Int J Clin Oncol (2008) 13:239–243 DOI 10.1007/s10147-007-0745-z

© The Japan Society of Clinical Oncology 2008

ORIGINAL ARTICLE Koji Okihara · Takumi Shiraishi · Osamu Ukimura Yoichi Mizutani · Akihiro Kawauchi · Tsuneharu Miki

Current trends in diagnostic and therapeutic principles for prostate cancer in Japan

Received: September 29, 2007 / Accepted: November 7, 2007

Abstract Background. This study aimed to clarify characteristics of the diagnosis and treatment of prostate cancer in Japan. Methods. In September 2005, questionnaire surveys were mailed to Japanese urologists (response rate, 43%; 474/1090) who were listed as voting members (VMs) of the Japanese Urological Association (JUA); the questionnaire surveys were also mailed to professors and chairmen (PCs) of urology departments at Japanese national, public, and private universities who were also VMs of the JUA (response rate, 76%; 68/90). The questionnaires asked about beliefs and practices regarding prostate cancer management. Results. The answers of the VMs and PCs to the questionnaire were very similar. About 60% of these urologists answered that they did not set an age limit for prostatespecific antigen (PSA) testing, and about 40% answered that they did not set an age limit for prostate needle biopsy in individuals with an intermediately elevated PSA level. The age limit for radical prostatectomy (RP) was set at 75 years by 69% (322/470) of the VMs and 66% (45/68) of the PCs. The order of priority of factors considered for the selection of RP for early prostate cancer was radicality, including tumor grade (mean, 1.97); patient’s wish for radical surgery (mean, 2.47); comorbidity (mean, 2.72); and age (mean, 2.81). Conclusion. There are trends in diagnostic and therapeutic principles for prostate cancer which are characteristic of Japan, and these trends are associated with the recent rapid extension of life expectancy in that country. Key words Prostate cancer · Management · Questionnaire · PSA testing K. Okihara (*) · T. Shiraishi · O. Ukimura · Y. Mizutani · A. Kawauchi · T. Miki Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kyoto 602-8566, Japan Tel. +81-75-251-5595; Fax +81-75-251-5598 e-mail: [email protected] A summary of this study was presented at the 43rd annual meeting of the Japan Society of Clinical Oncology in 2005.

Introduction Over the past 40 years, the mean lifespan of Japanese men has been increasing. In the late 1960s, it was 67–68 years, similar to those in Western countries, but its increase has been particularly notable in Japan among developed countries, and it reached 78.64 years according to a report by the Ministry of Health, Labour and Welfare in 2004.1 The extension of the mean lifespan has been accompanied by an extension of mean life expectancy, which at the age of 75 years is 11.23 years1 in Japanese men, or about 5 years longer than that in American men. This suggests an increase in cancer patients among elderly men with a good performance status and necessitates cancer screening and the preparation of guidelines for the selection of treatments for various cancers, e.g., surgical treatment vs medical treatment. Particularly, while the incidence of, and mortality due to, prostate cancer in Japan are still lower than those in Western countries, the age-adjusted mortality rate was about 16 times higher in 1997 compared with that in 1950, and the Cancer Statistics White Book expects that prostate cancer will show the highest increase in mortality rate among cancers of various organs in 2015.2 However, no screening system for the elderly according to the serum prostatespecific antigen (PSA) level, or guidelines for the selection of treatment for early prostate cancer, have yet been established in Japan. Prior to the establishment of diagnostic and therapeutic principles for prostate cancer in elderly patients, we mailed a questionnaire to voting members (VMs) of the Japanese Urological Association to clarify the present state of diagnosis and treatment of prostate cancer from the viewpoint of age and in comparison with the diagnosis and treatment of other urological cancers. The objective of this study was to clarify the decisionmaking process in the diagnostic procedures and treatment strategies for prostate cancer by Japanese urologists.

240 Table 1. Questionnaire used in this survey (translated from the original Japanese) For diagnosis (1) In regard to referral, what is the maximum age of patients that you include in PSA testing? Up to ( ) years/ Age not regarded (2) In patients with a gray-zone PSA level (4–10 ng/ml), up to what age do you perform biopsy? Up to ( ) years/ Age not regarded For treatment (3) For patients with early prostate cancer (PSA <10 ng/ml,
Patients, materials, and methods In September 2005, a questionnaire was mailed to each of 1090 VMs appointed as instructor physicians by the Japanese Urological Association from among its 7200 members (as of 2005). The questionnaire was to be answered anonymously. The same questionnaire was also mailed to 90 professors and chairmen (PCs) of urology departments at Japanese national, public, and private universities who were also VMs of the same society. Table 1 shows the questionnaire. The questionnaire consisted of six questions, of which questions 1 and 2 were related to diagnosis, and questions 3–6 to treatments. Concerning diagnosis, questions were asked about the age limits for performing PSA testing, and the age limits for performing prostate needle biopsy in patients with an intermediately elevated PSA level. Questions 3 and 4 concerned relationships between the age limit and treatment selection factors in patients with early prostate cancer. Question 5 was related to the selection of treatment in an 80-year-old patient with early prostate cancer who expressed a strong wish for radical prostatectomy (RP). Question 6 asked whether urologists who had treated prostate cancer patients for many years had expanded the indications for radical surgery in elderly patients.

