1. Top of page
  2. Introduction
  3. EBM-intended practice guidelines
  4. A. Epidemiology
  5. B. Diagnosis
  6. C. Treatment overview
  7. Conclusion
  8. Representative Persons of Subgroups in the Working Team for Formulation of Clinical Practice Guidelines for Prostate Cancer
  9. References

The present Clinical Practice Guidelines for Prostate Cancer (GL) were created mainly by the Japanese Urological Association as part of the 2003–2004 Ministry of Health, Labour and Welfare (MHLW) Scientific Research Fund-supported Thorough Researches for the Evaluation of Medical Technologies. The guidelines are aimed to be used by general urologists and radiation oncologists committed to the treatment of prostate cancer. The complete text of these guidelines (a total of 233 pages) supervised by the Japanese Urological Association was already published in May 2006. The present edition is a summary of the complete text of the GL.

The working team for the creation of the present clinical practice guidelines involved Sadao Kamidono (Chairman of the Japanese Urological Association, Kobe University), who served as the team leader; Shinichi Ohshima (National Center for Geriatrics and Gerontology), who coordinated the overall structure of the GL; Yoshihiko Hirao (Nara Medical University), who collected Evidence-based Medicine (EBM)-intended reports; Kazuhiro Suzuki (Gunma University School of Medicine), who was responsible for the epidemiology section; Yoichi Arai (Tohoku University), who contributed to the diagnosis section; Hiroyuki Fujimoto (National Cancer Center), who contributed to the surgical treatment section; Shin Egawa (The Jikei University), who contributed to the radiation therapy section; Hideyuki Akaza (University of Tsukuba), who contributed to the pharmacotherapy section; and Isao Hara (Kobe University), who contributed to the expectant management and supportive care sections. Tomonori Hasegawa (Toho University) served as the advisor, and evaluated the GL using the Appraisal of Clinical Guidelines for Research and Evaluation (AGREE) Instrument. All of these contributors were committee members of the MHLW Scientific Research Fund-Supported project. Shiro Hinotsu (Tsukuba University) also joined the Working Group in the research of published reports and in creating the structured abstract and Yoshiyuki Kakehi (Kagawa University) joined the Working Groups in the field of expectant management and supportive care. Furthermore, researchers were assisted by 30 urologists affiliated with the Japanese Urological Association, four experts in public health and literature search, eight members of the Japanese Society for Therapeutic Radiation and Oncology and two members of the Japan Society of Clinical Oncology. A total of 317 urologists from 46 institutions all over Japan took part in the compilation of structured abstracts as directed by the Japanese Urological Association. Urologists outside the GL creation team contributed to the external evaluation of the first draft version of the GL. Thus, the present GL was completed in fact by the aggregated dedication of the Japanese Urological Association as well as the united efforts of the Japan Society of Clinical Oncology and the Japanese Society for Therapeutic Radiology and Oncology.

EBM-intended practice guidelines

  1. Top of page
  2. Introduction
  3. EBM-intended practice guidelines
  4. A. Epidemiology
  5. B. Diagnosis
  6. C. Treatment overview
  7. Conclusion
  8. Representative Persons of Subgroups in the Working Team for Formulation of Clinical Practice Guidelines for Prostate Cancer
  9. References

‘Evidence-based Medicine’ (EBM) has been defined as ‘conscientious, accurate, careful utilization of optimal up-to-date information for making a medical decision for individual patients’. Practice guidelines have been defined as ‘systematically developed statements concerning appropriate insurance-registered healthcare modalities for specific illness that can help the treating doctor and the patient making a medical decision’. However, no matter how far the information communication system has developed, it is difficult for healthcare providers, who are fully occupied with doing routine healthcare practices, to collect and read a huge volume of data in order to find out up-to-date optimal evidence. Therefore, there is a need for a systematically organized tool that helps the treating doctor as well as the patient making a medical decision. EBM is such a tool and practice guidelines are an aggregation of EBM for the treatment of specific diseases. EBM and practice guidelines may have to be revised according to changes in social and environmental circumstances along with the transition of time. The formulation of medical evidence is academic work, whereas the creation of practice guidelines is considered to be heavy-load labor. In the fields of medicine where one evolution is brought about after another, revisions needs to be made periodically to practice guidelines. Therefore, it is necessary to follow standardized processes when devising these guidelines.

The original draft of the present guidelines was made with reference to three guidelines that were prepared in the USA and Europe and have established evaluation, respectively. They are the Physicians Data Query (PDQ) Concerning Prostate Cancer issued by the National Cancer Institute (NCI), the guidelines prepared by the European Association of Urology (EAU), and the National Comprehensive Cancer Network (NCCN) devised by the American Cancer Society. Our team elucidated the present status of the diagnostic and treatment modalities for prostate cancer presented in these guidelines when they were created (1999).

Intending to incorporate findings obtained after 1999 and characteristics of prostate cancer in Japanese patients into the draft guidelines, clinical questions were raised for each specific subject and assumed clinical questions were set up in a standardized form. Clinical questions for the selection of relevant reports were selected. The selected clinical questions were reviewed and modified in order to improve the readability of the guidelines.

Eventually, 13 epidemiological clinical questions, 17 diagnostic clinical questions, 18 clinical questions concerning surgical treatment, 45 clinical questions concerning radiation therapy, 11 clinical questions related to pharmacotherapy, 6 clinical questions concerning expectant management and 4 clinical questions related to supportive care were selected.

To search the relevant reports that provided evidence for the draw answers (clinical answers), keywords were selected and a search formula was set up. The report search was limited to articles published after 1999, when the overseas reference guidelines were created. For the epidemiology section, clinical questions and keywords were set up that were separate from the American and European guidelines because this section was assumed to contain a large volume of statements inherent to Japan. For the search of the PubMed reports, the major topics of the Medical Subject Headings of the National Library of Medicine (MeSH) were used with reference to the selected keywords, and search formulae were devised. All of the search formulae have been described in the complete text to allow utilization in the case of future revision. Taking the work efficiency and future availability of journals into consideration, literature search was limited to a total of 26 journals, comprising 9 urological journals, 10 oncology journals, 3 journals for radiation therapy, and 4 general medical journals. A total of 4662 relevant reports were extracted, and 1033 articles that were considered by each subgroup to be important were selected. The selected articles were allotted to a total of 317 urologists at 46 nationwide institutions, who critically reviewed and edited each assigned article into an organized abstract of standardized form. These urologists flagged each prepared abstract with an evidence level rated according to the predefined criteria (Table 1). The evidence levels were summed up for an aggregation of information addressing each clinical question and each answer was prepared by assigning a recommendation class ranging from class A to class D. Class A recommendation indicates a best-recommended treatment or practice. Class B recommendation means a treatment or practice that is recommended in general. Class C recommendation represents a treatment or practice the value of which is equivocal due to a lack of adequate evidence. A Class D statement indicates a treatment or practice that should not be performed. All of the organized abstracts of the articles cited in the full text of the present guidelines were written on an electronic medium and have been attached as a CD-ROM to the Practice Guidelines for Prostate Cancer.

Table 1.  Evidence levels (criteria of the Committee for the Clinical Practice Guidelines in Oncology)
I.Evidence derived from a meta-analysis of multiple randomized controlled studies, or evidence from multiple randomized controlled studies.
II.Evidence from at least one randomized controlled study, or evidence from multiple well-designed non-randomized controlled studies.
III.Evidence from at least one well-designed semi-experimental research of other type, or evidence from well-designed non-experimental descriptive study such as comparative research, correlation research, and matched case-controlled study.
IV.Report or opinion of expertise committee, or clinical experience of knowledgeable person.

Despite the fact that the above-described compilation process was pursued when making up the present GL, some issues have evolved. Since these GL are mainly intended for use in Japan, studies on Japanese patients have been more closely searched and examined. However, most of the studies cited in these GL are studies performed overseas due to the levels of evidence. Thus, the present guidelines do not truly reflect the actual status of prostate cancer in Japanese patients. Regarding some subjects in the field of surgical treatment that are difficult to evaluate in randomized controlled studies, statements have been presented naturally with a low evidence level, or there is no study to obtain evidence. Recommendation classes as well as evidence levels presented in these guidelines were determined by the individual subgroups of our teams responsible for each section, based on global consideration of all the extracted evidence. Since it is difficult to determine an evidence level for statements in the field of epidemiology, statements in the epidemiology section are not flagged with any recommendation class. The Roman numeral in a parenthesis at the tail of the reference number denotes an evidence level as defined in Table 1.

A. Epidemiology

  1. Top of page
  2. Introduction
  3. EBM-intended practice guidelines
  4. A. Epidemiology
  5. B. Diagnosis
  6. C. Treatment overview
  7. Conclusion
  8. Representative Persons of Subgroups in the Working Team for Formulation of Clinical Practice Guidelines for Prostate Cancer
  9. References

1. Morbidity and mortality

Prostate cancer predominantly affects elderly men, compared with other cancer species. The global age-adjusted morbidity rate of prostate cancer (age-adjusted morbidity rate : percentage of patients per 100 000 men per year) is 19.8, which stands as the third highest following 37.5 for lung cancer and 24.5 for gastric cancer. The morbidity of prostate cancer greatly varies across regions in the world. The morbidities of prostate cancer in advanced countries are generally more than three times as high as those in developing countries. In Japan, the age-adjusted morbidity of prostate cancer in men (based on the 1985 population) is 19.9, which is the sixth highest following those of gastric cancer, lung cancer, colon cancer, hepatic cancer and rectal cancer. However, it is forecast that the incidence of prostate cancer will become the second most prevalent following lung cancer by 2020 in Japan.1,2

The global age-adjusted mortality rate of prostate cancer is 8.2, which is the fifth most prevalent following 33.7 for lung cancer, 19.1 for gastric cancer, 14.2 for hepatic cancer and 10.7 for colon/rectal cancer. In Japan, the 2001 age-adjusted mortality rate of prostate cancer in men is 8.4, which is the eighth highest following lung cancer, gastric cancer, hepatic cancer, colon cancer, pancreatic cancer, esophageal cancer and rectal cancer. The number of Japanese men dying of prostate cancer accounts for 4.2% of all Japanese men dying of any cancer.

2. Risk factors

Prostate cancer can be latent as it is sometimes detected incidentally by microscopic investigation of biopsy specimen collected during any interventional procedure. The incidence of latent prostate cancer increases along with the advancement of age. However, the incidence of latent prostate cancer is similar across regions of the world, in contrast to the overall morbidity of prostate cancer.3 It is generally believed that latent prostate cancer does not commonly grow into clinically apparent cancer, however, some of the latent prostate cancers may slowly grow into a clinical cancer.4–6

Since prostate cancer and benign prostatic hypertrophy (BPH) occur due to similar etiologies and at similar ages, both prostate cancer and BPH may be identified simultaneously in the same man. It has been reported in Japan and other countries that prostate cancer was found in 4–7% of men presenting to the outpatient sections of hospitals with dysuria.7,8 Therefore, it is necessary to investigate patients presenting with any urinating trouble to an outpatient section/clinic for the presence of prostate cancer by prostate specific antigen (PSA) testing and digital rectal examination (DRE).

Although the determinate risk factor of prostate cancer remains unknown, some plausible risk factors have been identified. Presently the strongest risk factor of prostate cancer is heredity. The risk of prostate cancer is increased if a family has multiple prostate cancer patients or a prostate cancer patient with onset at a younger age.9 Since prostate cancer represents an androgen-dependent cancer, the presence of androgens is essential for the onset of prostate cancer. An extrinsic factor that is suggested to contribute to the risk of prostate cancer is the Western style of diet in which animal fat is frequently ingested, although this has not been definitively validated.10 The incidence of prostate cancer is negatively correlated with the regular ingestion of beans and grains and positively correlated with the active ingestion of sugar, milk, and fat.11 Selected chemicals, including selenium; β carotin; vitamins A, E, D, and C; isoflavone; and lycopene, are being researched for possible preventive effects against prostate cancer.12–15

3. Screening

Since the PSA test provides the convenient and accurate detection of prostate cancer, it is used as a useful primary screening for prostate cancer. The guidelines of the American Cancer Society and the American Urological Association advocate that men aged over 50 years (45 or 40 years for black men and individuals with a familial history of prostate cancer) should be provided with an explanation about the merits and demerits of screening for prostate cancer. These guidelines recommend that a PSA test and DRE should be conducted for those who wish to check for prostate cancer.16,17 On the other hand, the American College of Preventive Medicine and the American College of Physicians have indicated that there is so far no evidence for recommending or not recommending the routine practice of screening for prostate cancer and have stated that a man who is going to have a medical checkup should decide whether or not to undergo screening for prostate cancer at his own discretion after receiving information about the screening and the subsequent treatment for prostate cancer.18,19

The contribution of the introduction of screening for prostate cancer for decreasing the mortality of men has been validated by the data obtained in an epidemiological study in Olmstead County, Minnesota, USA;20 epidemiological data collected in Quebec, Canada;21 and an intervention study in Tyrol, Austria.22 A prostate, lung, colorectal and ovarian cancer screening study (PLCO)23 and European randomized study of screening for prostate cancer (ERSPC)24 are large-scale randomized controlled studies currently ongoing in the USA and Europe, respectively.

