Prostate cancer

Seminar

Prostate cancer Jan-Erik Damber, Gunnar Aus Lancet 2008; 371: 1710–21 Department of Urology, Sahlgrenska University Hospital, Gothenburg, Sweden (Prof J E Damber MD, G Aus MD) Correspondence to: Prof Jan-Erik Damber, Department of Urology, Bruna stråket 11, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden [email protected]

In developed countries, prostate cancer is the second most frequently diagnosed cancer, and the third most common cause of death from cancer in men. Apart from age and ethnic origin, a positive family history is probably the strongest known risk factor. Clinically, prostate cancer is diagnosed as local or advanced, and treatments range from surveillance to radical local treatment or androgen-deprivation treatment. Androgen deprivation reduces symptoms in about 70–80% of patients with advanced prostate cancer, but most tumours relapse within 2 years to an incurable androgen-independent state. The recorded incidence of prostate cancer has substantially increased in the past two decades, probably because of the introduction of screening with prostate-specific antigen, the use of improved biopsy techniques for diagnosis, and increased public awareness. Trends in mortality from the disease are less clearcut. Mortality changes are not of the same magnitude as the changes in incidence, and in some countries mortality has been stable or even decreased. The disparity between reported incidence and mortality rates leads to the probable conclusion that only a small proportion of diagnosed low-risk prostate cancers will progress to life-threatening disease during the lifetime of the patient.

Causes Several studies have shown a familial aggregation of prostate cancer.1–3 One obvious possible reason for this aggregation is inheritance of genes that cause prostate cancer, some of which show high penetrance, whereas other genes show polymorphism and low penetrance. Some genes have been identified as potentially associated with prostate cancer. The first gene locus identified was named hereditary prostate cancer locus-1 (HPC1),4 for which RNASEL is the candidate allele.5 Since this discovery of a genetic link, several other candidate genes have been identified, although most of them would be of less importance because of low frequency in the atrisk population.6 The genes most plausibly linked to familial prostate cancer are EPAC2, RNASEL, MSR1, CHEK2, CAPZB, vitamin D receptor, and PON1.7–9 A germline mutation in BRCA2 can increase the risk of prostate cancer,10 and could cause about 5% of cases in men younger than 55 years. A genetic variant associated with prostate cancer in European and African populations has been identified on chromosome 8q24.11 This genetic variant also occurs at high frequency in African Americans, and could be the reason for the higher incidence of prostate cancer in African Americans than in Americans of European descent.11 Genetic polymorphism has also been reported in several genes for the androgen receptor, 5α-reductase type 2, and steroid hydroxylase—that bring about androgen metabolism.6 An important breakthrough in the search for novel pathogenetic mechanisms in prostate cancer was the finding of fusion oncogenes.12 Although not wholly understood, the high frequency of TMPRSS2-ERG fusions is intriguing.12 More genes will be discovered in the future and when we understand their crucial pathways, the staging and treatment of prostate cancer can be improved. However, gene testing for prostate cancer is not possible at present. Nevertheless, there is a major international consortium for prostate cancer genetics13 and a genome-wide search is in progress. 1710

The big difference in the incidence of prostate cancer between men in developed countries and Asian men is well established, and has been attributed to important differences in lifestyles. The incidence of prostate cancer in Japanese men in Hawaii is intermediate between that in Japan and that in white men in Hawaii.14 Diet, pattern of sexual behaviour, alcohol consumption, exposure to ultraviolet radiation, and occupational exposure are all important aetiological factors.15 Generally, Japanese men consume a low-fat diet with high content of soy products that have high concentrations of phyto-oestrogens.16 Phyto-oestrogens in soy have been suggested to be of protective importance in Asian countries,16 whereas rye has evoked interest in the Nordic countries because of regional differences in the rates of prostate cancer.17,18 Phyto-oestrogens can affect several intracellular processes in cancer cells, so they are candidates for natural cancer-protective agents.19 The importance of nutritional factors for development of prostate cancer was noted in a Swedish study, in which both body-mass index and lean body mass were positively associated with the risk of prostate cancer, and were more strongly related to mortality than to incidence.20 Even though dietary fat seems to be an important environmental risk factor for prostate cancer

Search strategy and selection criteria For patients with localised prostate cancer, we used metaanalyses and structured literature searches, and reviewed available publications in English. Some of the search terms were “prostate cancer” and “prostatic neoplasms”, from 2001 to 2004. For the other topics, we used guidelines from the European Association of Urology and the Swedish Board of Health and Welfare, which were based on meta-analyses. We referred to Cochrane reviews or other review articles, when relevant publications were not available. Key original references were selected, when we felt that they would provide more information than reviews.

www.thelancet.com Vol 371 May 17, 2008

Seminar

C

Poland

Sweden

E

UK

F

USA

19

19

Year

Year

19 79 19 8 19 1 8 19 3 8 19 5 87 19 8 19 9 91 19 9 19 3 9 19 5 97 19 9 20 9 01

Belgium

79

D

B

19 79 19 8 19 1 83 19 8 19 5 8 19 7 8 19 9 91 19 9 19 3 95 19 9 19 7 9 20 9 01

90 80 70 60 50 40 30 20 10 0

Australia

8 19 1 8 19 3 85 19 8 19 7 89 19 9 19 1 9 19 3 95 19 9 19 7 9 20 9 01

Age-standardised rate per 100 000 population Age-standardised rate per 100 000 population

A 90 80 70 60 50 40 30 20 10 0

Year

Figure 1: International trends in prostate-cancer mortality Adapted with permission from reference 40.

identified so far, the evidence is inconclusive. Only three of 14 studies reported a statistically significant increase in risk ratio for total fat intake.21 The relation between physical exercise and prostate cancer has been extensively studied, without any firm conclusions. However, three systematic reviews showed that most studies have a tendency towards decreased risk in the groups with the highest degree of physical activity.22–24 Smoking probably results in a small increase in the risk,25 whereas the relation with alcohol consumption is unknown. The strong antioxidants lycopenes, found for example in tomatoes, have been extensively studied as possible protective agents for the development of prostate cancer. In a meta-analysis, the intake of tomatoes was negatively correlated with the risk of cancer:26 the results showed a decrease in the relative risk for men who consumed the most tomatoes. Moreover, some other micronutrients and vitamins—such as selenium, vitamin E, and vitamin D—have been associated with the risk of prostate cancer. A trial noted that men who were given oral selenium had a reduced risk,27 and a systematic review also showed a protective effect of selenium.28 Vitamin E might also have a protective effect on prostate cancer. A Finnish study reported a 32% lower risk of prostate cancer and a 41% lower mortality for men who received vitamin E daily.29 On the basis of these studies, a placebo-controlled, prospective, and randomised study (the Selenium and Vitamin E Cancer Prevention Trial [SELECT]) is combining selenium and vitamin E in the intervention group and aims to recruit 32 000 men.30 Vitamin D has been also discussed in relation to prostate-cancer risk, but so far the evidence is fragmentary or inconsistent.31 www.thelancet.com Vol 371 May 17, 2008

The recently completed Prostate Cancer Prevention Trial (PCPT) showed that chemoprevention is possible with the 5α-reductase inhibitor finasteride,32 which reduced the rate of prostate cancer by 24·8% over 7 years. However, tumours of Gleason score 7–10 were more common in the group given finasteride than in those given placebo, perhaps because finasteride can cause morphological changes indistinguishable from those found in high-grade tumours, leading to misclassification.33 Moreover, shrinkage of the prostate with finasteride increases the probability that small high-grade tumours will be detected.33 Another trial, Reduction by Dutasteride of Prostate Cancer Events (REDUCE), is underway to ascertain whether dutasteride, another 5α-reductase inhibitor, can prevent prostate cancer.34

