Clinical Investigation
Experience With Carbon Ion Radiotherapy for WHO Grade 2 Diffuse Astrocytomas

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Purpose

To assess outcomes of carbon ion radiotherapy for diffuse astrocytomas in adults.

Methods and Materials

Between October 1994 and February 2002, 14 patients with diffuse astrocytoma, identified as eligible for carbon ion radiotherapy, were enrolled in a phase I/II clinical trial. Carbon ion radiotherapy was administered in 24 fractions over 6 weeks. The normal tissue morbidity was monitored carefully, and the carbon ion dose was escalated from 50.4 Gy equivalent (GyE) to 55.2 GyE. Patients were divided into two groups according to their carbon ion doses: a low-dose group in which 2 patients were irradiated with 46.2 GyE and 7 patients were irradiated with 50.4 GyE, and a high-dose group in which 5 patients were irradiated with 55.2 GyE.

Results

Toxicities were within acceptable limits, and none of the patients developed Grade 3 or higher acute or late reactions. The median progression-free survival (PFS) time was 18 months for the low-dose group and 91 months for the high-dose group (p = 0.0030). The median overall survival (OS) time was 28 months for the low-dose group and not reached for the high-dose group (p = 0.0208).

Conclusion

High-dose group patients showed significant improvement in PFS and OS rates compared to those in the low-dose group, and both dose groups showed acceptable toxicity.

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.

Section snippets

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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