There is an increase in the adoption of prostate cancer screening for local government-sponsored mass screening around Japan. PSA-based prostate cancer screening has also been included in complete physical examination, with an increasing number of individuals undergoing it. The prostate cancer detection rate by screening using PSA alone has been reported to be 0.09% in men of 50–54 years old, 0.22% in men of 55–59 years old, 0.42% in men of 60–64 years old, 0.83% in men of 65–69 years old, 1.25% in men of 70–74 years old and 1.75% in men of 75–79 years old.25 An increased detection rate of early cancer has also been shown as a result of the introduction of prostate cancer screening.26 It is also possible to set up a schedule for undergoing prostate cancer screening based on the baseline PSA test value. Investigations have thus been performed for the contribution of prostate cancer screening to the improvement of the cost-benefit ratio.27,28

Since the PSA test involves false negative as well as false positive results at the present and since cancer cells can elude a needle biopsy, screening for prostate cancer may cause drawbacks for recipients due to the issue of the accuracy of the test method and the complications of treatment. Nevertheless, in the USA, about three quarters of the male population aged over 50 years have been checking the PSA value despite the fact that varied levels of recommendation for prostate cancer screening have been issued by different medical societies/associations. It has been forecast that the morbidity of prostate cancer and the incidence of death from prostate cancer will increase in the future in Japan as well. Taking these facts into consideration, it is worthwhile making the merits and demerits of screening for prostate cancer widely known to the general public in Japan by distributing informative leaflets, etc. and to organize a structure that can provide an optimal screening program for prostate cancer to individuals wishing to check the presence/absence of prostate cancer.

4. Japanese prostate cancer registration program

The Japanese Urological Association has made the Japanese Prostate Cancer Registration Program into a CD-ROM and attached it to the Third Edition (issued in April 2001) of the General Rules for Clinical and Pathological Studies on Prostate Cancer to provide a system for extensive survey into the epidemiology, diagnosis, treatment, and prognosis of Japanese patients with prostate cancer. A total of 4529 prostate cancer patients diagnosed in 2000 at 173 institutions were registered and the clinical features of these patients were reported in 2005.29 It is expected that accurate trends of prostate cancer in Japanese men will become elucidated along with an increase in the number of institutions participating in this registration program and the accumulation of follow-up data for registered patients.

B. Diagnosis

  1. Top of page
  2. Introduction
  3. EBM-intended practice guidelines
  4. A. Epidemiology
  5. B. Diagnosis
  6. C. Treatment overview
  7. Conclusion
  8. Representative Persons of Subgroups in the Working Team for Formulation of Clinical Practice Guidelines for Prostate Cancer
  9. References

1. Digital rectal exam, PSA, and transrectal ultrasonography

An abnormality is detected by DRE in 15–40% of all patients diagnosed with prostate cancer, although this is in part dependent on the extent of the experience of the examining physician. When DRE has been performed in asymptomatic men who are not suspected for prostate cancer, the tumor detection rate was reported to be as low as 0.1–4%30,31 (V).

PSA is kallikrein-like serine protease released from the prostate gland epithelium. It is clinically prostate gland-specific but not specific to prostate cancer. Therefore, PSA levels may also be increased due to BPH, prostatitis or other benign prostatic diseases. The PSA test is, however, more sensitive than DRE and transrectal ultrasonography as an independent predictor of prostate cancer32 (III).

A variety of PSA assay kits are commercially available now, however none of the products have been recognized as an international standard. Prostate cancer is detected by biopsy in 25–30% of men with PSA levels of 4–10 ng/mL and 50–80% of men with PSA levels ≥ 10 ng/mL33 (III). It has generally been believed that prostate biopsy should be indicated for men who have PSA ≥ 10 ng/mL (but it is actually indicated at PSA ≥ 4 ng/mL) with no palpable tumor.

It should be noted that clinically insignificant cancer may be detected by biopsy by adopting a low level PSA threshold. To date, long-term clinical data remain unavailable to allow the recommendation of the optimal PSA value for the detection of prostate cancer which is impalpable but of clinical significance.

The following subclasses of PSA have been proposed to raise the specificity of PSA testing and the detection rate of early prostate cancer. They are PSA density, PSA density in the transitional zone, age-specific reference ranges of PSA thresholds, PSA molecular forms, PSA velocity, and PSA doubling time. These PSA subclasses may be useful to some extent for the differentiation of prostate cancer from BPH, particularly in men with PSA of 4–10 ng/mL. However, the introduction of these PSA subclasses to general healthcare practice remains controversial34,35 (III).

Such an expanded utilization of PSA in an attempt to detect prostate cancer early has led to the creation of a new category of disease stage: T1c. T1c denotes cancer detected by biopsy indicated due to a high PSA value in the absence of abnormality on DRE and imaging diagnosis. Clinical and histological investigations have revealed that 11–26% of T1c prostate cancers were clinically insignificant whereas 18–49% represented localized invasive carcinoma36 (III).

Transrectal ultrasonography is very beneficial for (1) the identification of the involved region and (2) the improvement of the precision of prostate biopsy. However, it is practically impossible to detect prostate cancer only by transrectal ultrasonography while no abnormality is found using DRE and a PSA test. A color Doppler probe for transrectal ultrasonography remains a prototype and has not yet been included in routine examinations for the detection and staging of prostate cancer.

Screening for prostate cancer that combines DRE, PSA, and transrectal ultrasonography attains a positive predictive value (PPV) of 20–80%. Prostate cancer is confirmed by biopsy in 6–25% of men who are shown to be positive in only one of these three tests, 18–60% of men who are positive in two of the above three tests, and 56–72% of men who are shown to be positive in all of the three tests37 (II),38 (III).

A man of linear kin (father or brother) to one or more prostate cancer patients would have more chances of detecting prostate cancer in the early stage by checking his PSA value39 (II).

2. Prostate biopsy

Transrectal ultrasound-guided insertion of an 18-G needle is the standard prostate biopsy procedure for the pathological diagnosis of prostate cancer40 (III). Either transrectal or transperineal access is used. These routes of prostate biopsy differ with respect to the anesthetic method, the site of specimen collection and complications, while it is difficult to judge which is more advantageous41 (II),42,43 (III). When a palpable nodule exists, target biopsy is indicated. However, when the patient is a candidate for radical prostatectomy and diagnostic accuracy should be increased, systematic biopsy is recommended. In recent years, sextant biopsy specimens tend to be collected from sites extending up to the lateral rim of the prostate, aiming to improve the cancer detection rate of prostate biopsy44,45 (III). Prostate biopsy specimens collected in such a manner contain the posterior lateral side of the periphery, in which early prostate cancer is most frequently located.

When a repeat biopsy is performed for a man who has been shown to be negative in the first biopsy but continues to have symptoms suggestive of cancer, cancer is reportedly detected by repeat biopsy at a rate of about 20%46,47 (III). However, no definitive criteria for repeat biopsy have been established. If high-grade prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP) is found, cancer is believed to coexist at a high incidence of 50–100%.48,49 Therefore, repeat biopsy is recommended in such a case.

3. Staging

For the staging of prostate cancer at initial diagnosis, not only DRE, a PSA test and bone scintigraphy are performed but also computed tomography (CT)/ magnetic resonance imaging (MRI). A chest X-ray is also performed in certain cases.

1) T staging

Initially, it should be distinguished whether a cancer is confined within the prostate capsule (T1, T2) or has spread beyond the prostate capsule (T3, T4). This is very important for the decision regarding a subsequent treatment strategy. As DRE is apt to underestimate local infiltration, the rate of coincidence between staging on DRE and histopathological staging has been reported to be less than 50%50 (III). However, further detailed evaluation of the primary lesion is recommended only when it is directly involved in making a treatment strategy or when radical prostatectomy is projected.

A PSA value increases with the progression of the disease stage. However, there are limitations in accurately predicting the final histopathological stage on the basis of an individual PSA value. A combination of PSA value, the Gleason score of the biopsy specimen and clinical staging is useful for the estimation of the final histopathological stage51 (III). Transrectal ultrasonography is not recommended as a routine testing for staging diagnosis since it is inadequate for accuracy in elucidating tumor extension52 (III). Seminal vesicle biopsy should be considered for patients whose treatment strategy may be modified according to the involvement of the seminal vesicle. In addition, more detailed analysis of the results of multifocal biopsy (with respect to the number of positive specimens, tumor grade and extension, and capsule penetration) may be useful.

CT may not be adequately accurate for the evaluation of local infiltration of neoplasm53 (IV). MRI has been reported to be useful for the identification of the stage of locally advanced disease (e.g. extra-capsular involvement and seminal vesicle involvement).54,55 However, MRI is still controversial for the introduction to routine practice for preoperative staging of prostate cancer.

2) N staging

Evaluation of the lymph nodes is only indicated when it is directly involved in making a treatment strategy. This is usually applicable to a patient who chooses radical prostatectomy. A patient who has a high PSA value, T2b or T3 lesion, poorly differentiated carcinoma or perineural involvement is at a high risk of lymph node involvement56 (IV). It is difficult to predict the presence/absence of lymph node involvement in individual patients based only on a PSA assay. The accuracy of predicting lymph node involvement can be increased by combining PSA assay, DRE and tumor grade.56

This is also applicable, in turn, to patients at a low risk (≤10%) of lymph node involvement. For a patient who has a PSA value ≤ 20 ng/mL + T2a lesion + Gleason score ≤ 6, it is warranted to omit the evaluation of lymph node involvement before carrying out radical prostatectomy56 (IV).

For the evaluation of lymph node involvement, the optimal approach is lymph node dissection by open surgery or laparoscopic surgery. Since both CT and MRI have low sensitivity with an accuracy of 0–70% for the evaluation of lymph node involvement, the usage of these diagnostic modalities is limited.54

3) M staging

Metastasis to the vertebral body is detected in 85% of patients dying of prostate cancer.57 The presence and progression of bone metastasis exactly reflects the prognosis of individual patients. Bone scintigraphy is the most sensitive diagnostic modality for the detection of bone metastasis58 (III). Semi-quantitative evaluation of bone lesion on bone scintigram has been shown to be correlated with the prognosis of prostate cancer patients59 (III). Prostate cancer can metastasize to various organs other than the bone. For instance, prostate cancer metastasizes to the distant lymph nodes, liver, lungs, brain, and skin. When metastasis to the soft tissues is suspected, the patient has indications for all of the diagnostic modalities including routine check-ups, chest X-rays, ultrasonography, CT and MRI.

A pre-treatment PSA value ≥ 100 ng/mL means, by itself, the presence of metastatic lesion with a probability of approximately 100%60 (IV). Rarely, however, bone metastasis may be found even in a patient who has a low PSA value. A PSA value ≤ 20 ng/mL reflects a status of prostate cancer without bone metastasis with a probability of approximately 99%61 (III). It has been reported that bone scintigraphy is not required for disease staging in a patient who is asymptomatic with a PSA value ≤ 10 ng/mL and a well- or moderately differentiated carcinoma62 (III).

C. Treatment overview

  1. Top of page
  2. Introduction
  3. EBM-intended practice guidelines
  4. A. Epidemiology
  5. B. Diagnosis
  6. C. Treatment overview
  7. Conclusion
  8. Representative Persons of Subgroups in the Working Team for Formulation of Clinical Practice Guidelines for Prostate Cancer
  9. References

1. History of treatment modality

Four therapies are currently widely used for the treatment of prostate cancer: (1) surgery (2) radiation therapy (3) pharmacotherapy (endocrine therapy) and (4) expectant management. The details of each therapy are described in the respective sections. The present section introduces the overall profile of the treatment for prostate cancer. The first effective treatment for prostate cancer was achieved in 1941 by Huggins and his colleagues, who performed castration in a man with progressive prostate cancer and obtained some improvement of the patient's symptoms and examination findings. Since then, endocrine therapy has been performed as a gold standard therapy for prostate cancer. However, it was found that the endocrine-dependent nature of prostate cancer becomes depleted and the disease relapses during long-term endocrine therapy. Formerly, prostate cancer has commonly been found to be progressive at the time when it is diagnosed. Since around 1990, when PSA was introduced as a diagnostic indicator of prostate cancer, localized prostate cancer has come to be commonly detected. Total prostatectomy has been introduced as a radical treatment of localized prostate cancer and has widely prevailed today as a standard therapy for localized prostate cancer. Furthermore, a remarkable advancement has been made in the technique of radiation therapy, and both radiation therapy and total prostatectomy are offered as a standard therapy for localized prostate cancer. Expectant management of prostate cancer is a method for watching the prostate cancer patient without treatment even after it has been diagnosed until an appropriate time when intervention is considered to be necessary. Expectant management is characteristic to prostate cancer and can be a beneficial treatment option because surgery, radiation therapy and endocrine therapy for prostate cancer significantly impact on sexual function; because PSA is available as a sensitive tumor marker for assessing the status of disease; and because some prostate cancers are biologically minimally malignant.

