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Japanese Journal of Clinical Oncology Advance Access originally published online on February 26, 2008
Japanese Journal of Clinical Oncology 2008 38(3):200-204; doi:10.1093/jjco/hyn008
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© The Author (2008). Published by Oxford University Press. All rights reserved

External-Beam Radiotherapy for Localized or Locally Advanced Prostate Cancer in Japan: A Multi-Institutional Outcome Analysis

Katsumasa Nakamura1,, Takashi Mizowaki2, Hajime Imada3, Katsuyuki Karasawa4, Takashi Uno5, Hiroshi Onishi6, Keiji Nihei7, Shigeru Sasaki8, Masakazu Ogura9 and Tetsuo Akimoto10

1 Department of Radiology, School of Medicine, Fukuoka University, Fukuoka
2 Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto
3 Department of Radiology, University of Occupational and Environmental Health, Kitakyushu
4 Department of Radiation Oncology, Tokyo Metropolitan Komagome Hospital, Tokyo
5 Department of Radiology, Graduate School of Medicine, Chiba University, Chiba
6 Department of Radiology, School of Medicine, Yamanashi University, Yamanashi
7 Radiation Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba
8 Department of Radiology, Shinshu University, Matsumoto
9 Department of Radiology, Tenri Hospital, Tenri, Nara
10 Department of Radiology, Tokyo Women's Medical University, Tokyo, Japan

For reprints and all correspondence: Katsumasa Nakamura, Department of Radiology, School of Medicine, Fukuoka University, Nanakuma 7-45-1, Jonan-ku, Fukuoka 814-0180, Japan. E-mail: nakam{at}fukuoka-u.ac.jp

Received November 21, 2007; accepted January 6, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Appendix
 References
 
Background: The outcomes of patients with localized or locally advanced prostate cancer treated with external-beam radiotherapy are not well known in Japan.

Methods: Thirty-four institutions combined data on 679 patients with localized or locally advanced prostate cancer treated with a total dose ≥60 Gy between 1995 and 2002.

Results: With a median follow-up of 46 months, the 5-year overall, clinical progression-free, and biochemical relapse-free survival rate were 93.0, 95.3 and 71.9% for all patients, respectively. The 5-year progression-free, and biochemical relapse-free survival rates according to the risk group were 100%, 90.8% in the low-risk group, 98.3%, 75.7% in the intermediate-risk group and 93.6%, 67.6% in the high-risk group, respectively. The multivariate analysis for biochemical relapse-free survival revealed that prostate-specific antigen (relative risk, 1.002; 95% CI, 1.001–1.003; P = 0.0041), Gleason score (relative risk, 1.166; 95% CI, 1.046–1.302; P = 0.0055), T classification (relative risk, 2.897; 95% CI, 1.999–4.230; P = 0.0000), pelvic irradiation (relative risk, 2.042; 95% CI, 1.328–3.273; P = 0.0008), and androgen abletion (relative risk, 0.321; 95% CI, 0.240–0.427; P = 0.0000) were significant prognostic factors. Only 1.1% of patients experienced late morbidity of Grade 3.

Conclusion: Radiotherapy for prostate cancer seemed to be effective, with little risk of normal tissue complications.

Key Words: prostatic neoplasms • radiotherapy • treatment outcome


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Appendix
 References
 
Incidence rates, pathological features, clinical manifestation and the management of prostate cancer vary around the world. Although Asian people have the lowest incidence and mortality rates of prostate cancer in the world, these rates have risen rapidly in most Asian countries (1). In particular, the mortality rates for prostate cancer have been constantly and dramatically increasing in Japan with the increasingly aged population (2). Although screening for prostate cancer using prostate-specific antigen (PSA) has recently been introduced (3,4), most of the Japanese patients treated with external-beam radiotherapy (EBRT) still have high-risk prostate cancer (5,6). Radical radiotherapy is increasingly being accepted as an option for the curative treatment of prostate cancer (6), but the outcomes of patients with prostate cancer treated with EBRT are not well known in Japan and other Asian countries (7,8).

In the present multi-institutional retrospective study, we reviewed the clinical records of patients with localized or locally advanced prostate cancer treated with EBRT to analyse the clinical outcome of EBRT for prostate cancer in Japan.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Appendix
 References
 
Of institutions belonging to the Japanese Radiation Oncology Study Group, 34 institutions with significant experience in radiotherapy collaborated in the present study (Appendix). We collected the clinical records of patients with localized or locally advanced prostate cancer who were irradiated with a total dose ≥60 Gy between 1995 and 2002. All patients had the following characteristics: a pretreatment PSA level, a biopsy Gleason score (GS), tumor classification (according to the International Union Against Cancer 2002 classification (9)), no clinical lymph node involvement, and a minimum follow-up interval of 2 years for living patients.

