Phase I Study of Carbon Ion Radiotherapy and Image-Guided Brachytherapy for Locally Advanced Cervical Cancer

Abstract

A phase I study was performed to determine the recommended dose of carbon ion radiotherapy and 3D image-guided brachytherapy for histologically confirmed stage II (≥4 cm), III, or IVA cervical cancer. Dose-limiting toxicities (treatment-related toxicities occurring within three months from the start of carbon ion radiotherapy) included Grade 3 non-hematological toxicity, Grade 4 hematological toxicity, or interruption of treatment for more than two weeks due to treatment-related toxicities. Carbon ion radiotherapy consisted of whole-pelvic irradiation with 36.0 Gy (relative biological effectiveness) in 12 fractions and local boost with 19.2 Gy in four fractions for the primary site, and for positive lymph nodes. Three sessions of three-dimensional (3D) image-guided brachytherapy were administered after completion of carbon ion radiotherapy. Weekly cisplatin at a dose of 40 mg/m² was given concurrently. At a dose level of one, a total rectosigmoid D2cc dose between 67.2 Gy and 71.3 Gy at a biological equivalent dose of 2 Gy per fraction from carbon ion radiotherapy and 3D image-guided brachytherapy was prescribed. Six patients were enrolled into this dose level. No patients developed the pre-defined dose-limiting toxicities. For late toxicities, however, one patient developed Grade 3 rectal hemorrhage requiring transfusion at 10 months after treatment. The median survival time was 50.0 months for the five surviving patients. No further dose escalation was performed, and we determined the dose of level one as the recommended rectosigmoid dose. Although our results are preliminary, the study regimen encourages further investigation (registration: UMIN000013340).

Keywords: carbon ion radiotherapy; cervical cancer; concurrent chemoradiotherapy; image-guided brachytherapy; phase I study.

Figure 1

A 57-year-old patient with uterine cervical adenocarcinoma was treated with carbon ion radiotherapy (C-ion RT) and three-dimensional (3D) image-guided brachytherapy (3D-IGBT). This figure shows the dose distribution of C-ion RT for whole-pelvis. (A) Boost to primary tumor and positive lymph nodes; (B) Dose distribution of C-ion RT boost in sagittal image; (C) A vaginal immobilization device was inserted to fix the upper vaginal position and to separate the rectum from the cervical tumor; Dose distribution of 3D-IGBT in a sagittal image (D) and a coronal image (E); T2-weighted magnetic resonance imaging before treatment (tumor size, 6.4 cm) (F); at the end of treatment (G); and 36 months after treatment (H).

Figure 2

Treatment schema applied for six patients with uterine cervical cancer. Compared with a reference from a previous study (Protocol 1001), the local boost for carbon ion radiotherapy was substituted with 3D image-guided brachytherapy in the present study. CDDP: cisplatin; C-ion RT: carbon ion radiotherapy; GTV: gross tumor volume; 3D-IGBT: 3D image-guided brachytherapy.

Figure 3

Endoscopic mucosal reaction of the patient (Number 3) who developed Grade 3 late rectal toxicity. (A) Before treatment; (B) Ten months after carbon ion radiotherapy (C-ion RT) and 3D image-guided brachytherapy (3D-IGBT). The Vienna Rectoscopy Score (VRS) was two. Endoscopic findings of the patient (Number 6) who developed Grade 1 late rectal toxicity; (C) Before treatment; (D) One year after treatment. The VRS was one.