2. Issue of literature analysis

The results of Japanese clinical studies that have involved Japanese prostate cancer patients have been incorporated, as much as possible, into the source data used when devising the present guidelines. Nevertheless, the majority of clinical studies concerning prostate cancer have been conducted abroad, and the treatment recommendations and grades of recommendations in the present guidelines were eventually determined based on overseas clinical data. So far, it has not been confirmed to be reasonable to apply overseas clinical study data directly to Japanese individuals. In fact, there are data showing that the incidence of clinically significant prostate cancer and the progression speed from latent cancer to clinically apparent cancer differ between foreign patients and Japanese patients. Therefore, the working group emphasizes that recommendations presented herein need to be carefully interpreted for application to clinical practices.

3. Surgery

(1) Evidences for surgery

Radical prostatectomy is the standard technique of surgical treatment, in which the prostate gland and seminal vesicle is removed and the bladder neck is anastomosed to the urethra. In general, the obturator lymph nodes are dissected simultaneously. A retropubic approach to the prostate is most common while a perineal approach or laparoscopic resection is also used according to institutional strategy.

Since it is relatively difficult to perform a randomized controlled trial (RCT) for the evaluation of surgical treatment, the evidence level for the recommendation of surgical treatment is lower in general. In this context, there is a comment that numerous findings are available from comparative studies other than RCT as well as observatory epidemiological surveys but treatment recommendations should be supported by adequate evidence.63 It is also necessary to consider whether or not the malignant potential of prostate cancer in Japanese patients is equal to that in American and European patients.

(2) Endpoint of surgery

Since the prognosis of localized prostate cancer is generally favorable after prostatectomy, survival, which is generally used as an endpoint of cancer treatment, hardly serves as an endpoint of surgical treatment for prostate cancer. Therefore, a PSA failure is used as a surrogate endpoint. However it is disputable whether a PSA failure can really be an adequate surrogate endpoint or not. It has been suggested that PSA failure can be a valid surrogate endpoint in high risk patients64 (IV),65 (III),66 (IV) while PSA failure is not correlated with survival in low to intermediate risk patients67–69 (III),70 (IV). Thus, PSA doubling time (PSADT), which is considered to depend on the growth speed of remnant cancer cells after prostatectomy, may be a more appropriate endpoint66 (IV),67 (III).

(3) Curability of radical prostatectomy

Radical prostatectomy for localized prostate cancer is very likely to provide a curative treatment71,72 (II). Taking into account the safety of the current surgical procedure of prostatectomy and the availability of salvage radiation therapy and endocrine therapy for postoperative relapse, radical prostatectomy is considered to result in most long-term survival. However, it has been reported that endocrine therapy delayed by expectant management is comparable to radical prostatectomy in terms of the 10-year disease-specific survival rate in patients with a Gleason score of 2–471 (II),73 (III). Taking the improved outcomes of radiation therapy in recent years also into consideration, radical prostatectomy cannot be concluded to be definitively superior to expectant management-delayed endocrine therapy and radiation therapy74 (II).

(4) Curability of radical prostatectomy

The ideal indication criteria for radical prostatectomy may be defined as a life expectancy ≥10 years + PSA < 10 ng/mL + Gleason score ≤ 7 + T1c to T2b lesion75–79 (III). In this patient population, the five-year PSA relapse-free postoperative survival rate is 70–80%, and the 10-year PSA relapse-free survival rate is 50–70%80–84 (III). Concerned postoperative complications include urinary incontinence and the impairment of erectile function.

Meanwhile, no reason is established for excluding localized prostate cancer in an elderly patient from the option of radical prostatectomy where there is a Gleason score ≥ 8, PSA ≥ 20 ng/mL, or T3 disease85–87 (III). As a matter of course, radical prostatectomy is not always indicated in such patients. It is important to consider life expectancy and quality of life (QOL) when making a decision regarding radical prostatectomy88 (IV),89 (III). Since the accumulated experience of the surgeon in radical prostatectomy is related to outcomes of surgery and the extent of postoperative complications90 (II),91 (III), radical prostatectomy for localized prostate cancer with a Gleason score ≥ 8, PSA ≥ 20 ng/mL, or T3 disease in an elderly patient should be performed by an experienced urologist who is able to cope with extensive local resection and surgical complications92 (II).

(5) Neoadjuvant endocrine therapy

RCTs showed that three-month neoadjuvant endocrine therapy is not effective in the improvement of results of radical prostatectomy, so three-month neoadjuvant endocrine therapy is not recommended93–95 (II). However, further studies are required with regard to the benefits of neoadjuvant endocrine therapy, such as the longer survival period and its relevance as a treatment for localized advanced prostate cancer. Only limited benefits can be obtained with monotherapy.

(6) Surgical procedures

Radical prostatectomy is performed usually via the retropubic approach, the perineal approach or the laparoscopic approach. Each of these procedures seems to have an individual disadvantage96 (III), and there is no robust evidence to determine which procedure is best.

Reportedly, the positive surgical margin is commonly found in the apex of the prostate when prostatectomy is performed via the retropubic approach, in the bladder neck according to the perineal approach and on the lateral posterior side of the prostate according to the laparoscopic procedure97 (III). Issues characteristic to the retropubic prostatectomy procedure include massive bleeding and the marked incidence of postoperative inguinal hernia98,99 (III). The perineal procedure is characterized by rectal complications98–101 (III). Laparoscopic radical prostatectomy has been reported to be more frequently associated with postoperative complications when it is performed by an inexperienced surgeon102 (III),103 (II),104 (III),105 (III).

Although urinary incontinence is a major morbidity of radical prostatectomy, there is no evidence to recommend the sparing of the pubic prostate ligament or the bladder neck. It has been indicated that there is a risk of the presence of cancer cells in the margin of the resected specimen in sparing the bladder neck if the prostate capsule has been involved106 (III). A large-scale follow-up survey revealed that urinary continence is unsatisfactory, more than expected by the treating physician and surgeon107 (III).

No criteria have been established for the safe indication of nerve sparing radical prostatectomy108 (IV). Moreover, it has been revealed that sexual function is impaired more severely than was expected by healthcare providers109 (I).

When the nomogram of Japanese patients with prostate cancer has been compliled, it may become possible to identify a patient who allows one to exclude lymph node dissection110 (III). Regarding ‘whether expanded lymph node dissection can provide survival benefit or not’, the conclusion may be dependent on the disease status of the patient indicated for radical prostatectomy. An RCT that involved a substantial number of low-grade, low-stage patients concluded that expanded lymph node dissection had no meaning for survival benefit110 (II). In contrast, another RCT that predominantly involved high-risk patients showed that expanded lymph node dissection had meaning and concluded that it is appropriate to remove the internal and external lymph nodes and obturator lymph nodes111 (III). Therefore, no recommendation can be made up with regard to lymph node dissection.

(7) Postoperative follow-up and diagnosis of recurrence

It is a dominant opinion that the cut-off for PSA failure should be 0.2 ng/mL in patients receiving no adjuvant therapy after radical prostatectomy, and this seems to be realistic67,69,112 (III). In general, PSA failure has been recognized as the first event of recurrence. It has been reported that recurrence or metastasis can take place in the presence of an undetectable level of PSA, but this is very rare and may be limited to the case of undifferentiated carcinoma68,113 (III). Therefore, it is unnecessary to consider extra-examination such as DRE so long as a patient is free from PSA failure68,113–115 (III).

(8) Post-recurrence treatment

In an RCT, prostate cancer patients who were found to have involved lymph nodes during radical prostatectomy were divided into two groups to begin endocrine therapy in the stage of clinical failure (not PSA failure) and to receive adjuvant therapy immediately. This study showed that patients who received adjuvant therapy immediately had a better prognosis116 (II). In patients who have pT3 (to 4) N0 M0 disease, adjuvant radiation therapy may decrease the risk of PSA failure117–119 (III). Nevertheless, even in a patient with pT3 N0 M0 disease, adjuvant radiation therapy is likely to be ineffective if he has a Gleason score of 7–10, pT3b disease or a preoperative high PSA value (≥25 ng/mL)120 (III). Furthermore, it was reported that patients who have a positive surgical margin plus a Gleason score of ≥8 plus preoperative PSA value > 10.9 ng/mL are still at a high risk of recurrence even when undergoing adjuvant radiation therapy121 (III).

It is controversial whether to introduce radiation therapy as an adjuvant therapy for postprostatectomy patients or as a rescue treatment after PSA failure in such patients. There is a report advocating that adjuvant radiation therapy is more advantageous122 (III), and another report insists that the outcome is equivalent between adjuvant radiation therapy and rescue radiation therapy started after the occurrence of PSA failure123 (II). So, no consensus has been reached yet in this aspect.

4. Radiation therapy

(1) History of radiation therapy

Radiation therapy (RT) can be largely classified into external beam and interstitial irradiation according to the mode of treatment. Assisted by the great advancement of computer technology, an innovative change has been brought about to RT for prostate cancer. Since RT therapy is a local therapy, like radical prostatectomy, it is best indicated for localized cancer, generating comparable results with those of radical prostatectomy124 (III). However, based on the long-term results of large-scale randomized studies conducted from the middle of the 1980s through the 1990s in the USA and Europe, it has been recognized that the overall survival rate can be increased even in patients with locally advanced prostate cancer by combining RT with endocrine therapy (neoadjuvant or adjuvant) and in more recent years, a marked modification has been thus made to the treatment strategy for prostate cancer125–131 (II),132 (III),133–135 (II). Because the indications and treatment options of RT have been expanded, it has been advocated to stratify individual patients by risk stratification on PSA, biopsy Gleason score, and clinical stage, in order to choose the optimal treatment strategy136 (III),137 (II),138 (III). Usually, the risk categories of prostate cancer patients are broadly stratified into low, intermediate and high risk, although there is no consensus about the definition of these risk classes. So, the details for each risk stratification differ from study to study.

Moreover, in recent years, not only the results of the specific treatment strategy but also the cost, possible complications and side-effects, toxicity, and QOL tend to be taken into account when a first-line therapy is chosen. It is important to consider RT strategies from such viewpoints. Otherwise, RT is often indicated as palliation therapy and salvage treatment for recurrence after other first-line therapies.

(2) External beam radiation

Radiation strategies available in Japan include conventional photon beam radiation with linear accelerator, three-dimensional conformation radiation therapy (3D-CRT), and intensity modulated radiation therapy (IMRT). Particle beam RT is also performed, although this is available only in limited institutions and has not been covered by the : Please provide an expansion for the abbreviation National Health Insurance(NHI) reimbursement scheme. To obtain local control of cancer using external photon beam radiation alone, a dose ≥ 70 Gy is necessary according to the fractionated RT139 (II). Various treatment techniques have been developed to administer a sufficient dose effectively while suppressing the incidence of adverse events.

It is still controversial whether radiation should target the prostate alone or whether the whole pelvic radiation should be combined. However, a study by the Radiation Therapy Oncology Group 9413 showed a significant improvement of relapse-free survival rate in a cohort treated by whole pelvic radiation + neoadjuvant/concomitant endocrine therapy.134 (II).

Regarding the duration of adjuvant endocrine therapy, a long-term therapy (>24 months) is generally believed to be necessary for high-risk patients. For intermediate-risk patients, a benefit was obtained even with a shorter-term adjuvant therapy for six months, while it was suggested that low-risk patients do not need adjuvant endocrine therapy125–131 (II),132 (III),133–137 (II),136 (II). However, further studies are necessary to elucidate what regimen of endocrine therapy is optimal and how long it should be administered.

(3) Interstitial radiation

125I permanent brachytherapy and 192Ir high-dose-rate interstitial RT are among the representative interstitial RT currently available in Japan. The 125I permanent brachytherapy, which has been widely used in the USA, is performed by implanting radioactive metal chips in the prostate under ultrasound guidance. In Japan, this radiation method was approved in March 2003. 125I permanent brachytherapy is commonly done as monotherapy in low-risk patients and in combination with external radiation in some intermediate- and most high-risk patients140 (III),141 (II). No prospective randomized controlled study has been conducted to date for the evaluation of the efficacy of brachytherapy + endocrine therapy. This is because seed implantation alone is best indicated for low-risk patients, who do not necessarily require endocrine therapy to maximize disease control. Usually, 192Ir high-dose-rate interstitial RT is combined with external radiation and is indicated to treat localized, regional or invasive prostate cancer. Complications associated with either interstitial or external RT include rectal dysfunction, dysuria, and erectile dysfunction.

(4) Relapse after radiation therapy

Much debate has been made with regard to the definition and implications of biochemical and clinical recurrence after RT142 (IV),143 (III),144 (IV), and145 (II). Arguments generally have been focused on the implications of post-therapy biopsy for the evaluation of clinical relapse timing of serum prostate-specific antigen (PSA) tests, and criteria for significant changes in PSA for the evaluation of biochemical relapse.