Epidemiology Prostate cancer is the most common cancer in men in Europe, with about 190 000 new cases every year.35,36 About 80 000 deaths a year result from this cancer in Europe.37 Prostate-cancer mortality in the USA increased at a mean rate of 2·8% per year between 1988 and 1991, then decreased by 1·2% per year from 1991 to 1994 and more rapidly by 5·1% per year from 1994 to 1999.38 By 1997, mortality rates in the USA for white men younger than 85 years were lower than those documented in 1986.38,39 A fall in mortality rates has also been recorded in some other countries, whereas in many others mortality has either been stable (eg, Belgium) or has shown a slow increase over time (eg, Poland) (figure 1).41,42 The clinical pattern of prostate cancer has also changed noticeably over the past few years.43 The proportion of men diagnosed at ages younger than 70 years has increased, as has the proportion of moderately 1711

Seminar

differentiated tumours. These temporal trends in the rates and clinical presentation are consistent with the presumed effect of screening. Programmes of screening for prostate-specific antigen (PSA) and early detection have been undertaken, with the aim that such a strategy, and subsequent treatment with curative intent, will result in reduced mortality. Although evidence shows a decline in the mortality rate in the USA,38,44 the effect of early detection and treatment on mortality is probably not fully understood because of the long natural history of prostate cancer and the inherent delay in measurable treatment effects.

Screening Several features (panel 1) raise the question of whether screening for prostate cancer is a suitable strategy to reduce mortality rates. In some parts of the world, screening programmes have been introduced, although no randomised controlled trials have been completed, to assess the effectiveness of such an approach. The reduction in mortality in the USA is frequently attributed to the widely adopted aggressive case-finding policy, although there is no proof that PSA screening is the reason for reduced mortality.45,46 Further evidence that early detection and treatment might be effective comes from the non-randomised screening project in Tyrol, Austria. The early detection programme, along with free availability of treatment, has been used as an explanation

Panel 1: Features of prostate cancer Prostate cancer: • is a common disease • is a common cause of death in developed countries • can be cured when treated early • cannot be cured when it has metastasised • has a long natural course in most cases, with a window of opportunity for screening

700 600

Number of men

500 400 300 200 100 0

45–49

50–54

55–59

60–64

65–69

70–74

Age at death (years)

Figure 2: Age at death from prostate cancer in Sweden for 2002

1712

75–79

80–84

85–89

≥90

for the 20% risk reduction in mortality seen in Tyrol compared with the rest of Austria.47 On the other hand, Lu-Yao and co-workers48 did a study comparing many patients from the Seattle area (highly screened population) and Connecticut (much less screened population); despite large differences in PSA testing and the use of curative treatments, no difference in prostate-cancer mortality was noted. To assess the possible efficacy of prostate-cancer screening, prospective, preferably population-based, randomised trials are needed. Two such large trials have been started: the Prostate, Lung, Colorectal and Ovary (PLCO) trial in the USA and European Randomized Screening for Prostate Cancer (ERSPC).49 The first analyses of the main endpoint of these trials, differences in prostate-cancer mortality, are planned for 2008–10. The ERSPC is a pan-European screening trial, in which more than 250 000 men are randomly assigned to PSA screening or no active testing. Men with high PSA concentrations are recommended to have an ultrasound-guided prostate biopsy. After diagnosis, they are offered treatment according to clinical practice of the participating centre. The Gothenburg branch of the ERSPC enrolled 20 000 men aged 50–65 years on Jan 1, 1995; 10 000 of those have been offered PSA testing every second year, and the other 10 000 are part of the control group. There is a high acceptance rate for a PSA-based screening programme, with about 75% of men accepting the invitation for testing.50 Agreement to proceed with an ultrasound-guided prostate biopsy is also high, 90%. No mortality data have been presented or analysed as yet from the ERSPC. A requirement for an effective screening programme is that the number of patients with advanced or metastatic disease actually decreases, which was seen in the Gothenburg branch of the ERSPC. The number of patients with advanced prostate cancer at diagnosis was around 50% lower in the screening group (24) than in control group (47), after 9 years of screening.51 However, the absolute difference was small because the proportions diagnosed with advanced disease were tiny (0·24% in the screened group and 0·74% in the control group). The obvious reason for this low rate of advanced prostate cancer irrespective of whether screening was done or not is related to the age of the study population. They have still not reached the age when death from prostate cancer is more common— older than 75 years (figure 2). A similar finding, of a reduction of metastatic cases at diagnosis, was noted in the Rotterdam group of the ERSPC.52 An important conclusion from the screening studies was that the rescreening interval can be tailored to the initial PSA value. Men with a serum PSA concentration of less than 1 ng/mL (50% of the screened population) do not need to be tested more often than once every 3 years.53 This knowledge can be directly applied to clinical practice, and affect a large group of men. Other studies54,55 have www.thelancet.com Vol 371 May 17, 2008

Seminar

reached the same conclusion: that the baseline PSA measurement can be used as a risk stratifier. The table shows the 7-year risk of patients being diagnosed with prostate cancer, in relation to the baseline PSA measurement. Since the effect of mass screening for prostate cancer on mortality is not yet known from randomised controlled trials, and quality-of-life issues have scarcely been studied, a general recommendation for screening cannot yet be made. However, this restriction does not apply to case-finding or early detection efforts in the clinical setting, when the patient and doctor make an informed decision to start an individual screening programme. Several efforts have been made to find markers for early detection of prostate cancer, other than total serum PSA. In 2004, WHO arranged an international consultation to assess new markers.56 This consultation noted that total serum PSA is still the best marker, although no specific cut-off point for a normal PSA (indicating a zero risk for prostate cancer) could be defined. Nevertheless, urinary markers are being developed.57

Number of Number of cancer Cancer men (n=5855) cases (n=539) detection rate 0·0–0·49 ng/mL

958 (16%)

0·5–0·99 ng/mL

1992 (34%)

17 (3%)

0

0%

1·0–1·49 ng/mL

1138 (19%)

54 (10%)

4·7%

1·5–1·99 ng/mL

571 (10%)

70 (13%)

12·3%

0·85%

2·0–2·49 ng/mL

313 (5%)

67 (12%)

21·4%

2·5–2·99 ng/mL

222 (4%)

56 (10%)

25·2%

3·0–3·99 ng/mL

267 (5%)

89 (17%)

33·3%

4·0–6·99 ng/mL

265 (5%)

103 (19%)

38·9%

7·0–9·99 ng/mL

60 (1%)

30 (6%)

50·0%

≥10 ng/mL

69 (1%)

53 (10%)

76·8%

Data from 1995–96. Reproduced with permission from reference 53.

