Phase II study of concurrent chemoradiotherapy with high-dose-rate intracavitary brachytherapy in patients with locally advanced uterine cervical cancer: Efficacy and toxicity of a low cumulative radiation dose schedule☆
Highlights
► The radiotherapy dose for cervical cancer differs between the US and Japan. ► This is a prospective study of chemoradiotherapy using the dose prescribed in Japan. ► Pelvic disease control and survival rates are similar to those demonstrated in the US trials.
Introduction
Concurrent chemoradiotherapy (CCRT) has been shown to be superior to definitive radiotherapy (RT) alone in several randomized controlled trials (RCTs), and is now the standard of care for loco-regionally advanced uterine cervical cancer [1]. Standard definitive RT consists of whole pelvic external beam RT (EBRT) and either high or low dose rate intracavitary brachytherapy (ICBT). The previously mentioned RCTs utilized only low dose-rate ICBT (LDR-ICBT) [1]. High dose-rate ICBT (HDR-ICBT) has become widely used in Japan [2], and many centers worldwide are also shifting to HDR-ICBT [3].
Several RCTs have demonstrated clinical equivalence in terms of both local control and toxicity between HDR-ICBT and LDR-ICBT in the setting of definitive RT (without chemotherapy) [4]. In CCRT, many investigators also reported favorable treatment results using HDR-ICBT in single institutional retrospective series [5], [6], [7], [8], [9], [10], [11], [12], [13]. The Gynecologic Oncology Group (GOG) and the Radiation Therapy Oncology Group (RTOG) now allow the use of HDR-ICBT as well as LDR-ICBT in recent clinical trials of CCRT for cervical cancer [14], [15], [16], [17], [18]. In these trials, however, the patients treated with HDR-ICBT were not evaluated separately. It is unclear whether concurrent chemotherapy delivery with RT increases late complications [19]. In view of potential narrow therapeutic window of HDR-ICBT, the optimum RT dose should be carefully determined especially in the CCRT setting. Late RT complications, even when mild to moderate (i.e., Grades 1–2), significantly reduce quality of life [20]. Recently, image-guided brachytherapy (IGBT) using CT/MRI has been investigated in order to decrease late toxicity as well as improve local control [21].
Japanese centers use lower cumulative dose schedules than those of the US and Europe [2], [3]. Favorable local control results have been obtained with these lower dose schedules in retrospective series of RT alone [22], [23]. However, these lower dose schedules have not been accepted in the US and Europe given the lack of prospective data. In this situation, prospective clinical trials on the efficacy and safety of the CCRT using HDR-ICBT with the low cumulative dose schedules are encouraged.
Based on this background, we conducted a phase II multi-institutional clinical trial on CCRT for locally advanced cervical cancer patients. Herein, we report the data of outcomes and late toxicity observed in the trial.
Section snippets
Study design
The JGOG1066 trial was a multicenter phase II prospective study aimed at evaluating the efficacy and late toxicity of CCRT using HDR-ICBT for locally advanced uterine cervical cancer patients. This study was designed by the JGOG Cervical Cancer Committee in collaboration with the Japanese radiation oncologists with expertise in the cervical cancer treatment. The study was approved by the JGOG Clinical Trial Review Committee, and the local institutional review boards (IRB) of the participating
Patient characteristics
Seventy-two patients were enrolled from 25 institutions between March 2008 and January 2009. One patient was ineligible because she had para-aortic lymphadenopathy of 10 mm in the shortest diameter assessed on pretreatment abdominal CT. She never received treatment on protocol and was not included into the following analyses. Therefore, 71 patients formed the patient cohort for this report. The clinical characteristics of the 71 patients are listed in Table 2.
Feasibility
Sixty-three of the 71 patients (89%)
Discussion
This prospective multi-institutional phase II study (JGOG1066) demonstrated that CCRT using HDR-ICBT with a low cumulative dose schedule (EQD2 = 62–65 Gy prescribed at point A) achieved a 2-year PFS rate of 66% with a low incidence (4%) of severe late toxicity in stage III and IVA uterine cervical cancer patients. The lower limit of the 95% CI for PFS was 54%, which was higher than the threshold of 40%, confirming the superiority of CCRT over historical outcomes of RT alone, although the
Conflict of interest statement
No conflict of interest.
Acknowledgments
This study was supported in part by grants from the Ministry of Health, Labor and Welfare (Grants-in-Aid for Cancer Research nos. 16-12, 20S-5 and 23-A-21), and a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Nos. 18591387 and 21591614). We thank all staff of the Kitasato University Research Center for Clinical Pharmacology, especially Ms. Miki Fukutani, for their assistance in data management.
The following Japanese Gynecologic Oncology Group
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Presented in part at the 2012 Annual Meeting on Women's Cancer, Austin, Texas, March 24–27, 2012, and World Congress of Brachytherapy, Barcelona, Spain, 10–12 May, 2012.