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© 2002 American Society for Clinical Oncology Efficacy and Safety of Carbon Ion Radiotherapy in Bone and Soft Tissue SarcomasByFrom the Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, and Chiba University Graduate School of Medicine, Chiba, Japan. Address reprint requests to Tadashi Kamada, MD, Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, Anagawa-4-9-1, Inage-Ku, Chiba 261, Japan; email: t_kamada{at}nirs.go.jp
PURPOSE: To evaluate the tolerance for and effectiveness of carbon ion radiotherapy in patients with unresectable bone and soft tissue sarcomas. PATIENTS AND METHODS: We conducted a phase I/II dose escalation study of carbon ion radiotherapy. Fifty-seven patients with 64 sites of bone and soft tissue sarcomas not suited for resection received carbon ion radiotherapy. Tumors involved the spine or paraspinous soft tissues in 19 patients, pelvis in 32 patients, and extremities in six patients. The total dose ranged from 52.8 to 73.6 gray equivalent (GyE) and was administered in 16 fixed fractions over 4 weeks (3.3 to 4.6 GyE/fraction). The median tumor size was 559 cm3 (range, 20 to 2,290 cm3). The minimum follow-up was 18 months. RESULTS: Seven of 17 patients treated with the highest total dose of 73.6 GyE experienced Radiation Therapy Oncology Group grade 3 acute skin reactions. Dose escalation was then halted at this level. No other severe acute reactions (grade > 3) were observed in this series. The overall local control rates were 88% and 73% at 1 year and 3 years of follow-up, respectively. The median survival time was 31 months (range, 2 to 60 months), and the 1- and 3-year overall survival rates were 82% and 46%, respectively. CONCLUSION: Carbon ion radiotherapy seems to be a safe and effective modality in the management of bone and soft tissue sarcomas not eligible for surgical resection, providing good local control and offering a survival advantage without unacceptable morbidity.
MANAGEMENT STRATEGIES for bone and soft tissue sarcomas (BSTSs) have changed dramatically in the last three decades.1 Aggressive chemotherapy and/or radiation in combination with limb preservation surgery is now the treatment of choice for most patients. In cases when BSTSs are unresectable, radioresistant, and/or located near critical organs, various particle beams offer promising results.2 Among the high linear energy transfer (LET) particle beams used on BSTSs, the carbon ion beam possesses unique physical and biologic properties.3,4 It has a well-defined range and insignificant scatter in tissues, and the energy release is enormous at the end of its range. This well-localized energy deposition (high-dose peak) at the end of the beam path, called the Bragg peak, is a unique physical characteristic of charged particle beams, as is the induction of more cell cycle– and oxygenation-independent, irreversible cell damage than that observed with low LET radiation. To investigate these useful properties, we conducted a phase I/II carbon ion radiotherapy trial in patients with BSTSs unsuitable for resection.
Patient Eligibility Patients were included in the study if they had histologically confirmed BSTSs that were judged unresectable by the referring surgeon, if they were poor surgical candidates, or if they declined surgery. Patients who had undergone chemotherapy within 4 weeks before carbon ion radiotherapy or those who had prior radiation therapy at the same site were excluded from the study. The tumor had to be grossly measurable, but the size could not exceed 15 cm. Eligibility criteria included Karnofsky performance status score  60, age 14 years, and estimated life expectancy of at least 6 months. Exclusion criteria were having another primary tumor, infection at the tumor site, and craniofacial tumors. A complete history was obtained and a physical examination was performed before registration, which included x-ray radiography, computed tomography (CT), magnetic resonance imaging (MRI), and carbon-11–methionine positron emission tomography (PET) to determine the extent and size of the tumor. Chest and upper abdominal CT scans were mandatory at the time of entry onto the trial. To confirm the pathologic diagnosis of BSTS, and to determine the histologic subtype and grade, a review of the tumor specimen by the working group pathologists was carried out. All patients signed an informed consent form approved by the local institutional review board.
