Japanese Journal of Clinical Oncology 33:327-330 (2003)
© 2003 Foundation for Promotion of Cancer Research
Review Article |
The Trail of the Development of High-dose-rate Brachytherapy for Cervical Cancer in Japan
Osaka University, Osaka, Japan
ABSTRACT
The differences in radiotherapeutic treatment systems for cervical cancer between the United States and Japan can be attributed either to the tolerance of high-risk organs, or dosimetry itself. High-dose-rate (HDR) brachytherapy is the standard treatment for uterine cervix carcinoma in Japan. In addition, HDR Co-60 afterloading machines have been gradually replaced with Ir-192 micro-source afterloading machines during the past ten years. This implies that it has now become impossible to conduct a prospective comparative study of HDR versus low-dose-rate (LDR) brachytherapy for cervical cancer in Japan. An examination of the history of HDR intracavitary radiotherapy for uterine cervix carcinoma in Japan led us to the conclusion that HDR intracavitary brachytherapy for the treatment of cervical cancer is as effective as LDR intracavitary brachytherapy in terms of both survival and complications. In Japan, studies on the former can be drawn from a long experience of more than 35 years.
INTRODUCTION
In November 2001, the first US-Japan PCS Workshop was held in San Francisco (1). One of the main topics discussed at this workshop was the differences in radiotherapeutic treatment systems for cervical cancer between the US and Japan. The main reason for the difference in the prescribed intracavitary dose seems to be the difference in the tolerance of high-risk organs, or in the dosimetry itself. To offer some clues to the reasons for these differences, this paper presents a brief history of the development of high-dose-rate (HDR) brachytherapy in the treatment of cervical cancer in Japan.
HIGH-DOSE-RATE BRACHYTHERAPY FOR CERVICAL CANCER BEFORE 1972
Wakabayashi et al. developed the first remote afterloader in Japan (2). However, their treatment was not successful due to the over-dosage that resulted from ignorance of the biological effects of the HDR treatment combined with hypo-fractionation.
Arai et al. collected the clinical data of 318 cervical cancer patients who had been treated with low-dose-rate (LDR) brachytherapy from 1961 to 1968, and 318 patients who had been treated with HDR brachytherapy from 1968 to 1971, at the National Institute of Radiological Sciences in Chiba; 199 patients treated with HDR brachytherapy from 1970 to 1972, at the Cancer Institute Hospital in Tokyo; and 171 patients treated with LDR brachytherapy from 1966 to 1971, at Tokyo Women’s Medical College. The results of this retrospective study of a total of 1,066 clinical cases showed the same survival rates for LDR and HDR intracavitary radiotherapy for uterine cervix carcinoma (Table 1) (3).
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Their report also dealt with the dose fractionation relationship of HDR and LDR intracavitary brachytherapy. The total dose to point A, uncorrected for the overall time, was plotted against the number of fractions for HDR and LDR intracavitary brachytherapy for stage I and II uterine cervix carcinoma. The range of the optimal point A dose for various fractionation schemes for HDR and LDR intracavitary brachytherapy is shown in Table 2. The report concluded that the dose rate effect, i.e., the LDR dose versus the HDR dose, was 1.8–2.0 in 3–5 fractions (3). The merits and demerits of HDR remote afterloading therapy using the Ralstron system were also summarized (Table 3). We consider it advisable for staff and co-medicals to completely avoid exposure. The average Japanese has a strong radiation exposure phobia, owing to the history of the atomic bombs that were dropped on Hiroshima and Nagasaki.
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JAPANESE RADIOTHERAPY STANDARD FOR UTERINE CERVIX CARCINOMA
In the 1970s, HDR remote afterloading therapy for uterine cervix carcinoma quickly gained popularity in Japan, which made it necessary to compile a manual for the safe use of the remote afterloader (4). Shigematsu et al. conducted a single institutional prospective study comparing LDR and HDR brachytherapy (5). They organized a project team to establish a standard dose prescription, and to compare the dose calculations used at various institutions involved in the project team. The dose fractionation pattern for HDR intracavitary brachytherapy showed different dose time schedules among the institutions. The fraction doses ranged from 3 to 10 Gy, and the number of fractions administered per week ranged from 3 to 1 Gy. However, the total dose was nearly the same, at 30 Gy (Table 4).
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Arai et al. later published the Japanese radiotherapeutic standard for uterine cervix carcinoma (Table 5) (6). According to the stage of the disease, they proposed doses by combining external beam radiotherapy and intracavitary radiotherapy. External radiotherapy was delivered using parallel opposing whole pelvic portals of AP and PA with or without central shielding. The intracavitary brachytherapy was administered with an HDR or LDR regimen. These guidelines were based on the authors’ 15-year experience.