The total number of prostate cancer patients surveyed was 679. On the bases of PSA, GS and clinical T classification, risk groups were defined as low (T1–T2, GS ≤ 6 and PSA ≤ 10 ng/ml), intermediate (T1–T2, GS ≤ 7 and 10 < PSA ≤ 20 ng/ml or T1–T2, GS = 7 and PSA ≤ 10 ng/ml) and high (T3–T4, GS > 7, or PSA > 20 ng/ml) (10). The patients' characteristics are shown in Table 1. More than 45% of the patients had T3 or T4 tumors. The median pretreatment PSA level was 17.7 ng/ml (range, 1.5–1250 ng/ml). Most of the patients (86.9%) belonged to the intermediate- or the high-risk group.


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  		Table 1. Patients and disease characteristics

 
The treatment characteristics are shown in Table 2. Over 80% of patients received a combination of EBRT and hormonal therapy. Neoadjuvant hormonal therapy was performed in 76.7% of patients, while adjuvant hormonal therapy was used in 34.8%. The median durations of hormonal therapy before and after radiotherapy were 6 months (range, 1–68 months) and 38 months (1–109 months), respectively.


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  		Table 2. Treatment characteristics

 
Megavoltage photon equipment was used to deliver radiation. Patients were treated with a variety of radiotherapy techniques (Table 2). The treatment plan included a moving field in 62.7% of patients. More than 80% of patients were treated using a conformal technique. Intensity-modulated radiation therapy (IMRT) was performed in only 2.4% of patients. Fraction sizes of 1.5, 1.8, 2.0, 2.4 and 3.0 Gy to the prostate were used in 1 (0.1%), 10 (1.5%), 643 (94.7%), 4(0.6%) and 21 patients (3.1%), respectively. The median total prescribed dose was 70.0 Gy (range, 60.0–78.0 Gy).

In most patients with PSA failure, the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition (11) was used: three consecutive rises in PSA level, backdating the time of failure to the midpoint between the last non-rising and the first rising PSA measurements. Also included as failure criteria were administration of hormonal therapy before three PSA rises, clinical failure as the first event, or a rise above a certain level of PSA. The median PSA level at the administration of salvage hormonal therapy was 3.2 ng/ml (0.024–341.3 ng/ml). Patients were categorized as having clinical failure if they developed local, regional or distant failure. The median follow-up was 46 months (range, 3–109 months) for all patients.

The overall survival rate and the progression-free survival rate were calculated from the first day of radiotherapy using the Kaplan–Meier method. Log-rank statistics were used to identify significant prognostic factors for survival. Cox's proportional hazard model was used in multivariate analysis. The Common Terminology Criteria for Adverse Events version 3.0 were used to assess the late morbidity.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 Conflict of interest statement
 Appendix
 References
 
Patterns of failure are shown in Table 3. PSA failure was seen in 160 patients (23.6%). Clinically, there were four local, four regional, three regional and distant and 17 distant failures after completion of radiotherapy. In patients in the low-risk group, there was no clinical failure. Only seven patients in the high-risk group died of prostate cancer, 31 died of intercurrent diseases and two died of unknown causes.


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  		Table 3. Distribution of failures

 
The 5-year overall, clinical progression-free and biochemical relapse-free survival rates were 93.0, 95.3 and 71.9% for all patients, respectively. The 5-year clinical progression-free, and biochemical relapse-free survival rates according to the risk group were 100%, 90.8% in the low-risk group, 98.3%, 75.7% in the intermediate-risk group and 93.6%, 67.6% in the high-risk group, respectively (Figs 1 and 2). Table 4 presents the results of multivariate analysis for biochemical relapse-free survival. PSA (relative risk, 1.002; 95% CI, 1.001–1.003; P = 0.0041), GS (relative risk, 1.166; 95% CI, 1.046–1.302; P = 0.0055), T classification (relative risk, 2.897; 95% CI, 1.999–4.230; P = 0.0000), pelvic irradiation (relative risk, 2.042; 95% CI, 1.328–3.273; P = 0.0008), and androgen abletion (relative risk, 0.321; 95% CI, 0.240–0.427; P = 0.0000) were identified as significant prognostic factors.


Figure 1
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  		Figure 1. Clinical progression-free survival rates as a function of risk group.

 

Figure 2
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  		Figure 2. Biochemical relapse-free survival rates as a function of risk group.

 

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  		Table 4. Multivariate analysis of prognostic factors for biochemical relapse-free survival

 
Table 5 shows late morbidity after irradiation. Only 1.1% of patients experienced late morbidity of Grade 3. There were no cases of Grade 4 toxicity.


