Radical Radiation Therapy for Prostate Cancer in Japan: a Patterns of Care Study Report

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1 Jpn J Clin Oncol 2003;33(3) Original Articles Radical Radiation Therapy for Prostate Cancer in Japan: a Patterns of Care Study Report Katsumasa Nakamura 1, Teruki Teshima 2, Yutaka Takahashi 2, Atsushi Imai 3, Masahiko Koizumi 4, Norio Mitsuhashi 5, Toshihiko Inoue 3 and Japanese PCS Working Subgroup of Prostate Cancer 1 Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 2 Department of Medical Engineering, Osaka University Faculty of Medicine, Suita, Osaka, 3 Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, 4 Department of Radiation Therapy, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka and 5 Department of Radiology, Tokyo Women s Medical University, Tokyo, Japan Received July 24, 2002; accepted January 31, 2003 Background: The patterns of radical radiation therapy for prostate cancer are unclear in Japan. A Patterns of Care Study was performed throughout Japan to examine the patterns of radiation therapy for prostate cancer. Methods: From 1999 to 2000, extramural audits were performed on 50 randomly selected institutions (~7% of all institutions in Japan). Detailed information was collected on a total of 311 prostate cancer patients without evidence of distant metastases, who were treated by radiation therapy between 1996 and Of these 311 patients, 162 treated radically using photon beams were analyzed in this study. Results: Eighty percent of the patients had high-risk diseases defined as T3 or T4 tumors, a pretreatment prostate-specific antigen level >20 ng/ml or poorly differentiated adenocarcinoma. Androgen ablation was performed in 85.8% of patients and the median duration of hormonal therapy before and after radiation therapy was 5.3 and 21.4 months, respectively. The median total dose of radiation therapy to the prostate was 65.0 Gy (range: Gy). The 3-year overall and biochemical relapse-free survival rates were 86.7 and 86.1%, respectively. Late toxicity was mild, with only nine patients (5.6%) exhibiting grade 2 late morbidity. Conclusions: The majority of the patients who received radical radiation therapy in Japan have high-risk disease. Androgen ablation plus radiation therapy was commonly used to treat these patients and resulted in high rates of initial control with a low risk of complications. Key words: prostate cancer radiation therapy Patterns of Care Study INTRODUCTION The incidence rate and death rate for prostate cancer is low in Asian countries (1). In the 1980s, four per men died of prostate cancer in Japan, whereas in Western Europe and North America the annual mortality rate ranged from 16 to 18 per men (2). Gu et al. reported that the incidence of and mortality from prostate cancer in China was about 20 times less than that observed in Western countries (3). However there For reprints and all correspondence: Katsumasa Nakamura, Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3 1 1, Higashi-ku, Fukuoka , Japan. nakam@radiol.med.kyushu-u.ac.jp are few reports on the treatment of prostate cancer with radiation therapy in Asia and the patterns of treatment have not been previously examined. In Asian countries, most patients with prostate cancer have high-risk disease. Zhau et al. (4) reported that 74.5% of Chinese patients with adenocarcinoma of the prostate had poorly differentiated disease, compared with 28.6% of patients in the United States. A study of 95 patients treated in a Thailand hospital reported that 7.5% had stage A disease, 1.1% stage B, 67.7% stage C and 23.7% stage D (5). In contrast, most of patients in the United States have localized prostate cancers (6). Because of the interracial differences in the pathologic features and clinical manifestation of prostate cancer, it is valuable to examine the patterns of the treatment in Asia, 2003 Foundation for Promotion of Cancer Research

2 Jpn J Clin Oncol 2003;33(3) 123 which may be affected by cultural, racial, ethnic or social background. The Patterns of Care Study (PCS), a widely known quality assurance program in the USA (7), was conducted in Japan (8) in an attempt to obtain data on the national standards of radiation therapy for several diseases. The purpose of this study was to examine the patterns of radical treatment of prostate cancer with radiation therapy, as the mortality rates are lower and radiation therapy is less frequently employed than in Western countries. Patient outcome was also assessed. The majority of these patients were treated by a combination of radiation therapy and hormonal therapy. PATIENTS AND METHODS The methods used in data collection for the PCS have been described previously (9). From