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SINGLE INSTITUTIONAL PROSPECTIVE STUDY AND WORLDWIDE DATA
Teshima et al. reported the final results of their prospective randomized comparative study of HDR and LDR intracavitary brachytherapy for uterine cervix carcinoma with a longer follow-up conducted at Osaka University Hospital (7). Due to the limited availability of highly shielded rooms for LDR patients, strict randomization could not be achieved after 1979. They found that older patients were usually referred to HDR brachytherapy because it has a shorter treatment period and causes less distress. They analyzed 430 previously untreated patients with stage I–III disease from 1975 through 1983. The 5-year cause-specific survival rates of stage I–III patients treated with HDR brachytherapy were 85, 73, and 53%, respectively. The corresponding figures for LDR brachytherapy were 93, 78, and 47%, respectively. Comparatively, more stage I patients in the HDR group died from intercurrent diseases. One of the reasons for this is a higher proportion of older patients in the HDR group than in the LDR group. There was no significant difference between the survival rates for the two groups. Moderate to severe complications developed in 10% of the patients treated with HDR and 4% of those treated with LDR, and this difference was statistically significant. However, the incidence itself was considered to be within acceptable limits, i.e., 10%, because the reported incidence of complications of LDR therapy is between 5% and 20%. However, it is obvious that HDR therapy needs a carefully monitored dose and source arrangement system. The dose rate conversion factor used to estimate the HDR dose from the corresponding LDR dose ranged between 0.5 and 0.53.
Orton et al. accumulated and analyzed worldwide data for intracavitary brachytherapy (8). They used the resultant data for a comparative analysis of survival and adverse effects associated with HDR and LDR brachytherapy, and found better clinical results for the former than the latter, with the morbidity rate being considerably lower for HDR. They concluded that for conversion from LDR to HDR the total dose to Point A should be reduced on average by a factor of 0.54 ± 0.06.
GLOBAL TENDENCY TOWARDS HDR INTRACAVITARY BRACHYTHERAPY FOR CERVICAL CANCER OVER THE LAST 20 YEARS
In general, HDR intracavitary brachytherapy for uterine cervix carcinoma successfully prevailed in Japan, and also in German-speaking countries, while in France and the US, LDR intracavitary brachytherapy was widely used until recently. However, some trailblazers in the UK and the US intensively used the HDR technique 40 years ago.
In 1995, only 14 reports in the English and German journals concerning trials and results comparing HDR and LDR intracavitary brachytherapy for carcinomas of the uterine cervix had been published to the best of our knowledge (9). These included one national, five randomized, two concurrent non-randomized, three historically controlled, and three retrospective surveys. The results were not extremely different among various clinical experiences. At that time, HDR intracavitary brachytherapy had shown excellent results for uterine cervix carcinoma. Most centers preferred to purchase HDR brachytherapy equipment at the time of replacement of the classical LDR device.
Although LDR brachytherapy had disadvantages such as radiation exposure to medical staff, prolonged treatment time, mandatory hospitalization, and applicator movement, cervical carcinoma has traditionally been treated with LDR brachytherapy in the US. HDR brachytherapy has encountered considerable resistance in the US because of the concerns regarding its potential toxicity. Several studies have compared LDR brachytherapy to HDR brachytherapy in the management of cervical cancer. These have demonstrated comparable local control, survival, and morbidity (7,8). HDR brachytherapy has gradually been gaining acceptance in the US over the last decade.
However, more recently, the American Brachytherapy Society (ABS) has published recommendations for HDR intracavitary brachytherapy for uterine cervix carcinoma to promote wider and more intensive use of this technique in the US (10). They predict that image-based treatment will become more widely available in the future. There is evidence that US investigators had planned to survey the differences in prescribed doses for definitive HDR intracavitary brachytherapy in uterine cervix carcinoma between the US and Japan in the PCS Workshop. In early 2002, a manufacturer announced the discontinuation of the supply of Cesium-137 source for Selectron-LDR/MDR by the end of 2005, owing to the decrease in users, and therefore reduced demand for the source supply (11). Accordingly, these global tendencies described above will be accelerated in the next 5 years.
These various findings make it clear that HDR intracavitary brachytherapy for cervical cancer is as effective as LDR in terms of both survival and complications. Studies on HDR brachytherapy for cervical cancer in Japan can be drawn from an experience of more than 35 years. Presently, HDR brachytherapy is the standard treatment for uterine cervix carcinoma in Japan (1). In addition, HDR Co-60 afterloading machines have been gradually replaced with Ir-192 micro-source afterloading machines during the past 10 years (12). This implies that now, it is not possible to conduct a prospective comparative study of HDR and LDR brachytherapy for cervical cancer in Japan. This leads us to conclude that our standard treatment schedule is appropriate for Japanese patients with uterine cervix carcinoma.
CONCLUSION
This study originated at the first US–Japan PCS Workshop at San Francisco, where one of the major topics was radiotherapy systems for uterine cervix carcinoma. An examination of the Japanese history of HDR intracavitary radiotherapy for uterine cervix carcinoma led to the conclusion that HDR intracavitary brachytherapy for cervical cancer is as effective as LDR in terms of both survival and complications. HDR studies of cervical cancer in Japan can be drawn from a long experience of more than 35 years.
FOOTNOTES
+ For reprints and all correspondence: Toshihiko Inoue, Honorary Director, Soseikai General Hospital, 1 Hiroosacho Shimotoba, Fushimi-ku, Kyoto, 612-8473, Japan. E-mail: toinoue{at}kcn.ne.jp 
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Received May 22, 2003; accepted July 1, 2003
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