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  		Table 5. Late gastrointestinal and genitourinary morbidity

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 Conflict of interest statement
 Appendix
 References
 
The present study revealed the practical patterns of EBRT for prostate cancer in Japan. The majority of patients with prostate cancer who received radical radiotherapy had high-risk disease. The median radiation doses employed were 70 Gy, and EBRT was commonly combined with hormonal therapy. Radiotherapy seemed to be effective with little risk of normal tissue complications, although limited by its retrospective nature.

Radical prostatectomy (RP) has been established as one of the standard management options for prostate cancer. However, very few outcome studies have been reported on RP in Japan and Asian countries. Yokomizo et al. (12) have recently reported the treatment results of 1192 patients with clinical T1-2N0M0 prostate cancer, who had a RP from 1993 to 2002 without hormonal therapy at 37 institutions in Japan and whose PSA level after RP decreased to undetectable levels. With a median follow-up of 45.6 months, seven patients (0.6%) died from prostate cancer-related causes and 302 patients (25.3%) had a PSA recurrence. Although the characteristics of patients were totally different from those in our study, EBRT seems to be similarly effective.

A limitation of this study was the use of the ASTRO definition of biochemical failure in most patients. The new definition ‘nadir of PSA + 2 ng/ml’ is considered as the current standard definition for biochemical failure after radiotherapy with or without hormonal therapy (13). When this study was planned, the ASTRO definition of biochemical failure was still being used, although the adequacy of the ASTRO definition has come into question. We should keep in mind that the old ASTRO definition will result in worse short-term and better long-term results, and should be applied basically in patients treated with radiotherapy alone (13). In addition, another limitation of this study was the use of institutional GSs. It should be noted that central review of pathological specimens is essential to ensure the quality of analysis.

The radiation doses employed in Japanese institutions used to be lower than those typically used in the USA (5–7). However, the median dose to the prostate was 70 Gy in this study, and 58.9% of the patients were irradiated with doses ≥70 Gy. Several studies have revealed the radiation dose dependency on progression-free survival as well as biochemical relapse-free survival. However, radiation dose was not a significant prognostic factor in this study. It should be carefully evaluated whether higher doses improve survival, in the situation that the majority of the patients received hormone therapy.

Long-term hormonal therapy in combination with EBRT has been shown to be effective in high-risk patients (14). In the present study, adjuvant hormonal therapy was used in 34.8% of patients, and the median duration of hormonal therapy after radiotherapy was 38 months. However, the median follow-up was only 46 months. Although hormonal therapy and its duration was a prognostic factor in the multivariate analysis, assessment of the effects of long-term hormonal therapy is warranted in future studies.

The survey results demonstrated that more than 80% of patients were treated with a conformal technique, and treatments were delivered frequently using rotational conformal techniques. Because conformal radiotherapy using rotation techniques was developed by Takahashi (15), this technique has been particularly popular in Japan. In constrast, IMRT was performed in only 2.4% of patients. However, IMRT is gradually becoming widespread in Japan (16), and it may become one of the preferred treatment options for prostate cancer in Japan in the near future.

There is a great controversy regarding the effectiveness of elective pelvic radiotherapy in patients with high-risk prostate cancer. The analysis of a recent randomized trial has demonstrated that pelvic irradiation is associated with an improvement in the progression-free survival when neoadjuvant hormonal therapy is used in conjunction with EBRT (17). In the present study, pelvic irradiation was a prognostic factor for biochemical relapse-free survival. However, more studies are needed to determine the best treatment for patients with high-risk prostate cancer.

To our knowledge, this study constitutes the largest series of prostate cancer patients treated with EBRT in Japan. EBRT is feasible for Japanese patients and produces favorable survival results. Although patients with T3–T4 tumor, high GSs, or high level of PSA had a poorer prognosis, the results of EBRT in Japan are generally promising. We believe it worthwhile to show the treatment results of EBRT for prostate cancer not only in Japan, but also in other Asian countries, because the number of patients with prostate cancer treated with radiotherapy in Asian countries will increase rapidly in the near future.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
Conflict of interest statement
 Appendix
 References
 
This study was supported in part by the Japanese Radiation Oncology Study Group and a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Sciences. We thank all radiation oncologists who participated in this study. Their effort providing us information makes these surveys possible.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
Appendix
 References
 
None declared.


