International Journal of Radiation Oncology*Biology*Physics
Clinical investigationDose escalation study of carbon ion radiotherapy for locally advanced head-and-neck cancer☆
Introduction
There are potential biologic advantages to high linear energy transfer (LET) radiotherapy with fast neutrons and heavy ions: (1) there is less variation in radiosensitivity during the cell cycle phases (1), (2) there is reduction of repair of radiation injury to cells (2), and (3) there is a lower oxygen enhancement ratio (OER) (3). Fast neutrons, which are uncharged particles, have been used to treat head-and-neck tumors for many years (4). From the results of clinical trials, the indication of fast neutron radiotherapy has been limited to several tumor sites (e.g., the salivary glands, paranasal sinuses), because of unacceptable damage to the surrounding normal tissues 5, 6, 7. High LET charged particles such as carbon and neon ions have excellent dose localizing properties compared with fast neutrons, and this potentiality can cause severe damage to the tumor while lessening the effects on normal tissue. A charged particle beam's maximum depth of range can be adjusted by varying the energy. Beam modulations by bolus absorbers and collimator blocks can construct precise beam penetration and sharp lateral edges in three dimensions. The resulting isodose distribution can be made to conform closely to the target volume, allowing a high dose to the tumor while minimizing irradiation to surrounding normal tissues.
In 1984, the Heavy Ion Medical Accelerator in Chiba (HIMAC) was constructed at the National Institute of Radiological Sciences (NIRS) as a part of the comprehensive 10-year strategy for cancer control in Japan (8). The HIMAC has made high LET charged particle beams of carbon ions available in sufficient intensity for human trials since June 1994. Carbon ions have been selected for clinical trials because they have the biologic characteristics of high LET with 78 KeV/μ at the distal part of the spread out Bragg peak (SOBP), and because they show good dose localizing properties compared with other heavier ions (9).
This article describes the results of a Phase I/II clinical trial of carbon ions for locally advanced head-and-neck cancer, which was the first systemic clinical trial of carbon ions in the world. The purpose of this clinical trial was to determine the effect of carbon ions on both normal tissues and on the tumors of head-and-neck cancer patients, escalating the radiation doses as high as possible without excess injury to normal tissues.
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Patients
Because the main purpose of this Phase I/II clinical study was to examine the tolerance dose of normal tissues irradiated by carbon ions, patient eligibility for data collection was determined by whether the patients had locally advanced, histologically proven, new, or recurrent cancer in the head-and-neck region with little or no possibility of cure by other treatments such as conventional photon therapy, surgery, or chemotherapy. All patients were to be 80 years old or younger, with a
Results
Between June 1994 and February 1997, 36 patients were entered into a Phase I/II study of carbon ion radiotherapy. Follow-up data were obtained until the death or until the last follow-up time in all cases, and expected follow-up periods ranged from 77 to 108 months (median, 90 months). The general characteristics of the patients are described in Table 1a, Table 1b. There was no difference in patients' characteristics between Group A and Group B. In 10 cases involving the nasal and paranasal
Discussion
Based on our preclinical experiments of carbon ions, we assumed the RBE of carbon ions to be 3.0 at the distal part of the SOBP for the acute skin reactions, which was the same value as that of fast neutrons (11). The maximum acute reaction of the skin was Grade 3 in both groups, observed in 50% of the patients on the 70.2 GyE arm of Group A, and in two- thirds of the patients (67%) on the 64.0 GyE arm in Group B. From these results, we concluded that the maximum tolerance dose of the carbon
Acknowledgements
The authors thank Ms. Nobuko Maeda, who assisted in the presentation of the manuscript.
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Supported in part by the research project with heavy ions at NIRS-HIMAC.