Results The response rate of the VMs was 43% (474/1090), and the mean age of the 474 respondents was 46.8 years (range, 35–70 years). The response rate of the PCs was 76% (68/90), and the mean age of the 68 respondents was 52.6 years (range, 38–65 years).

Question 1. Age limit for PSA screening Of the VMs and PCs, 1% (6/474) and 1% (1/68) respectively, did not answer the question. Of the VMs and PCs who answered, 67% (313/468) and 63% (42/67) respectively, answered that they performed PSA screening regardless of the patients’ age. Of the 155 VMs and 25 PCs who set an age limit, 116 (75%) and 16 (64%), respectively, set it at 80 years or less.

Question 2. Age limit for prostate needle biopsy in patients with an intermediately elevated PSA level Of the VMs, 0.4% (2/474) did not answer the question, while all the PCs answered the question. Of the VMs and PCs, 40% (187/472) and 49% (33/68) respectively, did not set an age limit for performing prostate needle biopsy. Of the 285 VMs (60%) and 35 PCs (51%) who set an age limit, 213 (75%) and 24 (69%) respectively, set it at 80 years or less.

Question 3. Relationships of age limits and various treatments For the VMs, the response rates for the answers about RP, radiation therapy (RT), and endocrine therapy (ET) were 99% (470/474), 98% (463/474), and 99% (470/474), respectively. For the PCs, the response rates for the answers about RP, RT, and ET were 100% (68/68), 99% (67/68), and 99% (67/68), respectively. Of the VMs and PCs, 69% (322/470) and 66% (45/68), respectively, set the age limit for RP at 75 years, but 43% and 34%, respectively, set no age limit for RT. In contrast to the responses about RP and RT, 76% and

241 Fig. 1. Responses to the question focusing on age limitation for treatment in men with localized prostate cancer (responses from voting members of the Japanese Urological Association). RP, Radical prostatectomy; RT, radiation therapy; ET, endocrine therapy; y. o., years old

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75%. respectively, of the VMs and PCs set no age limit for ET (Fig. 1). Question 4. Factors considered for the selection of RP Of the VMs, 96% mentioned (1) age, (2) wish for radical surgery, (3) radicality based on tumor grade, and (4) comorbidity as factors considered for the selection of RP, with only 17 (4%) mentioning other items. The order of priority of these four factors was: radicality including tumor grade (mean, 1.97), wish for radical surgery (mean, 2.47), comorbidity (mean, 2.72), and age (mean, 2.81). Ninety-four percent of the PCs (64/68) also checked these four factors similarly to the VMs. Many of the 17 VMs who mentioned other items considered the degree of understanding of the family about surgical treatment and the patient’s fitness as important factors, but 1 commented that it was impossible to determine the order of priority, because the selection was made by a comprehensive evaluation. Question 5. Treatment of an 80-year-old patient with early prostate cancer Of the VMs, 99% answered (1) selecting RP by following the patient’s wishes; (2) referring the patient to another hospital for a second opinion; (3) starting RT and/or ET in discussion with the patient and his family, or (3) persuading the patient and his family that the patient should start RT and/or ET; and (4) watchful waiting (WW) as the top four factors, with only 4 VMs (1%) mentioning other options. The order of priority among these approaches was starting RT and/or ET (mean, 1.43), referring the patient to another hospital for a second opinion (mean, 2.41), selecting RP by following the patient’s wishes (mean, 2.53), and WW (mean, 2.86). Of the PCs, 66 (97%) also selected these four items as the most probable options, and starting RT and/or ET

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was the first in order of priority (mean, 1.26), but for the PCs, this was followed by WW (mean, 2.38), selecting RP by following the patient’s wishes (mean, 2.41), and referring the patient to another hospital for a second opinion (mean, 2.67). Selecting RP by following the patient’s wishes was mentioned as the first choice by 21% (102/474) and 19% (13/68), respectively, of the VMs and PCs. Question 6. Expansion of indications for radical surgery in elderly patients Of the VMs and PCs, 17% (80/474) and 25% (17/68), respectively, answered that they had expanded the indications.

