgery for Cushing syndrome, expressing a desire to have nonsurgical low-invasive radical treatment. Upon her request, she was referred to our hospital for C-ion RT. In her first visit to our hospital, because she was younger than the selection criteria for our study, we explained that breast-conserving therapy is standard treatment with the highest cure rate, and radiofrequency wave ablation was also suggested as another nonsurgical treatment. We also explained that our treatment was experimental and that there was no previous case treated with C-ion RT. Nonetheless, she refused all other alternative treatments and strongly desired to be treated with C-ion RT. After some discussions, we finally decided to treat her as the first patient. Before treatment, a confirmation diagnostic workup was conducted by enhanced magnetic resonance (MR) imaging and 18F-fluorodeoxyglucose positron emission tomography
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Fig. 1 MR imaging of the left breast revealed that the mass was isointense on transverse T1-weighted images (a) and transverse T2weighted images (b); the boundary with the surrounding breast tissue was unclear, but showed a high signal on transverse diffusionweighted images (c) (b 1,000 s/mm2). Contrast-enhanced threedimensional gradient-echo T1-weighted MR images showed an inhomogeneous enhancement mass with an irregular and spiculated
border (d, e). Transverse Gd-enhanced maximum intensity projection (MIP) images (f) demonstrated a mass in the upper inner quadrant of the left breast with a diameter of about 2 cm, as well as other multiple small nodules. The small nodules were diagnosed as mastopexy. On FDG-PET/CT, the left breast tumor showed a maximum standardized uptake value (SUV) of 2.4 in early stage (a) and 2.5 in delay stage before treatment (g)
CT (FDG-PET/CT) in our institution. All breast MR imaging was performed by 3.0-T MR scanner (Magnetom Skyra; Siemens, Erlangen, Germany). Two breast MR imaging examinations, one for diagnosis and the other for therapy planning, were performed before C-ion RT. The diagnostic MR imaging was performed with a breast fourchannel phased-array coil in the prone position for diagnosis of the spread of the breast cancer, judgement of C-ion RT and negation of multiple breast cancer. The diagnostic breast MR imaging protocol includes pre-contrast T1weighted imaging, T2-weighted imaging with fat saturation, diffusion-weighted imaging, dynamic contrast enhanced (DCE) imaging and post-contrast high spatial resolution T1-weighted imaging with fat saturation. DCE imaging and post-contrast high spatial resolution imaging were performed using T1-weighted three-dimensional gradient echo sequence (FLASH; Siemens) with parallel imaging; 0.1 mmol/kg of body weight of gadoterate meglumine (Gd) (Magnescope; Terumo, Tokyo, Japan) was injected at 2 ml/s by using a programmable power injector, followed by a saline flush. DCE imaging acquisition consisted of eight continuous image volume sets with a temporal resolution of 40 s. High spatial resolution imaging was performed immediately after DCE imaging and was obtained with 0.8-mm isotropic spatial resolution.
Apparent diffusion coefficient (ADC) maps were calculated using diffusion-weighted images with b values of 0 and 1,000 s/mm2. DCE images were analyzed by the shape of the time-signal intensity curves using software integrated in the MR scanner. Transverse, coronal and sagittal sections of the single breast were reconstructed, and coronal and transverse maximum intensity projection (MIP) images were generated from high spatial resolution images. Follow-up MR examinations after C-ion RT were performed by the same protocol to determine the therapeutic effect. By the MR examination before C-ion RT, an iso-intense mass was revealed on transverse T1-weighted images (Fig. 1a) and transverse T2-weighted images with fat saturation (Fig. 1b). The boundary with the surrounding breast tissue was unclear, but a high signal on transverse diffusion-weighted images was observed (Fig. 1c). Contrast-enhanced three-dimensional gradient-echo T1weighted MR images showed a heterogeneous enhancement mass with an irregular and spiculated border (Fig. 1d, e). Transverse Gd-enhanced MIP images demonstrated the mass in the upper inner quadrant of the left breast with a diameter of about 2 cm and other multiple small nodules (Fig. 1f). In DCE images, the mass showed significant rapid wash-in and wash-out. This enhancement kinetic was