5. Pharmacotherapy

(1) Endocrine therapy for prostate cancer

None of the currently available chemotherapies exceed endocrine therapy for the treatment of prostate cancer. Different endocrine medications are remarkably proximate in their efficacy for the control of prostate cancer, whereas their efficacy lasts no longer than two to three years in the case of progressive disease. Furthermore, endocrine therapy causes sex-related adverse reactions such as erectile dysfunction (ED) and impairment of the libido146,147 (II). Because of these issues, endocrine therapy has limitations in its indications.

The first attempt of effective endocrine therapy was made by performing surgical castration. Female hormone preparations were used subsequently, but they are now seldom used due to adverse cardiovascular reactions. The most commonly used endocrine medications are luteinizing hormone-releasing hormone (LH-RH) agonists and anti-androgens, which are used either as monotherapy or combined therapy. As LH-RH agonists, one-month and three-month formulations of goserelin or leuprorelin are available. Steroidal and non-steroidal anti-androgens have been approved in Japan. LH-RH agonist therapy causes a transient rise in testosterone level in the early treatment stage, ensuing flare-up symptoms such as urinary tract obstruction, bone pain arising from metastatic lesions, and bone marrow compression. When such adverse reactions are concerned, combined use with an anti-androgen should be considered. The efficacy of an LH-RH agonist is considered to be equivalent to that of surgical castration, while the efficacy of anti-androgen alone has been reported to be weaker than an LH-RH agonist although no significant difference has been shown. Nevertheless, because non-steroidal anti-androgens are associated with less sex-related adverse reactions, anti-androgen monotherapy has been indicated to be beneficial for selected patients. The benefit of bicalutamide adjuvant therapy was evaluated in patients with localized regional or invasive prostate cancer who had undergone radical prostatectomy, radiation therapy and watchful observation. The study showed a significant prolongation of PSA doubling time and a reduction in objective progression risk148–150 (II).

A large-scale study is ongoing now for the assessment of the survival benefit of bicalutamide adjuvant therapy.

Another issue being investigated is whether chemo-endocrine therapy is more beneficial for Stage IV patients than endocrine monotherapy.

(2) Validity of maximum androgen blockade (MAB)

In Stage III-IV prostate cancer patients, the survival benefit of endocrine therapy has been validated151 (II). In general, the standard therapy for metastasized advanced prostate cancer is androgen blockade by utilizing surgical (orchiectomy) or pharmaceutical (LH-RH agonist) castration. Testis-derived androgen is controllable by surgical or pharmaceutical castration. Reportedly, however, 40% of androgen existing in the prostatic cells is derived from the adrenal. Thus, maximum androgen blockade (MAB) therapy, which inhibits both testis- and adrenal-derived androgen by combining castration with non-steroidal anti-androgen, was evaluated and shown to be useful152 (III). Since then, MAB has come to be widely used as a treatment modality for advanced prostate cancer. Nevertheless, an issue that has been discussed is whether MAB improves long-term survival when compared with castration alone. A meta-analysis performed in the early days that included data with steroidal anti-androgens showed no significant difference for survival time between MAB therapy and castration alone153 (I). Another meta-analysis performed by excluding data with steroidal anti-androgens (involving 2922 patients from 13 studies) revealed that MAB therapy is significantly superior in terms of both relapse-free survival time and overall survival time. Likewise, a recent meta-analysis also showed a significant increase in overall survival rate in patients receiving MAB using non-steroidal anti-androgens154 (I).

Meanwhile, in a large-scale RCT conducted by the Southwest Oncology Group (SWOG)155 (II), surgical castration + flutamide treatment was compared with surgical castration + placebo treatment, and no significant difference was found in terms of the overall survival rate. A recent meta-analysis that involved all the above RCTs indicated that MAB therapy is similar to castration alone in terms of a two-year survival rate whereas MAB therapy is significantly superior to castration alone in terms of a five-year survival rate156–158 (I). However, since the difference in the survival rate was small, it was indicated that the true clinical benefit of MAB should be judged by taking into account efficacy, adverse reactions, QOL, and the medical financial aspect. Recently, a double blind study was conducted for comparison between MAB therapy, which used bicalutamide as an anti-androgen, and LH-RH agonist monotherapy; it was found that the MAB therapy obviously prolonged the time to progression.

(3) Pharmacotherapy for recurrent cancer

When recurrent cancer is judged to be present, exacerbation may be transiently inhibited by withdrawing only the anti-androgen therapy (anti-androgen withdrawal syndrome). A decrease in PSA can be obtained in 14–60% of patients and clinical response in 0–25% of patients by withdrawing only the anti-androgen therapy or by combining hydrocortisone. However, it has been reported that the response of PSA is usually maintained no longer than 2–4 months.

Anticancer chemotherapy using a single drug or multiple drugs has been attempted for the control of relapsed cancer during endocrine therapy. Drugs used for single-drug anticancer chemotherapy include estramustine phosphate, CPA, fluorouracil (FU), and etoposide (ETP). However, none of the randomized controlled trials conducted so far showed an obviously extended survival time as a result of the introduction of chemotherapy. It was recently reported that docetaxel (TXT) + steroid159 (II) or TXT + estramustine phosphate160 (II) significantly increased the survival rate when compared with mitoxantrone + steroid. Presently, estramustine phosphate and FU have been covered by the NHI reimbursement scheme for the treatment of prostate cancer, while other chemotherapy drugs have not been approved for the treatment of prostate cancer.

6. Expectant management: watchful waiting

(1) Definition

Expectant management means, in a broad sense, to put off intervention until it becomes necessary in a patient diagnosed as having prostate cancer. Expectant management is pursued on the assumption either to introduce endocrine therapy as the second-line therapy for clinical progression (watchful waiting with deferred endocrine therapy) or to carry out radical intervention consisting of radiation therapy and/or radical prostatectomy as the second-line therapy in an appropriate timing (active surveillance; expectant management in a narrow sense). The present guidelines discriminate active surveillance from watchful waiting with deferred endocrine therapy, and this section individually provides guidance for the two modes of expectant management.

(2) Watchful waiting with deferred endocrine therapy for advanced prostate cancer

For patients with advanced prostate cancer, the advantage/disadvantage of immediate endocrine therapy versus watchful waiting with deferred endocrine therapy remains indefinitive. About half of patients with metastasizing prostate cancers experience relapse within 18–24 months and die within 30–36 months. Taking this into consideration, there will be a slight difference depending on whether watchful waiting with deferred endocrine therapy or immediate endocrine therapy is chosen. Watchful waiting with deferred endocrine therapy for metastasizing prostate cancer is not recommended by the Physicians Data Query (PDQ) for Prostate Cancer presented by the National Cancer Institute (NCI) nor by the Guidelines for Prostate Cancer of the European Association of Urology (EAU).

(3) Watchful waiting with deferred endocrine therapy for localized prostate cancer

The comparison of surgery versus watchful waiting with deferred endocrine therapy was performed for patients with localized prostate cancer. A large-scale randomized controlled trial (RCT) was conducted mainly in Northern Europe to compare radical prostatectomy versus watchful waiting with deferred endocrine therapy in patients with localized prostate cancer, and the results of this study have been published161 (II). Radical prostatectomy increased the prostate cancer-specific survival rate but not the overall survival rate in patients with moderately- to highly-differentiated localized prostate cancer. However, the results of analysis including data from the extended post-hoc follow-up period revealed that both the overall survival rate and prostate cancer-specific survival rate were superior in the cohort treated with radical prostatectomy162 (II).

Combining non-randomized clinical trials in patients with localized prostate cancer that were reported between 1985 and 1992, a meta-analysis was performed to analyze the benefit of watchful waiting with deferred endocrine therapy. A total of 828 patients were involved, and the 10-year prostate cancer-specific survival rate for patients with Grade 1 or Grade 2 carcinoma was shown to be 87% while the corresponding survival rate for patients with Grade 3 lesion (Gleason score of 8–10) was as low as 34%163 (II). Thus, it was indicated that tumor grade is the major prognostic determinant of watchful waiting with deferred endocrine therapy in patients with localized prostate cancer.

(4) Active surveillance for localized prostate cancer

Since PSA-based monitoring has become prevalent today, a comparison was made between radical prostatectomy immediately performed in patients with early prostate cancer and radical prostatectomy performed after PSA-based watch but before progression of the lesion into invasive prostate cancer. With regard to the type of patients that should be treated for PSA watch management, the criteria may be made up of a Gleason score of ≥6, PSA ≤ 20 ng/mL, and a clinical stage of T1 to T2, although no consensus has yet been obtained. Life expectancy and the risk of needle biopsy-mediated cancer dissemination should also be taken into account. During active surveillance, a DRE and PSA check should be implemented every three to six months, and repeat biopsy should also be done as necessary. As for the timing to proceed to a second-line therapy, PSA doubling time was generally considered in reported studies, and the second-line therapy was commonly introduced in patients who had PSA doubling within two years164,165 (III).

Due to the prevalence of the PSA test, low-risk prostate cancer tends to be more frequently detected. Nevertheless, the US data indicate that patients who choose active surveillance have been decreasing in number. This trend for a decreased percentage of patients undergoing active surveillance reflects an increase in the percentage of patients undergoing brachytherapy and endocrine therapy166 (III). Both the circumstances of the healthcare providers and the patient's preference in choosing a treatment option may be underlying reasons for the change in the choice of treatment option, while further detailed analysis involving a QOL survey is awaited. While information is still insufficient to compare QOL across treatment options for prostate cancer, a cross-sectional data analysis was conducted in the USA, involving approximately 800 patients. This analysis revealed that patients on active surveillance experienced a significant deterioration of QOL in terms of the physical functioning and the general health perception out of the eight subscales of the RAND SF-36 when compared with patients who were immediately treated with radical prostatectomy. Nevertheless, patients on external radiation therapy or endocrine therapy had significant deterioration of QOL in terms of virtually all of the 8 subcategories of the SF-36 as compared with patients with radical prostatectomy. Based on these results, it seems unlikely that the deterioration of QOL during active surveillance is an exact reason for patients not to choose active surveillance167 (III). A likely reason seems to be that patients would generally feel uneasy about being left without treatment despite the disclosed diagnosis of cancer. Whether a patient chooses active surveillance or not would be greatly affected by the physician's explanation168 (IV). Therefore, it is thought to be an urgent need to compile scientific information that is useful for the counseling of prostate cancer patients, especially data for Japanese prostate cancer patients. Currently, a feasibility study is ongoing in Japan to evaluate active surveillance treatment for patients suggested to have a well differentiated carcinoma that is small in size according to the predefined criteria169 (III)

7. Indications for therapeutic modalities

(1) T1a, N0, M0 prostate cancer
  • 1
    T1a, N0, M0 prostate cancer with a Gleason score ≤ 6

T1a prostate cancer with a Gleason score ≤ 6 is generally highly differentiated and localized. Most T1a prostate cancer patients do not require any specific treatment other than active surveillance. For younger (50–60 years old) patients, however, use of definitive treatments such as radical prostatectomy or radiation therapy should be considered as they have longer life expectancy.

  • 2
    T1a, N0, M0 prostate cancer with a Gleason score ≥ 7

Active surveillance is a recommended treatment option for T1a prostate cancer with a Gleason score ≥ 7. Definitive treatment may be considered for younger patients whose life expectancy is at least 15 years.

(2) T1b-c/T2, N0, M0 prostate cancer
  • 1
    T1b-c/T2, N0, M0 prostate cancer with a Gleason score ≤ 6 with serum PSA ≤ 20 ng/mL

Therapy options recommended for T1b-c/T2 prostate cancer with a Gleason score ≤ 6 with serum PSA ≤ 20 ng/mL include radical treatments (total prostatectomy and radiation therapy) and active surveillance. In any case, definitive treatment is selected for patients whose life expectancy is at least 10–15 years at the time of treatment, while endocrine therapy or irradiation may be indicated for patients whose life expectancy is less than 10 years.

  • 2
    T1b-c/T2, N0, M0 prostate cancer with a Gleason score ≥ 7 with serum PSA ≤ 20 ng/mL

Active surveillance is not recommended for localized prostate cancer with a Gleason score ≥ 8. Although definitive treatments should be considered if the patient has a life expectancy of at least 10–15 years, no published studies have demonstrated significant survival benefits of any radical therapeutic options in patients with poorly differentiated localized prostate cancer.

  • 3
    T1b-c/T2, N0, M0 prostate cancer with serum PSA ≥ 20 ng/mL

Few published articles have advocated active surveillance for T1b-c/T2 prostate cancer with serum PSA > 20 ng/mL, although PSA alone cannot provide reliable basis for any therapeutic decision. Even under the radiological diagnosis of T1b-c/T2, N0, M0 prostate cancer, the indication for surgery should be considered carefully in the presence of serum PSA > 20 ng/mL, which is a likely sign of more advanced (specifically T3) prostate cancer. In most cases, serum PSA > 100 ng/mL has been associated with distant metastases, which are difficult to control by locoregional therapy alone. Even if initially treated locoregionally, prostate cancer patients with serum PSA > 100 ng/mL are very likely to become candidates for endocrine therapy.