Discussion In the past 40 years until the early 1990s, the mortality rate of prostate cancer increased in Western Europe and the United States, and it has continued to increase in Eastern Europe and Japan.3 Because of the differences in mortality rates and mean life expectancies, it is suggested that some differences may exist in the diagnostic and therapeutic principles for prostate cancer among Japanese urologists compared with those in Western Europe and the United States. From the substantial response rate and age of the respondents in the present survey, including the PCs, the answers are considered to reflect the contemporary diagnostic and therapeutic principles of experienced Japanese urologists. In 2000, Fowler et al.4 reported the results of a questionnaire concerning PSA testing in elderly individuals returned by 559 radiation oncologists and 504 urologists in the United States. Among the results, 43% of the radiation oncologists but only 16% of the urologists answered that they would perform PSA testing in patients aged 81 years and above. This difference reflected the evidence that many radiation

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oncologists were likely to offer external beam radiotherapy or brachytherapy, treatments which were beneficial even in patients with a life expectancy of less than 10 years. At present, in Japan, in practice, the determination of whether PSA testing should be performed at the time of the diagnosis of prostate cancer depends on the judgment of the urologist. It is reported that 36% of American men aged 85 years or above who visited the Veterans Affairs Facility due to bad health in 2003 underwent PSA testing.5 In the present study, more than 60% of VMs, who were the leading providers of clinical urology services in Japan, answered that they did not set an age limit for PSA testing. We, intentionally, did not include digital rectal examination (DRE) findings or a family history of prostate cancer in the question on age and PSA testing, because the main purpose of this study was to survey the fundamental beliefs of Japanese urologists about PSA testing. If positive DRE findings had also been described in the question, we believe that the proportion of answers which set no age limit would have increased. In the present study, age does not appear to be regarded as an important factor in PSA testing, probably because the majority of experienced Japanese urologists know that the mean life expectancy of the Japanese male population is longer than that in the West, and they are aware of the need to avoid misdiagnosis based on the recent increase in the mortality rate. The result of the present study showing that more than 60% of urologists would perform prostate needle biopsy in patients with an intermediately elevated PSA level regardless of age could be surprising for European and United States urologists, who closely restrict indications for biopsy according to life expectancy. Similar to our concerns about question 1, a description of DRE findings and a status of comorbidity might have influenced the this result; however, the evidence that all the PCs replied stating their own age limits without leaving the answer blank leads us to conclude that, at present, Japanese urologists carry out biopsies even in elderly patients if there are findings suspicious for prostate cancer. Nevertheless, in Japan, also, continuation of routine PSA testing in individuals aged 80 years or above with an initial negative biopsy is being questioned.6 In the present study, more than 60% of experienced urologists set the age limit for RP for early prostate cancer at 75 years. This judgment is based on evidence that the mean life expectancy of Japanese men aged 75 years is 11.23 years.1 Our survey revealed that the mean life expectancy was considered to be an important factor in the selection of radical surgery for the treatment of prostate cancer, following Western trends. Alibhai et al.7 analyzed the correlations between age and therapeutic options for early prostate cancer in a Caucasian population, and reported that the probability of receiving RP was higher than that of receiving RT or watchful waiting (WW), and was about 50% at the age of 60 years, but that, at the age of 70 years, the probability of receiving RP was less than 10%, while the probability of receiving WW was about 60%. In Japan, RP is a major option for patients with localized cancer aged 70–75 years, and it was performed in about 50% of patients aged

70–74 years with localized cancer (T1c-T2) according to a survey by the Japanese Urological Association (JUA) in 2000.8 Interestingly, only 5% of those aged 70–74 years received WW. The concepts of Western and Japanese urologists concerning WW are clearly different. One cause of this difference may be that ET is more acceptable than WW for patients with early prostate cancer in Japan.9 Akaza and Hinotsu9 demonstrated that individuals desire therapy because they have been told that they have cancer. Furthermore, this observation is consistent with the result of the present study, showing that 75% of urologists set no age limit for selecting ET. In addition to mean life expectancy, the tumor grade of the prostate biopsy specimen and comorbidity are frequently considered in selecting treatments for early prostate cancer. Dahm et al.10 calculated the expected survival period based on the Gleason score (GS) at radical surgery in elderly patients aged 70 years and above. They maintained that RP should be performed in patients aged 70 years and above with high-grade tumors (e.g., GS 7–8) without too much attention to the life expectancy, because survival for 10 years or longer is expected from radical surgery, but they noted that the efficacy of RP was small in those aged 70 years and above with low-grade tumors (e.g., GS4), because survival for 18 years or longer is expected without radical surgery. Alibhai et al.11 also suggested that RP should be performed more frequently in elderly patients with high-grade tumors, because radical surgery is expected to bring about a large benefit even in patients aged 75 years and above with high-grade tumors. In answering question 4 of our questionnaire, the highest percentages of both the VMs and PCs mentioned radicality, including tumor grade, as the first factor to be considered in the selection of treatment. However, in consideration of the situation in Japan, where WW is rarely selected, as noted above, these answers are considered to imply that RT or ET rather than RP is regarded as the first choice, because, even when a diagnosis of localized prostate cancer has been made by DRE or imaging studies such as transrectal ultrasonography, the probability of pathological organ-confined disease is decreased in high tumor grades, based on the concept of the Partin Tables.12 It is probably for this reason that RP is performed frequently in patients with low-grade and middle-grade tumors aged 75 years and above in Japan, unlike in Western countries. Albertsen et al.13 proposed that the remaining life expectancy (RLE) in patients with localized prostate cancer should be calculated from age, comorbidity, and tumor grade and that even elderly patients should be treated radically if the RLE is 5 years or longer. In our study, also, comorbidity was given a higher priority than age. Hall et al.14 have emphasized the importance of the introduction of quantitative indices such as the Charlson Comorbidity Index for the prediction of survival outcomes and treatment patterns in prostate cancer. In Japan, there has been no report on the use of the Comorbidity Index for the selection of treatment, and validation studies of such indices are urgently needed.

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A higher level of respect for patients’ wishes was another marked difference in Japan. The characteristic tendency in Japan to respect the patients’ wishes was reflected in the answers to question 5; RP was selected even in an 80-yearold patient by a substantial percentage (20%) of urologists, following his wishes. In Japan, the mean lifespan of men has been increased by about 4 years (from 74.78 to 78.64 years) during the 20 years from 1985 to 2004 with the acceleration of aging of the society. Under these circumstances, experienced urologists with a clinical career of 20 years or longer are considered to have experienced continuous increases in the numbers of healthy elderly people aged over 80 years, and this is believed to have contributed to the establishment of patients’ wishes as an independent factor. Also, 25% of the PCs had expanded the indications for radical surgery in elderly patients, probably because of these demographic changes, as well as because of improvements in surgical techniques.

References 1. Ministry of Health, Labour and Welfare of Japan (2004) International comparison in average life span: home page address http:// www.mhlw.go.jp/toukei/saikin/hw/life/life05/03.html 2. Hirao Y, Cho M (2002) Statistical analysis of prostate cancer in Japan. Nippon Rinsho: 60 (Suppl 11):53–58 3. Levi F, Lucchini F, Negri E, et al. (2001) Changed trends of cancer mortality in the elderly. Ann Oncol 12:1467–1477

4. Fowler FJ, Collins MM, Altertsen PC, et al. (2000) Comparison of recommendations by urologists and radiation oncologists for treatment of clinically localized prostate cancer. JAMA 283:3217–3222 5. Walter LC, Bertenhal D, Lindquist K, et al. (2006) PSA screening among elderly men with limited life expectancy. JAMA 296: 2336–2342 6. Nishida S, Masumori N, Fukuta F, et al. (2006) Clinical course of patients with negative initial prostate biopsy. Hinyokika Kiyo 52:523–527 7. Alibhai SM, Krahn MD, Cohen MM, et al. (2004) Is there age bias in the treatment of localized prostate carcinoma? Cancer 100: 72–81 8. Cancer Registration Committee of the Japanese Urological Association (2005) Clinicopathological statistics on registered prostate cancer patients in Japan:2000 report from the Japanese Urological Association. Int J Urol 12:46–61 9. Akaza H, Hinotsu S (2006) The case for androgen deprivation as primary therapy for early stage disease: results from J-CaP and CaPSURE. J Urol 176 (6 Pt 2):S47–49 10. Dahm P, Silverstein AD, Weizer AZ, et al. (2003) When to diagnose and how to treat prostate cancer in the “not too fit” elderly. Hematol Oncol 48:123–131 11. Alibhai SM, Naglie G, Nam R, et al. (2003) Do older men benefit from curative therapy of localized prostate cancer? J Clin Oncol 21:3318–3327 12. Partin AW, Mongold LA, Lamm DM, et al. (2001) Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology 58:843–848 13. Albertsen PC, Fryback DG, Storer BE, et al. (1996) The impact of co-morbidity on life expectancy among men with localized prostate cancer. J Urol 156:127–132 14. Hall WH, Jani AB, Ryu JK, et al. (2005) The impact of age and comorbidity on survival outcomes and treatment patterns in prostate cancer. Prostate Cancer Prostatic Dis 8:22–30