Carbon Ion Radiotherapy In brief, there are three treatment rooms with fixed vertical and horizontal beam lines. The accelerated energy of the vertical carbon ion beam is 290 MeV or 350 MeV, and that of the horizontal beam is 290 MeV or 400 MeV. The range of the 290-MeV carbon ion beam is approximately 15 cm in water, that of the 350-MeV beam is 20 cm, and that of the 400-MeV carbon ion beam is 25 cm. For modulation of the Bragg peak of the beam to conform to a target volume, the beam lines in the treatment room are equipped with a pair of wobbler magnets, beam scatterers, ridge filters, multileaf collimators, and a compensation bolus. An appropriately sized ridge filter, which corresponds to and determines the size of the spread-out Bragg peak (SOBP), is selected to avoid an unnecessary dose along the beam range to normal tissues in each port. We can choose from 12 different sizes of ridge filters covering 2 to 15 cm. The compensation bolus is fabricated for each patient to make the distal configuration of the SOBP similar to any irregular shape of the target volume. The collimator defines the margins of the target volume. The patients were positioned in customized cradles (Moldcare; Alcare, Tokyo, Japan) and immobilized with a low-temperature thermoplastic (Shellfitter; Kuraray Co, Ltd, Osaka, Japan). A set of 5-mm-thick CT images was taken for treatment planning with the immobilization devices. Respiratory gating of both the CT acquisition and the therapy was performed when indicated.8 Three-dimensional treatment planning was performed using HIPLAN software (National Institute of Radiological Sciences, Chiba, Japan), which was developed for carbon ion radiotherapy.9 A margin of 5 mm was usually added to the clinical target volume to create the planning target volume. When the tumor was located close to critical organs, such as the spinal cord or bowel, the margin was reduced accordingly. The clinical target volume was covered by at least 90% of the prescribed dose. Dose was calculated for the target volume and any nearby critical structures and expressed in gray equivalent (GyE = carbon physical dose (Gy) x relative biologic effectiveness [RBE]). Radiobiologic studies were carried out in mice and in five human cell lines cultured in vitro to estimate RBE values relative to megavoltage photons. Irrespective of the size of the SOBP, the RBE value of carbon ions was estimated to be 3.0 at the distal part of the SOBP, and ridge filters were designed to produce a physical dose gradient of the SOBP so that the biologic effect along the SOBP became uniform. This was based on the biologic response of human salivary gland tumor cells at a 10% survival level. The biologic response flatness along the SOBP was checked by measurements of physical dose distributions and dose-averaged LET, which were in satisfactory agreement with the calculated results.10 Carbon ion radiotherapy was given once daily, 4 days a week (Tuesday to Friday), for a fixed 16 fractions in 4 weeks. Patients were treated with one to eight irregularly shaped ports (median, two ports). One port was treated in each session. At every treatment session, the patient’s position was verified with a computer-aided, on-line positioning system. The patient was positioned on the treatment couch with the immobilization devices, and digital orthogonal x-ray television images were taken in that position and transferred to the positioning computer. They were compared with the reference image on the computer screen and the differences were measured. The treatment couch was then moved to the matching position until the largest deviation from the field edge and the isocenter position was less than 2 mm.
Dose Escalation and Toxicity Criteria We used 52.8 GyE in 16 fractions, 3.3 GyE/fraction, for the spine and pelvis groups as the starting dose, and 57.6 GyE in 16 fractions, 3.6 GyE/fraction, for the limb and other sites group. For late reactions, the Late Effects of Normal Tissues/Subjective, Objective, Management, and Analytic scoring system was used in addition to the RTOG/European Organization for Research and Treatment of Cancer late scoring system.11,13 Scores for late reactions were the highest late reactions observed 3 months or later after carbon ion radiotherapy.
Tumor Response and Local Control Criteria
Systemic Chemotherapy
Follow-Up
Statistics
Patient Characteristics Between June 1996 and December 1999, 59 patients were enrolled onto this study. One patient was ineligible due to benign histologic subtype, and one patient was excluded because of a rapidly deteriorating general condition. Thus, 64 lesions in 57 eligible patients (37 men and 20 women) were treated with carbon ion radiotherapy. Patient characteristics are summarized in Table 1. The median age was 52 years (range, 15 to 85 years), and the median Karnofsky performance status score was 80. Tumor sites included the spine or paraspinous soft tissues in 19 patients (21 lesions), pelvis in 32 patients (36 lesions), extremities in five patients (six lesions), and chest wall in one patient. There were 47 bone sarcomas in 41 patients and 17 soft tissue sarcomas in 16 patients. There were 56 unresectable lesions. Five additional lesions were seen in five patients deemed not to be surgical candidates, and three lesions were seen in three patients who declined surgery. Eleven patients received chemotherapy after carbon ion radiotherapy.