a stratified Facilities Master list, a random sample of radiation therapy facilities was selected. Each of the 50 randomly chosen facilities was visited from 1999 to 2000 and a total of up to 20 medical records from each institute were randomly selected and reviewed. The following eligibility criteria were used in the process survey: the patients were required to have adenocarcinoma of the prostate without evidence of distant metastases; they must have been treated with radiation therapy between January 1996 and December 1998; and they must not have been diagnosed with any other malignancy or have been previously treated with radiation therapy. Patients who had a radical prostatectomy or hormonal therapy prior to radiation therapy were included in this survey. The total number of prostate cancer patients surveyed was 311, which included 162 patients treated with radical radiation therapy using photon beams, 69 patients treated after prostatectomy, 61 patients who received radiation therapy after progression on hormonal therapy, 14 patients treated with high-dose rate brachytherapy and five patients treated with protons. For simplification of analysis, the patterns of treatment and outcome of 162 patients treated with radical radiation therapy using photon beams are reported here. The results from patients with hormone-refractory or surgically removed cancers will be published elsewhere. The patients analyzed here were treated in 36 institutions. Of them, 87 were treated at 14 A1 institutions (university hospital/ cancer center treating 300 patients/year), 35 were treated at 10 A2 institutions (university hospital/cancer center treating <300 patients/year), 30 were treated at eight B1 institutions (other institutions treating 120 patients/year) and 10 were treated at four B2 institutions (other institutions treating <120 patients/year). Biochemical relapse-free survival was defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition (10). Clinical relapse was determined by physical examination, biopsy or radiological findings. The overall survival rate and the biochemical relapsefree survival rate were calculated using the Kaplan Meier Table 1. Patients and disease characteristics No. patients 162 Age (years) Median 70 Range Differentiation Well 24 (14.8%) Moderate 80 (49.4%) Poor 45 (27.8%) Unknown 13 (8.0%) T-Stage/1997 UICC T1 8 (4.9%) T2 47 (29.0%) T3 81 (50.0%) T4 22 (13.6%) Unknown 4 (2.5%) N-Stage/1997 UICC N0 131 (80.9%) N1 18 (11.1%) Unknown 13 (8.0%) Pretreatment PSA level (ng/ml) Median 22.0 Range PSA, prostate-specific antigen; UICC, International Union Against Cancer. method. The Radiation Therapy Oncology Group (RTOG) late toxicity scales were used to assess the late morbidity. RESULTS PATIENTS AND DISEASE CHARACTERISTICS Patients characteristics are shown in Table 1. More than 60% of the patients had T3 or T4 tumors. The median prostatespecific antigen (PSA) level was >20 ng/ml. Only 14.8% of patients had well differentiated adenocarcinoma. The number of high-risk patients, defined as either T3 or T4 tumors, a pretreatment PSA level >20 ng/ml or poorly differentiated tumors, was 130 (80.2%). TREATMENT The reasons for the particular choice of radiation therapy given to these patients are shown in Table 2. Most of the cases were treated with radiation therapy because of their advanced stage or old age. Only 4.9% of the patients received radiation therapy because of the patients wishes. The treatment characteristics are shown in Table 3. Over 80% of patients received a combination of radiation therapy and hormonal therapy. Luteinizing hormone-releasing agonists

3 124 Radiotherapy for prostate cancer Table 2. Percentage of reason for selection of radiation therapy Advanced stage 44 (27.2%) Old age 37 (22.8%) Patient choice 8 (4.9%) Medical contraindication 7 (4.3%) Others 8 (4.9%) Unknown 58 (35.8%) and antiandrogen agents were frequently used, but estrogen agents were given in 11.1% of patients. Orchiectomy was performed in 9.9% of patients. Hormonal therapy was performed before, during and after radiation therapy in 74.7, 68.5 and 66.7% of patients, respectively. The median duration of hormonal therapy before and after radiation therapy was 5.3 and 21.4 months, respectively. Regarding radiation therapy, a linear accelerator of 10 MV was used in two-thirds of patients. Patients were treated with a variety of radiation therapy techniques. The treatment plan included a moving field in 40.1% of patients. More than twothirds of conformal therapy was performed with a rotational conformation using a dynamic multileaf collimator. The median dose delivered to the prostate was 65.0 Gy (range: Gy). The median daily fraction size to the prostate was 200 cgy (range: cgy). Most (83.5%) patients received doses of cgy per day. The patients treated with conformal and conventional radiation therapy were irradiated with a median dose of 65.0 and 60.0 Gy, respectively. Pelvic irradiation was performed in about half of the patients. OUTCOME At a median follow-up of 27.5 months, five patients had died of prostate cancer, two of cerebrovascular diseases and two of other unknown causes. Biochemical failure was noted in 17 patients. Clinically, local progression was observed in five patients and distant metastases were seen in 10. No regional lymph node metastases were observed. The 3-year overall and biochemical relapse-free survival rates were 86.7 and 86.1%, respectively (Fig. 1). Late morbidity of RTOG grade 2 was seen in nine patients (5.6%). There were no cases of grade 3 4 toxicity. Three of these patients were treated with conformal therapy and six with conventional therapy. Rectal bleeding was seen in six patients and hematuria, incontinence or urethral stricture in three patients. DISCUSSION The present study revealed that the majority of patients with prostate cancer who received radical radiation therapy in Japan had high-risk disease. The radiation doses employed were lower than those typically used in the USA. However, radiation therapy was commonly combined with hormonal therapy. Table 3. Treatment characteristics Hormonal therapy Yes 139 (85.8%) Content Orchiectomy 16 (9.9%) Estrogen agent 18 (11.1%) LH-RH agonist 113 (69.8%) Antiandrogen 94 (58.0%) Period (median) Before RT 121 (74.7%) (4.9 months) During RT 111 (68.5%) After RT 108 (66.7%) (21.4 months) Radiation therapy Energy <10 MV 56 (34.6%) 10 MV 63 (38.9%) >10 MV 31 (19.1%) Unknown 12 (7.4%) Field arrangement for the prostate Anterior-posterior 30 (18.5%) 4 field 43 (26.5%) >4 field 4 (2.5%) Moving 65 (40.1%) Others 8 (4.9%) Unknown 12 (7.4%) Conformal therapy Yes 80 (49.4%) Rotational 62 (38.3%) Static 18 (11.1%) Pelvic irradiation Yes 70 (43.2%) LH-RH, luteinizing hormone-releasing hormone; RT, radiation therapy. Although the follow-up period was short, the combination therapy seemed to be effective, with little risk of tissue complications. However, this is a preliminary study for future outcome analysis. Although the survival of the patients seems to be excellent, we should keep in mind that the outcome in the present study may have been affected by the short follow-up period and patients lost to follow-up. Longer follow-up is required to confirm the trends seen in this preliminary report. It is acknowledged that conventional radiation alone has little curative potential in high-risk prostate cancer (defined as a pretreatment PSA level >20 ng/ml, a Gleason score of 8 10 or stage T3 T4 disease) (11). A meta-analysis of RTOG prostate cancer trials in the USA suggested that patients in these high-risk groups may experience a substantial improvement in overall and disease-specific survival with a combination of

4 Jpn J Clin Oncol 2003;33(3) 125 Figure 1. (a) Overall survival and (b) biochemical relapse-free survival curves for prostate cancer patients treated with radical radiation therapy. radiation therapy and long-term hormonal therapy (12). Taking into account the high percentage of high-risk patients in this study, the therapeutic strategy of long-term androgen suppression with radiation therapy may be appropriate for a majority of Japanese patients. However, prolonged androgen ablation may lead to side effects such as impotence, hot flushes, fatigue and osteoporosis. Questions concerning the optimal timing and duration of androgen ablation should be addressed in future studies. Estrogen therapy is associated with serious side effects with, in particular, an increased risk of cardiovascular complications reported for patients in Western countries (13). However, 11.1% of patients in this study were treated with estrogen agents. Because cardiovascular complications appear to be a relatively rare side effect of estrogen therapy in Japan (14,15), estrogen administration remains an option for androgen suppression. However, it should be noted that the increase in serum cholesterol in Japan may affect the future rates of coronary heart disease (16). The radiation doses employed in Japanese institutions were lower than those typically used in the USA. External beam radiation alone, in modest doses of Gy, is insufficient to eradicate prostate tumors (17). PCS studies in the USA revealed that the median radiation dose employed had increased from 66 to 68.4 Gy between 1978 and 1994 (18). There had also been a dramatic decrease in the use of adjuvant hormonal therapy, from 59% in 1978 to 9% in 1994 (19). However, it should be noted that, in contrast to Japanese patients, most of the patients in the USA have T1 T2 diseases with lower pretreatment PSA levels (18). Patients with unfavorable prognostic features, who may have micrometastatic disease, are not ideal candidates for dose-escalation studies and should be treated by combination treatment. It is well known that radiation dose is a strong, independent predictor of failure (17). However, if radiation therapy is combined with long-term androgen ablation, which may have synergistic effects with radiation therapy (19), higher doses may not have a major impact on local control. In fact, although the median dose delivered in this series was 65.0 Gy, local failure was seen in only five patients (3.1%). However, the optimal dose in these patients remains to be defined. The survey results indicated that treatments were delivered frequently using rotational conformal techniques. This technique may be popular in Japan because conformal radiation therapy using rotation techniques was developed by Takahashi (20). However, only modest doses were delivered to the prostate and an advantage of conformal therapy was not demonstrated in this survey. There is great controversy regarding the effectiveness of elective radiation therapy of the pelvic lymphatics in patients with high-risk prostate cancer. The prospective randomized trials conducted by the Radiation Therapy Oncology Group (RTOG 75 06, 77 06) showed no better survival for patients who received pelvic or paraaortic irradiation (21,22). Therefore, pelvic irradiation was no longer advocated. However, reanalysis showed several problems with the study design (23). For example, patients with T1 T2 diseases, who were not at high risk of pelvic lymph node metastases, were investigated in RTOG (22). In contrast, the preliminary analysis of a recent randomized trial (RTOG 9413) has demonstrated that pelvic irradiation is associated with an improvement in the progression-free survival in patients with an estimated risk of lymph node metastases >15% (24). In the present study, pelvic irradiation was performed in 43.2% of patients, although the majority of patients had high-risk disease. Each radiation oncologist has to make his or her own decision regarding pelvic radiotherapy as there is no standard treatment. In the near future, this issue will be addressed. This PCS study showed that only 4.9% of the patients chose radiation therapy as their treatment of choice. In most cases, patients were treated with radiation therapy because of old age or advanced cancer stage. This is because Japanese patients rarely ask for a second opinion from a radiation oncologist in Japan. However, this is changing rapidly. Patients have become more informed about the available treatment options and the general public has become more aware of the advantages of radiation therapy. The number of patients with prostate cancer is still small, but increasing very rapidly, in Asian counties (1). In Japan, the incidence of prostate cancer in 1996 was reported to be double that observed in 1980 (25). In addition, screening for prostate

5 126 Radiotherapy for prostate cancer cancer using PSA has been introduced (26), leading to the detection of patients with early-stage prostate cancer. The standard treatment of care for prostate cancer used to be either prostatectomy or hormonal therapy in Japan. In particular, hormonal therapy was commonly utilized, in part because of the considerable number of prostate cancer patients with advanced disease or poorly differentiated tumors. However, the use of radical radiation therapy is being increasingly accepted as an alternative option for the curative treatment of these cancers (27) and early-stage prostate cancer will be treated by radiation therapy more frequently in the near future. This report serves to delineate the patterns of radiation therapy for prostate cancer in Japan between 1996 and However, the characteristics of prostate cancer and the patterns of radiation therapy in Japan are changing rapidly, resulting in the recent initiation of a new series of Patterns of Care Studies. Acknowledgments This study was supported in part by a Grant-in Aid for Cancer Research (Nos and 14-6) from the Ministry of Health, Labor and Welfare and a Grant from Japan Society for the Promotion of Sciences. We thank all radiation oncologists who participated in this study. Their efforts in providing us with information makes these surveys possible. This paper was presented in part at the 87th Scientific Assembly and Annual Meeting of the Radiological Society of North America (RSNA), Chicago, IL, November References 1. Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and mortality. 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