(3) T3, N0, M0 prostate cancer

For T3 prostate cancer definitely indicated radiologically or by digital rectal examination (DRE), radical prostatectomy is not recommended generally because of the high probability of positive surgical margin and microscopic lymph node involvements. Particularly poor outcomes of radical surgery have been reported in patients with T3b prostate cancer (with the involvement of the seminal vesicle). However, findings in the published reports of surgically curable T3 prostate cancer have reserved prostatectomy as a viable option for some tumors at this stage in those with a life expectancy of at least 10 years. As suggested recently, T3 prostate cancer may be better controlled by irradiation followed by adjuvant endocrine therapy. More evidence is needed to make a definitive statement regarding the optimal treatment of T3 prostate cancer.

(4) T4, N0, M0, N1, or M1 prostate cancer

As prostate cancer at these advanced stages cannot be controlled by locoregional therapy, endocrine therapy should be considered as a first-line treatment, regardless of the life expectancy of the patient.

8. Surgery vs radiation therapy

As mentioned above, two definitive treatment options, radical prostatectomy and radiation therapy, are recommended for localized prostate cancer, and their relative utility is of great interest. A direct comparison between treatments has not been possible, however, owing to the inclusion of different patient populations and the use of different response criteria. The long natural history of the disease, due to its low to medium biological aggressiveness, and the availability of salvage endocrine therapy after failure also prevent a definitive conclusion as to their relative efficacy. A true comparison of the two modalities can only be made possible in a large RCT designed to evaluate overall survival as the primary endpoint in a long-term follow-up. Such an RCT appears impractical in the present medical environment in Japan and there is a question about the validity of data from such an RCT. Even in the presence of overseas such studies that answer this issue it is also questionable whether the results can be extrapolated to Japanese patients.

When conventional radiation techniques have only allowed the delivery of 60–70 Gy, surgery has achieved significantly better outcomes in the treatment of localized prostate cancer. In more recent years, the above-mentioned advancement of radiation techniques has enabled the delivery of higher doses (>70 Gy) as external or interstitial irradiation and has remarkably improved the outcome of radiation therapy. The therapeutic outcome of modern radiotherapy for localized prostate cancer now seems to be as favorable as that of surgery. One of the disadvantages of using radiation as a first-line treatment for localized prostate cancer is that PSA failure following radiation may be an insufficient indicator for salvage surgery, in contrast to the applicability of radiation for postoperative PSA failure. Thus, choice between radiation therapy and surgery may largely depend on the nature and severity of the complications/adverse effects of these modalities. Urinary incontinence and sexual dysfunction are major complications of surgery, while possible adverse effects of radiation on the rectal, micturition and sexual function are of concern. Delayed radiation toxicities and increased risk of secondary cancers after radiotherapy should also be taken into account in deciding the therapeutic strategy for nonelderly patients with prostate cancer.

9. Palliative medicine

(1) Palliative medicine in prostate cancer

While responding to hormonal therapy, even patients with advanced prostate cancer can often remain almost free of severe cancer-related symptoms (e.g. dysuria, hematuria and bone metastatic pain). Once prostate cancer has become refractory to hormones, however, cancer related symptoms also become intractable and unresponsive even to a combination of chemotherapy and hormonal therapy. Thus, most patients with hormone refractory prostate cancer eventually require palliative medicine. Important considerations in palliative medicine for prostate cancer include: (1) how to control bone metastatic pain, (2) spinal paralysis due to spinal metastasis, (3) micturition disorders and hematuria, and (4) postrenal renal failure associated with ureteral obstruction.170

(2) Cancer pain relief

Painful bone metastasis presents a therapeutic challenge to practitioners who are treating prostate cancer patients. Many measures are available for the palliation of bone metastatic pain, including analgesics, radiation, corticosteroids, bone-seeking radionuclides, gallium nitrate and bisphosphonates.171 As analgesics play an important role in cancer pain relief, appropriate analgesic choice is required. According to the World Health Organization (WHO) recommendations, the ‘three step ladder’ approach is widely used. Briefly, this approach consists of the use of a non-steroidal anti-inflammatory drug (NSAID) at Step 1, combined with the use of a weak opioid and an NSAID at Step 2, and the use of morphine (powder or sustained release formulation) at Step 3. At the last step, the dose of morphine may be escalated according to response, while taking measures for reducing its adverse effects. For further details of the management of cancer related pain, refer to the Evidence-Based Clinical Practice Guidelines for the Management of Cancer Pain (2000), published by the Japanese Society for Palliative Medicine.172 External beam radiation is very useful for the relief of bone pain in patients with a localized painful bone metastasis173 (II). For the relief of pain from multiple bone metastases, total or half body radiation has sometimes been used. Recent studies have shown that radioisotopes (e.g. strontium 89) are effective for the osteogenic metastasis of prostate cancer and other malignancies. In RCTs comparing external beam radiation with strontium 89, strontium 89 was as effective as local or half body radiation in relieving existing bone pain and was significantly more effective than local radiation in reducing pain from new bone metastases174,175 (I). Unfortunately, strontium 89 has not yet been approved in Japan.

Bone metastases of prostate cancer are often osteogenic, characterized by accelerated bone turnover and bone resorption. Because of their ability to inhibit the bone resorptive activity of osteoclasts, bisphosphonates may be useful for the relief of bone metastatic pain and for the prevention of pathological fractures of metastatic bones in prostate cancer patients. An RCT demonstrated that an intravenous bisphosphonate significantly reduced the incidence of complications of bone metastases, including pathological fractures, and was also useful for the relief of bone pain176 (II). A systematic review has revealed that continued treatment with bisphosphonates since the diagnosis of bone metastasis of prostate cancer significantly reduces the morbidity of bone metastasis, though not affecting the survival of prostate cancer patients with bone metastasis. When bisphosphonates are used for this indication, the intravenous route of administration is preferable to the oral route because bisphosphonates are poorly absorbed from the gastrointestinal tract177 (I). In Japan, osteoporosis is the only approved indication for oral bisphosphonates, while parenteral formulations of some bisphosphonates have been approved for the management of hypercalcemia due to malignant tumors.

(3) Treatment of spinal paralysis

Treatment options available for the management of spinal paralysis due to spinal metastasis include corticosteroids, radiation therapy and surgery. Corticosteroid therapy has been used as an adjunct to radiation therapy or surgery and has an established utility for this indication based on data from a RCT178 (II). However, corticosteroids have caused significant adverse effects and their optimal dose (large or standard dose) for this indication is still controversial. The standard regimen of radiation therapy may be 30 Gy/10 fractions. The most commonly used surgical procedure is spine laminectomy; there is no concern about bone fragility when spinal metastasis of prostate cancer causes spinal paralysis. An RCT comparing radiation therapy alone with spine laminectomy has failed to show any difference in the response rate between the two modalities179 (II).

(4) Treatment of local symptoms

A recent report suggests that ‘palliative’ transurethral resection of the prostate (TURP) may be useful for the improvement of micturition disorders in advanced prostate cancer patients and is worthy to be considered for this indication180 (III). Compared with TURP for benign prostatic hypertrophy, however, palliative TURP for prostate cancer may be more likely to allow the recurrence of urinary retention or may be associated with a greater need for re-operation. Another paper reported that palliative radiation therapy effectively resolved severe hematuria that might cause a tamponade181 (III).

(5) Measures against hydronephrosis

Urinary obstruction has been reported to occur in 3.3–16% of patients with advanced prostate cancer and seems to be a significant negative prognostic factor in patients with prostate cancer182 (III). Hydronephrosis resulting from lower urinary tract obstruction due to enlarged prostate cancer is a good indication for urinary catheterization or ‘palliative’ TURP (see the previous section). Ureteral stenting, ureterocutaneous fistula, or percutaneous nephrostomy (PNS) is indicated for the resolution of ureteral opening stenosis resulting from direct bladder invasion of prostate cancer and for the treatment of hydronephrosis due to ureteral pressurization by lymph node involvement. For patients to be treated with endocrine therapy for non-recurrent prostate cancer, aggressive methods should be used to treat hydronephrosis because their disease is expected to improve, even if transiently. For patients with prostate cancer refractory to hormonal and various other therapies, however, use of PNS for the resolution of hydronephrosis should be considered carefully because of a generally very poor prognosis of refractory prostate cancer183 (III). Although no RCTs have made comparisons among various therapeutic measures for hydronephrosis (e.g. ureteral stenting, ureterocutaneous fistula and PNS), ureteral stenting or PNS is less invasive than ureterocutaneous fistula. In particular, PNS performed under an ultrasound guide should be considered as a treatment of choice because of its low invasiveness, simple procedure and long life. Ureteral stenting is more convenient for patients but is more likely to allow the recurrence of ureteral obstruction due to malignant tumors184 (IV).

10. External appraisal of the quality of the 2006 Practice Guidelines for Prostate Cancer

A member of our team (Tomonori Hasegawa, Toho University School of Medicine, Social Medicine Group) appraised the quality of the present Practice Guidelines for Prostate Cancer, using the Appraisal of Clinical Guidelines for Research and Evaluation (AGREE) Instrument. This section presents a description of the internationally standardized appraisal method for the quality of practice guidelines and the results of the appraisal on the quality of the present guidelines.

(1) Evaluation of the quality of clinical guidelines using the AGREE instrument

A checklist devised by a collaborative team for the AGREE was used to assess the quality of the present Practice Guidelines for Prostate Cancer. The AGREE Collaboration devised an internationally standardized assessment frame for the quality of practice guidelines in an attempt to make the smooth creation of guidelines possible, to make it possible for guideline users (government officers, healthcare providers, etc.) to judge which guidelines to use, and to eventually improve the quality of guidelines. This was a collaborative project in which researchers from 12 countries, including the European Union (EU), Canada, and the USA, took part. The AGREE instrument has been recommended by the EU and WHO as an assessment means of practice guidelines.

The AGREE Collaboration has conducted several exploratory researches on clinical guidelines since the middle of 1990s and reported the following findings: (1) Clinical guidelines created in a country/by an organization which has a program for devising clinical guidelines are superior in quality to those created in a country/by an organization which has no such program. (2) A comparison of clinical guidelines created in multiple countries for the same disease indicates that domestic literatures are preferentially cited, and only a few literatures are cited in common by all clinical guidelines created in multiple countries. (3) The contents of recommendations are similar across different countries even when cited literatures differ across countries, suggesting that information is closely communicated among expertise doctors. The results of large-scale clinical studies (so-called mega-studies) and the opinions of leading medical societies are most influential on the contents of recommendations. (4) It is possible to down-scale the checklist for guidelines to some extent, and it is possible to make-up a convenient checklist that enables one to complete the assessment of one set of guidelines in about an hour. However, it still remains unknown whether the quality of the guidelines is improved according to checklist configuration or not.

The current AGREE instrument was designed based on the above-mentioned finding (4). The AGREE instrument has been translated into eight languages and a Japanese version is available.185 The AGREE instrument has 23 check items in six fields, consisting of a total of 24 check items including one for global assessment. Each check item is rated into one of four classes ranging from ‘well fitted = 4 points’ to ‘not fitted = 1 point’ or into the ‘no information’ class. The point of each check item is summed up by the field. The AGREE instrument is aimed to profile the guidelines and ultimately to show that the guidelines have room for improvement in the fields scoring low points; that is, it is not intended for the summing-up of points in their respective fields to present a global evaluation.

The AGREE instrument consists of the following 23 items in 6 fields: 1. Scope and Purpose: (1) Specific description of the overall objective(s) of the guidelines, (2) Specific description of the clinical question(s) covered by the guidelines, (3) Specific description of patients to whom the guidelines are meant to apply; 2. Stakeholder Involvement: (4) Involvement of representatives from relevant professional groups in the guidelines development group, (5) Consideration of the patient's view and preference, (6) Clear definition of targeted users, (7) Pilot use among targeted users; 3. Rigor of Development: (8) Systematic search for evidence, (9) Clear description of the criteria for selecting the evidence, (10) Clear description of the methods for formulating the recommendations, (11) Consideration of health benefits, side-effects and risks in formulating the recommendations, (12) Explicit link between the recommendations and the supporting evidence, (13) External review of the guideline prior to publication, (14) Procedure for updating the guidelines; 4. Clarity and Presentation: (15) Specific and unambiguous contents of recommendations, (16) Presentation of different options corresponding to the conditions of patients, (17) Clarity of key recommendations, (18) Availability of tools for the application of the recommendation; 5. Applicability: (19) Potential organizational/regulatory barriers in applying the recommendations, (20) Possible cost implications of applying the recommendations, (21) Presentation of key review criteria for monitoring and audit purposes; 6. Editorial Independence: (22) Description of editorial independence from the funding body, (23) Description of conflicts of interest among the guideline development members. Furthermore, the appraisal of the guidelines as a whole is graded into one of four categories: ‘strongly recommended’, ‘recommended in general (applicable upon a condition or may be modified)’, ‘not recommended’ and ‘equivocal’.

