9. TREATMENT: RADICAL PROSTATECTOMY 9.1 Introduction 9.2 Low-risk localised PCa: cT1-T2a AND Gleason score 2-6 and PSA < 10 9.2.1 Stage T1a-T1b PCa 9.2.2 Stage T1c and T2a PCa 9.3 Intermediate-risk localised PCa: cT2b-T2c OR Gleason score = 7 or PSA 10-20 9.3.1 Oncological results of RP in low- and intermediate risk PCa 9.4 High-risk localised PCa: cT3a OR Gleason score 8-10 or PSA > 20 9.4.1 Locally-advanced PCa: cT3a 9.4.2 High-grade PCa: Gleason score 8-10 9.4.3 PCa with PSA > 20 9.5 Very high-risk localised PCa: cT3b-T4 N0 or any T, N1 9.5.1 cT3b-T4 N0 9.5.2 Any T, N1 184.108.40.206 Indication and extent of extended pelvic lymph node dissection (eLND) 220.127.116.11 Therapeutic role of eLND 18.104.22.168 Morbidity 22.214.171.124 Summary of eLND 9.6 Summary of RP in high-risk localised disease 9.7 Neoadjuvant hormonal therapy and RP 9.7.1 Summary of neoadjuvant and adjuvant hormonal treatment and RP 9.8 Complications and functional outcome 9.9 Summary of indications for nerve-sparing surgery 9.10 Guidelines and recommendations for RP 9.11 References
10.8.5 Short-term or long-term adjuvant hormonal treatment 10.8.6 Dose escalation with hormonal therapy Very high-risk prostate cancer: c or pN1 M0 Summary of definitive radiation therapy References
63 63 63 64 64
11. EXPERIMENTAL LOCAL TREATMENT OF PROSTATE CANCER 11.1 Background 11.2 Cryosurgery of the prostate (CSAP) 11.2.1 Indication for CSAP 11.2.2 Results of modern cryosurgery for PCa 11.2.3 Complications of CSAP for primary treatment of PCa 11.2.4 Summary of CSAP 11.3 High-intensity focused ultrasound (HIFU) of the prostate 11.3.1 Results of HIFU in PCa 11.3.2 Complications of HIFU 11.4 Radiofrequency interstitial tumour ablation (RITA) 11.5 Summary of experimental therapeutic options to treat clinically localized PCa 11.6 References
70 70 70 71 71 71 72 72 72 73 73 73 73
12. HORMONAL THERAPY 12.1 Introduction 12.2 Basics of hormonal control of the prostate 12.3 Different types of hormonal therapy 12.3.1 Testosterone-lowering therapy (castration) 126.96.36.199 Bilateral orchiectomy 188.8.131.52 Oestrogens 184.108.40.206 LHRH agonists 220.127.116.11 LHRH antagonists 12.3.2 Anti-androgens 18.104.22.168 Steroidal anti-androgens Cyproterone acetate (CPA) Megestrol acetate and medroxyprogesterone acetate 22.214.171.124 Non-steroidal anti-androgens Nilutamide Flutamide Bicalutamide 12.3.3 Combination therapies 126.96.36.199 Complete androgen blockade 188.8.131.52 Minimal androgen blockade (or peripheral androgen blockade) 184.108.40.206 Intermittent vs continuous androgen deprivation therapy 220.127.116.11 Immediate vs deferred ADT 12.4 Indications for hormonal therapy 12.5 Contraindications for various therapies 12.6 Outcome 12.7 Side-effects, QoL and cost of hormonal therapy 12.7.1 Side-effects 12.7.2 Quality of Life (QoL) 12.7.3 Cost-effectiveness of hormonal therapy options 12.8 Summary of hormonal therapy 12.9 References
14 FOLLOW-UP: AFTER PRIMARY TREATMENT WITH CURATIVE INTENT 14.1 Definition 14.2 Why follow-up? 14.3 How to follow-up? 14.3.1 PSA monitoring 14.3.2 Definition of PSA progression
99 99 99 99 99 99
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14.4 14.5 14.6
14.3.3 PSA monitoring after radical prostatectomy 14.3.4 PSA monitoring after radiation therapy 14.3.5 Digital rectal examination (DRE) 14.3.6 Transrectal ultrasonography (TRUS) and biopsy 14.3.7 Bone scintigraphy 14.3.8 Computed tomography (CT) and magnetic resonance imaging (MRI) When to follow-up? Guidelines for follow-up after treatment with curative intent References
100 100 100 100 100 100 100 101 101
15. FOLLOW-UP AFTER HORMONAL TREATMENT 15.1 Introduction 15.2 Purpose of follow-up 15.3 Methods of follow-up 15.3.1 Prostate-specific antigen monitoring 15.3.2 Creatinine, haemoglobin and liver function monitoring 15.3.3 Bone scan, ultrasound and chest X-ray 15.4 When to follow-up 15.4.1 Stage M0 patients 15.4.2 Stage M1 patients 15.4.3 Hormone-refractory patients 15.5 Guidelines for follow-up after hormonal treatment 15.6 References
16. TREATMENT OF BIOCHEMICAL FAILURE AFTER TRATMENT WITH CURATIVE INTENT 16.1 Background 16.2 Definitions 16.2.1 Definition of treatment failure 16.2.2 Definition of recurrence 16.3 Local or systemic relapse 16.3.1 Definition of local and systemic failure 16.4 Evaluation of PSA progression 16.5 Diagnostic procedures in patients with PSA relapse 16.6 Treatment of PSA-only recurrences 16.6.1 Radiation therapy for PSA-only recurrence after radical prostatectomy (RP) 16.6.2 Hormonal therapy 16.6.3 Observation 16.6.4 Management of PSA relapse after radical prostatectomy 16.7 Management of PSA failures after radiation therapy 16.7.1 Salvage cryosurgical ablation of the prostate (CSAP) for radiation failures 16.7.2 Salvage brachytherapy for radiation failures 16.7.3 Observation 16.7.4 Management of PSA-relapse after radiation therapy 16.8 Guidelines for second-line therapy after treatment with curative intent 16.9 References
17.8.3 Anti-androgen withdrawal accompanied by simultaneous ketoconazole 17.8.4 Oestogens 17.9 Non-hormonal therapy (cytotoxic agents) 17.9.1 Timing of chemotherapy in metastatic HRPC Taxanes in combination therapy Mitroxantrone combined with corticosteroids Alternative combination treatment approaches Estramustine in combination therapies Oral cyclophosphamide Suramin Salvage chemotherapy 17.10 Palliative therapeutic options 17.10.1 Painful bone metastases 17.10.2 Common complications due to bone mestatases 17.10.3 Bisphosphonates 17.11 Summary of treatment after hormonal therapy 17.12 Guidelines and recommendations for cytotoxic therapy in HRPC 17.13 Guidelines for palliative management of HRPC 17.14 Recommendations for palliative management of HRPC 17.15 References
1. introduction The European Association of Urology (EAU) Guidelines Group for Prostate Cancer have prepared this guidelines document to assist medical professionals assess the evidence-based management of prostate cancer. The multidisciplinary panel of experts include urologists, radiation oncologists, a medical oncologist and a pathologist. The recommendations provided in the current guidelines are based on a systemic literature search using Medline, the Cochrane Central Register of Controlled Trials, and reference lists in publications and review articles. Where possible a level of evidence (LE) and/or grade of recommendation (GR) have been assigned (1). Recommendations are graded in order to provide transparency between the underlying evidence and the recommendation given (Tables 1 and 2). Prior to publication external review has taken place. It has to be emphasised that the current guidelines contain information for the treatment of an individual patient according to a standardised general approach. Publication history information: The Prostate Cancer Guidelines were first published in 2001, with partial updates in 2003 and 2007, followed by the current full text update. But for one section (Chapter 14), all topics have been revised. Additionally, a quick reference guide is available. All texts can be viewed and downloaded for personal use at the society website: http://www.uroweb.org/professional-resources/guidelines/. Table 1: Level of evidence Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities Modified from Sackett et al. (1). Table 2: Grade of recommendation Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality Modified from Sackett et al. (1).
1.1 REFERENCE 1.
Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. http://www.cebm.net/index.aspx?o=1025 [accessed February 2009].
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2. BACKGROUND Cancer of the prostate (PCa) is now recognized as one of the most important medical problems facing the male population. In Europe, PCa is the most common solid neoplasm, with an incidence rate of 214 cases per 1000 men, outnumbering lung and colorectal cancer (1). Furthermore, PCa is currently the second most common cause of cancer death in men (2). In addition, since 1985, there has been a slight increase in most countries in the number of deaths from PCa, even in countries or regions where PCa is not common (3). Prostate cancer affects elderly men more often than young men. It is therefore a bigger health concern in developed countries with their greater proportion of elderly men. Thus, about 15% of male cancers are PCa in developed countries compared to 4% of male cancers in undeveloped countries (4). It is worth mentioning that there are large regional differences in incidence rates of PCa. For example, in Sweden, where there is a long life expectancy and mortality from smoking-related diseases is relatively modest, PCa is the most common malignancy in males, accounting for 37% of all new cases of cancer in 2004 (5).
2.1 REFERENCES 1. 2.
Boyle P, Ferlay J. Cancer incidence and mortality in Europe 2004. Ann Oncol 2005;16(3):481-8. http://www.ncbi.nlm.nih.gov/pubmed/15718248 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71-96. http://www.ncbi.nlm.nih.gov/pubmed/18287387 Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int 2002;90(2):162-73. http://www.ncbi.nlm.nih.gov/pubmed/12081758 Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000: the global picture. Eur J Cancer 2001;37(Suppl 8):S4-66. http://www.ncbi.nlm.nih.gov/pubmed/11602373 Cancer incidence in Sweden 2004. The National Board of Health and Welfare: Stockholm, 2005. http://www.socialstyrelsen.se/NR/rdonlyres/A23BCC9E-23B5-4747AAA923BB9CDF4B75/4753/20054291.pdf
3. CLASSIFICATION The 2002 TNM (Tumour Node Metastasis) classification for PCa is shown in Table 3 (1). The new TNM system is due to be published early in 2009, but was not yet available for citation. Table 3: Tumour Node Metastasis (TNM) classification of PCa*. T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Clinically inapparent tumour not palpable or visible by imaging T1a Tumour incidental histological finding in 5% or less of tissue resected T1b Tumour incidental histological finding in more than 5% of tissue resected T1c Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA] level) T2 Tumour confined within the prostate1 T2a Tumour involves one half of one lobe or less T2b Tumour involves more than half of one lobe, but not both lobes T2c Tumour involves both lobes T3 Tumour extends through the prostatic capsule2 T3a Extracapsular extension (unilateral or bilateral) T3b Tumour invades seminal vesicle(s) T4 Tumour is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, or pelvic wall N - Regional lymph nodes3 NX Regional lymph nodes cannot be assessed
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N0 No regional lymph node metastasis N1 Regional lymph node metastasis M - Distant metastasis4 MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Non-regional lymph node(s) M1b Bone(s) M1c Other site(s) 1
umour found in one or both lobes by needle biopsy, but not palpable or visible by imaging, is classified as T1c. T Invasion into the prostatic apex, or into (but not beyond) the prostate capsule, is not classified as T3, but as T2. 3 Metastasis no larger than 0.2 cm can be designated pN1mi. 4 When more than one site of metastasis is present, the most advanced category should be used. 2
*At the time of the publication of this document the updated TNM system was not yet available for citation.
3.1 Gleason score The Gleason score is the most commonly used system for grading adenocarcinoma of the prostate (2). The Gleason score can only be assessed using biopsy material (core biopsy or operative specimens). Cytological preparations cannot be used. The Gleason score is the sum of the two most common patterns (grades 1-5) of tumour growth found. The Gleason score ranges between 2 and 10, with 2 being the least aggressive and 10 the most aggressive. In needle biopsy, it is recommended that the worst grade always should be included, even if it is present in < 5% of biopsy material (3).