Table: Cumulative risk of diagnosis of prostate cancer in relation to baseline prostate-specific antigen

Diagnosis At present, diagnosis is based on examination of histopathological or cytological specimens from the gland. The most common way to obtain the necessary tissue specimen is by several systematic transrectal core biopsies, with guidance by transrectal ultrasound (figure 3). For many years, sextant biopsy was the standard procedure for the diagnosis of prostate cancer.58 By directing the biopsy needle more laterally into the gland or increasing the number of cores to eight to 12, the detection rate can be increased. There is no accepted universal standard on how the samples should be taken, but to do around ten laterally directed biopsies for a prostate gland of up to 50 mL, and 12–14 biopsies for glands exceeding this size, seems reasonable, based on available evidence.59 To obtain this number of biopsy cores, the patient needs some form of anaesthesia. Periprostatic local anaesthetic injection combines ease of use with effectiveness.59,60 The most serious complication after prostate biopsy is urinary-tract infection or sepsis. Antibiotic prophylaxis is always recommended; nonetheless, around 0·5–1·0% of patients who have had biopsy samples taken develop infections. The use of periprostatic anaesthesia does not increase the risk of infection. The most commonly used system for grading adenocarcinoma of the prostate is the Gleason score.61 Biopsy material (core biopsy or operative specimens) is needed to assess the Gleason score; cytological preparations cannot be used. The system describes a score between 2 and 10, with 2 being the least aggressive and 10 the most aggressive. This score is the sum of the two most common patterns (grades 1–5) of tumour growth. In needle biopsy, the worst grade should always www.thelancet.com Vol 371 May 17, 2008

Figure 3: Finger used as a prognostic guide for prostate biopsies Transrectal ultrasound has replaced the finger technique.

be included even if present in less than 5% of samples.62 Local staging of prostate cancer (T staging) is still mainly done on the basis of a careful digital rectal examination.63 Imaging modalities such as conventional MRI or CT scans are of little use. High-resolution MRI with endorectal coils is not yet available for widespread clinical use.64 Instead nomograms based on common clinical features—such as serum PSA concentration, tumour grade (Gleason score) of the biopsy, and stage by digital rectal examination—are used to establish the patient’s risk of having microscopic extracapsular extension of the tumour.65,66 The risk that a prostate cancer will have metastasised is closely associated with a high serum PSA concentration, a locally advanced prostate cancer, or a poorly differentiated tumour. In practice, this association means that a staging bone scan is not routinely recommended to patients with a PSA concentration of less than 20 ng/mL in the absence of poorly differentiated cancer.59 1713

Seminar

Prognostic factors

For more on nomograms see www.nomograms.org

For patients with newly diagnosed prostate cancer, any information on the prognosis is much sought after. Generally, patients with a high tumour burden do poorly, whereas patients with a low tumour burden will do much better, irrespective of treatment regimen. In other words, the disease establishes the prognosis more than the choice of treatment. For patients with distant metastases (stage M1), the prognosis is poor, with an average survival of 24–48 months. The prognosis depends on the disease burden at diagnosis, which could be depicted as more metastases on bone scan, raised serum PSA concentration, or high concentrations of bone-turnover markers.67–69 Palliative hormonal therapy is the standard treatment for patients with stage M1 disease, and the PSA nadir after castration provides prognostic information; the lower the PSA, better the prognosis.70–72 For patients with stage N1 disease (metastasis to regional lymph nodes), the median survival is substantially better than for those with distant metastasis—a population-based tumour registry reported a median cancer-specific survival of 8 years .73 For patients treated by radical prostatectomy and who had node metastases, the survival was even better, with a projected 10-year overall survival of 77%.74 Prognostic risk groups are now commonly used for patients with localised prostate cancer. These groups are usually based on variables—such as clinical T stage, serum concentration of PSA, and biopsy grade or Gleason score—available before treatment has been initiated. Panel 2 shows a frequently used risk grouping.75,76 Risk groups can then be used to establish post-treatment outcome after various curative treatments such as surgery77 or radiotherapy.78 Another way to use these widely available clinical variables is as validated risk calculators or nomograms for which the 5-year outcome after various treatments can be related to each patient’s clinical characteristics (risk factors). Are there other risk factors that might aid in the prognosis or treatment decision for patients with newly diagnosed, non-metastatic prostate cancer? Several studies show that the risk of recurrence after surgery is associated with more extensive cancer in the diagnostic cores;79,80 but stage, grade, and PSA are strong predictors and other markers seem to, so far, add little prognostic information.80 Tissue markers of prostate needle-biopsy specimens have generally failed to provide useful Panel 2: Risk group classification for localised prostate cancer • Low risk: stage T1c to T2a disease, and PSA 10 ng/mL or less, and Gleason score of 6 or less • Intermediate risk: stage T2b disease, or PSA greater than 10 ng/mL but less than 20 ng/mL, and Gleason score of 7 • High risk: stage T2c disease, or PSA 20 ng/mL or greater, and Gleason score of 8 or greater PSA=prostate-specific antigen.

1714

additional prognostic information, even though many of the markers provide independent prognostic evidence on post-prostatectomy specimens (ie, too late to be of real value). The main reason for this failure is that the small amount of tissue available in the biopsy cores is not representative of the whole prostate or cancer specimen. The change over time in the serum concentrations of PSA (PSA doubling time or PSA velocity) shows promise in the ability to predict the outcome for patients with non-metastatic prostate cancer. A high PSA velocity before treatment with curative intent is associated with a high risk of disease recurrence and death from prostate cancer.81 A short PSA doubling time (ie, a rapidly increasing PSA) for patients with a rising PSA after treatments with curative intent is similarly associated with a poor prognosis.82,83 The main difficulties with the dynamic PSA test as a predictor is that several PSA measurements are needed for the calculation, which means that the information is a bit too late to be of real clinical use.

Treatment of clinically localised prostate cancer Localised prostate cancer is the most commonly diagnosed stage. The choice of treatment (active monitoring, radical prostatectomy, or any type of radiotherapy) is based on factors such as tumour characteristics and the patient’s life expectancy. The reason why treatment with intent to cure is not used for all patients with prostate cancer is that many cases of highly to moderately differentiated prostate cancers have a very indolent course even when left without active treatment.84,85 The high rate of prostate cancers present in the population without ever giving rise to clinical symptoms (as seen in autopsy findings) further complicates this issue. Figure 4 shows the complex relation between cancers seen on autopsy examination, those that have been diagnosed clinically, and those that cause death. Thus, these findings have led to the recommendation that men with a life expectancy of less than 10 years who have early-stage prostate cancer should be actively monitored as their first choice of treatment,59 and that this approach is an option for all men in the low-risk group (panel 2). Men with more poorly differentiated tumours and those with a long life expectancy (ie, younger men) are usually offered some form of treatment with curative intent. Since there is no absolute cut-off limit for age when active therapy might be of value, clinicians have to define an individual patient’s life expectancy. Even older men can benefit from curative treatment if they live long enough.86 Of the treatments available, only radical prostatectomy has a survival advantage over watchful waiting. After 7 years of follow-up, the study showed that 17 men needed to undergo surgery to save one life.87 Radical surgery can also be done by laparoscopic techniques both conventional and robot assisted. In a systematic review, the oncological and functional results of open, robot-assisted, and laparoscopic radical prostatectomy were similar.88 www.thelancet.com Vol 371 May 17, 2008

Seminar

All men Prostate cancer at autopsy* Prostate cancer diagnosed Prostate cancer deaths

Figure 4: Relation between prevalence of prostate cancer at autopsy, clinically diagnosed, and prostate cancer deaths *Prostate cancer at autopsy implies examination of prostate in men dying from reasons other than prostate cancer and undergoing autopsy.

No other studies have compared the effectiveness of the various treatments for men with localised prostate cancer, which should not be interpreted as a suggestion that radiotherapy should not be used. During the past decade, the methods for delivery of radiotherapy in a sufficiently high dose to a precise target (thus minimising damage to surrounding tissue) has improved. For patients receiving external-beam radiotherapy, the American Urological Association has issued guidelines on prostate cancer (panel 3). Other randomised trials also support the use of high radiation doses.93,94 Whether high-dose radiation needs to be combined with hormonal therapy when used in patients with clinically localised disease is not clear, but there seems to be some benefit for the combination.93 Other ways to deliver radiotherapy precisely are to use high-dose brachytherapy, with iridium-192, together with external-beam radiotherapy, or to implant radioactive seeds, either as monotherapy or in combination with external-beam radiation.95 Although no comparative studies exist, these radiotherapy options are recommended as equal choices to surgery in some patients with localised prostate cancer.59 Other treatment options for men diagnosed with localised prostate cancer that have been used are high-intensity focused ultrasound and cryosurgery.96 Although both treatments were noted to decrease the serum PSA values and retain negative biopsy result post-therapy in many men, no long-term follow-up data are available.97

Treatment with curative intent for locally advanced prostate cancer Some patients with extracapsular extension of the tumour can still be offered treatment with curative intent. Radiotherapy has long been the standard option for these men. There are two main ways to increase the effectiveness of radiotherapy in men with locally www.thelancet.com Vol 371 May 17, 2008

advanced prostate cancer. First, dose escalation to greater than 70 Gy seems to result in good biochemical control rates, but survival advantages are yet to be seen.98,99 Second, the outcome for these patients can be improved by the combination of radiation with neoadjuvant hormonal therapy or adjuvant hormonal therapy. The use of short-term neoadjuvant hormonal therapy might result in improved biochemical control or local control and also in disease-specific survival. Longer periods of adjuvant hormonal therapy (up to 3 years after radiotherapy or indefinitely) will also result in an overall benefit in survival although benefit seems to be limited to patients with high Gleason scores in some studies.100,101 Whether patients who receive dose-escalated radiotherapy should receive neoadjuvant or adjuvant hormonal therapy, and for how long, and when, any adjuvant should be given, has not been sufficiently studied. Thus, the following treatment recommendations can be made: patients with locally advanced prostate cancer should be given either dose-escalated radiotherapy (greater than 70 Gy) or a combination of radiotherapy and adjuvant hormonal therapy, as long as they are willing to accept the side-effects.59 Radical prostatectomy is a less clearcut option, because of the difficulties in obtaining a free margin of resection (ie, total removal of the tumour), in patients who have extracapsular disease. However, some patients with small tumours that extend outside the gland might still be candidates for surgery.59,101 A special group of patients with locally advanced prostate cancer are those who have non-organ-confined prostate cancer (stage pT3) after histopathological examination of the resected tumour (radical prostatectomy). In one study by Thompson and others,102 425 men with stage pT3 prostate cancer were randomly assigned to immediate postoperative radiation (60–64 Gy) or observation and standard care (ie, hormonal therapy when needed). There was a difference in biochemical recurrence, but no significant difference Panel 3: American Urological Association’s guidelines for treatment • Low-risk patients: radiation dose higher than 70 Gy might decrease the risk of PSA recurrence, but no difference in survival has been shown89,90 • Intermediate-risk patients: a conventional-dose radiotherapy of 70 Gy or less with the use of neoadjuvant and concurrent hormonal therapy for 6 months might extend survival of patients.91 Higher radiation doses might reduce the risk of PSA recurrence, but no difference in survival has been shown89,90 • High-risk patients: a combination of long-term hormonal therapy (up to 3 years) might extend survival compared with external-beam radiotherapy alone91,92

For more on the American Urology Association’s guidelines for the management of prostate cancer see http:// www.auanet.org/guidelines/ main_reports/proscan07/ content.pdf

PSA=prostate-specific antigen.

1715

Seminar

in metastasis-free survival or overall survival.102 Bolla and co-workers103 showed that immediate postoperative radiotherapy given to patients with high-risk features was better than watchful waiting and delayed therapy, and it also reduced biochemical failure. However, both these studies had two drawbacks. First, few patients in the control group were offered second-line radiotherapy immediately at the time of PSA relapse as suggested in the European Association of Urology’s guidelines.59 Second, there is a substantial risk of overtreatment when all the patients are given immediate radiotherapy, without waiting for a substantiated biochemical recurrence. 40% of the patients in the control group did not show biochemical progression after 9 years of observation, in the European Organisation for Research and Treatment of cancer (EORTC) study.103

Second-line treatment after failed primary surgery or radiotherapy The first sign of failure after treatment with curative intent is generally a rising serum PSA concentration, occurring months to years before clinical symptoms or radiographic signs of recurrent disease. Thus, the choice of treatment for these men with rising PSA concentration after curative therapy is generally made without the contribution of any other objective signs of where the disease has recurred (ie, local or systemic failure). Generally, after either surgery or radiotherapy, local failure is characterised by a late PSA increase (more than 12 months after primary treatment), a long PSA-doubling time (ie, a slow rise in PSA over time), and a not too aggressive disease at diagnosis (no Gleason 8–10 score, or no invasion of seminal vesicle or lymph nodes). For patients with the opposite features, such as early PSA increase, rapid PSA doubling time, or adverse pathological changes, systemic failure is to be expected.104,105 Most patients with presumed local failure have a protracted course before clinical signs of disease recurrence become obvious, which means that men with a remaining long life expectancy (more than 5–10 years) could be offered a second treatment with curative attempt. After surgery, such treatment is a course of external-beam radiotherapy although the approach for patients with failure after radiotherapy is less clear. Attempts at radical surgery or other experimental therapies, such as high-intensity focused ultrasound or cryotherapy, are hampered by high complication rates and a low chance of permanent success.104,105 For men with short life expectancy and many men who have received primary radiotherapy, the advice is watchful waiting with delayed hormonal therapy if needed. For most patients who are at high risk of systemic failure, some form of hormonal therapy is recommended and frequently started before the metastatic disease can be detected with the available imaging modalities.105 1716

Treatment of metastatic prostate cancer Since the 1940s, androgen-ablative therapy has been the mainstay for management of advanced prostate cancer.106 Patients for whom endocrine therapy is advisable are those with prostate cancer with extraprostatic growth, with or without lymph-node metastases, or cancer with distant metastases. Testicular androgens can be eliminated by surgical removal of the testicles, inhibition of pituitary secretion of luteinising hormone or follicle-stimulating hormone by downregulation of the gonadotropin-releasing hormone (GnRH) receptors with agonist and antagonist, or administration of oestrogens to reduce the secretion of GnRH by the hypothalamus. Blocking the effect of androgens on the prostate with antiandrogens has become a viable approach. About 70–80% of treated patients with metastatic disease will have symptomatic relief—ie, reduced bone pain, improved performance status, and a general improvement with an increased sense of wellbeing after androgen ablation.106 In many treated patients, an objective response can be seen. Side-effects and toxic effects associated with endocrine manipulation are common, although mild compared with those of some other anticancer therapies. Loss of sexual function is the most obvious, whereas other side-effects such as osteoporosis, changes to body composition (ie, more fat and less muscle tissue), fatigue, depression, vasomotor symptoms, and lethargy are poorly defined, but together they might result in reduced quality of life.107 Randomised placebo-controlled studies of oestrogen therapy (diethylstilbestrol) in men with newly diagnosed advanced prostate cancer were done in the early 1970s.108 These studies clearly showed that immediate hormonal therapy delayed disease progression, but the excessive risk of cardiovascular toxic effects associated with diethylstilbestrol confounded any survival advantage. With this background, clinicians routinely deferred hormonal treatment until symptomatic progression occurred. The availability of GnRH agonists and non-steroidal antiandrogens from the 1980s made immediate hormonal intervention seem more attractive, to patients and clinicians. Although endocrine therapy is palliative and not biologically curative, increased uptake of this treatment could be contributing to the decline in mortality rates by delaying death from prostate cancer long enough for the patient to die of unrelated causes.109 Survival could be affected by the timing of hormonal therapy. Experiments in animals have shown that initiation of hormonal manipulation early in the course of tumour growth can substantially improve survival.110 Such findings in experimental prostate cancer models are supported by evidence from randomised controlled clinical trials. Some studies that investigated adjuvant hormonal therapy, with a GnRH agonist or bilateral orchiectomy, after radiotherapy have reported beneficial survival results.92,111–115 www.thelancet.com Vol 371 May 17, 2008

Seminar

A study by the Medical Research Council noted benefits of immediate hormonal therapy in men with previously untreated locally advanced or asymptomatic metastatic disease.115,116 938 patients were randomly assigned medical or surgical castration either at diagnosis or delayed until they developed symptoms. In the first analysis, done after 74% of the patients had died, overall mortality was significantly lower with immediate endocrine therapy.115 However, when patients were stratified by metastatic status at study entry, the difference in mortality between the two treatment groups remained significant only in patients without distant metastases. A second analysis after 86% of patients had died also showed a significant difference in overall survival favouring immediate therapy, but this difference was no longer statistically significant for patients without metastasis although it was significant for patients with metastasis.116 Results have also been reported from an EORTC study that compared early hormonal therapy with delayed hormonal therapy in men who had nodal metastases but without skeletal metastases. After a median follow-up of 8·7 years, a 23% survival difference in favour of early treatment was seen, but this result did not reach statistical significance.117 The value of non-steroidal antiandrogen, bicalutamide, given in addition to standard care was compared with placebo in 8113 patients with localised or locally advanced prostate cancer in the Early Prostate Cancer programme.118,119 Early bicalutamide treatment significantly improved survival in patients with locally advanced disease but not in men with localised disease.120–122 The notion of total androgen blockade, in which chemical castration was combined with an antiandrogen to block the action of adrenal androgens, was supported by early reports from non-randomised studies.123 These results led to several controlled trials to test the hypothesis that men with advanced prostate cancer survived longer after total androgen blockade than after monotherapy. However, the results from these controlled trials were partly contradictory. In a meta-analysis124 and a systematic review,125 a small survival advantage was described after combined treatment at 5-year follow-up. However, this small (2·9%) benefit in survival should be balanced against the increased risk of adverse effects and high costs of total androgen blockade.124 The treatment strategy of intermittent androgen ablation means that periods of androgen-ablative therapy (medical) are stopped when PSA concentration reaches its nadir (generally less than 4 ng/mL), followed by a period when the patients are not on any endocrine therapy. Therapy is reintroduced when PSA starts to increase again. Intermittent androgen suppression is based on the hypothesis that malignant prostate cancer cells remain in a hormone-dependent stage longer than under continuous treatment, thus leading to extended survival.126 This hypothesis is supported by the results of experimental studies on rat models with prostate cancer.127 The idea of intermittent treatment has been tested in www.thelancet.com Vol 371 May 17, 2008

several open clinical studies and seems feasible;128 however, no data are available as yet from prospective randomised trials with relevant endpoints. Therefore, intermittent androgen blockade should still be regarded as experimental.

Treatment of hormone-refractory prostate cancer The progression of metastatic androgen-independent prostate cancer is the final stage of this disease and constitutes a substantial threat of morbidity and mortality. For many years, cytotoxic chemotherapy was regarded as Panel 4: Complications related to treatment of prostate cancer Side-effects of radical prostatectomy • Erectile dysfunction (20–100%) • Urinary incontinence (any 0–70%; severe 0–4%) • Stricture (0–12%) • Mortality (<1%) Side-effects of radiotherapy • Gastrointestinal toxic effects (any 2–100%, severe 0–20%) • Genitourinary toxic effects (any 0–70%, severe 0–20%) • Urinary incontinence (any 0–60%, severe 2–15%) • Erectile dysfunction (10–85%) • Mortality (<1%)

For more on the European Association of Urology’s guidelines on prostate cancer see http://www.uroweb.org/ fileadmin/user_upload/Guidelines/ Prostate%20Cancer.pdf For more on the American Urology Association’s guidelines for the management of clinically localised prostate cancer see http://www.auanet. org/guidelines/main_reports/ proscan07/content.pdf

Side-effects of hormonal therapy Castration • Loss of libido • Erectile dysfunction • Hot flushes (55–80% of patients during androgen deprivation therapy) • Gynaecomastia and breast pain (49–80% diethylstilbestrol, 50% CAB, 10–20% castration) • Increase in body fat • Muscle wasting • Anaemia (severe in 13% CAB) • Decrease in bone mineral density • Cognitive decline Oestrogens • Cardiovascular toxic effects (acute myocardial infarction, congestive heart failure, cerebrovascular accident, deep-vein thrombosis, pulmonary embolism) Antiandrogens Steroidal • Pharmacological side-effects are loss of libido, erectile dysfunction, but rarely gynaecomastia • Non-pharmacological side-effects are related to individual drugs Non-steroidal • Pharmacological side-effects are gynaecomastia (49–66%), breast pain (40–72%), hot flushes (9–13%) • Non-pharmacological side-effects are related to individual drugs CAB=complete androgen blockade.

1717

Seminar

ineffective. However, two large clinical trials showed that docetaxel, alone or in combination with estramustine, improved the survival of men with hormone-refractory prostate cancer in comparison with mitoxantrone and corticosteroids.129,130 These reports represent a new era of systemic treatment for advanced prostate cancer.131 Moreover, new biologically active drugs such as inhibitors of angiogenesis and signal transduction, vaccines, and other immunomodulators are under investigation.132 The vaccine approach is interesting, since prostate cancer expresses potentially unique targets that enable the development of specific vaccines to recognise the cancer cells without affecting the benign tissue.132 In a randomised phase III trial of 127 patients who had metastatic, hormone-refractory prostate cancer and were given a dendritic-cell vaccine (sipuleucel-T; Provenge; Dendreon Corp, Seattle, USA),133 a median survival benefit of about 5 months was seen in the vaccinated group. Examples of targeted therapy for prostate cancer are the endothelin-receptor antagonist (atrasentan); Abbott Laboratories, Illinois, USA), the vascular endothelial growth factor monoclonal antibody (avastin; Genentech, South San Francisco, USA), and an antisense compound to BCL2, which have all been tried in prostate cancer trials as single agents and in combination with chemotherapy.134 The results so far are interesting, although no effect of targeted therapies on survival has yet been shown. The role of these therapeutic options in the treatment of prostate cancer will hopefully be proven in the future.

Complications of treatment Panel 4 lists an overview of possible complications for the most common primary treatments of prostate cancer. The rate of complications is related to characteristics of the patient (eg, age, comorbidity, previous disturbances), the timing of the treatment although modern surgical and radiotherapeutic techniques have decreased the risk of complications substantially, and how the treatment was given: nerve-sparing versus non-nerve-sparing surgery, surgical approach, conformal versus nonconformal radiation dose. (Conformal radiation dose means a specific radiation technique limiting the radiation dose to the prostate, thus allowing higher doses without toxic effects on surrounding tissues.) Many men diagnosed with prostate cancer are very old. For patients with metastatic disease, the trade-off between the mild side-effects of treatment and effectiveness—ie, symptomatic relief—is easy to make and nearly all these patients are recommended to have immediate hormonal therapy. Patients diagnosed with locally advanced prostate cancer but without proven distant metastases (stage T3–T4, N0–Nx, M0) will show a high progression rate without therapy and most will opt for immediate treatment. For the large group of patients diagnosed with apparently localised prostate cancer of low-to-intermediate risk, the choice of therapy is more complicated. For most 1718

patients with a life expectancy of less than 10 years, the recommended approach is watchful waiting with palliative treatment if needed. For men with a longer life expectancy, the low risk of serious but immediate side-effects—eg, erectile dysfunction, incontinence, or bowel disturbances—from treatment with curative intent should be weighed against the low risks of progression of the cancer to metastasis or death. Active monitoring and delayed treatment with curative intent has emerged as an option for those men in whom a clearcut treatment decision cannot be made immediately.

Conclusions Nowadays, we can recognise patients with aggressive prostate cancer who will need some form of immediate therapy. These men include not only patients with advanced or metastatic stage disease but also those with clinically localised disease with aggressive features. The main difficulty that clinicians face is the large number of men diagnosed with early stage disease, of whom a small proportion will have disease progression and ultimately die from prostate cancer if not treated. Such progression could be a result of future random mutations in the tumour; in that scenario, indolent tumours could not be distinguished from aggressive tumours at the time of diagnosis. Alternatively, as yet undiscovered markers of aggressiveness might be already present early in the course of the disease. The first possibility is taken into account in clinical practice by the treatment strategy of active monitoring, and the second is being investigated in many studies in progress. The treatment strategy, with surgical removal or local extinction by other treatment approaches for men with locally confined tumours and systemic, palliative therapy for men with disseminated disease, will probably not change in the near future. Conflict of interest statement JED has received honoraria for his work on the Advisory Board of Sanofi-Aventis, Stockholm, Sweden. GA has received honoraria for work on the Advisory Board of BK Medical AS, Herlev, Denmark. No specific comments related to products from these companies have been mentioned in the Seminar. Neither of the authors have any other conflict of interest. References 1 Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of prostate cancer. Prostate 1990; 17: 337–47. 2 Cannon L, Bishop DT, Skolnick M, Hunt S, Lyon JL, Smart CR. Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Survey 1982; 1: 47–69. 3 Grönberg H, Damber L, Damber JE. Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 1996; 77: 138–43. 4 Smith JR, Freje D, Carpten JD, et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 1996; 274: 1371–74. 5 Wiklund F, Jonsson BA, Brookes AJ, et al. Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer. Clin Cancer Res 2004; 10: 7150–56. 6 Kopper L, Timar J. Genomics of prostate cancer: is there anything to “translate”? Pathol Oncol Res 2005; 11: 197–203. 7 Deutsch E, Maggiorella L, Eschwege P, et al. Environmental, genetic, and molecular features of prostate cancer. Lancet Oncol 2004; 5: 303–13.

www.thelancet.com Vol 371 May 17, 2008

Seminar

8 9 10 11

12

13

14

15

16 17 18

19

20

21 22 23 24 25

26

27

28

29

30

31

32

Porkka KP, Visakorpi T. Molecular mechanisms of prostate cancer. Eur Urol 2004; 45: 683–91. Dong J-T. Prevalent mutations in prostate cancer. J Cell Biochem 2006; 97: 433–47. Edwards SM, Eeles RA. Unravelling the genetics of prostate cancer. Am J Med Genet C Semin Med Genet 2004; 129: 65–73. Amundadottir LT, Sulem P, Gudmundsson J, et al. A common variant associated with prostate cancer in European and African populations. Nat Genet 2006; 38: 652–58. Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–48. Schaid DJ, Chang BL, and the International Consortium For Prostate Cancer Genetics. Description of the International Consortium for Prostate Cancer Genetics, and failure to replicate linkage of hereditary prostate cancer to 20q13. Prostate 2005; 63: 276–90. Parkin DM, Muir CS, Whelan S, Ferlay J, Raymond L, Young J. Cancer incidence in five continents. vol. VII. Lyon: International Agency for Research on Cancer, 1997: 120. Kolonel LN, Altshuler D, Henderson BE. The multiethnic cohort study: exploring genes, lifestyle and cancer risk. Nat Rev Cancer 2004; 4: 519–27. Adlercreutz H, Mazur W. Phyto-oestrogens and western diseases. Ann Med 1997; 29: 95–120. Pukkala E, Gustavsson N, Teppo L. Atlas of cancer incidence in Finland. Helsinki: Cancer Society of Finland, 1987: 37. Kleemola P, Virtanen M, Pietinen P. Dietary survey of Finnish adults. Helsinki: Publications of the National Public Health Institute B2/1994. Sonoda T, Nagata Y, Mori M, et al. A case-control study of prostate cancer in Japan: possible protective effect of traditional Japanese diet. Cancer Sci 2004; 95: 238–42. Andersson S-O, Wolk A, Bergström R, et al. Body size and prostate cancer: a 20-year follow-up study among 135 006 Swedish construction workers. J Natl Canc Inst 1997; 89: 385–89. Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk. Lancet Oncol 2002; 3: 565–74. IARC. Weight control and physical activity. IARC Handbooks of Cancer Prevention. Lyon, France: IARC Press, 2002; 6: 117–20. Friedenreic CM, Thune I. A review of physical activity and prostate cancer risk. Cancer Causes Control 2001; 12: 461–75. Torti DC, Matheson GO. Exercise and prostate cancer. Sports Med 2004; 34: 363–69. Plaskon LA, Penson DF, Vaughan TL, Stanford JL. Cigarette smoking and risk of prostate cancer in middle-aged men. Cancer Epidemiol Biomarkers Prev 2003; 12: 604–09. Etminan M, Takkouche B, Caamano-Isorna F. The role of tomato products and lycopenes in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev 2004; 13: 340–45. Duffield-Lilico AJ, Dalkin BL, Reid ME, et al. Selenium supplementation, base line plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional prevention of cancer trial. BJU Int 2003; 91: 608–12. Dagnelie PC, Schuurman AG, Goldbohm RA, van den Brandt PA. Diet anthropometric measures and prostate cancer risk: a review of prospective cohort and intervention studies. BJU Int 2004; 93: 1139–50. Hartman TJ, Albanes D, Pietinen P, et al. The association between baseline vitamin E, selenium and prostate cancer in the alfa-tocopherol, beta-carotene prevention study. Cancer Epidemiol Biomarkers Prev 1998; 7: 335–40. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the Selenium and Vitamin E Cancer Prevention Trial: rationale and design. Prostate Cancer Prostatic Dis 2000; 3: 145–51. Stampfer MJ, Gann PH, Hough HL, et al. Vitamin D receptor polymorphisms, circulating vitamin D metabolites, and risk for prostate cancer in United States physicians. Cancer Epidemiol Biomarkers Prev 1998; 7: 385–90. Thompson IM, Goodman PJ, Tangen CM, et.al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349: 215–24.

www.thelancet.com Vol 371 May 17, 2008

33

34

35 36 37

38

39

40

41 42

43

44 45 46

47

48

49

50

51

52

53

54

Andriole G, Bostwick D, Civantos F, et al. Re: the effects of 5alpha-reductase inhibitors on the natural history, detection and grading of prostate cancer: current state of knowledge. J Urol 2006; 176: 408. Andriole G, Bostwick D, Brawley O, et al. Chemoprevention of prostate cancer in men with high risk: rationale and design of the reduction by dutasteride of prostate cancer events. J Urol 2004; 172: 1314–17. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. C A Cancer J Clin 2005; 55: 74–108. Boyle P, Ferlay J. Cancer incidence and mortality in Europe, 2004. Ann Oncol 2005; 16: 481–88. Ferlay J, Bray F, Pisani P, Parkin DM. Cancer incidence, mortality and prevalence worldwide, version 1.0. IARC Cancer Base No. 5 book. Lyon: IARC Press, 2001. Baade PD, Coory MD, Aitken JF. International trends in prostate-cancer mortality: the decrease is continuing and spreading. Cancer Causes Control 2004; 15: 237–41. Sarma AV, Schottenfeld D. Prostate cancer incidence, mortality, and survival trends in the United States: 1981–2001. Semin Urol Oncol 2002; 20: 3–9. Baade PD, Coory MD, Aitken JF. International trends in prostatecancer mortality: the decrease is continuing and spreading. Cancer Causes Control 2004; 15: 237–41. Oliver SE, May MT, Gunnell D. International trends in prostate-cancer mortality in the ‘PSA era’. Int J Cancer 2001; 92: 893–98. Boyle P, Baglietto L, Severi G, Gandini S, Robertson C. Trends in prostate cancer mortality world-wide: results of a systematic analysis. Proceedings of the Conference of the American Urology Association, Anaheim, June 2–7, 2001: Abstr 250. Mettlin CJ, Murphy GP, Ho R, Menck HR. The National Cancer Data Base report on longitudinal observations on prostate cancer. Cancer 1996; 77: 2162–66. Hoeksema MJ, Law, C. Cancer mortality rates fall: a turning point for the nation. J Natl Cancer Inst 1996; 88: 1706–07. Mettlin C. Impact of screening on prostate cancer rates and trends. Microsc Res Tech 2000; 51: 415–18. Potosky AL, Feuer EJ, Levin DL. Impact of screening on incidence and mortality of prostate cancer in the United States. Epidemiol Rev 2001; 23: 181–86. Oberaigner W, Horninger W, Klocker H, Schonitzer D, Stuhlinger W, Bartsch G. Reduction of prostate cancer mortality in Tyrol, Austria after introduction of prostate-specific antigen testing. Am J Epidemiol 2006; 164: 376–84. Lu-Yao G, Albertsen PC, Stamford JL, Stukel TA, Walker-Corkery ES, Barry MJ. Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut. BMJ 2002; 325: 740–47. De Koning HJ, Liem MK, Baan CA, Boer R, Schroder FH, Alexander FE. Prostate cancer mortality reduction by screening: power and time frame with complete enrolment in the European Randomized Screening for Prostate Cancer (ERSPC) trial. Int J Cancer 2002; 98: 268–73. Hugosson J, Aus G, Lilja H, Lodding P, Pihl C-G. Results of a randomized, population-based study of biennial screening using serum prostate-specific antigen measurement to detect prostate carcinoma. Cancer 2004; 100: 1397–405. Aus G, Bergdahl S, Lodding P, Lilja H, Hugosson J. Prostate cancer screening decreases the absolute risk of being diagnosed with advanced prostate cancer—results from a prospective, population-based randomized controlled trial. Eur Urol 2007; 51: 659–64. Van der Cruisjen-Koeter IW, Vis AN, Rooboll MJ, et al. Comparison of screen detected and clinically diagnosed prostate cancer in the European Randomized study of screening for prostate cancer, section Rotterdam. J Urol 2005; 174: 121–25. Aus G, Damber JE, Khatami A, Lilja H, Stranne J, Hugosson J. Individualized screening interval for prostate cancer based on prostate-specific antigen level. Results from a prospective populationbased randomized controlled trial. Arch Intern Med 2005; 165: 1857–61. Ito K, Yamamoto T, Ohi M, et al. Possibility of re-screening interval of more than one year in men with PSA levels of 4 ng/ml or less. Prostate 2003; 57: 8–13.

1719

Seminar

55

56

57

58

59 60 61

62

63 64

65

66

67

68

69

70

71

72

73

74

75

76

77

1720

Crawford D, Chia D, Andriole G. PSA testing interval, reduction in screening intervals: data from the prostate, lung colorectal and ovarian cancer (PLCO) trial (abstract). J Urol 2002; 167 (suppl 4): 99–100. Stenman UH, Abrahamsson PA, Aus G, Lilja H, Bangma C, et al. Prognostic value of serum markers for prostate cancer. Scand J Urol Nephrol 2005; 39: 64–81. Müller H, Brenner H. Urine markers as possible tools for prostate cancer screening: Review of performance characteristics and practicality. Clin Chem 2006; 52: 562–73. Hodge KK, McNeal JE, Terris MK, Stamey TA. Random systematic versus directed ultrasound-guided transrectal core biopsies of the prostate. J Urol 1989; 142: 71–74. Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005; 48: 546–51. Aus G, Damber JE, Hugosson J. Prostate biopsy and anaesthesia: an overview. Scand J Urol Nephrol 2005; 39: 124–29. Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 1974; 111: 58–64. Amin M, Boccon-Gibod L, Egevad L, et al. Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. Scand J Urol Nephrol 2005; 39: 20–33. Sobin LH, Wittekind C, eds. TNM classification of malignant tumours. 6th edn. New York: Wiley-Liss, 2002. Kirkham AP, Emberton M, Allen C. How good is MRI in detecting and characterising cancer within the prostate? Eur Urol 2006; 50: 1163–74. Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JL, Pearson JD. Contemporary updates of the prostate cancer staging nomograms (Partin Tables) for the new millenium. Urology 2001; 58: 843–48. Ohori M, Kattan MV, Koh H, et al. Predicting the presence and side of extracapsular extension: a nomogram for staging prostate cancer. J Urol 2004; 17: 1844–49. Jorgensen T, Muller C, Kaalhus O, Danielsen HE, Tveter KJ. Extent of disease based on initial bone scan: important prognostic predictor for patients with metastatic prostate cancer. Experience from the Scandinavian Prostatic Cancer Group Study No. 2 (SPCG-2). Eur Urol 1995; 28: 40–46. Glass TR, Tangen CM, Crawford ED, Thompson I. Metastatic carcinoma of the prostate: identifying prognostic groups using recursive partitioning. J Urol 2003; 169: 164–49. Brasso K, Christensen IJ, Johansen JS, et al. Prognostic value of PINP, bone alkaline phosphatase, CTX-I and YKL-40 in patients with metastatic prostate carcinoma. Prostate 2006; 66: 503–13. wak C, Jeong SJ, Park MS, Lee E, Lee SE. Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol 2002; 168: 995–1000. Morote J, Esquena S, Abascal JM, et al. Usefulness of prostate-specific antigen nadir as predictor of androgen-independent progression of metastatic prostate cancer. Int J Biol Markers 2005; 20: 209–16. Kiper A, Yigitbasi O, Imamoglu A, Tuygun C, Turan C. The prognostic importance of prostate specific antigen in the monitorisation of patients undergoing maximum androgen blockade for metastatic prostate cancer. Int Urol Nephrol 2006; 38: 571–76. Aus G, Nordenskjöld K, Robinson D, Rosell J, Varenhorst E. Prognostic factors and survival in node-positive (N1) prostate cancer: a prospective study based on data from a Swedish population based cohort. Eur Urol 2003; 43: 627–31. Kroepfl D, Loewen H, Roggenbuck U, Musch M, Klevacka V. Disease progression and survival in patients with prostate carcinoma and positive lymph nodes after radical retropubic prostatectomy. BJU Int 2006; 97: 985–91. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: 969–74. Thompson I, Trasher JB, Aus G, Burnett AL et al. Guideline for the mangement of clinically localized prostate cancer: 2007 update. J Urol 2007; 177: 2106–131. D’Amico AV, Whittington R, Malkowicz SB, et al. Predicting prostate specific antigen outcome preoperatively in the prostate specific antigen era. J Urol 2001; 166: 2185–88.

78

79

80

81

82

83

84 85

86

87

88

89

90

91

92

93

94

95

96 97

98 99

Beard C, Chen MH, Cote K, et al. Pretreatment predictors of posttreatment PSA doubling times for patients undergoing three-dimensional conformal radiotherapy for clinically localized prostate cancer. Urology 2005; 66: 1020–23. Greene KL, Elkin EP, Karapetian A, Duchane J, Carroll PR, Kane CJ; CaPSURE Investigators. Prostate biopsy tumour extent but not location predicts recurrence after radical prostatectomy; results from CaPSURE. J Urol 2006; 175: 125–29. Graefen M, Ohori M, Karakiewicz PI, et al. Assessment of the enhancement in predictive accuracy provided by systemic biopsy in predicting outcome for clinically localized prostate cancer. J Urol 2004; 171: 200–03. D’Amico AV, Renshaw AA, Sussman B, Chen MH. Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA 2005; 294: 440–47. D’Amico AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen MH. Surrogate end point for prostate cancer-specific mortality after radical prostaectomy or radiation therapy. J Natl Cancer Inst 2003; 95: 1376–83. Maffezini M, Bossi A, Collette L. Implications of prostate specific antigen doubling time as indicator of failure after surgery or radiation therapy for prostate cancer. Eur Urol 2007; 51: 605–13. Johansson JE, Andren O, Andersson SO, et al. Natural history of early, localised prostate cancer. JAMA 2004; 291: 2713–19. Albertssen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005; 293: 2095–3101. Wong YN, Mitra N, Hudes G, et al. Survival associated with treatment vs observation of localized prostate cancer in elderly men. JAMA 2006; 296: 2683–93. Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatecomy versus watchful waiting in early prostate cancer. N Engl J Med 2005; 352: 1977–84. Herrmann TR, Rabenalt R, Stolzenburg JU, et al. Oncological and functional results of open, robot-assisted and laparoscopic radical prostatectomy: does surgical approach and surgical experience matter? World J Urol 2007; 25: 149–60. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the MD Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002; 53: 1097–105. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 2005; 294: 1233–39. 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 randomised controlled trial. JAMA 2004; 292: 821–17. 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): a phase III randomised trial. Lancet 2002; 360: 103–08. Dearnalay DP, Sydes MR, Graham JD, et al. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007; 8: 475–87. Peeters S, Heemsbergeren W, Koper P, et al. Dose-response in radiotherapy for localized prostate cancer: Results of the Dutch multicenter randomized phase III trial comparing 58 Gy of radiotherapy with 78 Gy. J Clin Oncol 2006; 24: 1990–96. Pickles T, Pollack A. The case for dose escalation versus adjuvant androgen deprivation therapy for intermediate risk prostate cancer. Can J Urol 2006; 13 (suppl 2): 68–71. Aus G. Current status of HIFU and cryotherapy in prostate cancer—a review. Eur Urol 2006; 50: 927–34. Mangar SA, Huddart RA, Parker CC, Dearnaley DP, Khoo VS, Horwich A. Technological advances in radiotherapy for the treatment of localised prostate cancer. Europ J Cancer 2005; 41: 908–21. Nilsson S, Norlén BJ, Widmark A. A systemic overview of radiation therapy effects in prostate cancer. Acta Oncol 2004; 43: 316–81. Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. Cochrane Database Syst Rev 2006; 4: CD006019.

www.thelancet.com Vol 371 May 17, 2008

Seminar

100 Gerber GS, Thisted RA, Chodak GW, et al. Results of radical prostatectomy in men with locally advanced prostate cancer; multi-institutional pooled analysis. Eur Urol 1997; 32: 385–90. 101 Hsu CY, Joniau S, Oyen R, Roskams T, van Poppel H. Outcome of surgery for clinical unilateral T3a prostate cancer: a single-institution experience. Eur Urol 2007; 51: 121–28. 102 Thompson IM Jr, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomised clinical trial. JAMA 2006; 296: 2329–35. 103 Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005; 366: 572–78. 104 Simmons MN, Stephenson AJ, Klein EA. Natural history of biochemical recurrence after radical prostatectomy: risk assessment for secondary therapy. Eur Urol 2007; 51: 1175–84. 105 Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. http://www.uroweb.org/fileadmin/user_upload/Guidelines/ Prostate%20Cancer.pdf (accessed March 1, 2007). 106 Huggins C, Hodges CV. Studies on prostate cancer. 1 The effect of castration, of estrogen and of androgen injection on serum phosphatase in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293–97. 107 Varenhorst E. Prostate cancer treatment: tolerance of different endocrine regimens. In: Klosterhalfen H, ed. New development in biosciences 4, endocrine management of prostatic cancer. Berlin, New York: Walter de Gruyter, 1988: 105–13. 108 Byar DP. The Veterans Administration Cooperative Urological research Group’s studies of cancer of the prostate. Cancer 1973; 32: 1126–30. 109 Damber JE. Decreasing mortality rates for prostate cancer: possible role of hormonal therapy? BJU Int 2004; 93: 695–701. 110 Isaacs JT. The timing of androgen ablation therapy and/or chemotherapy in the treatment of prostatic cancer. Prostate 1984; 5: 1–17. 111 Granfors T, Modig H, Damber JE, Tomic R. Long-term followup of a randomized study of locally advanced prostate cancer treated with combined orchiectomy and external radiotherapy versus radiotherapy alone. J Urol 2006; 176: 544–47. 112 Pilepich MV, Caplan R, Byhardt RW, et al. Phase III trial of androgen suppression using goserelin in unfavourable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group protocol 85-31. J Clin Oncol 1997; 15: 1013–21. 113 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: 295–300. 114 Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. 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: 1781–88. 115 The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997; 79: 235–46. 116 Kirk D. Immediate vs. deferred hormone treatment for prostate cancer: how safe is androgen deprivation? Br J Urol 2000; 86 (suppl 3): 220. 117 Schröder FH, Kurth KH, Fossa SD, et al. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846—a phase III study. J Urol 2004; 172: 923–27.

www.thelancet.com Vol 371 May 17, 2008

118 See WA, McLeod D, Iversen P, Wirth M. The bicalutamide Early Prostate Cancer Program: demography. Urol Oncol 2001; 6: 43–47. 119 See WA, Wirth MP, McLeod DG, et al. Bicalutamide (‘Casodex’) 150 mg as immediate therapy either alone or as adjuvant to standard care in patients with localized or locally advanced prostate cancer: first analysis of the Early Prostate Cancer program. J Urol 2002; 168: 429–35. 120 Wirth MP, See WA, McLeod D, Iversen P, Morris T, Caroll K, on behalf of the Casodex early prostate cancer trialists’ group. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: result from the second analysis of the early prostate cancer program at median follow up of 5·4 years. J Urol 2004; 172: 1865–70. 121 Iversen P, Johansson JE, Lodding P, et al. 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: 1871–76. 122 Iversen P, Johansson J-E, Lodding P, et al. Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Group study 6 at 7·1-years median follow-up. Scand J Urol Nephrol 2006; 40: 441–52. 123 Labrie F, Dupont A, Belanger A, et al. Combination therapy with flutamide and castration (LHRH agonist or orchidectomy) in advanced prostate cancer: a marked improvement in response and survival. J Steroid Biochem Mol Biol 1985; 23: 833–41. 124 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: 361–76. 125 Schmitt B, Bennett C, Seidenfeldt J Samson D, Wilt T. Maximal androgen blockade for advanced prostate cancer (Cochrane Review). The Cochrane Library 2004; 4.http://www.cochrane.org/ resources/clibtrain.htm (accessed Feb 1, 2007). 126 Bruchovsky N, Rennie PS, Coldman AJ, Goldenberg SL, To M, Lawson D. Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma. Cancer Res 1990; 50: 2275–82. 127 Trachtenberg J. Experimental treatment of prostatic cancer by intermittent hormonal therapy. J Urol 1987; 137: 785–88. 128 Albrecht W, Collette L, Fava C, et al. Intermittent maximal androgen blockade in patients with metastatic prostate cancer: an EORTC feasibility study. Eur Urol 2003; 44: 505–11. 129 Petrylak DP, Tangen CM, Hussain MH, et al. Docotaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2005; 351: 1513–20. 130 Tannock IF, de Wit R, Berry WR, et al. Doxetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–12. 131 Kantoff P. Recent progress in management of advanced prostate cancer. Oncology 2005; 19: 631–36. 132 Sowery RD, So AI, Gleave ME. Therapeutic options in advanced prostate cancer: present and future. Curr Urol Rep 2007; 8: 53–59. 133 Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24: 3089–94. 134 Dorff TB, Quek ML, Daneshmand S, Pinski J. Evolving treatment paradigms for locally advanced and metastatic prostate cancer. Expert Rev Anticancer Ther 2006; 6: 1639–51.

1721