(2) AGREE instrument (Japanese version)-based quality assessment of Japanese clinical guidelines

In Japan, since 1999, the formation of clinical guidelines by medical societies has been aided by an MHLW research fund. Moreover, clinical practice guidelines have also often been formulated independently by medical societies. In recent years, about 20 guidelines have been formulated annually in Japan, so the procedure for formulating a set of guidelines may have been substantially established. A total of 53 Japanese clinical guidelines created before 2004 were assessed for their qualities based on the AGREE instrument; the results are presented in Figure 1. Overall, it was indicated that the guidelines formulated more recently have better qualities. It was also suggested that the guideline formulating manner has been markedly improved while Japanese clinical guidelines still have room for improvement with respect to editorial independency and the applicability of recommendations.


Figure 1. Results of the Appraisal of Clinical Guidelines for Research and Evaluation (AGREE) instrument-based quality assessment of Japanese guidelines.

Download figure to PowerPoint

(3) Evaluation of the practice guidelines for prostate cancer

The results of the AGREE instrument-based assessment of the Practice Guidelines for Prostate Cancer at the time of proof are presented in Figure 2a, together with the results of the assessments of the above 53 Japanese clinical guidelines. The present guidelines are superior to other Japanese guidelines formed previously with respect to ‘rigor of development’, ‘clarity and presentation’, ‘applicability’, ‘editorial independency’, and ‘total’, while it was rather inferior with respect to ‘scope and purpose’ and ‘stakeholder involvement’. Before final editing, the AGREE instrument was delivered to each subgroup of our guideline formulation team so that they might well recognize the assessment criteria. After the final editing, the results of the assessment were greatly improved, as shown in Figure 2b. Since the presence of clear descriptions of specific matters is checked according to the AGREE instrument, the targeted disease and targeted patients, which had before been thought self-evident from the title of the guidelines, were clearly described. It was also clearly described that a number of radiation oncologists and clinical oncologists also participated in the formulation of the present guidelines. These modifications are thought to have resulted in a great improvement in the quality assessment of these guidelines. It is thus emphasized that any clinical guidelines should be formulated in pursuance to the international standardized criteria for the evaluation of clinical guidelines. Further efforts are necessary for the introduction of these clinical practice guidelines to actual healthcare scenes, investigation into the effects of the recommendations on the selection and outcomes of treatment strategy, the review of these guidelines by stakeholders other than urologists and the formulation of commentary from the patients' and their family members' points of view.


Figure 2. Results of Appraisal of Clinical Guidelines for Research and Evaluation (AGREE) instrument-based quality assessment of the clinical practice guidelines for prostate cancer versus other Japanese clinical guidelines.

Download figure to PowerPoint


  1. Top of page
  2. Introduction
  3. EBM-intended practice guidelines
  4. A. Epidemiology
  5. B. Diagnosis
  6. C. Treatment overview
  7. Conclusion
  8. Representative Persons of Subgroups in the Working Team for Formulation of Clinical Practice Guidelines for Prostate Cancer
  9. References

In Japan, the society has been experiencing a prominent expansion of the elderly population in recent years. People are becoming more alert to prostate diseases and prostate cancer has increasingly been arresting social attention.

State-of-the-art advancement has been made to the clinical practices for prostate cancer in Japan, owing to the progress of epidemiological researches associated with the prevalence of local fundamental mass health screening, the promotion of PSA-based minimally invasive diagnosis and the accurate diagnosis associated with the popularization of systematic needle biopsy, and the development and spread of various treatment modalities including surgery, radiation therapy, and pharmacotherapy.

The present Clinical Practice Guidelines for Prostate Cancer have been formulated by the aggregated dedication of the individual members of the Japanese Urological Association as well as the united efforts of the members of the Japan Society of Clinical Oncology and the Japanese Society for Therapeutic Radiation and Oncology, so it is a great fortune of medicine in Japan. Moreover, the present working team pursued precisely the standard processes required for the formulation of the guidelines, as a result of which our society has acquired the know-how for formulating a set of EMB-intended clinical guidelines. This knowledge is a significant resource that can be further utilized for the formulation of guidelines for various diseases in the field of urology as well as future revision of the present guidelines.

The present clinical practice guidelines are believed to be helpful for routine healthcare work, while medicine for prostate cancer is ever-progressing and updated findings are being accumulated every day. The evaluation of the present set of guidelines has already commenced and the process towards the next revision should begin without delay.

Representative Persons of Subgroups in the Working Team for Formulation of Clinical Practice Guidelines for Prostate Cancer

  1. Top of page
  2. Introduction
  3. EBM-intended practice guidelines
  4. A. Epidemiology
  5. B. Diagnosis
  6. C. Treatment overview
  7. Conclusion
  8. Representative Persons of Subgroups in the Working Team for Formulation of Clinical Practice Guidelines for Prostate Cancer
  9. References

(Present post and office at July 2007)

Research Coordination and Administration:
Sadao Kamidono(Board Chairman of Kobe University, President of Kobe Red-Cross Hospital)
Structured Framework:
Shinichi Ohshima(President of National Center for Geriatrics and Gerontology)
Literature Review:
Yoshihiko Hirao(Professor at the Department of Urology, Nara Medical University)
Kazuhiro Suzuki(Professor at the Department of Urological Diseases, Gunma University Graduate School of Medicine)
Yoichi Arai(Professor at the Urology Department, Tohoku University Graduate School of Medicine)
Surgical Therapy:
Hiroyuki Fujimoto(Chief of Urology Division, National Cancer Center Hospital)
Radiation Therapy
Shin Egawa(Professor at the Department of Urology, Jikei University School of Medicine)
Hideyuki Akaza(Professor and Chairman, Urology and Andrology, Functional and Regulatory Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba)
Expectant Management and Supportive Care:
Isao Hara(Professor of Department of Urology, Wakayama Medical University)
Yoshiyuki Kakehi(Professor at the Department of Urology, Kagawa University School of Medicine)
Literature Search & Structured Abstract:
Hinotsu Shiro(Lecturer, Urology and Andrology, Functional and Regulatory Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba)
Guideline Formulation Advisory:
Tomonori Hasegawa(Professor at Department of Social Medicine, Toho University School of Medicine)