3.2 REFERENCES 1.
Sobin LH and Wittekind Ch (eds). TNM Classification of Malignant Tumours. 6th edn. Wiley-Liss: New York, 2002. http://www.wiley.com/WileyCDA/WileyTitle/productCd-0471222887.html Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 1974;111(1):58-64. http://www.ncbi.nlm.nih.gov/pubmed/4813554 Amin M, Boccon-Gibod L, Egevad L, Epstein JI, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R. Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. Scand J Urol Nephrol 2005 (Suppl);216:20-33. http://www.ncbi.nlm.nih.gov/pubmed/16019757
4. RISK FACTORS The factors that determine the risk of developing clinical PCa are not well known, although a few have been identified. There are three well-established risk factors for PCa: increasing age, ethnical origin and heredity. If one first-line relative has PCa, the risk is at least doubled. If two or more first-line relatives are affected, the risk increases 5- to 11-fold (1, 2). A small subpopulation of individuals with PCa (about 9%) has true hereditary PCa. This is defined as three or more affected relatives or at least two relatives who have developed earlyonset disease, i.e. before age 55 (3). Patients with hereditary PCa usually have an onset 6-7 years prior to spontaneous cases, but do not differ in other ways (4). The frequency of autopsy-detected cancers is roughly the same in different parts of the world (5). This finding is in sharp contrast to the incidence of clinical PCa, which differs widely between different geographical areas, being high in the USA and Northern Europe and low in Southeast Asia (6). However, if Japanese men move from Japan to Hawaii, their risk of PCa increases; if they move to California their risk increases even more, approaching that of American men (7) (level of evidence: 2). These findings indicate that exogenous factors affect the risk of progression from so-called latent PCa to clinical PCa. Factors such as food consumption, pattern of sexual behaviour, alcohol consumption, exposure to ultraviolet radiation and occupational exposure have all been discussed as being of aetiological importance (8). Prostate cancer is an ideal candidate for exogenous preventive measures, such as dietary and pharmacological prevention, due to some specific features: high prevalence, long latency, endocrine dependency, availability of serum markers (PSA) and histological precursor lesions (PIN). Dietary/nutritional
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factors that may influence disease development include total energy intake (as reflected by body mass index), dietary fat, cooked meat, micronutrients and vitamins (carotenoids, retinoids, vitamins C, D, and E), fruit and vegetable intake, minerals (calcium, selenium), and phyto-oestrogens (isoflavonoids, flavonoids, lignans). Since most studies reported to date are case-control analyses, there remain more questions than evidence-based data available to answer them. Several ongoing large randomised trials are trying to clarify the role of such risk factors and the potential for successful prostate cancer prevention (9). In summary, hereditary factors are important in determining the risk of developing clinical PCa, while exogenous factors may have an important impact on this risk. The key question is whether there is enough evidence to recommend lifestyle changes (lowered intake of animal fat and increased intake of fruit, cereals and vegetables) in order to decrease the risk (10). There is some evidence to support such a recommendation and this information can be given to male relatives of PCa patients who ask about the impact of diet (level of evidence: 2-3).
4.1 REFERENCES 1.
Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of prostate cancer. Prostate 1990;17(4):337-47. http://www.ncbi.nlm.nih.gov/pubmed/2251225 Gronberg H, Damber L, Damber JE. Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 1996;77(1):138-43. http://www.ncbi.nlm.nih.gov/pubmed/8630920 Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 1992;89(8):3367-71. http://www.ncbi.nlm.nih.gov/pubmed/1565627 Bratt O. Hereditary prostate cancer: clinical aspects. J Urol 2002;168(3):906-13. http://www.ncbi.nlm.nih.gov/pubmed/12187189 Breslow N, Chan CW, Dhom G, Drury RAB, Franks LM, Gellei B, Lee YS, Lundberg S, Sparke B, Sternby NH, Tulinius H. Latent carcinoma of prostate at autopsy in seven areas. The International Agency for Research on Cancer, Lyons, France. Int J Cancer 1977;20(5):680-8. http://www.ncbi.nlm.nih.gov/pubmed/924691 Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int 2002;90(2):162-73. http://www.ncbi.nlm.nih.gov/pubmed/12081758 Zaridze DG, Boyle P, Smans M. International trends in prostatic cancer. Int J Cancer 1984;33(2): 223-30. http://www.ncbi.nlm.nih.gov/pubmed/6693200 Kolonel LN, Altshuler D, Henderson BE. The multiethnic cohort study: exploring genes, lifestyle and cancer risk. Nat Rev Cancer 2004;4(7):519-27. http://www.ncbi.nlm.nih.gov/pubmed/15229477 Schmid H-P, Engeler DS, Pummer K, Schmitz-Dräger B J. Prevention of prostate cancer: more questions than data. Cancer Prevention. Recent Results Cancer Res 2007;174:101-7. http://www.ncbi.nlm.nih.gov/pubmed/17302190 Schulman CC, Zlotta AR, Denis L, Schroder FH, Sakr WA. Prevention of prostate cancer. Scand J Urol Nephrol 2000;205(Suppl):50-61. http://www.ncbi.nlm.nih.gov/pubmed/11144904
5. SCREENING AND EARLY DETECTION Population or mass screening is defined as the examination of asymptomatic men (at risk). It usually takes place as part of a trial or study and is initiated by the screener. In contrast, early detection or opportunistic screening comprises individual case findings, which are initiated by the person being screened (patient) and/or his physician. The primary endpoint of both types of screening has two aspects: 1. Reduction in mortality from PCa. The goal is not to detect more and more carcinomas, nor is survival the endpoint because survival is strongly influenced by lead-time from diagnosis. 2. The quality of life is important as expressed by quality-of-life adjusted gain in life years (QUALYs). Prostate cancer mortality trends range widely from country to country in the industrialised world (1). Decreased mortality rates due to PCa have occurred in the USA, Austria, UK and France, while in Sweden, 10
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the 5-year survival rate has increased from 1960 to 1988, probably due to increased diagnostic activity and greater detection of non-lethal tumours (2). However, this trend was not confirmed in a similar study from the Netherlands (3). The reduced mortality seen recently in the USA is often attributed to the widely adopted aggressive screening policy, but there is still no absolute proof prostate-specific antigen (PSA) screening reduces mortality due to PCa (4) (level of evidence: 2). A non-randomised screening project in Tyrol (Austria) may support the hypothesis that screening can be effective in reducing mortality from PCa. An early detection programme and free treatment have been used to explain the 33% decrease in the PCa mortality rate seen in Tyrol compared to the rest of Austria (5) (level of evidence: 2b). In addition, a Canadian study has claimed lower mortality rates in men randomised to active PCa screening (6), though these results have been challenged (7). Positive findings attributed to screening have also been contradicted by a comparative study between the US city of Seattle area (highly screened population) and the US state of Connecticut (seldom screened population) (8). The study found no difference in the reduction in the rate of PCa mortality (level of evidence: 2b), even allowing for the very great diversity in PSA testing and treatment. Prospective, preferably population-based, randomised trials are needed to properly evaluate the efficacy of PCa screening. Two large trials are underway, the PLCO (Prostate, Lung, Colorectal and Ovary) trial in the USA and the ERSPC (European Randomized Screening for Prostate Cancer) in Europe (9, 10). The main endpoint of these trials is difference in PCa mortality, with first results due in 2009 (level of evidence: 1b). Thus, there is currently no evidence for introducing widespread, population-based, screening programmes for early PCa detection in all men in a given population (4) (level of evidence: 2). A less controversial programme, which is also recommended by most guidelines, is using PSA with digital rectal examination (DRE) as an aid to early diagnosis (11) (see Section 6.1) (level of evidence: 3). Nevertheless, a few conclusions about screening intervals can be deduced from the ERSPC study (12): • A screening interval of 2 or 4 years had no impact on outcome in a cohort of 17,505 men aged 55-74 years • The rate of interval cancer, especially aggressive interval cancer, was low in this study (0.43% vs 0.74%) • Although the 2-year screening interval had a higher detection rate for PCa than the 4-year interval (13.14% vs 8.42%), it did not lead to lower incidences of interval PCa (0.11%) and aggressive interval PCa (0.12%) • A screening interval of 8 years might be enough in men with initial PSA levels ≤ 1 ng/ml (13) • A total of 1703 men had a PSA level ≤ 1 ng/ml when they first presented for screening. A total of 1327 men (79.3%) attended the second screening visit during which 13 men (0.98%) had PSA levels ≥ 3.0 ng/mL and three cancers were detected (0.23%) • A total of 1017 men (76.8%) attended the third screening visit during which 34 men (3.3%) had a PSA level ≥ 3.0 ng/mL and five cancers were detected (0.49%) • The 2344 subsequent PSA determinations during an 8-year period following the initial screening visit resulted in the detection of eight cancers (0.47%) • Thus, PSA screening every 8 years for men with PSA levels ≤ 1.0 ng/mL would mean fewer screening visits (with less cost and stress), with a minimal risk of missing aggressive cancer at a curable stage. The decision to undergo early PSA testing should be a shared decision between the patient and his physician (14, 15). PSA testing and digital rectal examination should be offered from the age of 45 years to men with a life expectancy of at least 10 years. The most recent research suggests further PSA testing is unnecessary in men ≥ 75 years and a PSA level ≤ 3 ng/mL at their first screening visit. This is because these men have a very low risk of dying from PCa (16).
5.1 REFERENCES 1.
Oliver SE, May MT, Gunnell D. International trends in prostate-cancer mortality in the ‘PSA-ERA’. Int J Cancer 2001;92(6):893-8. http://www.ncbi.nlm.nih.gov/pubmed/11351313 2. Helgesen F, Holmberg L, Johansson JE, Bergstrom R, Adami HO. Trends in prostate cancer survival in Sweden, 1960 through 1988, evidence of increasing diagnosis of non-lethal tumours. J Natl Cancer Inst 1996;88(17):1216-21. http://www.ncbi.nlm.nih.gov/pubmed/8780631
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Post PN, Kil PJ, Coebergh JW. Trends in survival of prostate cancer in southeastern Netherlands 1971-1989. Int J Cancer 1999;81(4):551-4. http://www.ncbi.nlm.nih.gov/pubmed/10225443 Ilic D, O’Connor D, Green S, Wilt T. Screening for prostate cancer: a Cochrane systematic review. Cancer Causes Control 2007;18(3):279-85. http://www.ncbi.nlm.nih.gov/pubmed/17206534 Bartsch G, Horninger W, Klocker H, Reissigl A, Oberaigner W, Schönitzer D, Severi G, Robertson C, Boyle P; Tyrol Prostate Cancer Screening Group. Prostate cancer mortality after introduction of prostate specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 2001;58(3):417-24. http://www.ncbi.nlm.nih.gov/pubmed/11549491 Labrie F, Candas B, Dupont A, Cusan L, Gomez JL, Suburu RE, Diamond P, Lévesque J, Belanger A. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999;38(2):83-91. http://www.ncbi.nlm.nih.gov/pubmed/9973093 Boer R, Schroeder FH. Quebec randomized controlled trial on prostate cancer screening shows no evidence of mortality reduction. Prostate 1999;40(2):130-4. http://www.ncbi.nlm.nih.gov/pubmed/10386474 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(7367):740. http://www.ncbi.nlm.nih.gov/pubmed/12364300 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(2):268-73. http://www.ncbi.nlm.nih.gov/pubmed/11857418 Schröder FH, Bangma CH, Roobol MJ. Is it necessary to detect all prostate cancers in men with serum PSA levels < 3 ng/ml? A comparison of biopsy results of PCPT and outcome-related information from ERSPC. Eur Urol 2008;53(5):901-8. http://www.ncbi.nlm.nih.gov/pubmed/18262712 Schmid H-P, Riesen W, Prikler L. Update on screening for prostate cancer with prostate-specific antigen. Crit Rev Oncol Hematol 2004;50(1):71-8. http://www.ncbi.nlm.nih.gov/pubmed/15094160 Roobol MJ, Grenabo A, Schröder FH, Hugosson J. Interval cancers in prostate cancer screening: comparing 2- and 4-year screening intervals in the European Randomized Study of Screening for Prostate Cancer, Gothenburg and Rotterdam. J Natl Cancer Inst 2007;99(17):1296-303. http://www.ncbi.nlm.nih.gov/pubmed/17728218 Roobol MJ, Roobol DW, Schröder FH. Is additional testing necessary in men with prostate-specific antigen levels of 1.0 ng/mL or less in a population-based screening setting? (ERSPC, section Rotterdam). Urology 2005;65(2):343-6. http://www.ncbi.nlm.nih.gov/pubmed/15708050 Smith RA, Cokkinides V, von Eschenbach AC, Levin B, Cohen C, Runowicz CD, Sener S, Saslow D, Eyre HJ; American Cancer Society. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 2002;52(1):8-22. http://www.ncbi.nlm.nih.gov/pubmed/11814067 Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 2009;59:27-41. http://www.ncbi.nlm.nih.gov/pubmed/19147867 Carter HB, Kettermann AE, Ferrucci L, Landis P, Trock BJ, Metter EJ. Prostate specific antigen testing among the elderly: when to stop. J Urol 2008;179 (Suppl):600, abstract 1751.