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Fig. 2 Immobilization cast fitting/placement. The patient’s shoulders were back, with a chest-out posture in supine position and puffing of chest when the fixation body shell and cast were placed. The contralateral breast was pressed with the shell to be lower than the affected breast
compatible with patterns of invasive breast cancers. Other multiple small nodules were diagnosed as mastopathy by time-signal intensity-curve analysis. Two radiologists evaluated the enhanced MR images of tumor extension including ductal spread. FDG-PET images showed increased metabolism in the tumor, with a maximal standardized uptake value (SUV) of 2.4 in early stage and 2.5 in delay stage (Fig. 1g). Since October 2003, our institute has been approved for carrying out advanced medical care under the name ‘‘heavy particle beam treatment for solid tumors’’ by the Ministry of Health, Labour and Welfare. This advanced medical care corresponds to the diversification of needs for health care and new medical technology, and it has been allowed in certain medical institutions. Advanced medical review boards are in place in our institutions to evaluate the eligibility of patients and treatment. Further, we perform medical judgment of the eligibility of the patient in the ‘‘heavy particle beam therapy adaptation study group.’’ We informed the patient about the risk of acute adverse events including skin reaction, chest pain and radiation pneumonitis after C-ion irradiation. We also explained about the risk of late adverse effects to the skin, sub-cutaneous tissue, breast, bone, lung, heart and induced cancer after C-ion RT using a similar document of informed consent as that for the clinical trial of breast cancer. The patient was allowed to receive C-ion RT by ‘‘advanced medical treatment protocol of localized solid tumor’’ in our institute, and written informed consent for the treatment was obtained. Treatment For C-ion RT, the treatment-positioning setup with the immobilization device is very important. The basic position of the treatment was 0° supine, and the best beam direction was decided using a maximum rotation of 20°. Body shape varies slightly because of the rotation of the
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bed, and treatment planning CT at all beam angles was performed and used for the target input, then synthesized. Both a cast and fixation body shell are used for each C-ion RT session. The cast (Mold care; Alcare, Tokyo, Japan) was made for the supine position, slightly head up to the lower area of both upper limbs. The fixation body shell (Shellfitter; Kerary Co., Ltd., Osaka, Japan) was made of three parts: neck, breast and abdomen (Fig. 2). The contralateral breast was placed lower than the affected breast by pressing with the shell. As for the breast shell, a hole was opened for the circumference of the nipple of the affected breast. Tumor positioning at the same placement for every treatment is extremely important, and thus the nipple was guided through the hole and fixed. Tumor positioning at every treatment was guided with inserted fiducial markers. With confirmation of the tumor by ultrasound, two fiducial markers (VisicoilTM; IBA, Schwarzenbruck, Germany) were implanted 5 mm apart from the upper and lower border of the ductal spread (Fig. 3). The upper and lower markers were 20 and 50 mm apart from the skin, respectively. Planning CT was performed using the immobilization device, 2.5-mm thickness per slice. Four-dimensional (4D) CT according to the respiratory phase was applied. Breast MR imaging for treatment planning was performed with a body 18-channel phased-array coil put on with the immobilization device in the supine position in the same position as for C-ion RT, for identifying the location of the markers inserted for C-ion RT and for fusion of MR images with CT images for treatment planning. MR imaging for the planning protocol includes the three-dimensional fast imaging with steady-state precession (FISP) and postcontrast high spatial resolution T1-weighted imaging with fat saturation using 0.1 mmol/kg of body weight of gadoterate meglumine (Magnescope). Both images were at 1.2mm isotropic spatial resolution. This was applied for treatment planning by dynamic MR image fusion (Fig. 3). Following the image acquisitions, XiO-N (Elekta, Stockholm, Sweden) was used for radiation treatment planning. The gross tumor volume (GTV) was defined as the gross tumor and intraductal component detected by MR images. The clinical target volume (CTV) includes GTV and the region suspected to contain the tumor by MR images. The planning target volume (PTV) was created by adding 5 mm to CTV, and an anterior margin of 5 mm was also added (Fig. 4). Radiation dose and fractionation were decided based on our experience with other T1 adenocarcinomas. We have treated stage IA lung cancer with 52.8 GyE and stage IB lung cancer with 60.0 GyE in 4 fractions/1 week. In breast cancer treatment, similar to lung cancer irradiation, adjacent organs of the skin, ribs, lungs and heart must be taken into account, and as tumor size is also similar to stage I
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Fig. 3 Insult fiducial markers in the affected breast. Two fiducial markers were implanted 5 mm apart from the upper and lower border of ductal spread on MR images by guiding ultrasound. On axial
planning CT and MRI, the two fiducial markers were used for treatment planning and position collation
lung cancer, we decided on the same dose description as for stage I lung cancer. We decided to treat her tumor with four fractions of 13.2 GyE, amounting to a total dose of 52.8 GyE [8]. Treatment was given daily from Tuesday to Friday, within 1 week. Irradiation was performed using respiratory gating. The C-ion beam is on around exhalation in the treatment. By the respiratory gating system, intrafraction motion does not have much influence on the accuracy of the treatment. We could immobilize the treatment field with less than 2-mm positioning error using these tools. For positioning collation, not only the sites of the Visicoils, but also the skin border and location of the ribs were considered. From five to seven fiducial points were collated in three dimensions of each beam field. The mean shift length of fiducial points was -1.3 mm in right– left (range -1.3 to 0.7), -0.4 mm in superior–inferior (range -1.0 to 0.5) and 0.0 mm in anterior–posterior (range -0.4 to 1.3) directions, respectively. Figure 4 shows the mean shift length of fiducial points in 4 treatment days. Figure 5 shows the dose distribution of the breast, and D95 of CTV was 50.8 GyE. Maximum dose to normal tissue was 21 GyE in skin, 33.7 GyE in the left lung and 48.4
GyE in the left ribs, respectively. Figure 6 shows the dose volume histogram of this treatment. No acute toxicity was observed at the time of completion of C-ion RT. Follow-up study was performed monthly for 3 months after the completion of C-ion RT. One and 3 months after treatment, MR imaging and ultrasound (US) were performed. On MR imaging, the tumor had slightly shrunk after 1 month and had shrunk even more at 3 months (Fig. 7a–c). Reduction of tumor size was observed, but the tumor did not completely disappear. However, in diffusionweighted images, abnormal high signal of the tumor was decreased, and in DCE images the early intensely enhanced area was decreased. By enhancement kinetic analysis, the time to peak enhancement of the tumor was prolonged, and wash-out from the tumor was obscured. These findings suggested that the viability of the tumor was decreased. The surrounding normal mammary gland had shrunk, but obvious signal change and strong enhancement were not observed. At 2 months after C-ion RT, FDG-PET/CT showed the disappearance of the pre-treatment increased metabolism of the left breast tumor (Fig. 7g). For the time being, the tumor was under control. A grade 1 adverse skin
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Jpn J Radiol Fig. 4 Dose distribution of the breast. Three-field C-ion beam used the anterior oblique angle and posterior oblique angle and a maximum rotation of 20°. This dose distribution showed the dose to skin as \50 %, and doses to lung, heart and contralateral breast as minimal or not measurable
Fig. 6 Dose volume histogram of the C-ion RT of the breast in this patient. D95 of CTV was 50.8 GyE. The dose to the breast skin and left lung were reduced to \50 % of the prescribed dose Fig. 5 This chart shows the mean shift length of fiducial points in 4 treatment days. From five to seven fiducial points were collated in three dimensions of each beam field with \2 mm
Discussion
reaction (pigmentation) was observed at the irradiated site from 2 to 6 weeks after the treatment (Fig. 8). No other adverse reactions were observed. Tamoxifen was started from 1 month after C-ion RT.
This report presents the world’s first case of breast irradiation with C-ions. The purpose of this preliminary report is to provide our experience as a reference for other institutes that may be planning to perform the same kind of
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Fig. 7 Pre-treatment (a), 1 month after start of C-ion RT (b), 3 months later (c); transverse maximum intensity projection (MIP) images of the left breast. Enhancement of the tumor (arrow) in the upper inner region of the breast shrank gradually after the start of C-ion RT. Pre-treatment (d), 1 month after the start of C-ion RT (e), 3 months later (f); transverse early phase images subtracted from
DCE images of the left breast. The area of early intense enhancement in the center of the tumor was gradually reduced in size. Reduction of early enhancement was faster than reduction of tumor observed in MIP images. Two months after C-ion RT, the increased metabolism in the left breast had successfully disappeared (g)
Fig. 8 Early adverse skin reaction after radiotherapy. Along the radiation field, grade 1 subcutaneous toxicity appeared at 1 month after radiotherapy. The pigmentation disappeared at 1.5 months after radiotherapy
irradiation. For this reason, we would like to add our investigation results to the information leading to treatment decisions. After we decided to treat breast cancer, we first investigated the treatment position and immobilization method. We initially discussed the possibility of the prone breastdrooping position, but taking advantage of our extensive experience with treatment techniques, we finally decided to treat the patient in a supine position with an immobilization cast and shell. Cast and shell are normally used in our facilities. The shell was made to correspond to the beams
from left and right by heaping up at the therapeutic side of the breast while compressing the breast on the opposite side. Of course, immobilization methods depend on each facility’s circumstances. The prone breast-drooping position has often been reported, but we could perform precise treatment in the supine position with a fixation body shell. Within a few years, we expect to be able to use a rotation gantry in our facility, and then we will re-consider the prone breast-drooping position. The treatment position is matched by the position X-ray image in our institution, and the insertion of markers must
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be verified by X-ray image. We took images of each type of Visicoil inserted in the phantom to ensure visibility and its artifact to confirm the effect of dose distribution when entering the beam pass. We decided to use a 5-mm length with a 0.5-mm diameter. The distances between tumor and nipple and between tumor and skin were measured by MIP image, deciding the puncture site of insertion of the metal markers. The fixation body shell for inserting Visicoils was made, and the breast shape was set as closely as possible to the taken MR images. A balanced field echo (BFE) after insertion of the Visicoils was not useful for the inflammatory change by the insertion. MR imaging post-insertion was better at least 1 day later. The team radiologist had inserted two Visicoils under US imaging with reference to MR imaging. The appropriate position of the Visicoils was considered as up and down, about 5 mm apart from CTV, where it can be easily set up without affecting the beam. MR imaging was more useful than other imaging modalities for determining the irradiation field. Tumor extension was determined by the contrast effect of dynamic MR, and enhanced spiculated margins were included in CTV. Other nodules were distinguished from the tumor by the time–intensity curve pattern by making the lesion the region of interest (ROI). In this case, the shape and relationship between the two Visicoils were kept constant during the treatment. The usefulness of the two Visicoils for position collation was obvious. Tumor positioning was checked for every treatment at four points of head to tail of the two fiducial markers. For positioning collation, not only the sites of the Visicoils, but also the skin border and location of ribs were considered. It took from 5 min minimum to 34 min maximum for treatment positioning after putting on the body shell in the correct position. Total treatment time each day was approximately 1 h. Some techniques for putting on the shell accurately within a shorter time are thought to be necessary, so we made a window in the breast shell and marked three points on the shell and skin of the breast for the next case. As early adverse events after treatment, only a grade 1 skin reaction between 2 and 6 weeks was observed. The first C-ion RT for breast cancer was performed without problems. Tumor reduction after C-ion RT could not be detected by US. MR imaging was most useful for determining the treatment result. Tumor shrinkage was slower than we expected. The dose to breast skin was reduced to \50 % of the prescribed dose, and doses to the lung, heart and contralateral breast were minimal or not measurable. In comparison, the reported dose to breast skin was more than 50 % of the prescribed dose by APBI using the threedimensional conformal radiotherapy (3D-CRT) technique
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or proton beam [9]. It was also reported that 3D-CRT for APBI had a high rate of moderate-to-severe late toxicity in 10 % of the patients [10]. Sung et al. reported that nonPTV breast volume receiving 50 % of the prescribed dose by APBI using a proton beam was a mean of 16.5 % [6]. C-ion RT showed superior dose distribution to proton RT, IMRT and 3D-CRT [6]. The final result of treatment outcome will need a longer follow-up period, but the initial therapeutic effect was good, with minimal acute adverse effects. If the biological effects of carbon radiotherapy on breast cancer are as good as on other cancers, we might be able to treat breast cancer without surgery. We think our experience can be used as a reference by other institutes trying to perform radical partial breast irradiation. Conflict of interest of interest.
The authors declare that they have no conflict
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