  1. Top of page
  2. Introduction
  3. EBM-intended practice guidelines
  4. A. Epidemiology
  5. B. Diagnosis
  6. C. Treatment overview
  7. Conclusion
  8. Representative Persons of Subgroups in the Working Team for Formulation of Clinical Practice Guidelines for Prostate Cancer
  9. References
  • 1
    Ohno Y, Nakamura T, Oshima A et al. The future estimates of cancer prevalence rate in Japan. In: OshimaA, KuroishiT, TajimaK (eds). Gan Tohkei Hakusho-Morbidity/Death/Prognosis-2004. Shinohara Publisher, Tokyo, 2004; 201217.
  • 2
    Cancer Statistics in Japan ′03: Age-adjusted Death Rates of Malignant Neoplasms by Site, Sex and Calendar Year (1950–2001). [Cited 27 July 2004.] Available from URL:
  • 3
    Yatani R, Chigusa I, Akazaki K et al. Geographic pathology of latent prostatic carcinoma. Int. J. Cancer 1982; 29: 61116.
  • 4
    Etzioni R, Cha R, Feuer EJ et al. Asymptomatic incidence and duration of prostate cancer. Am. J Epidemiol. 1998; 148: 77585.
  • 5
    Hiraishi T et al. Latent Prostatic Carcinoma. Clinical Practice Manual for Prostate Cancer, The Japanese Foundation for Prostate Research, Kanehara & Co., LTD., Tokyo, 1995; 1324.
  • 6
    Watanabe H. Studies on the Natural History of Prostate Cancer. Clinical Practice Manual for Prostate Cancer, The Japanese Foundation for Prostate Research, Kanehara & Co., LTD., Tokyo, 1995; 112.
  • 7
    Fukuta F, Masumori N, Tanaka Y et al. The detection rate of prostate cancer in outpatients presenting lower urinary tract symptoms. Jpn. J. Clin. Urol. 2005; 59: 1338.
  • 8
    Lepor H, Owens RS, Rogenes V et al. Detection of prostate cancer in males with prostatism. Prostate 1994; 25: 13240.
  • 9
    Steinberg GD, Carter BS, Beaty TH et al. Family history and the risk of prostate cancer. Prostate 1990; 17: 33747.
  • 10
    Giovannucci E, Rimm EB, Colditz GA et al. A prospective study of dietary fat and risk of prostate cancer. J. Natl. Cancer Inst. 1993; 85: 15719.
  • 11
    Nakata S, Imai K, Yamanaka H, Yashima H. Correlation Analysis between Mortality for Prostate Cancer and Dietary Pattern in Japan and the World. Jpn. J. Cancer Clin. 1994; 40: 8316.
  • 12
    Hebert JR, Hurley TG, Olendzki BC et al. Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study. J. Natl. Cancer Inst. 1998; 90: 163747.
  • 13
    Eichholzer M, Stahelin HB, Ludin E et al. Smoking, plasma vitamins C, E, retinol, and carotene, and fatal prostate cancer: seventeen-year follow-up of the prospective Basel study. Prostate 1999: 38: 18998.
  • 14
    Clark LC, Dalkin B, Krongrad A et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br. J. Urol. 1998; 81: 7304.
  • 15
    Hartman TJ, Albanes D, Pietinen P et al. The association between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol, beta-carotene cancer prevention study. Cancer Epidemiol. Biomarkers Prev. 1998; 7: 33540.
  • 16
    Smith RA, Cokkinides V, Eyre HJ et al. American Cancer Society guidelines for the early detection of cancer, 2004. CA Cancer J. Clin. 2004; 54: 4152.
  • 17
    American Urological Association (AUA). Prostate-specific antigen (PSA) best practice policy. Oncology (Williston Park) 2000; 14: 26772, 277–28, 280 passim.
  • 18
    Recommendations and Rationale. Screening for Prostate Cancer: U.S. Preventive Services Task Force (USPSTF). [Cited 12 November 2004.] Available from URL:
  • 19
    Harris R, Lohr KN. Screening for prostate cancer: an update of the evidence for the U.S. Preventive Services Task Force. Ann. Intern. Med. 2002; 137: 91729.
  • 20
    Roberts RO, Bergstralh EJ, Katusic SK et al. Decline in prostate cancer mortality from 1980 to 1997, and an update on incidence trends in Olmsted County, Minnesota. J. Urol. 1999; 161: 52933.
  • 21
    Meyer F, Moore L, Bairati I et al. Downward trend in prostate cancer mortality in Quebec and Canada. J. Urol. 1999; 161: 118991.
  • 22
    Bartsch G, Horninger W, Klocker H et al. Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 2001; 58: 41724.
  • 23
    Prorok PC, Andriole GL, Bresalier RS et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Control. Clin. Trials 2000; 21 (6 Suppl): 273S309S.
  • 24
    Schröder FH, Denis LJ, Roobol M et al. The story of the European randomized study of screening for prostate cancer. BJU Int. 2003; 92 (Suppl 2): 113.
  • 25
    The Prostate Cancer Screening Council, The Japanese Foundation for Prostate Research. The survey of prostate cancer screening tests in Ningen Dock in Japan (1989–1999). The survey of prostate cancer mass screening in Japan (1986–1999). Jpn. J. Urol. Surg. 2003; 16: 102338.
  • 26
    Kubota Y, Ito K, Imai K et al. Effectiveness of mass screening for the prognosis of prostate cancer patients in Japanese communities. Prostate 2002; 50: 2629.
  • 27
    Ito K, Yamamoto T, Suzuki K et al. The risk of rapid prostate specific antigen increase in men with baseline prostate specific antigen 20 ng/ml or less. J. Urol. 2004; 171: 65660.
  • 28
    Ito K, Yamamoto T, Ohi M et al. Possibility of re-screening intervals of more than one year in men with PSA levels of 40 ng/ml or less. Prostate 2003; 57: 813.
  • 29
    Cancer Registration Committee of the Japanese Urological Association. Clinicopathological statistics on registered prostate cancer patients in Japan: 2000 report from the Japanese Urological Association. Int. J. Urol. 2005; 12: 4661.
  • 30
    Chodak GW. Early detection and screening for prostatic cancer. Urology 1989; 34: 10.
  • 31
    Pedersen KV, Carlsson P, Varenhorst E et al. Screening for carcinoma of the prostate by digital rectal examination in a randomly selected population. BMJ 1990; 300: 1041.
  • 32
    Catalona WJ, Richie JP, Ahmann FR et al. Comparison of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer: results of a multicenter clinical trial of 6630 men. J. Urol. 1994; 151: 128390.
  • 33
    Haas GP, Monyie JE, Pontes JE. The state of prostate cancer screening in the United States. Eur. Urol. 1993; 23: 33747.
  • 34
    Gretzer MB, Partin AW. PSA markers in prostate cancer detection. Urol. Clin. North Am. 2003; 30: 67786.
  • 35
    Okihara K, Cheli CD, Partin AW et al. Comparative analysis of complexed prostate specific antigen, free prostate specific antigen and their ratio in detecting prostate cancer. J. Urol. 2002; 167: 201723.
  • 36
    Elgamal AA, van Poppel HP, van de Voorde WM et al. Impalpable, invisible stage T1c prostate cancer: characteristics and clinical relevance in 100 radical prostatectomy specimens–a different view. J. Urol. 1997; 157: 24450.
  • 37
    Gustavsson O, Norming U, Almgard LE et al. Diagnostic methods in the detection of prostate cancer: a study of a randomly selected population of 2400 men. J. Urol. 1992; 148: 182731.
  • 38
    Mettlin C, Murphy GP, Babaian RJ et al. The results of a five-year early prostate cancer detection intervention. Investigators of the American Cancer Society National Prostate Cancer Detection Project. Cancer 1996; 77: 1509.
  • 39
    Punglia RS, D'Amico AV, Catalona WJ et al. Effect of verification bias on screening for prostate cancer by measurement of prostate–specific antigen. N. Engl. J. Med. 2003; 349: 33542.
  • 40
    Hodge KK, McNeal JE, Terris MK et al. Random systemic versus directed ultrasound guided transrectal core biopsies of the prostate. J. Urol. 1989; 142: 714.
  • 41
    Emiliozzi P, Corsetti A, Tassi B et al. Best approach for prostate cancer detection: a prospective study on transperineal versus transrectal six-core prostate biopsy. Urology 2003; 61: 9616.
  • 42
    Emiliozzi P, Longhi S, Scarpone P et al. The value of a single biopsy with 12 transperineal cores for detecting prostate cancer in patients with elevated prostate specific antigen. J. Urol. 2001; 166: 84550.
  • 43
    Raaijmakers R, Kirkels WJ, Roobol MJ et al. Complication rates and risk factors of 5802 transrectal ultrasound-guided sextant biopsies of the prostate within a population-based screening program. The Neth. Urol. 2002; 60: 82630.
  • 44
    Babaian RJ, Toi A, Kamoi K et al. A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy. J. Urol. 2000; 163: 1527.
  • 45
    Presti JC Jr, Chang JJ, Bhargava V et al. The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. J. Urol. 2000; 163: 1636; discussion 166–7.
  • 46
    Keetch DW, Catalona WJ, Smith DS. Serial prostate biopsies in men with persistently elevated serum prostate specific antigen levels. J. Urol. 1994; 151: 15714.
  • 47
    Roerhborn CG, Pickers GJ, Sanders JS. Diagnostic yield of repeated ultrasound guided biopsies stratified by specific histopathologic diagnosis and prostate specific antigen levels. Urology 1996; 47: 34752.
  • 48
    Zlotta AR, Raviv G, Schulman CC. Clinical prognostic criteria for later diagnosis of prostate carcinoma in patients with initial isolated prostatic intraepithelial neoplasia. Eur. Urol. 1996; 30: 24955.
  • 49
    Haggman MJ, Macoska JA, Wojno KJ et al. The relationship between prostatic intraepithelial neoplasia and prostate cancer: critical issues. J. Urol. 1997; 158: 1222.
  • 50
    Spigelman SS, McNeal JE, Freiha FS et al. Rectal examination in volume determination of carcinoma of the prostate: clinical and anatomical correlations. J. Urol. 1986; 136: 122830.
  • 51
    Partin AW, Mangold LA, Lamm DM et al. Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology 2001; 58: 8438.
  • 52
    Rorvik J, Halvorsen OJ, Servoll E et al. Transrectal ultrasonography to assess local extent of prostatic cancer before radical prostatectomy. Br. J. Urol. 1994; 73: 659.
  • 53
    Lee N, Newhouse JH, Olsson CA et al. Which patients with newly diagnosed prostate cancer need a computed tomography scan of the abdomen and pelvis? An analysis based on 588 patients. Urology 1999; 54: 4904.
  • 54
    Jager GJ, Severens JL, Thornbury JR et al. Prostate cancer staging: should MR imaging be used? A decision analytic approach. Radiology 2000; 215: 44551.
  • 55
    Heenan SD. Magnetic resonance imaging in prostate cancer. Prostate Cancer Prostatic Dis. 2004; 7: 2828.
  • 56
    Partin AW, Yoo J, Carter HB et al. The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J. Urol. 1993; 150: 11014.
  • 57
    Whitmore WF Jr. Natural history and staging of prostate cancer. Urol. Clin. North Am. 1984; 11: 20920.
  • 58
    Gerber G, Chodak GW. Assessment of value of routine bone scans in patients with newly diagnosed prostate cancer. Urology 1991; 37: 41822.
  • 59
    Soloway MS, Hardeman SW, Hickey D et al. Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer 1988; 61: 195202.
  • 60
    Rana A, Karamanis K, Lucas MG et al. Identification of metastatic disease by T category, Gleason score and serum PSA level in patients with carcinoma of the prostate. Br. J. Urol. 1992; 69: 27781.
  • 61
    Oesterling JE. Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J. Urol. 1991; 145: 90723.
  • 62
    Oesterling JE. Using PSA to eliminate the staging radionuclide bone scan. Significant economic implications. Urol. Clin. North Am. 1993; 20: 70511.
  • 63
    Nakayama T. Guide to Developing and Using Evidence-Based Practice Guidelines. Kanehara & Co., LTD., Tokyo, 2004.
  • 64
    D'Amico AV, Moul JW, Carroll PR et al. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J. Natl. Cancer Inst. 2003; 95: 137683.
  • 65
    Iselin CE, Robertson JE, Paulson DF. Radical perineal prostatectomy: oncological outcome during a 20-year period. J. Urol. 1999; 161: 1638.
  • 66
    D'Amico AV. Predicting prostate-specific antigen recurrence established: now, who will survive? J. Clin. Oncol. 2002; 20: 318890.
  • 67
    Schild SE, Wong WW, Novicki DE et al. Detection of residual prostate cancer after radical prostatectomy with the Abbott IMx PSA assay. Urology 1996; 47: 87881.
  • 68
    Oefelein MG, Smith N, Carter M et al. The incidence of prostate cancer progression with undetectable serum prostate specific antigen in a series of 394 radical prostatectomies. J. Urol. 1995; 154: 212831.
  • 69
    Pound CR, Partin AW, Eisenberger MA et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281: 15917.
  • 70
    Scher HI. Management of prostate cancer after prostatectomy: treating the patient, not the PSA. JAMA 1999; 281: 16425.
  • 71
    Lu–Yao GL, Yao SL. Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 1997; 349 (9056): 90610.
  • 72
    Graversen PH, Nielsen KT, Gasser TC et al. Radical prostatectomy versus expectant primary treatment in stages I and II prostatic cancer. A fifteen-year follow-up. Urology 1990; 36: 4938.
  • 73
    Barry MJ, Albertsen PC, Bagshaw MA et al. Outcomes for men with clinically nonmetastatic prostate carcinoma managed with radical prostactectomy, external beam radiotherapy, or expectant management: a retrospective analysis. Cancer 2001; 91: 230214.
  • 74
    Holmberg L, Bill-Axelson A, Helgesen F et al. Scandinavian Prostatic Cancer Group Study Number 4. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N. Engl. J. Med. 2002; 347: 7819.
  • 75
    Elgamal AA, Van Poppel HP, Van de Voorde WM et al. Impalpable invisible stage T1c prostate cancer: characteristics and clinical relevance in 100 radical prostatectomy specimens–a different view. J. Urol. 1997; 157: 24450.
  • 76
    Oesterling JE, Suman VJ, Zincke H et al. PSA-detected (clinical stage T1c or B0) prostate cancer. Pathologically significant tumors. Urol. Clin. North Am. 1993; 20: 68793.
  • 77
    Epstein JI, Walsh PC, Brendler CB. Radical prostatectomy for impalpable prostate cancer: the Johns Hopkins experience with tumors found on transurethral resection (stages T1A and T1B) and on needle biopsy (stage T1C). J. Urol. 1994; 152: 17219.
  • 78
    Gibbons RP. Total prostatectomy for clinically localized prostate cancer: long-term surgical results and current morbidity. NCI Monogr. 1988; 7: 1236.
  • 79
    Pound CR, Partin AW, Epstein JI et al. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol. Clin. North Am. 1997; 24: 395406.
  • 80
    Catalona WJ, Smith DS. 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J. Urol. 1994; 152: 183742.
  • 81
    Trapasso JG, deKernion JB, Smith RB et al. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J. Urol. 1994; 152: 18215.
  • 82
    Zincke H, Oesterling JE, Blute ML et al. Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J. Urol. 1994; 152: 18507.
  • 83
    Han M, Partin AW, Pound CR et al. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol. Clin. North Am. 2001; 28: 55565.
  • 84
    Hull GW, Rabbani F, Abbas F et al. Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J. Urol. 2002; 167: 52834.
  • 85
    Lau WK, Bergstralh EJ, Blute ML et al. Radical prostatectomy for pathological Gleason 8 or greater prostate cancer: influence of concomitant pathological variables. J. Urol. 2002; 167: 11722.
  • 86
    van den Ouden D, Hop WC, Schroder FH. Progression in and survival of patients with locally advanced prostate cancer (T3) treated with radical prostatectomy as monotherapy. J. Urol. 1998; 160: 13927.
  • 87
    Alibhai SM, Naglie G, Nam R et al. Do older men benefit from curative therapy of localized prostate cancer? J. Clin. Oncol. 2003; 21: 331827.
  • 88
    Coen JJ, Zietman AL, Shipley WU. Prostatectomy or watchful waiting in prostate cancer. N. Engl. J. Med. 2003; 348: 1701;author reply 170–1.
  • 89
    Grimm MO, Kamphausen S, Hugenschmidt H et al. Clinical outcome of patients with lymph node positive prostate cancer after radical prostatectomy versus androgen deprivation. Eur. Urol. 2002; 41: 62834.
  • 90
    Lu-Yao GL, McLerran D, Wasson J et al. An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. JAMA 1993; 269: 26336.
  • 91
    Eastham JA, Kattan MW, Riedel E et al. Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J. Urol. 2003; 170: 22925.
  • 92