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6. DIAGNOSIS* The main diagnostic tools used to look for evidence of PCa include DRE, serum concentration of PSA and transrectal ultrasonography (TRUS). Diagnosis depends on the presence of adenocarcinoma in operative specimens, prostate biopsy cores or aspiration needle cytology. Histopathological examination also allows grading of the tumour.
6.1 Digital rectal examination (DRE) Most prostate cancers are located in the peripheral zone of the prostate and may be detected by DRE when the volume is about 0.2 mL or larger. A suspect DRE is an absolute indication for prostate biopsy. In about 18% of all patients, PCa is detected by a suspect DRE alone, irrespective of the PSA level (1) (level of evidence: 2a). A suspect DRE in patients with a PSA level of up to 2 ng/mL has a positive predictive value of 5-30% (2) (level of evidence: 2a).
6.2 Prostate-specific antigen (PSA) The measurement of PSA level has revolutionised the diagnosis of PCa (3). Prostate-specific antigen (PSA) is a kallikrein-like serine protease produced almost exclusively by the epithelial cells of the prostate. For practical purposes, it is organ-specific but not cancer-specific. Thus, serum levels may be elevated in the presence of benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. The level of PSA as an independent variable is a better predictor of cancer than suspicious findings on DRE or TRUS (4). There are many different commercial test kits for measuring PSA, but no commonly agreed international standard exists (5). The level of PSA is a continuous parameter: the higher the value, the more likely is the existence of PCa (Table 4). This means there is no universally accepted cut-off or upper limit. The finding that many men may harbour PCa, despite low levels of serum PSA, has been underscored by recent results from a US prevention study (6) (level of evidence: 2a). Table 4 gives the rate of PCa in relation to serum PSA for 2950 men in the placebo-arm and with normal PSA values. Table 4: Risk of PCa in relation to low PSA values PSA level (ng/mL) • 0-0.5 • 0.6-1 • 1.1-2 • 2.1-3 • 3.1-4
Risk of PCa 6.6% 10.1% 17.0% 23.9% 26.9%
PSA = prostate-specific antigen. These findings highlight an important issue about lowering the PSA-level threshold, which is how to avoid detecting insignificant cancers with a natural history unlikely to be life threatening (7). As yet, there is no long-term data to help determine the optimal PSA threshold value for detecting non-palpable, but clinically significant, PCa (level of evidence: 3). Several modifications of serum PSA value have been described, which may improve the specificity of PSA in the early detection of PCa. They include: PSA density, PSA density of the transition zone, age-specific reference ranges and PSA molecular forms. However, these derivatives and certain PSA isoforms (cPSA, proPSA, BPSA, iPSA) have limited usefulness in the routine clinical setting and have therefore not been considered for inclusion in these guidelines. 6.2.1 Free/total PSA ratio (f/t PSA) The free/total PSA ratio (f/t PSA) is the concept most extensively investigated and most widely used in clinical practice to discriminate BPH from PCa, and has been used to stratify the risk of PCa for men with total PSA levels between 4 and 10 ng/mL and with a negative DRE. In a prospective multicentre trial, PCa was found on biopsy in 56% of men with a f/t PSA < 0.10, but in only 8% of men with f/t PSA > 0.25 (8) (level of evidence: 2a). Nevertheless, the concept must be used with caution as several pre-analytical and clinical factors may influence the f/t PSA. For example, free PSA is unstable at both 4°C and at room temperature. In addition, * Acknowledgment: Section 6.4 is partly based on the Guidelines of the AUO Study Group Urologic Oncology of the Austrian Society of Urologists and Andrologists (W. Höltl, W. Loidl, M. Rauchenwald, M. Müller, M. Klimpfinger, A. Schratter-Sehn, C. Brössner). Update march 2009
assay characteristics may vary and concomitant BPH in large prostates may result in a ‘dilution effect’ (9). Furthermore, f/t PSA is clinically useless in total serum PSA values > 10 ng/mL and in follow-up of patients with known PCa. 6.2.2 PSA velocity (PSAV), PSA doubling time (PSADT) There are two methods of measuring PSA over time. These are: • PSA velocity (PSAV), defined as an absolute annual increase in serum PSA (ng/mLyear) (10) (level of evidence: 1b). • PSA doubling time (PSADT), which measures the exponential increase of serum PSA over time reflecting a relative change (11). These two concepts may have a prognostic role in patients with treated PCa (12). However, they have limited use in the diagnosis of PCa because of several unresolved issues, including background noise (total volume of prostate, BPH), the interval between PSA determinations, and acceleration/deceleration of PSAV and PSADT over time. Prospective studies have not shown these measurements can provide additional information compared to PSA alone (13, 14). 6.2.3 PCA3 marker In contrast to the serum markers discussed above, PCA3 is measured in urine sediment obtained after prostatic massage (15). Determination of this PCa-specific gene is experimental. In the near future, several molecular diagnostic tests may move out of the laboratory into the clinical setting (16). So far, none of the above biomarkers can be used to counsel an individual patient on the need to perform a prostate biopsy to rule out PCa.
Transrectal ultrasonography (TRUS)
The classic picture of a hypoechoic area in the peripheral zone of the prostate will not always be seen (17). Gray-scale TRUS does not detect areas of PCa with adequate reliability. Replacing systematic biopsies by targeted biopsies of suspect areas is therefore unproductive. However, additional biopsies of suspect areas may be useful.
6.4 Prostate biopsy 6.4.1 Baseline biopsy The need for prostate biopsies should be determined on the basis of the PSA level and/or a suspicious DRE. The patient’s biological age, potential co-morbidities (ASA Index and Charlson Comorbidity Index) and the therapeutic consequences should also be considered. The first elevated PSA level should not prompt an immediate biopsy. The PSA level should be verified after a few weeks by the same assay under standardised conditions (i.e. no ejaculation and no manipulations, such as catheterisation, cystoscopy or TUR, and no urinary tract infections) in the same diagnostic laboratory, using the same methods (18, 19) (level of evidence: 2a). The ultrasound-guided perineal approach is a useful alternative in special situations, e.g. after rectal amputation. Its detection rates are comparable to those of the transrectal approach (20) (level of evidence: 1b). 6.4.2 Repeat biopsy Indications are rising and/or persistent PSA, suspicious DRE and atypical small acinar proliferation (ASAP). The optimal timing is uncertain and depends on the histological outcome of the baseline ASAP biopsy and the index of a persistent suspicion of PCa (high or dramatically rising PSA, suspect DRE, family history). The later the repeat biopsy is done, the higher the detection rate (21). High-grade prostatic intraepithelial neoplasia (PIN) is no longer considered an indication for re-biopsy (22) (level of evidence: 2a). A repeat biopsy should therefore be prompted by other clinical features, like DRE findings and PSA level. If PIN is extensive (i.e. in several biopsies) this could be a reason for early re-biopsy. 6.4.3 Saturation biopsy The incidence of PCa detected by saturation repeat biopsy is between 30% and 43% and depends on the number of cores sampled during earlier biopsies (23) (level of evidence: 2a). In special situations, saturation biopsy may be performed with the transperineal technique. This will detect an additional 38% of PCa. The high rate of urinary retention (10%) is a drawback (3D- stereotactic biopsy) (24) (level of evidence: 2b). 6.4.4 Sampling sites and number of cores On baseline biopsies, the sample sites should be as far posterior and lateral in the peripheral gland as possible. 14
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Additional cores should be obtained from suspect areas by DRE/TRUS. These should be chosen on an individual basis. Sextant biopsy is no longer considered adequate. At a glandular volume of 30-40 mL, at least eight cores should be sampled. More than 12 cores are not significantly more conclusive (25) (level of evidence: 1a). The British Prostate Testing for Cancer and Treatment Study has recommended 10-core biopsies (26) (level of evidence: 2a). 6.4.5 Diagnostic transurethral resection of the prostate (TURP) The use of diagnostic TURP instead of repeat biopsies is of minor importance. Its detection rate is no better than 8% and makes it a poor tool for cancer detection (27) (level of evidence: 2a). 6.4.6 Seminal vesicle biopsy Indications for seminal vesicle biopsies are not well defined. At PSA levels > 15-20 ng/mL, a biopsy is only useful if the outcome will have a decisive impact on treatment, i.e. if the biopsy result rules out radical removal for tumour involvement or radiotherapy with intent to cure. At PSA levels > 15-20 ng/L, the odds of tumour involvement are 20-25% (28) (level of evidence: 2a). 6.4.7 Transition zone biopsy Transition zone (TZ) sampling during baseline biopsies provides a very low detection rate and TZ sampling should therefore be confined to repeat biopsies (29) (level of evidence: 1b). 6.4.8 Antibiotics Oral or intravenous antibiotics are state-of-the-art treatment. Optimal dosing and treatment time vary. Quinolones are the drugs of choice, with ciprofloxacin superior to ofloxacin (30) (level of evidence: 1b). 6.4.9 Local anaesthesia Ultrasound-guided peri-prostatic block is state-of-the-art (31) (level of evidence: 1b). It does not make any difference whether the depot is apical or basal. Intrarectal instillation of a local anaesthetic is clearly inferior to peri-prostatic infiltration (32) (level of evidence: 1b). 6.4.10 Fine-needle aspiration biopsy Fine-needle aspiration biopsy is not as effective as TRUS-guided transrectal core biopsy because of the lack of uropathologists experienced in cytology. In addition, TRUS-guided transrectal core biopsies provide more information on the extent of the tumour. 6.4.11 Complications Complication rates are low (Table 5) (33). Minor complications include macrohaematuria and haematospermia. Severe post-procedural infections have been reported in < 1% of cases. The recent increase in the number of biopsy cores performed has not increased the rate of severe complications requiring treatment. Low-dose aspirin is no longer an absolute contraindication (34) (level of evidence: 1b). Table 5: Percentage given per biopsy session, irrespective of the number of cores* Complications • Haematospermia • Bleeding from urethra, urinary bladder (> 1 day) • Fever • Urosepsis • Rectal bleeding • Urine retention • Prostatitis • Epididymitis
% of biopsies 37.4 14.5 0.8 0.3 2.2 0.2 1.0 0.7
* Adapted from Consensus Guidelines NCCN, Version 1.2007 (33).
6.5 Pathology of prostate needle biopsies 6.5.1 Grossing and processing Prostate core biopsies taken from different sites are usually sent to the pathology laboratory in separate vials and should be processed in separate cassettes. Before processing, record the number of cores per vial and
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length of each core. There is a significant correlation between the length of prostate biopsy tissue on the histological slide and the detection rate of PCa (35). To achieve optimal flattening and alignment of individual cores, embed a maximum of three cores per cassette and use sponges or paper to keep the cores stretched and flat (36, 37). To optimise the detection of small lesions, blocks should be cut in three levels (38). It may be of help if intervening tissue sections are routinely mounted in case additional immunostaining is needed. 6.5.2 Microscopy and reporting Diagnosis of prostate cancer is based on histological examination. However, immunostaining may also be helpful (39, 40). Ancillary staining techniques (e.g. basal cell staining) and additional (deeper) sections should be considered if a suspect glandular lesion is identified (38, 40). For suspicious lesions in biopsies, diagnostic uncertainty may often be resolved by intradepartmental consultation and a second opinion from an external institution (39). Use concise clear terminology to report prostate biopsies (37) (Table 6) and avoid terms such as ’atypia‘, ’atypical glands‘ or ‘possibly malignant‘. Table 6: Diagnostic terms used to report prostate biopsy findings* • Benign/negative for malignancy. If appropriate, include a description (e.g. atrophy). Chronic inflammation may be added (optional) • Active inflammation, negative for malignancy • Atypical adenomatous hyperplasia/adenosis, no evidence of malignancy • Granulomatous inflammation, negative for malignancy • High-grade PIN, negative for adenocarcinoma • High-grade PIN with atypical glands suspicious for adenocarcinoma • Focus of atypical glands/lesion suspicious for adenocarcinoma • Adenocarcinoma *From Van der Kwast, 2003 (36). PIN = prostatic intra-epithelial neoplasia. For each biopsy site, report the proportion of biopsies positive for carcinoma and the Gleason score, using the system adopted in 2005 (41). According to current international convention, the (modified) Gleason score of cancers detected in a prostate biopsy consists of the Gleason grade of the dominant (most extensive) carcinoma component plus the highest grade, irrespective of its extent (no 5% rule). When the carcinoma largely consists of grade 4/5 carcinoma, identification of a small portion (< 5% of the carcinoma) of Gleason grade 2 or 3 glands should be ignored. A diagnosis of Gleason score 4 or lower should not be given on prostate biopsies (41). The presence of high-grade PIN and extraprostatic extension should be reported. In addition to a report of the carcinoma features for each biopsy site, provide an overall Gleason score based on findings in the individual biopsies. The presence of perineural invasion is usually reported, even though there is conflicting evidence about its usefulness as a prognosticator of unfavourable disease (42, 43). The proportion (%) or length (mm) of tumour involvement per biopsy site correlates with tumour volume, extraprostatic extension and prognosis after prostatectomy (43-45) and should therefore be recorded. The length of carcinoma (mm) and the percentage of carcinoma involvement of the biopsy have equal prognostic impact (46). The extent of a single, small focus of adenocarcinoma, which is located in only one of the biopsies, should be clearly stated (e.g. < 1 mm or < 1%), as this might be an indication for further diagnostic work-up before selecting therapy. In some studies, a finding of < 3 mm carcinoma in one biopsy with a Gleason score 5–6 has often been associated with insignificant cancer and with an increased risk of vanishing cancer (4749). A prostate biopsy that does not contain glandular prostate tissue could be reported as inadequate for diagnostics, except on staging biopsies. A recent study evaluated the concordance of pattern and change of prognostic groups for the conventional and the modified Gleason grading (50). The evaluation was based on 172 prostatic needle biopsies of patients who subsequently underwent RP. Four prognostic Gleason grading groups were considered, divided into scores of 2–4, 5–6, 7 and 8–10. To check the discriminative power of the modified Gleason grading, the time of biochemical progression-free outcome, according to prognostic groups, was compared between standard and revised grading. The greatest impact of the International Society of Urological Pathology consensus recommendations for Gleason grading was seen on the secondary pattern, which had the lowest percentage of concordance and was reflected in a change toward higher Gleason prognostic groups. Of 172 patients in whom the Gleason prognostic group was changed (to higher grades) based solely on the consensus criteria, 46 (26.7%) had a higher pre-operative PSA level, more extensive tumours and positive surgical
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margins, and a higher pathological stage. In this series, the revised Gleason grading identified more patients in the aggressive prognostic group Gleason score 8–10, who had a significantly shorter time to biochemical progression-free outcome after radical prostatectomy (log rank p = 0.011). These findings have shown that the recommendations of the International Society of Urological Pathology are a valuable refinement of the standard Gleason grading system.
6.6 Pathohistology of radical prostatectomy (RP) specimens 6.6.1 Processing of the RP specimen The histopathological examination of RP specimens aims to provide information about the actual pathological stage, grade and surgical margin status of the prostate cancer. The weight and dimensions of the specimen are recorded before embedding it for histological processing. It is generally recommended that RP specimens are totally embedded to enable the best assessment of location, multifocality and heterogeneity of the cancer. However, for cost-efficiency purposes, partial embedding using a standard method may also be considered, particularly for large-sized prostates (> 60 g). The most acceptable method includes the complete embedding of the posterior (dorsal) part of the prostate in addition to a single mid-anterior left and right section. Compared to total embedding, this method of partial embedding permitted detection of 98% of prostate cancers with a Gleason score ≥ 7 and accurate staging in 96% of cases (51). Upon receipt in the histopathology lab, the entire RP specimen is inked in order to appreciate the surgical margin status. The specimen is fixed in buffered formalin, preferably prior to incision of the sample, as incision causes distortion of the tissue. Generally, appropriate fixation is achieved by immersing the RP specimen in fixative for a few days. Fixation can be enhanced by injecting formalin using 21-gauge syringes, which provides a more homogeneous fixation and sectioning after 24 hours (52). After fixation, the apex is removed and cut with (para)sagittal or radial sections; the shave method is not recommended (53). Separate sagittal sectioning of the bladder neck is optional. The remainder of the RP specimen is generally cut in transverse sections at 3-4 mm steps, perpendicularly to the posterior surface. The resulting tissue slices can be embedded and processed either as whole-mounts or after quadrant sectioning. Whole-mount processing provides better topographic visualisation of the carcinoma and a faster histopathological examination. However, it is a more time-consuming and more expensive technique requiring specialised equipment and personnel. Although whole-mount sectioning may be necessary for research, its advantages do not outweigh its disadvantages for routine sectioning. Recommendations • Total embedding of a prostatectomy specimen is preferred, either by conventional (quadrant sectioning) or by whole-mount sectioning • The entire surface of RP specimens should be inked before cutting in order to evaluate the surgical margin status • The apex should be separately examined using the cone method with sagittal or radial sectioning.
6.6.2 RP specimen report The pathology report provides essential information on the prognostic characteristics relevant for making clinical decisions. The report includes: • typing (> 95% of PCa represent conventional (acinic) adenocarcinomas) • grading according to the Gleason score • (sub)staging and surgical margin status of the tumour • if appropriate, location and extent of extraprostatic extension, sidedness of extraprostatic extension or seminal vesicle invasion, location and extent of positive surgical margins • additional information may be provided on multifocality, diameter of the dominant tumour and the zonal location (transition zone, peripheral zone, anterior horn) of the dominant tumour. Given the complex information to be provided on each RP specimen, the use of synoptic-(like) or checklist reporting is recommended (see table 7). Synoptic reporting of surgical specimens results in more transparent and complete pathology reporting (54).
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Table 7: Example checklist - reporting of prostatectomy specimens Histologic type Type of carcinoma (e.g. conventional acinar, ductal, etc.) Histologic grade Primary (predominant) grade Secondary grade Tertiary grade (if applicable) Total / global Gleason score Approximate percentage of Gleason grade 4 or 5 (optional) Tumour quantitation (optional) Percentage of prostatic gland involved Tumour size of dominant nodule (if identified), greatest dimension in mm Pathologic staging (pTNM) Presence of extraprostatic extension (focal or extensive) If present: specify site(s) Presence of seminal vesicle invasion If applicable: Regional lymph nodes: - Location - Number of lymph nodes retrieved - Number of lymph nodes involved Surgical margins Presence of carcinoma at margin If present: specify site(s) and extra- or intraprostatic Other If identified: presence of angioinvasion Location (site, zone) of dominant tumour (optional) Perineural invasion (optional) If present: specify extra-or intra-prostatic 18.104.22.168. Gleason score Grading of conventional prostatic adenocarcinomas using the (modified) Gleason score system (41) is the single strongest prognostic factor for clinical behaviour and treatment response. The Gleason score is therefore one of the parameters incorporated in nomograms that predict the risk of recurrence after prostatectomy (55). 22.214.171.124. Interpreting the Gleason score The Gleason score is the sum of the most dominant and second most dominant (in terms of volume) Gleason grade. If only one grade is present, the primary grade is doubled. If a grade comprises ≤ 5% of the cancer volume, this grade is not incorporated in the Gleason score (5% rule). Both the primary and the secondary grade should be reported in addition to the Gleason score (e.g. Gleason score 7 [4 + 3]). A global Gleason score is given when there are multiple tumours, but a separate tumour focus with a higher Gleason score should also be mentioned. A tertiary Gleason grade 4 or 5, particularly if exceeding 5% of the prostate cancer volume, is an unfavourable prognosticator for biochemical recurrence. The presence of the tertiary grade and its approximate proportion of the cancer volume should also be reported (56), in addition to the Gleason score. 126.96.36.199 Definition of extraprostatic extension The TNM staging system of the International Union Against Cancer (UICC) is recommended for pathological staging of carcinomas of the prostate (53, 57). It measures the anatomical extension of the cancer, which may (e.g. pT3 substaging) or may not (e.g. pT2 substaging) be prognostic. Extraprostatic extension is the recommended term for the presence of tumour beyond the confines of the prostate. Extraprostatic extension is defined as carcinoma admixed with periprostatic adipose tissue, or bulging out beyond the contour of the prostate gland, e.g at the neurovascular bundle or the anterior prostate. It is useful to report not only the location, but also the extent of extraprostatic extension because the extension is related to the risk of recurrence (58, 59). There are no well-established and internationally accepted definitions of the terms ‘focal’ and ‘non-focal’ or ‘extensive extraprostatic extension’. Some authors describe focal as ‘a few glands‘ (60) or extension less than 1 high power field (59), while others measure the depth of extent in mm (61). Currently, it is considered clinically useful to measure the extent of extraprostatic extension (e.g. less or more than 1 high power field or 1 mm). At the site of the apex, there is no agreed definition on how to determine extraprostatic extension. Here,
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tumour admixed with skeletal muscle does not constitute extraprostatic extension, and it should be noted that at the apex, a diagnosis of stage pT4 is not rendered. In the bladder neck, microscopic invasion of small fibres of smooth muscle is not equated to bladder wall invasion (62). Some consider tumour invasion of large bundles of smooth muscle to be gross invasion (63), as determined by the urologist, or a positive bladder neck margin to be equivalent to pT4 (64). 6.6.3 Prostate cancer volume The prognostic value of determining the volume of PCa in RP specimens is controversial with several conflicting studies either demonstrating or refuting its independent prognostic impact (59, 65-68). Nevertheless, a prostate cancer volume cut-off of 0.5 mL continues to be an important parameter to distinguish insignificant from clinically relevant cancers (65). Furthermore, continued improvement in radio-imaging of the prostate glands has allowed more accurate measurements of cancer volume before surgery. For these reasons, it may be recommended that, if present, the greatest dimension of the dominant tumour nodule should be provided in millimeters. 6.6.4 Surgical margin status Surgical margin status is an independent risk factor for biochemical recurrence. It is usually possible to provide clear information about the surgical margin status: positive if tumour cells are in touch with the ink on the surface of the specimen, and negative if not. The margin is negative if tumour cells are very close to the inked surface of the margin (66) or when they are at the surface of the tissue lacking any ink. If the tissue has severe crush artifacts (usually at the apex), it may not be possible to assign a surgical margin status (69). Surgical margin status is independent of the pathological stage and a positive margin is not evidence of extraprostatic extension (70). There is insufficient evidence to prove a relationship between the extent of positive margin and the risk of recurrence (59). However, it is recommended that some indication is given of the (multi)-focality and extent of margin positivity (e.g. linear extent in millimeters, or number of blocks with positive margin involvement). 6.6.5 Other factors According to the College of American Pathologists consensus statement (71), additional potential biomarkers, such as perineural invasion, neuroendocrine differentiation, microvessel density, nuclear roundness, chromatin texture, other karyometric factors, proliferation markers, prostate-specific antigen derivatives, and other factors (oncogenes, tumor suppressor genes, apoptosis genes, etc) have not been sufficiently studied to demonstrate their additional prognostic value and clinical usefulness outside the standard patient care setting (category III).
6.7 REFERENCES 1.
Richie JP, Catalona WJ, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL. Effect of patient age on early detection of prostate cancer with serum prostate-specific antigen and digital rectal examination. Urology 1993:42(4):365-74. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/7692657 Carvalhal GF, Smith DS, Mager DE, Ramos C, Catalona WJ. Digital rectal examination for detecting prostate cancer at prostate specific antigen levels of 4 ng/ml or less. J Urol 1999;161:835-9. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/10022696 Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317(15):909-16. http://www.ncbi.nlm.nih.gov/pubmed/2442609 Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994;151(5):1283-90. http://www.ncbi.nlm.nih.gov/pubmed/7512659 Semjonow A, Brandt B, Oberpenning F, Roth S, Hertle L. Semjonow A, Brandt B, Oberpenning F, Roth S, Hertle L. Discordance of assay methods creates pitfalls for the interpretation of prostate-specific antigen values. Prostate Suppl 1996;7:3-16. http://www.ncbi.nlm.nih.gov/pubmed/8950358
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Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA Jr. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med 2004:350(22):2239-46. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/15163773 7. Stamey TA, Freiha FS, McNeal J, Redwine EA, Whittemore AS, Schmid H-P. Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 1993;71(3 Suppl):933-8. http://www.ncbi.nlm.nih.gov/pubmed/7679045 8. Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, deKernion JB, Walsh PC, Scardino PT, Lange PH, Subong EN, Parson RE, Gasior GH, Loveland KG, Southwick PC. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998:279(19):1542-7. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/9605898 9. Stephan C, Lein M, Jung K, Schnorr D, Loening SA. The influence of prostate volume on the ratio of free to total prostate specific antigen in serum of patients with prostate carcinoma and benign prostate hyperplasia. Cancer 1997;79(1):104-9. http://www.ncbi.nlm.nih.gov/pubmed/8988733 10. Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, Fozard JL, Walsh PC. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992:267(16):2215-20. (level of evidence: 1b) http://www.ncbi.nlm.nih.gov/pubmed/1372942 11. Schmid H-P, McNeal JE, Stamey TA. Observations on the doubling time of prostate cancer. The use of serial prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume. Cancer 1993;71(6):2031-40. http://www.ncbi.nlm.nih.gov/pubmed/7680277 12. Arlen PM, Bianco F, Dahut WL, D’Amico A, Figg WD, Freedland SJ, Gulley JL, Kantoff PW, Kattan MW, Lee A, Regan MM, Sartor O; Prostate Specific Antigen Working Group. Prostate Specific Antigen Working Group guidelines on prostate specific antigen doubling time. J Urol 2008;179(6):2181-5; discussion 2185-6. http://www.ncbi.nlm.nih.gov/pubmed/18423743 13. Heidenreich A. Identification of high-risk prostate cancer: role of prostate-specific antigen, PSA doubling time, and PSA velocity. Eur Urol 2008;54(5):976-7. http://www.ncbi.nlm.nih.gov/pubmed/18640768 14. Ramirez ML, Nelson EC, Devere White RW, Lara PN Jr, Evans CP. Current applications for prostatespecific antigen doubling time. Eur Urol 2008;64(2):291-302 http://www.ncbi.nlm.nih.gov/pubmed/18439749 15. Hessels D, Klein Gunnewiek JMT, van Oort I, Karthaus HFM, van Leenders GJL, van Balken B, Kiemeney LA, Witjes JA, Schalken JA: DD3 (PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol 2003;44:8-15; discussion 15-6. http://www.ncbi.nlm.nih.gov/pubmed/12814669 16. Shappell SB. Clinical utility of prostate carcinoma molecular diagnostic tests. Rev Urol 2008;10(1):4469. http://www.ncbi.nlm.nih.gov/pubmed/18470278 17. Lee F, Torp-Pedersen ST, Siders DB, Littrup PJ, McLeary RD. Transrectal ultrasound in the diagnosis and staging of prostate cancer. Radiology 1989;170(3 Pt 1):609-15. http://www.ncbi.nlm.nih.gov/pubmed/2644656 18. Eastham JA, Riedel E, Scardino PT, Shike M, Fleisher M, Schatzkin A, Lanza E, Latkany L, Begg CB; Polyp Prevention Trial Study Group. Variation of serum prostate-specific antigen levels: an evaluation of year-to-year fluctuations. JAMA 2003:289(20):2695-700. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/12771116 19. Stephan C, Klaas M, Muller C, Schnorr D, Loening SA, Jung K. Interchangeability of measurements of total and free prostate-specific antigen in serum with 5 frequently used assay combinations: an update. Clin Chem 2006:52(1):59-64. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/16391327 20. Emiliozzi P, Corsetti A, Tassi B, Federico G, Martini M, Pansadoro V. Best approach for prostate cancer detection: a prospective study on transperineal versus transrectal six-core prostate biopsy. Urology 2003:61(5):961-6. (level of evidence: 1b) http://www.ncbi.nlm.nih.gov/pubmed/12736016
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Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol 2006:175(3 Pt 1):820-834. http://www.ncbi.nlm.nih.gov/pubmed/16469560 Moore CK, Karikehalli S, Nazeer T, Fisher HA, Kaufman RP, Jr., Mian BM. Prognostic significance of high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation in the contemporary era. J Urol 2005:173(1):70-2. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/15592031 Walz J, Graefen M, Chun FK, Erbersdobler A, Haese A, Steuber T, Schlomm T, Huland H, Karakiewicz PI . High incidence of prostate cancer detected by saturation biopsy after previous negative biopsy series. Eur Urol 2006:50(3):498-505. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/16631303 Moran BJ, Braccioforte MH, Conterato DJ. Re-biopsy of the prostate using a stereotactic transperineal technique. J Urol 2006:176(4 Pt 1):1376-81. (level of evidence: 2b) http://www.ncbi.nlm.nih.gov/pubmed/16952636 Eichler K, Hempel S, Wilby J, Myers L, Bachmann LM, Kleijnen J. Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. J Urol 2006:175(5):160512. (level of evidence: 1a) http://www.ncbi.nlm.nih.gov/pubmed/16600713 Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, Jewell D, Powell P, Gillatt D, Dedman D, Mills N, Smith M, Noble S, Lane A; ProtecT Study Group. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study. Health Technol Assess 2003:7(14):1-88. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/12709289 Zigeuner R, Schips L, Lipsky K, Auprich M, Salfellner M, Rehak P, Pummer K, Hubmer G. Detection of prostate cancer by TURP or open surgery in patients with previously negative transrectal prostate biopsies. Urology 2003:62(5):883-7. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/14624913 Linzer DG, Stock RG, Stone NN, Ratnow R, Ianuzzi C, Unger P. Seminal vesicle biopsy: accuracy and implications for staging of prostate cancer. Urology 1996:48(5):757-61. (level of evidence: 2a) http://www.ncbi.nlm.nih.gov/pubmed/8911521 Pelzer AE, Bektic J, Berger AP, Halpern EJ, Koppelstatter F, Klauser A, Rehder P, Horninger W, Bartsch G, Frauscher F. Are transition zone biopsies still necessary to improve prostate cancer detection? Results from the Tyrol screening project. Eur Urol 2005:48(6):916-21. (level of evidence: 1b) http://www.ncbi.nlm.nih.gov/pubmed/16126324 Aron M, Rajeev TP, Gupta NP. Antibiotic prophylaxis for transrectal needle biopsy of the prostate: a randomized controlled study. BJU Int 2000:85(6):682-5. (level of evidence: 1b) http://www.ncbi.nlm.nih.gov/pubmed/10759665 von Knobloch R, Weber J, Varga Z, Feiber H, Heidenreich A, Hofmann R. Bilateral fine-needle administered local anaesthetic nerve block for pain control during TRUS-guided multi-core prostate biopsy: a prospective randomised trial. Eur Urol 2002;41(5):508-14; discussion 514. (level of evidence: 1b) http://www.ncbi.nlm.nih.gov/pubmed/12074792 Adamakis I, Mitropoulos D, Haritopoulos K, Alamanis C, Stravodimos K, Giannopoulos A. Pain during transrectal ultrasonography guided prostate biopsy: a randomized prospective trial comparing periprostatic infiltration with lidocaine with the intrarectal instillation of lidocaine-prilocain cream. World J Urol 2004:22(4):281-4. (level of evidence: 1b) http://www.ncbi.nlm.nih.gov/pubmed/14689224 NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer Early Detection V.2.2007. Page: PROSD-A, 3. http://www.nccn.org/professionals/physician_gls/PDF/prostate_detection.pdf Giannarini G, Mogorovich A, Valent F, Morelli G, De Maria M, Manassero F, Barbone F, Selli C. Continuing or discontinuing low-dose aspirin before transrectal prostate biopsy: results of a prospective randomized trial. Urol 2007;70(3):501-5. (level of evidence: 1b) http://www.ncbi.nlm.nih.gov/pubmed/17688919 Iczkowski KA, Casella G, Seppala RJ, Jones GL, Mishler BA, Qian J, Bostwick DG. Needle core length in sextant biopsy influences prostate cancer detection rate. Urology 2002;59(5):698-703. http://www.ncbi.nlm.nih.gov/pubmed/11992843
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Van der Kwast TH, Lopes C, Santonja C, Pihl CG, Neetens I, Martikainen P, Di Lollo S, Bubendorf L, Hoedemaeker RF; Members of the pathology committee of the European Randomised Study of Screening for Prostate Cancer. Guidelines for processing and reporting of prostatic needle biopsies. J Clin Pathol 2003;56(5):336-40. http://www.ncbi.nlm.nih.gov/pubmed/12719451 37. Rogatsch H, Moser P, Volgger H, Horninger W, Bartsch G, Mikuz G, Mairinger T. Diagnostic effect of an improved preembedding method of prostate needle biopsy specimens. Hum Pathol 2000;31(9):1102-7. http://www.ncbi.nlm.nih.gov/pubmed/11014578 38. Reyes AO, Humphrey PA. Diagnostic effect of complete histologic sampling of prostate needle biopsy specimens. Am J Clin Pathol 1998;109(4):416-22. http://www.ncbi.nlm.nih.gov/pubmed/9535395 39. Novis DA, Zarbo RJ, Valenstein PA. Diagnostic uncertainty expressed in prostate needle biopsies. A College of American Pathologists Q-probes Study of 15,753 prostate needle biopsies in 332 institutions. Arch Pathol Lab Med 1999;123(8):687-92. http://www.ncbi.nlm.nih.gov/pubmed/10420224 40. Iczkowski KA. Current prostate biopsy interpretation: criteria for cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and use of immunostains. Arch Pathol Lab Med 2006;130(6):835-43. http://www.ncbi.nlm.nih.gov/pubmed/16740037 41. Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL; ISUP grading committee. The 2005 International Society of Urologic Pathology (ISUP) Consensus Conference on Gleason grading of Prostatic Carcinoma. Am J Surg Pathol 2005;29:1228-42. http://www.ncbi.nlm.nih.gov/pubmed/16096414 42. De la Taille A, Katz A, Bagiella E, Olsson CA, O’Toole KM, Rubin MA. Perineural invasion on prostate needle biopsy: an independent predictor of final pathologic stage. Urology 1999;54(6):1039-43. http://www.ncbi.nlm.nih.gov/pubmed/10604705 43. Sebo TJ, Cheville JC, Riehle DL, Lohse CM, Pankratz VS, Myers RP, Blute ML, Zincke H. Predicting prostate carcinoma volume and stage at radical prostatectomy by assessing needle biopsy specimens for percent surface area and cores positive for carcinoma, perineural invasion, Gleason score, DNA ploidy and proliferation, and preoperative serum prostate specific antigen: a report of 454 cases. Cancer 2001;91(11):2196-204. http://www.ncbi.nlm.nih.gov/pubmed/11391602 44. Grossklaus DJ, Coffey CS, Shappell SB, Jack GS, Chang SS, Cookson MS. Percent of cancer in the biopsy set predicts pathological findings after prostatectomy. J Urol 2002;167(5):2032-5. http://www.ncbi.nlm.nih.gov/pubmed/11956432 45. Freedland SJ, Terris MK, Csathy GS, Kane CJ, Amling CL, Presti JC Jr, Dorey F, Aronson WJ; Search Database Study Group. Preoperative model for predicting prostate specific antigen recurrence after radical prostatectomy using percent of biopsy tissue with cancer, biopsy Gleason grade and serum prostate specific antigen. J Urol 2004;171(6 Pt 1):2215-20. http://www.ncbi.nlm.nih.gov/pubmed/15126788 46. Brimo F, Vollmer RT, Corcos J, Kotar K, Bégin LR, Humphrey PA, Bismar TA. Prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue. Histopathology 2008;53(2):177-83. http://www.ncbi.nlm.nih.gov/pubmed/18752501 47. Herkommer K, Kuefer R, Gschwend JE, Hautmann RE, Volkmer BG. Pathological T0 prostate cancer without neoadjuvant therapy: clinical presentation and follow-up. Eur Urol 2004;45(1):36-41. http://www.ncbi.nlm.nih.gov/pubmed/14667513 48. Postma R, de Vries SH, Roobol MJ, Wildhagen MF, Schröder FH, van der Kwast TH. Incidence and follow-up of patients with focal prostate carcinoma in 2 screening rounds after an interval of 4 years. Cancer 2005;103(4):708-16. http://www.ncbi.nlm.nih.gov/pubmed/15648082 49. Trpkov K, Gao Y, Hay R, Yimaz A. No residual cancer on radical prostatectomy after positive 10-core biopsy: incidence, biopsy findings, and DNA specimen identity analysis. Arch Pathol Lab Med 2006;130(6):811-6. http://www.ncbi.nlm.nih.gov/pubmed/16740032 50. Billis A, Guimaraes MS, Freitas LL, Meirelles L, Magna LA, Ferreira U. The impact of the 2005 international society of urological pathology consensus conference on standard Gleason grading of prostatic carcinoma in needle biopsies. J Urol 2008;180(2):548-52; discussion 552-3.
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Sehdev AE, Pan CC, Epstein JI. Comparative analysis of sampling methods for grossing radical prostatectomy specimens performed for nonpalpable (stage T1c) prostatic adenocarcinoma. Hum Pathol 2001;32(5):494-9. http://www.ncbi.nlm.nih.gov/pubmed/11381367 52. Ruijter ET, Miller GJ, Aalders TW, van de Kaa CA, Schalken JA, Debruyne FM, Boon ME. Rapid microwave-stimulated fixation of entire prostatectomy specimens. Biomed-II MPC Study Group. J Pathol 1997;183(3):369-75. http://www.ncbi.nlm.nih.gov/pubmed/9422995 53. Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL; ISUP grading committee. The 2005 International Society of Urologic Pathology (ISUP) Consensus Conference on Gleason grading of Prostatic Carcinoma. Am J Surg Pathol 2005;29(9):1228-42. http://www.ncbi.nlm.nih.gov/pubmed/16096414 54. Chan NG, Duggal A, Weir MM, Driman DK. Pathological reporting of colorectal cancer specimens: a retrospective survey in an academic Canadian pathology department. Can J Surg 2008;51(4):284-8. http://www.ncbi.nlm.nih.gov/pubmed/18815652 55. Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of the prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001;58(6):843-8. http://www.ncbi.nlm.nih.gov/pubmed/11744442 56. Harnden P, Shelley MD, Coles B, Staffurth J, Mason MD. Should the Gleason grading system for prostate cancer be modified to account for high-grade tertiary components? A systematic review and meta-analysis. Lancet Oncology 2007;8(5):411-9. http://www.ncbi.nlm.nih.gov/pubmed/17466898 57. Ohori M, Kattan M, Scardino PT, Wheeler TM. Radical prostatectomy for carcinoma of the prostate. Mod Pathol 2004;17(3):349-59. http://www.ncbi.nlm.nih.gov/pubmed/14765206 58. Wheeler TM, Dillioglugil O, Kattan MW, Arakawa A, Soh S, Suyama K, Ohori M, Scardino PT. Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-2 prostate cancer. Hum Pathol 1998;29(8):856-62. http://www.ncbi.nlm.nih.gov/pubmed/9712429 59. Marks M, Koch, Lopez-Beltran A, Montironi R, Juliar B, Cheng L. The relationship between the extent of surgical margin positivity and prostate specific antigen recurrence in radical prostatectomy specimens. Human Pathology 2007;38(8):1207-11. http://www.ncbi.nlm.nih.gov/pubmed/17490720 60. Epstein JI, Carmichael MJ, Pizov G, Walsh PC. Influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term followup. J Urol 1993;150(1): 135-41. http://www.ncbi.nlm.nih.gov/pubmed/7685422 61. Sung MT, Lin H, Koch MO, Davidson DD, Cheng L. Radial distance of extraprostatic extension measured by ocular micrometer is an independent predictor of prostate-specific antigen recurrence: A new proposal for the substaging of pT3a prostate cancer. Am J Surg Pathol 2007;31(2):311-8. http://www.ncbi.nlm.nih.gov/pubmed/17255778 62. Aydin H, Tsuzuki T, Hernandez D, Walsh PC, Partin AW, Epstein JI. Positive proximal (bladder neck) margin at radical prostatectomy confers greater risk of biochemical progression. Urology 2004;64(3):551-5. http://www.ncbi.nlm.nih.gov/pubmed/15351591 63. Hoedemaeker RF, Vis AN, Van Der Kwast TH. Staging prostate cancer. Microsc Res Tech 2000;51(5):423-9. http://www.ncbi.nlm.nih.gov/pubmed/11074612 64. Srigley JR, Amin MB, Epstein JI, Grignon DJ, Humphrey PA, Renshaw AA, Wheeler TM; Members of the Cancer Committee, College of American Pathologists. Updated protocol for the examination of specimens from patients with carcinomas of the prostate gland. Arch Pathol Lab Med 2006;130(7):936-46. http://www.ncbi.nlm.nih.gov/pubmed/16831046 65. Stamey TA, Yemoto CM, McNeal JE, Sigal BM, Johnstone IM. Prostate cancer is highly predictable: a prognostic equation based on all morphological variables in radical prostatectomy specimens. J Urol 2000;163(4):1155-60. http://www.ncbi.nlm.nih.gov/pubmed/10737486
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Epstein JI, Amin M, Boccon-Gibod L, Egevad L, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic lymphadenectomy specimens. Scand J Urol Nephrol Suppl 2005;216:34-63. http://www.ncbi.nlm.nih.gov/pubmed/16019758 Kikuchi E, Scardino PT, Wheeler TM, Slawin KM, Ohori M. Is tumor volume an independent prognostic factor in clinically localized prostate cancer? J Urol 2004;172(2):508-11. http://www.ncbi.nlm.nih.gov/pubmed/15247716 Van Oort IM, Witjes JA, Kok DE, Kiemeney LA, Hulsbergen-vandeKaa CA. Maximum tumor diameter is not an independent prognostic factor in high-risk localized prostate cancer. World J Urol 2008;26(3):237-41. http://www.ncbi.nlm.nih.gov/pubmed/18265988 Evans AJ, Henry PC, Van der Kwast TH, Tkachuk DC, Watson K, Lockwood GA, Fleshner NE, Cheung C, Belanger EC, Amin MB, Boccon-Gibod L, Bostwick DG, Egevad L, Epstein JI, Grignon DJ, Jones EC, Montironi R, Moussa M, Sweet JM, Trpkov K, Wheeler TM, Srigley JR. Interobserver variability between expert urologic pathologists for extraprostatic extension and surgical margin status in radical prostatectomy specimens. Am J Surg Pathol 2008;32(10):1503-12. http://www.ncbi.nlm.nih.gov/pubmed/18708939 Chuang AY, Epstein JI. Positive surgical margins in areas of capsular incision in otherwise organconfined disease at radical prostatectomy: histologic features and pitfalls. Am J Surg Pathol 2008;32(8):1201-6. http://www.ncbi.nlm.nih.gov/pubmed/18580493 Bostwick DG, Grignon DJ, Hammond ME, Amin MB, Cohen M, Crawford D, Gospadarowicz M, Kaplan RS, Miller DS, Montironi R, Pajak TF, Pollack A, Srigley JR, Yarbro JW. Prognostic factors in prostate cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124(7):995-1000. http://www.ncbi.nlm.nih.gov/pubmed/10888774
7. STAGING The primary extension assessment of prostate cancer (PCa) is usually made by digital rectal examination (DRE), prostate-specific antigen (PSA) measurement and bone scan, supplemented with computed tomography (CT) or magnetic resonance imaging (MRI) and chest X-ray in specific situations.
The first level is the assessment of local tumour stage, where the distinction between intracapsular (T1-T2) and extracapsular (T3-T4) disease has the most profound impact on treatment decisions. DRE often underestimates the tumour extension; a positive correlation between DRE and pathological tumour stage was found in fewer than 50% of cases (1). However, more extensive examinations for adequate T-staging are only recommended in selected cases when more precise staging directly affects the treatment decision, i.e. when curative treatment is an option. Serum PSA levels increase with advancing stage. Nevertheless, when PSA level is measured in an individual patient, it appears to have a limited ability to predict the final pathological stage accurately. Due to the production of PSA by benign and malignant prostatic tissue, there is no direct relationship between serum PSA concentration and the clinical and pathological tumour stage (2-4). A combination of serum PSA level, Gleason score on prostate biopsy and clinical T-stage, however, has been proven to be more useful in predicting the final pathological stage than the individual parameters per se (5). The ability of the molecular forms of PSA to predict T-stage is still controversial. Percentage-free serum PSA did not appear to be able to predict organ-confined disease in the overall population: it could significantly predict favourable pathology in a subset of patients where DRE is normal and total PSA ranges from 4.1-10.0 ng/mL (6). Total PSA and PSA complexed to antichymotrypsin (PSA-ACT) may be superior to their density derivatives in the prediction of post-surgical pathological stage, but it does not seem to justify the substitution of PSA-ACT data in the Partin’s nomogram (7). Large multicentre studies are needed before any form of PSA can be used as a single modality for staging.
Update march 2009
The most commonly used method for viewing the prostate is transrectal ultrasound (TRUS). However, only 60% of tumours are visible with TRUS, and the remainder are not recognised due to their echogenicity. A combination of DRE and TRUS can detect T3a PCa more accurately than either method alone (8). TRUS is not able to determine tumour extension with sufficient accuracy to be recommended for routine use in staging. About 60% of pT3 tumours will not be detected pre-operatively by TRUS (9) (level of evidence: 3). Three-dimensional ultrasound (3D-US) is a non-invasive method of reproducing whole volume images of solid structures with a suggested staging accuracy of 91% (10). Several adjuncts to 3D greyscale TRUS have been investigated. A greater sensitivity for cancer detection has been achieved with the addition of power colour Doppler and contrast agents: the presence or absence of vessels crossing the capsule to determine an extracapsular extension was considered a significant predictive sign (11, 12). Unfortunately, recognition of these findings is largely operator-dependent. Thus, differentiation between T2 and T3 tumours should not be based on TRUS alone (13, 14). Furthermore, in a large multi-institutional study, TRUS was no more accurate at predicting organ-confined disease than was DRE (15). These findings were supported by another large study, which showed that there was no meaningful superiority of TRUS over DRE (16). Seminal vesicle invasion is predictive of local relapse and distant failure. Seminal vesicle biopsies may be used to increase the accuracy of pre-operative staging (17). This is not recommended as a first-line examination, but should be reserved for patients with a substantial risk of seminal vesicle invasion in whom a positive seminal vesicle biopsy would modify treatment decisions. Patients with a clinical stage greater than T2a and a serum PSA level of more than 10 ng/mL could be candidates for seminal vesicle biopsies (18, 19). Patients with any of the basal biopsies positive for cancer are more likely to have positive seminal vesicle biopsies (20). The biopsy Gleason score, serum PSA level and clinical stage are known to be independent predictors of adverse pathological features after radical prostatectomy (RP). Of the prostate needle biopsy parameters examined, the percentage of tissue with cancer was the strongest predictor for positive surgical margins, seminal vesicle invasion and non-organ-confined disease (21). An increased number of biopsies involved with tumour independently predicts extracapsular extension, margin involvement and lymph node invasion (22). In a multivariate analysis, the best risk predictors of extracapsular extension on one side were the overall average of positive biopsy cores being 15% or greater, and the average from three ipsilateral biopsies being 15% or greater. When used in combination, these two factors yielded a model with a positive predictive value of 37%, and a negative predictive value of 95%. The high negative predictive value of the side-specific model identifies patients who are good candidates for nerve-sparing surgery (23). Furthermore, it may be useful to correlate the bioptic Gleason score with the final pathological stage: about 70% of patients have localised disease when the biopsy Gleason score is ≤ 6 (24). Both CT and MRI are now of a high technical standard, but neither modality is sufficiently reliable to make their use mandatory in the assessment of local tumour invasion (25-27). Endorectal MRI (e-MRI) may allow for more accurate local staging by complementing the existing clinical variables by improvements in spatial characterisation of the prostatic zonal anatomy and molecular changes (28). Image quality and localisation improves significantly with e-MRI compared with external coil MRI (29). When compared with DRE and TRUS prostate biopsy findings, e-MRI contributes significant incremental value for local PCa staging (30), particularly in the pre-operative identification of extracapsular extension (ECE) and seminal vesicle invasion (SVI) when interpreted by dedicated genitourinary radiologists (31, 32, 33). E-MRI could impact on the decision to preserve or resect the neurovascular bundle (NVB) at the time of radical surgery (34). Similarly, e-MRI could be accurate in evaluating the presence of SVI (35). Features associated with the identification of SVI include low signal intensity within the seminal vesicle, and lack of preservation of normal seminal vesicle architecture. Combining these features with the presence both of tumour at the base of the prostate and ECE is highly predictive for the presence of SVI (35, 36). When assessed for the ability to predict organ-confined PCa, the contribution of e-MRI to staging nomograms was significant in all risk categories, but the greatest benefit was seen in the intermediate and high risk groups (37). The combination of dynamic contrast-enhanced MR imaging and T2-weighted MR imaging yields improved assessment of ECE and better results for PCa staging compared with either technique independently (38) (level of evidence: 3). Update march 2009
MR spectroscopic imaging (MRSI) allows for the assessment of tumour metabolism by displaying the relative concentrations of citrate, choline, creatinine and polyamines. Differences in the concentrations of these chemical metabolites between normal and malignant prostate tissues allow for better tumour localisation within the peripheral zone, increasing the accuracy of ECE detection among less-experienced readers, and decreasing interobserver variability (39). Furthermore, correlations have been demonstrated between the metabolic signal pattern and a pathological Gleason score, suggesting the potential for a non-invasive assessment of PCa aggressiveness (40). Despite the proposed accuracy and benefit of e-MRI and MRSI in PCa characterisation and localisation, e-MRI has several limitations that hamper its widespread application in PCa staging, e.g. difficulties in interpreting signal changes related to post-biopsy haemorrhage and inflammatory changes of the prostate, and the unquantifiable but significant inter- and intra-observer variability seen between both non-dedicated and dedicated radiologists that may lead to under- or overestimation of tumour presence and the local extent of disease (level of evidence: 3). The overall accuracy of 11C-choline positron emission tomography (PET) in defining local tumour stage (pT2 and pT3a-4) has been reported to be around 70%. PET tends to understage PCa, and has a limited value for making treatment decisions in patients with clinically localised PCa, especially if a nerve-sparing procedure is being considered (41) (level of evidence: 2b).
N-staging should be performed only when the findings will directly influence a treatment decision. This is usually the case in patients for whom potentially curative treatments are planned. High PSA values, stages T2b-T3 disease, poor tumour differentiation and peri-neural tumour invasion have been associated with a higher risk of the presence of nodal metastases (5, 42, 43). The measurement of PSA level alone is unhelpful in predicting the presence of lymph node metastases for an individual patient. The nomograms could be used to define a group of patients with a low risk of nodal metastasis (< 10%, see reference number 44). In such cases, patients with a serum PSA level of less than 20 ng/mL, stage T2a or less, and a Gleason score of 6 or less may be spared N-staging procedures before potentially curative treatment (5). The extent of the Gleason 4 pattern in sextant biopsies has also been used to define the risk of N1 disease. If any core had a predominant Gleason 4 pattern, or > three cores any Gleason 4 pattern, the risk of nodal metastases was found to be 20-45%. For the remaining patients, the risk was 2.5%, supporting the idea that nodal staging is unnecessary in selected patients (45). In the current published literature, the results indicate that CT and MRI perform similarly in the detection of pelvic lymph node metastases, although CT seems to be slightly superior (46) (level of evidence: 2a). In either case, the decision about whether nodal involvement is present rests solely on whether there is enlargement of the investigated lymph nodes. The centimetre threshold used to decide whether a lymph node is pathologically involved varies between 0.5 cm and 2 cm. A threshold of 1 cm in the short axis for the oval nodes, and 0.8 cm for the round nodes, has been recommended as the criteria for the diagnosis of lymph node metastases (47). A fine-needle aspiration biopsy (FNAB) might provide a decisive answer in cases of positive imaging results. However, the lymph node can be difficult to reach because of the anatomical position. In addition, FNAB is not a highly sensitive staging procedure, and a false-negative rate of 40% has been reported (47). High-resolution MRI with lymphotrophic ultra-small super-paramagnetic iron oxide particles (USPIO) was more recently suggested in the detection of small and otherwise occult lymph node metastases in patients with PCa (48, 49). These iron nanoparticles are taken up by circulating macrophages, which travel to normal nodal tissue. The presence of the nanoparticles causes normal nodal tissue to turn black, and because malignant nodal tissue is unable to take up the agent, metastases will have a signal intensity higher than normal nodes, even in those that do not meet the standard size criteria for metastasis (50). In asymptomatic patients with newly diagnosed PCa and a serum PSA level of less than 20 ng/mL, the likelihood of positive findings on CT or MRI is approximately 1% (37). CT scanning may therefore be warranted in patients with a very high risk of harbouring lymph node metastases, as the specificity of a positive scan is high (93-96%). Patients with nodal metastases on CT can thus be spared operative lymphadenectomy (51). Radio-immunoscintigraphy and PET have been investigated in order to improve the diagnosis of metastatic disease to the lymph nodes. Both methods are still under investigation, and further evaluation is needed before they can be recommended for routine use in clinical practice, especially as negative results should
Update march 2009
be interpreted with caution (52). The results obtained using 18F-choline PET/CT scans for initial N-staging were discouraging, especially in terms of inability to detect small metastases/micrometastases (< 5 mm) (53). Furthermore, 11C-choline PET/CT has quite a low sensitivity for the detection of lymph node metastases, but performed better than clinical nomograms, with equal sensitivity and better specificity (54). The gold standard for N-staging is operative lymphadenectomy, either by open or laparoscopic techniques. It is worth pointing out that recent studies with more extensive lymphadenectomy have shown that the obturator fossa is not always the primary site for metastatic deposits in the lymph nodes, and pelvic lymph node dissection that is limited to the obturator fossa will therefore miss about 50% of lymph node metastases (55, 56). When deciding on pelvic lymph node dissection, extended lymphadenectomy should be considered, despite its disadvantages: it requires surgical experience; it is time-consuming; and it often leads to more complications than the limited procedures. Furthermore, it may fail to identify lymph node metastases, however present, even outside the region of extended dissection (57). The primary removal of the so-called sentinel lymph node (SLN), defined as the first lymph node that receives lymphatic drainage from PCa, has the main aim of reducing the eventual morbidity associated with an extended pelvic node dissection, while preserving maximal sensitivity for diagnosis of metastatic disease (58) (level of evidence: 3) (see section 188.8.131.52 ‘Treatment: radical prostatectomy, indication and extent of LND’).
The axial skeleton is involved in 85% of patients who die from PCa (59). The presence and extent of bone metastases accurately reflect the prognosis for an individual patient. Elevated skeletal alkaline phosphatase levels may indicate the presence of bony metastasis in 70% of affected patients (60). Furthermore, the measurement of skeletal alkaline phosphatase and PSA at the same time increases clinical effectiveness to approximately 98% (61). In a prospective study, multiple regression analysis showed the extent of bone disease to be the only variable influencing the serum levels of skeletal alkaline phosphatase and PSA. However, in contrast to serum PSA, skeletal alkaline phosphatase demonstrated a statistical correlation with the extent of bone disease (62). Early detection of bone metastases will alert the clinician to the possible complications inherent in skeletal destruction. Bone scintigraphy remains the most sensitive method of assessing bone metastases, being superior to clinical evaluation, bone radiographs, serum alkaline phosphatase measurement and prostatic acid phosphatase (PAP) determination (63, 64). Technetium diphosphonates are the optimum radiopharmaceuticals currently available because of their extremely high bone-to-soft tissue ratio (65). A semi-quantitative grading system based on the extent of disease observed on the bone scan was found to correlate with survival (66). Increased 18F-fluoride uptake in malignant bone lesions reflects the increase in regional blood flow and bone turnover that characterise these lesions. Studies have shown that 18F-fluoride PET/CT is a highly sensitive and specific imaging modality for detection of bone metastases (67, 68). However, no definitive results have been obtained and therefore no final recommendations can be made (69). Besides bone, PCa may metastasise to any organ, but most commonly it affects distant lymph nodes, lung, liver, brain and skin. Clinical examination, chest X-ray, ultrasound, CT and MRI scans are appropriate methods of investigation, but only if symptoms suggest the possibility of soft-tissue metastasis. The need for reliable serum markers to improve the pre-treatment staging of patients with PCa has long been recognised. At present, PSA is the marker of choice. A pre-treatment serum PSA level greater than 100 ng/ mL has been found to be the single most important indicator of metastatic disease, with a positive predictive value of 100% (70). Furthermore, it has helped to reduce the number of patients with newly diagnosed PCa who require a bone scan. Patients with a low serum PSA concentration have only rarely been found to harbour detectable skeletal metastases. The correlation between serum PSA and bone scintigraphy in patients with newly diagnosed untreated PCa has been further investigated (71-75). Results suggest that a staging bone scan may be superfluous if the serum PSA concentration is less than 20 ng/mL in asymptomatic patients with well or moderately differentiated tumours. In contrast, in patients with poorly differentiated tumours and locally advanced disease, a staging bone scan should be obtained irrespective of the serum PSA value (76, 77).
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7.4 Guidelines for the staging of PCa
An abnormal DRE result or elevated serum PSA measurement could indicate PCa. The exact cut-off level of what is considered to be a normal PSA value has not been determined, but values of approximately < 2-3 ng/mL are often used for younger men. 2. The diagnosis of PCa depends on histopathological (or cytological) confirmation. • Biopsy and further staging investigations are only indicated if they affect the management of the patient. 3. TRUS-guided systemic biopsy is the recommended method in most cases of suspected PCa. A minimum of 10 systemic, laterally directed, cores are recommended, with perhaps more cores in larger: • transition zone biopsies are not recommended in the first set of biopsies due to low detection rates • one set of repeat biopsies is warranted in cases with persistent indication (abnormal DRE, elevated PSA or histopathological findings suggestive of malignancy at the initial biopsy) for prostate biopsy • overall recommendations for further (three or more) sets of biopsies cannot be made; the decision must be made based on an individual patient. 4. Transrectal peri-prostatic injection with a local anaesthetic can be offered to patients as effective analgesia when undergoing prostate biopsies. 5. Local staging (T-staging) of PCa is based on findings from DRE and possibly MRI. Further information is provided by the number and sites of positive prostate biopsies, the tumour grade and the level of serum PSA. Despite its high specificity in the evaluation of ECE and SVI, TRUS is limited by poor contrast resolution, resulting in low sensitivity and tendency to understage PCa. Even with the advent of colour and power Doppler to assist in identifying tumour vascularity, the accuracy of TRUS in local staging remains inadequate. In comparison with DRE, TRUS, and CT, MRI demonstrates higher accuracy for the assessment of uni- or bilobar disease (T2), ECE and SVI (T3), as well as the invasion of adjacent structures (T4). However, the literature shows a wide range in the accuracy of T-staging by MRI, from 50-92%. The addition of dynamic contrast-enhanced MRI (DCE-MRI) can be helpful in equivocal cases. The addition of MRSI to MRI also increases accuracy and decreases interobserver variability in the evaluation of ECE. 6. Lymph node status (N-staging) is only important when potentially curative treatment is planned. Patients with stage T2 or less, PSA < 20 ng/mL and a Gleason score ≤ 6 have a lower than 10% likelihood of having node metastases and can be spared nodal evaluation. Given the significant limitations of pre-operative imaging in the detection of small metastases (< 5 mm), pelvic lymph node dissection remains the only reliable staging method in clinically localised. Currently, it seems that only methods of histological detection of lymph node metastases with high sensitivity, such as sentinel lymph node dissection or extended pelvic lymph node dissection, are suitable for lymph node staging in PCa. 7. Skeletal metastasis (M-staging) is best assessed by bone scan. This may not be indicated in asymptomatic patients if the serum PSA level is less than 20 ng/mL in the presence of well or moderately differentiated tumours. In equivocal cases, 18F-fluorodeoxyglucose-PET or PET/CT could be of value, especially to differentiate active metastases and healing bones. GR = grade of recommendation
