Clinical investigation
Dose escalation study of carbon ion radiotherapy for locally advanced head-and-neck cancer

https://doi.org/10.1016/j.ijrobp.2004.02.067Get rights and content

Abstract

Purpose

To evaluate the toxicity and efficacy of carbon ion radiotherapy for head-and-neck cancer in a Phase I/II dose escalation clinical trial.

Methods and materials

Between June 1994 and January 1997, 36 patients with locally advanced, histologically proven, and new or recurrent cancer of the head and neck were treated with carbon ions. A dose escalation study was conducted, delivering 18 fractions through 6 weeks for 17 patients (Group A) and 16 fractions through 4 weeks for 19 patients (Group B). Eligibility and ineligibility criteria were the same in both groups. The dosages were escalated in increments of 10% after careful observation of at least 3 patients treated with the same dosages. The endpoints of the study were a Grade 3 reaction of the skin and the mucous membrane or local control of the tumors.

Results

Follow-up time ranged from 77 to 108 months with a median of 90 months. Grade 3 acute reaction of the skin was detected in 1 of the 2 patients in Group A who were treated with 70.2 GyE/18 fractions/6 weeks. In Group B, Grade 3 acute skin reaction was detected in 20% (1/5), 27% (2/11), and 67% (2/3) patients treated with 52.8 GyE, 57.6 GyE, and 64.0 GyE through 16 fractions for 4 weeks, respectively. There was only 1 patient with a Grade 3 acute reaction of the mucous membrane. Only 1 patient developed a Grade 2 late reaction of the mucous membrane (superficial ulcer), which was located close to the tumor. No other Grade 2 or greater late reaction was noted until the time of analysis. Acute tumor reactions in 34 patients consisted of 10 patients of complete response 19 of partial response, 4 of no change, and 1 of progressive disease. Local control of 34 patients calculated by the Kaplan-Meier method was 75% at 5 years. Five years' local control of five malignant melanomas showed 100%, and that of 9 patients with adenoid cystic carcinoma was 90%. Also, local control of 8 patients of salivary glands and 4 patients of ears was 100% at 56 months and 5 years.

Conclusions

The dose fractionation methods of 70.2 GyE through 18 fractions for 6 weeks and 64.0 GyE through 16 fractions for 4 weeks showed equal clinical outcome in terms of morbidity and local control. The outcome of carbon ion radiotherapy showed a specific effectiveness in local control of non–squamous cell carcinoma such as adenoid cystic carcinomas and malignant melanomas. From the results of this study, it can be concluded that carbon ion radiotherapy will deliver a high local control rate without unacceptable injuries to the surrounding normal tissues.

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.

Section snippets

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.

References (24)

  • W. Duncan et al.

    Fast neutron therapy for squamous cell carcinoma in the head and neck regionResults of a randomized trial

    Int J Radiat Oncol Biol Phys

    (1987)
  • E.A. Blakely

    Cell inactivation by heavy charged particles

    Radiat Environ Biophys

    (1992)
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