    Van Poppel H, Collette L, Kirkali Z et al. EORTC GU Group. Quality control of radical prostatectomy: a feasibility study. Eur. J. Cancer 2001; 37: 8849.
  • 93
    Soloway MS, Pareek K, Sharifi R et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J. Urol. 2002; 167: 11216.
  • 94
    Aus G, Abrahamsson PA, Ahlgren G et al. Three-month neoadjuvant hormonal therapy before radical prostatectomy: a 7-year follow-up of a randomized controlled trial. BJU Int. 2002; 90: 5616.
  • 95
    Klotz LH, Goldenberg SL, Jewett MA et al. Long-term followup of a randomized trial of 0 versus 3 months of neoadjuvant androgen ablation before radical prostatectomy. J. Urol. 2003; 170: 7914.
  • 96
    Salomon L, Anastasiadis AG, Levrel O et al. Location of positive surgical margins after retropubic, perineal, and laparoscopic radical prostatectomy for organ-confined prostate cancer. Urology 2003; 61: 38690.
  • 97
    Artibani W, Grosso G, Novara G et al. Is laparoscopic radical prostatectomy better than traditional retropubic radical prostatectomy? An analysis of peri-operative morbidity in two contemporary series in Italy. Eur. Urol. 2003; 44: 4016.
  • 98
    Lance RS, Freidrichs PA, Kane C et al. A comparison of radical retropubic with perineal prostatectomy for localized prostate cancer within the Uniformed Services Urology Research Group. BJU Int. 2001; 87: 615.
  • 99
    Lodding P, Bergdahl C, Nyberg M et al. Inguinal hernia after radical retropubic prostatectomy for prostate cancer: a study of incidence and risk factors in comparison to no operation and lymphadenectomy. J. Urol. 2001; 166: 9647.
  • 100
    Lu–Yao GL, Albertsen P, Warren J et al. Effect of age and surgical approach on complications and short-term mortality after radical prostatectomy – a population-based study. Urology 1999; 54: 3017.
  • 101
    Bishoff JT, Motley G, Optenberg SA et al. Incidence of fecal and urinary incontinence following radical perineal and retropubic prostatectomy in a national population. J. Urol. 1998; 160: 4548.
  • 102
    Abbou CC, Salomon L, Hoznek A et al. Laparoscopic radical prostatectomy: preliminary results. Urology 2000; 55: 6304.
  • 103
    Guillonneau B, el-Fettouh H, Baumert H et al. Laparoscopic radical prostatectomy: oncological evaluation after 1,000 cases a Montsouris Institute. J. Urol. 2003; 169: 12616.
  • 104
    Rassweiler J, Sentker L, Seemann O et al. Laparoscopic radical prostatectomy with the Heilbronn technique: an analysis of the first 180 cases. J. Urol. 2001; 166: 21018.
  • 105
    Arai Y, Egawa S, Terachi T et al. Morbidity of laparoscopic radical prostatectomy: summary of early multi-institutional experience in Japan. Int. J. Urol. 2003; 10: 4304.
  • 106
    Marcovich R, Wojno KJ, Wei JT et al. Bladder neck-sparing modification of radical prostatectomy adversely affects surgical margins in pathologic T3a prostate cancer. Urology 2000; 55: 9048.
  • 107
    Stanford JL, Feng Z, Hamilton AS et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000; 283: 35460.
  • 108
    Sokoloff MH, Brendler CB. Indications and contraindications for nerve-sparing radical prostatectomy. Urol. Clin. North Am. 2001; 28: 53543.
  • 109
    Robinson JW, Moritz S, Fung T. Meta-analysis of rates of erectile function after treatment of localized prostate carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2002; 54: 10638.
  • 110
    Clark T, Parekh DJ, Cookson MS et al. Randomized prospective evaluation of extended versus limited lymph node dissection in patients with clinically localized prostate cancer. J. Urol. 2003; 169: 1457.
  • 111
    Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J. Urol. 2002; 167: 16816.
  • 112
    Freedland SJ, Sutter ME, Dorey F et al. Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy. Prostate-specific antigen. Urology 2003; 61: 3659.
  • 113
    Leibman BD, Dillioglugil O, Wheeler TM et al. Distant metastasis after radical prostatectomy in patients without an elevated serum prostate specific antigen level. Cancer 1995; 76: 25304.
  • 114
    Lattouf JB, Saad F. Digital rectal exam following prostatectomy: is it still necessary with the use of PSA? Eur. Urol. 2003; 43: 3336.
  • 115
    Niwakawa M, Tobisu K, Fujimoto H et al. Medically and economically appropriate follow-up schedule for prostate cancer patients after radical prostatectomy. Int. J. Urol. 2002; 9: 13440.
  • 116
    Messing EM, Manola J, Sarosdy M et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N. Engl. J. Med. 1999; 341: 17818.
  • 117
    Pisansky TM, Kozelsky TF, Myers RP et al. Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer. J. Urol. 2000; 163: 84550.
  • 118
    Duchesne GM, Dowling C, Frydenberg M et al. Outcome, morbidity, and prognostic factors in post-prostatectomy radiotherapy: an Australian multicenter study. Urology 2003; 61: 17983.
  • 119
    Song DY, Thompson TL, Ramakrishnan V et al. Salvage radiotherapy for rising or persistent PSA after radical prostatectomy. Urology 2002; 60: 2817.
  • 120
    Macdonald OK, Schild SE, Vora SA et al. Radiotherapy for men with isolated increase in serum prostate specific antigen after radical prostatectomy. J. Urol. 2003; 170: 18337.
  • 121
    Katz MS, Zelefsky MJ, Venkatraman ES et al. Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J. Clin. Oncol. 2003; 21: 4839.
  • 122
    Catton C, Gospodarowicz M, Warde P et al. Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiother. Oncol. 2001; 59: 5160.
  • 123
    Schild SE. Radiation therapy (RT) after prostatectomy: the case for salvage therapy as opposed to adjuvant therapy. Int. J. Cancer 2001; 96: 948.
  • 124
    Zietman AL, Chung CS, Coen JJ et al. 10-year outcome for men with localized prostate cancer treated with external radiation therapy: results of a cohort study. J. Urol. 2004; 171: 21014.
  • 125
    Pilepich MV, Krall JM, John MJ et al. Hormonal cytoreduction in locally advanced carcinoma of the prostate treated with definitive radiotherapy: preliminary results of RTOG 83–07. Int. J. Radiat. Oncol. Biol. Phys. 1989; 16: 81377.
  • 126
    Pilepich MV, Caplan R, Byhardt RW et al. Phase trial of androgen suppression using goserelin in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy: report of RTOG 85–31. J. Clin. Oncol. 1997; 15: 1013121.
  • 127
    Pilepich MV, Winter K, Lawton CA et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma–long term results of phase RTOG study 85–31. Int. J. Radiat. Oncol. Biol. Phys. 2005; 61: 1285190.
  • 128
    Lawton CA, Winter K, Murray K et al. Updated results of the phase RTOG trial 85–31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int. J. Radial Oncol. Biol. Phys. 2001; 49: 937146.
  • 129
    Bolla M, Gonzalez D, Warde P et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N. Engl. J. Med. 1997; 337: 295300.
  • 130
    Bolla M, Collette L, Blank L et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study). Lancet 2002; 360: 1036.
  • 131
    Pilepich MV, Krall JM, Al-Sarraf M et al. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995; 45: 61623.
  • 132
    Pilepich MV, Winter K, John MJ et al. Phase radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 2001; 50: 124352.
  • 133
    Hanks GE, Pajak TF, Porter A et al. Phase trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92–02. J. Clin. Oncol. 2003; 21: 397228.
  • 134
    Roach M 3rd, DeSilvio M, Lawton C et al. Phase trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J. Clin. Oncol. 2003; 21: 190411.
  • 135
    D'Amico AV, Manola J, Loffredo M et al. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004; 292: 8217.
  • 136
    D'Amico A, Whittington R, Malkowicz S et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: 96974.
  • 137
    Roach M, Lu J, Pilepich MV et al. Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on radiation therapy oncology group clinical trials. Int. J. Radiat. Oncol. Biol. Phys. 2000; 47: 60915.
  • 138
    Kattan M, Zelefsky M, Kupelian P et al. Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. J. Clin. Oncol. 2000; 18: 33529.
  • 139
    Pollack A, Zagars GK, Starkschall G et al. Prostate cancer radiation dose–response: results of the M.D. Anderson Phase randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 2002; 53: 1097105.
  • 140
    Deger S, Boehmer D, Turk I et al. High dose rate brachytherapy of localized prostate cancer. Eur. Urol. 2002; 41: 4206.
  • 141
    Wallner K, Merrick G, True L et al. 125I versus 103Pd for low-risk prostate cancer: preliminary PSA outcome from a prospective randomized multicenter trial. Int. J. Radiat. Oncol. Biol. Phys. 2003; 57: 1297303.
  • 142
    American Society for Therapeutic Radiology and Oncology Consensus Panel 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: 1035341.
  • 143
    Vicini FA, Kestin LL, Martinez AA. The importance of adequate follow-up in defining treatment success after external beam irradiation for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 1999; 45: 55361.
  • 144
    Taylor JM, Griffith KA, Sandler HM. Definitions of biochemical failure in prostate cancer following radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 2001; 50: 121219.
  • 145
    Pollack A, Zagars GK, Antolak JA et al. Prostate biopsy status and PSA nadir level as early surrogates for treatment failure: analysis of a prostate cancer randomized radiation dose escalation trial. Int. J. Radiat. Oncol. Biol. Phys. 2002; 54: 67785.
  • 146
    Tsushima T, Nasu Y, Saika T et al. Optimal starting time for flutamide to prevent disease flare in prostate cancer patients treated with a gonadotropin-releasing hormone agonist. Urol. Int. 2001; 66: 1359.
  • 147
    Boccardo F, Rubagotti A, Battaglia M et al. Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J. Clin. Oncol. 2005; 23: 808015.
  • 148
    Wirth M, Tyrrell C, Wallace M, et al. Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression. Urology 2001; 58: 1464151.
  • 149
    See W, Iversen P, Wirth M, McLeod D, Garside L, Morris T. Immediate treatment with bicalutamide 150 mg as adjuvant therapy significantly reduces the risk of PSA progression in early prostate cancer. Eur. Urol. 2003; 44: 5127;discussion 517–18.
  • 150
    Iversen P, Johansson JE, Lodding P, et al. Scandinavian Prostatic Cancer Group. Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3 year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J. Urol. 2004; 172: 187186.
  • 151
    Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostate cancer: initial results of the Medical Research Council Trial. Br. J. Urol. 1997; 79: 2353246.
  • 152
    Labrie F, Dupont A, Belanger A, et al. Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival. J. Steroid Biochem. 1985; 23: 8333841.
  • 153
    Prostate Cancer Trialists ‘Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 1995; 346: 2656269.
  • 154
    Prostate Cancer Trialists ‘Collaborative Group. Maximal androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 2000; 355: 149141498.
  • 155
    Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N. Engl. J. Med. 1998; 339: 103642.
  • 156
    Schmitt B, Wilt TJ, Schellhammer PF, et al. Combined androgen blockade with nonsteroidal antiandrogens for advanced prostate cancer: a systematic review. Urology 2001; 57: 7272732.
  • 157
    Samson DJ, Seidenfeld J, Schmitt B, et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002; 95: 3616376.
  • 158
    Klotz L. Combined androgen blockade in prostate cancer: meta-analyses and associated issues. BJU Int. 2001; 87: 806013.
  • 159
    Tannock IF, de Wit R, Berry WR et al. 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 2004; 351: 150212.
  • 160
    Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N. Engl. J. Med. 2004; 351: 151320.
  • 161
    Holmberg L, Bill-Axelson A, Helgesen F et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N. Engl. J. Med. 2002; 347: 7819.
  • 162
    Bill-Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N. Engl. J. Med. 2005; 352: 197784.
  • 163
    Chodak GW, Thisted RA, Gerber GS et al. Results of conservative management of clinically localized prostate cancer. N. Engl. J. Med. 1994; 330: 2428.
  • 164
    Carter CA, Donahue T, Sun L et al. Temporarily deferred therapy (watchful waiting) for men younger than 70 years and with low-risk localized prostate cancer in the prostate-specific antigen era. J. Clin. Oncol. 2003; 21: 40018.
  • 165
    Choo R, Klotz L, Danjoux C et al. Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. J. Urol. 2002; 167: 16649.
  • 166
    Cooperberg MR, Broering JM, Litwin MS et al. The contemporary management of prostate cancer in the United States: lessons from the cancer of the prostate strategic urologic research endeavor (CapSURE, a national disease registry. J. Urol. 2004; 171: 1393401.
  • 167
    Bacon CG, Giovannucci E, Testa M et al. The impact of cancer treatment on quality of life outcomes for patients with localized prostate cancer. J. Urol. 2001; 166: 180410.
  • 168
    George N. Therapeutic dilemmas in prostate cancer: justification for watchful waiting. Eur Urol. 1998; 34 (Suppl 3): 336.
  • 169
    Kakehi Y. Watchful waiting as a treatment option for localized prostate cancer in the PSA era. Jpn. J. Clin. Oncol. 2003; 33: 15.
  • 170
    Smith JA Jr, Soloway MS, Young MJ. Complications of advanced prostate cancer. Urology 1999; 54 (6A Suppl):814.
  • 171
    Scher HI, Chung LW. Bone metastases: improving the therapeutic index. Semin. Oncol. 1994; 21: 630356.
  • 172
    Japanese Society for Palliative Medicine, creation Committee of the clinical guideline for pain control in cancer patient. Evidence-Based Guideline for Pain Control in Cancer Patient. Shinko Trading Co., LTD., Tokyo, 2000.
  • 173
    Arcangeli G, Giovinazzo G, Saracino B et al. Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration. Int. J. Radiat. Oncol. Biol. Phys. 1998; 42: 111926.
  • 174
    Bolger JJ, Dearnaley DP, Kirk D et al. Strontium−89 (Metastron) versus external beam radiotherapy in patients with painful bone metastases secondary to prostatic cancer: preliminary report of a multicenter trial. UK Metastron Investigators Group. Semin. Oncol. 1993; 20 (3 Suppl 2): 3223.
  • 175
    Quilty PM, Kirk D, Bolger JJ et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother. Oncol. 1994; 31: 3340.
  • 176
    Saad F, Gleason DM, Murray R et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J. Natl. Cancer Inst. 2002; 94: 145868.
  • 177
    Ross JR, Saunders Y, Edmonds PM et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327 (7413): 469.
  • 178
    Sorensen S, Helweg-Larsen S, Mouridsen H et al. Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial. Eur. J. Cancer 1994; 30A: 227.
  • 179
    Young RF, Post EM, King GA. Treatment of spinal epidural metastases. Randomized prospective comparison of laminectomy and radiotherapy. J. Neurosurg. 1980; 53: 7418.
  • 180
    Crain DS, Amling CL, Kane CJ. Palliative transurethral prostate resection for bladder outlet obstruction in patients with locally advanced prostate cancer. J. Urol. 2004; 171: 66871.
  • 181
    Kraus PA, Lytton B, Weiss RM, Prosnitz LR. Radiation therapy for local palliative treatment of prostatic cancer. J. Urol. 1972; 108: 61214.
  • 182
    Oefelein MG. Prognostic significance of obstructive uropathy in advanced prostate cancer. Urology 2004; 63: 111721.
  • 183
    Watkinson AF, A’Hern RP, Jones A et al. The role of percutaneous nephrostomy in malignant urinary tract obstruction. Clin. Radiol. 1993; 47: 3225.
  • 184
    Docimo SG, Dewolf WC. High failure rate of indwelling ureteral stents in patients with extrinsic obstruction: experience at 2 institutions. J. Urol. 1989; 142: 2779.
  • 185
    Hasegawa T. Appraisal of Guidelines for Research and Evaluation Agree Instrument. [Cited 15 October 2004.]Available from URL: