International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationExperience With Carbon Ion Radiotherapy for WHO Grade 2 Diffuse Astrocytomas
Introduction
Diffuse astrocytomas, classified as World Health Organization Grade 2, are generally slow-growing brain tumors. Although surgery is the treatment of choice, radical resection of the tumor is very difficult in terms of the preservation of brain function, even if patients have long survival times. However, after partial or subtotal resection, the long-term prognosis is often poor because of malignant transformation. Therefore, adjuvant therapy is administered to prevent malignant transformation. Generally, tumor cells that remain after surgery are treated with photon radiotherapy; however, the therapy must incur minimal damage to the normal brain tissue and other adjacent normal structures, such as the optic nerve, eyeball, brainstem, and others. The close proximity of normal tissue is therefore a limiting factor for photon radiotherapy, often making it impossible to deliver an adequate radiation dose to the tumor site.
In 1993, the Heavy Ion Medical Accelerator in Chiba (HIMAC) was constructed at the National Institute of Radiological Sciences (NIRS) as a part of a comprehensive 10-year strategy for cancer control in Japan (1). The HIMAC produces a high-linear energy transfer (LET) charged-particle beam of carbon ions with sufficient intensity and has been used in human trials since June 1994. High-LET charged particle therapy, such as that with fast neutrons and heavy ions, has greater biological effectiveness than low-LET radiotherapy, such as that with photons and protons. In addition, charged particles, such as carbon ions, have excellent dose-localizing properties compared with fast neutrons and photons. Furthermore, a charged particle beam’s maximum depth of range can be adjusted by varying the energy. In carbon ion radiotherapy, the treatment beam lines are equipped with a pair of wobbler magnets, beam scatterers, ridge filters, multileaf collimators, and a compensation bolus to make the treatment volume conform to the target volume 2, 3. The resulting isodose distribution can be adjusted for the target volume with a high dose of irradiation to the tumor and a minimized dose of irradiation to the surrounding normal tissues. In this context, carbon ion radiotherapy is a promising option for the effective treatment of intractable brain tumors, owing to its specific properties of high relative biological effectiveness (RBE) and favorable dose distribution of charged particles.
From October 1994 to February 2002, phase I/II dose escalation studies of carbon ion radiotherapy were performed with patients with brain tumors including diffuse astrocytomas, malignant gliomas (4), and metastatic brain tumors. The purpose of this study was to estimate the outcomes of 14 diffuse astrocytomas in adults.
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Patients and study design
Eligibility criteria for this clinical trial required histologically proven astrocytoma, ages between 18 and 80 years old, a Karnofsky performance status (KPS) of 60% or more, neurological function status (NFS) of Grade I or II, absence of anticancer chemotherapy within the previous 2 weeks, survival expectancy of 6 months or more, and absence of meningeal dissemination. Only patients with diffuse astrocytoma were included. Twopathologists, one from our institution and one from each of the
Patients
Between October 1994 and February 2002, 15 patients were enrolled. One female patient, whose planned dose was 50.4 GyE, experienced a convulsion during carbon ion radiotherapy. MRI findings showed tumor progression, and carbon ion radiotherapy was stopped at 29.9 GyE in 13 fractions. She continued her treatment with photon radiotherapy and concomitant chemotherapy. Because her carbon ion dose was approximately 59% of the scheduled dose (50.4 GyE), she was excluded from the trial according to
Discussion
Diffuse astrocytomas are generally known as slow-growing tumors that constitute approximately 40% of all glial neoplasms. These tumors may often undergo malignant transformation 7, 8, 9. Watanabe et al. (8) indicated that p53 gene mutations were detected in 79% of postoperative recurrent low-grade astrocytomas that had progressed to anaplastic astrocytoma or glioblastoma. Also, van den Bent et al. (9) reported that the histological confirmation of recurrence showed high-grade tumors in 66% (no
Conclusions
In this phase I/II clinical trial of carbon ion radiotherapy for diffuse astrocytomas, we observed a clear improvement in PFS and OS in the high-dose group (55.2 GyE in 24 fractions over 6 weeks) compared with those in the low-dose group, without severe morbidity of normal tissues.
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