The median clinical target volume of all lesions was 559 cm3 (range, 20 to 2,290 cm3). The median volume was 752 cm3 (range, 32 to 2,290 cm3) for the pelvis, 370 cm3 (range, 74 to 1,232 cm3) for the spine and paraspinous soft tissues, and 470 cm3 (range, 20 to 1,059 cm3) for the extremities or other sites.
Toxicity
All patients were able to complete the planned carbon ion radiotherapy without interruption. All of the observed acute and late toxicities are listed in Table 3. Acute toxicity was evaluated for all patients (lesions). The skin was the critical organ, and grade 3 acute skin reactions were observed in eight patients (12.5%). One grade 3 acute skin reaction occurred among the 10 patients treated with a dose of 70.4 GyE, so we reduced the 10% dose increment to 5% for the next escalation. However, the remaining seven reactions were all observed among the 17 patients treated with a dose of 73.6 GyE. Thus, the maximum-tolerated dose (MTD) was deemed to be 73.6 GyE or less.
Six patients experienced grade 3 late skin/soft tissue reactions. Skin/soft tissue reactions at each dose level are listed in Table 4.
Despite the fact that various types of chemotherapies were given before or after carbon ion radiotherapy, there were no obvious effects of chemotherapy on the incidence of toxicities in this series. The incidence of sarcomas arising in spine is extremely low, and the number of cases not suitable for surgical treatment is even smaller. Thus, it was not possible to recruit a sufficient number of patients with spine or extremity sarcomas to have the opportunity to reach the highest dose level. However, the observed acute reactions did not differ among the specific sites. We concluded that further patient recruitment for spine or extremity sites was not required.
Tumor Response
CR was observed in three lesions and PR in 20. Forty lesions remained stable, and only one case of disease progression was observed. The overall tumor response rate (CR+PR) was 36% (95% CI, 24% to 48%). Some patients experienced delayed regression of tumors (tumor regression observed > 6 months after treatment). Evaluation for tumor regression at 6 months after treatment may in fact be too early for certain types of sarcomas, such as chordoma. An example of such delayed regression and the depth-dose distribution of the carbon ion beam is shown in Fig 1. A steep dose fall-off at the beam end and the lateral edge of the beam is also shown.
The median survival time was 31 months (range, 2 to 60 months), and the 1- and 3-year overall actuarial survival rates were 82% (95% CI, 72% to 92%) and 46% (95% CI, 26% to 66%), respectively. Figure 2 shows the overall actuarial survival curve and the local control curve.
Distant failure was observed in 33 patients, including 10 patients (11 lesions) whose distant failure was associated with local failure. Three patients had only local failure. One patient’s local failure was salvaged by surgery, and this patient has remained disease-free for 54 months. Twenty-one patients remained free from disease progression at the time of this writing.
In this study, carbon ion radiotherapy was well tolerated and demonstrated substantial activity against sarcomas. These results were obtained in patients with advanced and/or chemoresistant gross lesions not suited for surgical resection and located mainly in the trunk. We found a dose-response relationship for local control. The rate of actuarial local control increased as the total dose increased from 52.8 to 73.6 GyE, reaching more than 80% in patients treated with 64.0 GyE or more. The local control rates in patients receiving 64 GyE or more were significantly better than the rates for those receiving 52.8 to 57.6 GyE (84% at 3 years v 53% at 3 years, log-rank P = .035, Fig 3). The hitherto reported local control rates in patients with gross sarcomas treated by all types of radiotherapy including other particle beams were less than 70%.16-19 The local control rates in our high-dose group (64 GyE or higher) could be some of the best achieved without surgical resection.
Although the focus of this study was not directed at survival duration, nonetheless it is noteworthy that improved local control resulted in better survival in a selected subgroup. For 15 patients with unresectable osteosarcoma (pelvis, 10 patients; spine, five patients), the 3-year overall actuarial survival rate was 45% (95% CI, 7% to 83%); in the literature, the reported 3-year survival rates for unresectable osteosarcoma of the pelvis and/or spine were 10% or less.20-22 Since the purpose of this dose escalation study was to determine MTD defined by acute toxicity, some severe reactions were inevitable. Serious reactions were observed in the skin/soft tissues, with the rate of serious late complications (grade 3) so far being 9%. This is still relatively low when compared with rates for other high LET particle radiotherapies for sarcomas, which range from 7% to 59%, with most of them 20% or higher.19 Other complications that might have been directly related to the treatment were rare, as we were able to reduce the exposure of normal tissues and visceral organs with the use of accurate imaging/positioning methods, a beam with intrinsically superior depth-dose distribution, and a high-tech irradiation system. We checked the dose to skin and soft tissues that resulted in complications, as some parts of skin and soft tissues in close proximity to tumors actually received the prescribed dose in this series. The problem was the exact area or volume of skin and soft tissues receiving a certain dose level and its relationship with acute and late reactions. We performed an analysis using a dose-volume histogram, but because of the small number of patients, the results could hardly be interpreted in a definitive manner (data not shown). We recognized the importance of the patient/tumor geometry. It was considered that the likelihood of severe skin/soft tissue reactions would be greater in patients presenting with subcutaneous tumor invasion, leading us to assume that an MTD of 73.6 GyE was indicated for patients with no subcutaneous tumor. The MTD for those with subcutaneous tumor involvement may be 70.4 GyE or less. The patients in our series had been considered mostly to have tumors for which there were no other effective local treatments. Despite such dire conditions, patients experienced good tumor control and a relatively low incidence of complications with carbon ion radiotherapy. To confirm these findings, a phase II clinical trial using two fixed carbon ion doses (70.4 and 73.6 GyE) is warranted. In conclusion, carbon ion radiotherapy is an effective local treatment for patients with BSTSs for whom surgical resection is not a viable option, and it seems to represent a promising alternative to surgery. The morbidity rate of carbon ion radiotherapy has so far been quite acceptable, although the long-term safety of this approach for patients with sarcomas will need to be monitored.
APPENDIX The following investigators are members of the Working Group for Bone and Soft Tissue Sarcomas:S. Ishii, Department of Orthopedic Surgery, Sapporo Medical University, Sapporo; Y. Iwamoto, Department of Orthopedic Surgery, Kyushu University, Fukuoka; C. Kanehira, Department of Radiology, Tokyo Jikei Medical University, Tokyo; S. Kawaguchi, Department of Orthopedic Surgery, Cancer Institute Hospital, Tokyo; K. Kushida, Department of Orthopedic Surgery, Kanagawa Cancer Center, Yokohama; M. Machinami, Department of Pathology, Tokyo University, Tokyo; S. Minami, Department of Orthopedic Surgery, Chiba University, Chiba; K. Nagao, Department of Surgical Pathology, Teikyo University Ichihara Hospital, Ichihara; K. Sato, Department of Orthopedic Surgery, Aichi Medical University, Aichi; M. Takahashi, Department of Radiation Oncology, Kyoto University, Kyoto; A. Tateishi, Department of Orthopedic Surgery, Teikyo University, Tokyo; S. Tatezaki, Division of Orthopedic Surgery, Chiba Cancer Center, Chiba; M. Tsuneyoshi, Department of Pathology, Kyushu University, Fukuoka; A. Uchida, Department of Orthopedic Surgery, Mie University, Tsu; T. Umeda, Department of Orthopedic Surgery, National Cancer Center Hospital, Tokyo; H. Yabe, Department of Orthopedic Surgery, Keio University, Tokyo; S. Yamawaki, Department of Orthopedic Surgery, National Sapporo Hospital, Sapporo. The appendix listing the members of the Working Group for Bone and Soft Tissue Sarcomas is available online at www.jco.org.
Supported by the Research Project with Heavy Ions at National Institute of Radiological Sciences (NIRS)–Heavy Ion Medical Accelerator in Chiba (HIMAC). We thank the patients who participated in this study, Libby Cone, MD, for thoroughly reading the manuscript and giving valuable advice and criticism, and Arndt Gerz for his contributions to manuscript preparation.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