   Appendix
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Appendix
References
 
Participating Institutions: Akita University, Chiba University, Dokkyo Medical University Koshigaya Hospital, Gunma Prefectural Cancer Center, Gunma University, Hamamatsu University School of Medicine, Hyogo Cancer Center, Kitasato University, Kochi University, Kyorin University, Kyoto University, Kyushu Medical Center, Kyushu University, Mie University, Nara Medical University, National Cancer Center Hospital East, Niigata University, Nishi-Kobe Medical Center, Okayama University, Rinku General medical center, Saitama Medical Center, Shiga University, Shimane University, Shinshu University, Tenri Hospital, Toho University, Tokai University, Tokushima University, Tokyo Medical Center, Tokyo Metropolitan Fuchu Hospital, Tokyo Metropolitan Komagome Hospital, Tukuba University, University of Occupational and Environmental Health, Yamanashi University.


   Footnotes
 
Abbreviations: AHT, adjuvant hormonal therapy; ASTRO, American Society for Therapeutic Radiology and Oncology; EBRT, external-beam radiotherapy; GS, Gleason score; IMRT, Intensity-modulated radiation therapy; LHRH, Luteinizing hormone-releasing hormone; NHT, neoadjuvant hormonal therapy; PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiotherapy


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 Appendix
 References
 
1 Pu YS, Chiang HS, Lin CC, Huang CY, Huang KH, Chen J. Changing trends of prostate cancer in Asia. Aging Male (2004) 7:120–32.[CrossRef][Medline]

2 Marugame T, Mizuno S. Comparison of prostate cancer mortality in five countries: France, Italy, Japan, UK and USA from the WHO mortality database (1960–2000). Jpn J Clin Oncol (2005) 35:690–1.[Free Full Text]

3 Watanabe H. Mass screening program for prostatic cancer in Japan. Int J Clin Oncol (2001) 6:66–73.[Medline]

4 Akaza H, Moore MA, Chang SJ, Cheng C, Choi HY, Esuvaranathan K, et al. The 5th Conference on Asian Trends in Prostate Cancer Hormone Therapy. Asian Pac J Cancer Prev (2007) 8:3–12.[Medline]

5 Nakamura K, Ogawa K, Yamamoto T, Sasaki T, Koizumi M, Teshima T, et al. Trends in the practice of radiotherapy for localized prostate cancer in Japan: a preliminary patterns of care study report. Jpn J Clin Oncol (2003) 33:527–32.[Abstract/Free Full Text]

6 Ogawa K, Nakamura K, Onishi H, Sasaki T, Koizumi M, Shioyama Y, et al. Radical external beam radiotherapy for prostate cancer in Japan: results of the 1999–2001 patterns of care process survey. Jpn J Clin Oncol (2006) 36:40–5.[Abstract/Free Full Text]

7 Nakamura K, Teshima T, Takahashi Y, Imai A, Koizumi M, Mitsuhashi N, et al. Radical radiation therapy for prostate cancer in Japan: a patterns of care study report. Jpn J Clin Oncol (2003) 33:122–6.[Abstract/Free Full Text]

8 Mitsumori M, Sasaki Y, Mizowaki T, Takayama K, Nagata Y, Hiraoka M, et al. Results of radiation therapy combined with neoadjuvant hormonal therapy for stage III prostate cancer: comparison of two different definitions of PSA failure. Int J Clin Oncol (2006) 11:396–402.[CrossRef][Medline]

9 Sobin LH, Wittekind C. TNM classification of Malignant tumours. (2002) 6th edn. New York: Wiley Liss.

10 Chism DB, Hanlon AL, Horwitz EM, Feigenberg SJ, Pollack A. A comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with 3D conformal radiotherapy. Int J Radiat Oncol Biol Phys (2004) 59:380–5.[Medline]

11 Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys (1997) 37:1035–41.[CrossRef][ISI][Medline]

12 Yokomizo A, Murai M, Baba S, Ogawa O, Tsukamoto T, Niwakawa M, et al. Percentage of positive biopsy cores, preoperative prostate-specific antigen (PSA) level, pT and Gleason score as predictors of PSA recurrence after radical prostatectomy: a multi-institutional outcome study in Japan. BJU Int (2006) 98:549–53.[CrossRef][Medline]

13 Roach M 3rd, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys (2006) 65:965–74.[CrossRef][ISI][Medline]

14 Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet (2002) 360:103–6.[CrossRef][ISI][Medline]

15 Takahashi S. Conformation radiotherapy, rotation techniques as applied to radiography. Acta Radiol Suppl (1965) 242:1–142.

16 Nakano T. Status of Japanese radiation oncology. Radiat Med (2004) 22:17–9.[Medline]

17 Lawton CA, DeSilvio M, Roach M 3rd, Uhl V, Kirsch R, Seider M, et al. An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94–13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys (2007) 69:646–55.[Medline]


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