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Sala E, Akin O, Moskowitz CS, Eisemberg HF, Kuroiwa K, Ishill NM. Endorectal MRI in the evaluation of seminal vesicle invasion: diagnostic accuracy and multivariate feature analysis. Radiology 2006;238(3):929-37. http://radiology.rsnajnls.org/cgi/content/full/238/3/929 36. Wang L, Hricak H, Kattan MW, Chen HN, Kuroiwa K, Eisemberg HF. Prediction of seminal vesicle invasion in prostate cancer: incremental value of adding endorectal MRI to the Kattan Nomogram. Radiology 2007;242(1):182-8. http://radiology.rsnajnls.org/cgi/content/full/242/1/182 37. Wang L, Hricak H, Kattan MW, Chen HN, Scardino PT, Kuroiwa K. Prediction of organ confined prostate cancer: incremental value of MRI and MRI sprectroscopic imaging to staging nomograms. Radiology 2006;238(2):597-603. http://radiology.rsnajnls.org/cgi/content/full/238/2/597 38. Fuchsjager M, Shukla-Dave A, Akin O, Barentsz, Hricak H. Prostate cancer imaging. Acta Radiol 2008;49:107-20. http://www.informaworld.com/smpp/1906288645-11741620/content~db=all?content=10.1080/02841 850701545821 39. Scheidler J, Hricak H, Vigneron DB, Yu KK, Sokolov DL, Huang LR, Zaloudek CJ, Nelson SJ, Carroll PR, Kurhanewicz J. Prostate cancer: localization with three-dimensional proton MR spectroscopic imaging – clinicopathologic study. Radiology 1999;213(2):473-80. http://radiology.rsnajnls.org/cgi/content/full/213/2/473 40. Zakian KL, Sircar K, Hricak H, Chen HN, Shukla-Dave A, Eberhardt S. Correlation of proton MR spectroscopic imaging with Gleason score based on step section pathologic analysis after radical prostatectomy. Radiology 2005;234(3):804-14. http://radiology.rsnajnls.org/cgi/content/full/234/3/804 41. Rinnab L, Blumstein NM, Mottaghy FM, Hautmann RE, Küfer R, Hohl K, Reske SN. 11C-choline positron-emission tomography/computed tomography and transrectal ultrasonography for staging localized prostate cancer. BJU Int 2007;99(6):1421-6. http://www.ncbi.nlm.nih.gov/pubmed/17355373 42. Stone NN, Stock RG, Parikh D, Yeghiayan P, Unger P. Perineural invasion and seminal vesicle involvement predict pelvic lymph node metastasis in men with localized carcinoma of the prostate. J Urol 1998;160(5):1722-6. http://www.ncbi.nlm.nih.gov/pubmed/9783940 43. Pisansky TM, Zincke H, Suman VJ, Bostwick DG, Earle JD, Oesterling JE. Correlation of pretherapy prostate cancer characteristics with histologic findings from pelvic lymphadenectomy specimens. Int J Radiat Oncol Biol Phys 1996;34(1):33-9. http://www.ncbi.nlm.nih.gov/pubmed/12118563 44. Cagiannos I, Karakiewicz P, Eastham JA, Ohori M, Rabbani F, Gerigk C, Reuter V, Graefen M, Hammerer PG, Erbersdobler A, Huland H, Kupelian P, Klein E, Quinn DI, Henshall SM, Grygiel JJ, Sutherland RL, Stricker PD, Morash CG, Scardino PT, Kattan MW. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol 2003;170(5):1798-803. 45. Haese A, Epstein JI, Huland H, Partin AW. Validation of a biopsy-based pathologic algorithm for predicting lymph node metastases in patients with clinically localized prostate carcinoma. Cancer 2002;95(5):1016-21. http://www.ncbi.nlm.nih.gov/pubmed/12209685 46. Hoivels AM, Heesakkers RAM, Adang EM., Jager GJ, Strum S, Hoogeveen YL, Severens JL, Barentsz JO. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. Clinical Radiology 2008;63:387-95. http://linkinghub.elsevier.com/retrieve/pii/S0009-9260(07)00334-0 47. GJ Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Ruijs SJH. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR-imaging with a three-dimensional T1-weighted magnetizationprepared-rapid gradient-echo sequence. Am J Roentgenol 1996;167(6):1503-7. http://www.ncbi.nlm.nih.gov/pubmed/8956585 48. Harisinghani MG, Barentsz J, Hahn PF, Deserno WM, Tabatabaei S, van de Kaa CH, de la Rosette J, Weissleder R. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003;348(25):2491-9. http://www.ncbi.nlm.nih.gov/pubmed/12815134
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49. Heesakkers RA, Fütterer JJ, Hövels AM, van den Bosch HC, Scheenen TW, Hoogeveen YL, Barentsz JO. Prostate cancer evaluated with ferumoxtran-10-enhanced T2*-weighted MR imaging at 1.5 and 3.0 T: early experience. Radiology 2006;239(2):481-7. http://www.ncbi.nlm.nih.gov/pubmed/16641354 50. Bellin MF, Roy C, Kinkel K, Thoumas D, Zaim S, Vanel D, Tuchmann C, Richard F, Jacqmin D, Delcourt A, Challier E, Lebret T, Cluzel P. Lymph node metastases: safety and effectiveness of MR imaging with ultrasmall superparamagnetic iron oxide particles – initial clinical experience. Radiology 1998;207(3):799-808. http://www.ncbi.nlm.nih.gov/pubmed/9609907 51. Wolf JS Jr, Cher M, Dall’era M, Presti JC Jr, Hricak H, Carroll PR. The use and accuracy of crosssectional imaging and fine needle aspiration cytology for detection of pelvic lymph node metastases before radical prostatectomy. J Urol 1995;153(3Pt2):993-9. http://www.ncbi.nlm.nih.gov/pubmed/7853590 52. Salminen E, Hogg A, Binns D, Frydenberg M, Hicks R. Investigations with FDG-PET scanning in prostate cancer show limited value for clinical practice. Acta Oncol 2002;41(5):425-9. http://www.ncbi.nlm.nih.gov/pubmed/12442917 53. Husarik DB, Miralbell R, Dubs M, John H, Giger OT, Gelet A, Cservenyàk T, Hany TF. Evaluation of [(18)F]-choline PET/CT for staging and restaging of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35(2):253-63. http://www.ncbi.nlm.nih.gov/pubmed/17926036 54. Schiavina R, Scattoni V, Castellucci P, Picchio M, Corti B, Briganti A, Franceschelli A, Sanguedolce F, Bertaccini A, Farsad M, Giovacchini G, Fanti S, Grigioni WF, Fazio F, Montorsi F, Rigatti P, Martorana G. (11)C-choline positron emission tomography/computerized tomography for preoperative lymphnode staging in intermediate-risk and high-risk prostate cancer: comparison with clinical staging nomograms. Eur Urol 2008;54(2):392-401. http://www.ncbi.nlm.nih.gov/pubmed/18456393 55. 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(4):1681-6. http://www.ncbi.nlm.nih.gov/pubmed/11912387 56. Bader P, Burkhard FC, Markwalder R, Studer UE. Is a limited lymph node dissection an adequate staging procedure for prostate cancer? J Urol 2002;168(2):514-18, discussion 518. http://www.ncbi.nlm.nih.gov/pubmed/12131300 57. Weckermann D, Dorn R, Holl G, Wagner T, Harzmann R. Limitations of radioguided surgery in highrisk prostate cancer. Eur Urol 2007;51(6):1549-56. http://www.ncbi.nlm.nih.gov/pubmed/16996201 58. Weckermann D, Dorn R, Trefz M, Wagner T, Wawroschek F, Harzmann R. Sentinel lymph node dissection for prostate cancer: experience with more than 1,000 patients. J Urol 2007;177(3): 916-20. http://www.ncbi.nlm.nih.gov/pubmed/17296375 59. Whitmore WF Jr. Natural history and staging of prostate cancer. Urol Clin North Am 1984;11(2): 205-20. http://www.ncbi.nlm.nih.gov/pubmed/6375067 60. Wolff JM, Ittel TH, Borchers H, Boekels O, Jakse G. Metastatic workup of patients with prostate cancer employing alkaline phosphatase and skeletal alkaline phosphatase. Anticancer Res 1999;19(4A):2653-5. http://www.ncbi.nlm.nih.gov/pubmed/10470213 61. Lorente JA, Morote J, Raventos C, Encabo G, Valenzuela H. Clinical efficacy of bone alkaline phosphatase and prostate specific antigen in the diagnosis of bone metastasis in prostate cancer. J Urol 1996;155(4):1348-51. http://www.ncbi.nlm.nih.gov/pubmed/8632571 62. Lorente JA, Valenzuela H, Morote J, Gelabert A. Serum bone alkaline phosphatase levels enhance the clinical utility of prostate specific antigen in the staging of newly diagnosed prostate cancer patients. Eur J Nucl Med 1999;26(6):625-32. http://www.ncbi.nlm.nih.gov/pubmed/10369948 63. McGregor B, Tulloch AG, Quinlan MF, Lovegrove F. The role of bone scanning in the assessment of prostatic carcinoma. Br J Urol 1978;50(3):178-81. http://www.ncbi.nlm.nih.gov/pubmed/753456 64. O’Donoghue EP, Constable AR, Sherwood T, Stevenson JJ, Chisholm GD. Bone scanning and plasma phosphatases in carcinoma of the prostate. Br J Urol 1978;50(3):172-7. http://www.ncbi.nlm.nih.gov/pubmed/753455
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Buell U, Kleinhans E, Zorn-Bopp E, Reuschel W, Muenzing W, Moser EA, Seiderer M. A comparison of bone imaging with Tc-99m DPD and Tc-99m MDP: concise communication. J Nucl Med 1982;23(3):214-17. http://www.ncbi.nlm.nih.gov/pubmed/6460854 Soloway MS, Hardemann SW, Hickey D, Raymond J, Todd B, Soloway S, Moinuddin M. Stratification of patients with metastatic prostate cancer based on the extent of disease on initial bone scan. Cancer 1988;61(1):195-202. http://www.ncbi.nlm.nih.gov/pubmed/3334948 Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, singleand multifield-of-view SPECT, 18F-fluoride PET/CT. J Nucl Med 2006;47(2):287-97. http://www.ncbi.nlm.nih.gov/pubmed/16455635 Beheshti M, Vali R, Langsteger W. [18F]Fluorocholine PET/CT in the assessment of bone metastases in prostate cancer. Eur J Nucl Med Mol Imaging 2007;34(8):1316-7. http://www.ncbi.nlm.nih.gov/pubmed/17476505 Bouchelouche K, Oehr P. Recent developments in urologic oncology: positron emission tomography molecular imaging. Curr Opin Oncol 2008;20(3):321-6. http://www.ncbi.nlm.nih.gov/pubmed/18391633 Rana A, Karamanis K, Lucas MG, Chisholm GD. 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(3):277-81. http://www.ncbi.nlm.nih.gov/pubmed/1373666 Chybowski FM, Keller JJ, Bergstrahl EJ, Oesterling JE. Predicting radionuclide bone scan findings in patients with newly diagnosed, untreated prostate cancer: prostate specific antigen is superior to all other parameters. J Urol 1991;145(2):313-8. http://www.ncbi.nlm.nih.gov/pubmed/1703240 Kemp PM, Maguire GA, Bird NJ. Which patients with prostatic carcinoma require a staging bone scan? Br J Urol 1997;79(4):611-4. http://www.ncbi.nlm.nih.gov/pubmed/9126094 Lee N, Fawaaz R, Olsson CA, Benson MC, Petrylak DP, Schiff PB, Bagiella E, Singh A, Ennis RD. Which patients with newly diagnosed prostate cancer need a radionuclide bone scan? An analysis based on 631 patients. Int J Radiat Oncol Biol Phys 2000;48(5):1443-6. http://www.ncbi.nlm.nih.gov/pubmed/11121646 O’Donoghue JM, Rogers E, Grimes H, McCarthy P, Corcoran M, Bredin H, Given HF. A reappraisal of serial isotope bone scans in prostate cancer. Br J Radiol 1993;66(788):672-6. http://www.ncbi.nlm.nih.gov/pubmed/7536607 Wolff JM, Bares R, Jung PK, Buell U, Jakse G. Prostate-specific antigen as a marker of bone metastasis in patients with prostate cancer. Urol Int 1996;56(3):169-73. http://www.ncbi.nlm.nih.gov/pubmed/8860738 Wolff JM, Zimny M, Borchers H, Wildberger J, Buell U, Jakse G. Is prostate-specific antigen a reliable marker of bone metastasis in patients with newly diagnosed cancer of the prostate? Eur Urol 1998;33(4):376-81. http://www.ncbi.nlm.nih.gov/pubmed/9612680 Bruwer G, Heyns CF, Allen FJ. Influence of local tumour stage and grade on reliability of serum prostate-specific antigen in predicting skeletal metastases in patients with adenocarcinoma of the prostate. Eur Urol 1999;35(3):223-7. http://www.ncbi.nlm.nih.gov/pubmed/10072624
8. TREATMENT: DEFERRED TREATMENT (WATCHFUL WAITING/ACTIVE MONITORING) 8.1 Introduction 8.1.1 Definition There is a great difference between the incidence of and mortality from prostate cancer (PCa): in the USA in 2007, there were 218,900 new cases with only 27,050 deaths (1).
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Several autoptic studies of people dying from different causes have shown that while 60-70% of older men have histological PCa (2, 3), a large proportion of these tumours will not progress. PCa is diagnosed in only 15-20% of men during their lifetime, with a 3% lifetime risk of death (4). The incidence of small, localised, well-differentiated PCa is increasing, mainly as a result of prostate-specific antigen (PSA) screening and ‘multi-core’ schemes of prostate biopsy. These data suggest that a lot of the men with localised PCa would not, in fact, benefit from a definitive treatment. With the aim of reducing the risk of overtreatment in this subgroup of patients, two conservative management strategies have been proposed: • Watchful waiting (WW) Also known as ‘deferred treatment’ or ‘symptom-guided treatment’, this term was coined in the pre-PSA screening era (before 1990) and referred to the conservative management of PCa until the development of local or systemic progression, at which point the patient would be treated palliatively (transurethral resection of the prostate [TURP] or other procedures for urinary tract obstruction, and hormonal therapy or radiotherapy for the palliation of metastatic lesions). • Active surveillance (AS) Also known as ‘active monitoring’, this is the new term for the conservative management of PCa. Introduced in the past decade, it includes an active decision not to treat the patient immediately; to follow him with close surveillance and treat at pre-defined thresholds that classify progression (short PSA doubling time and deteriorating histopathological factors on repeat biopsy). In these cases, the treatment options are intended to be curative.
8.2 Deferred treatment of localised PCa (stage T1-T2, Nx-N0, M0) 8.2.1 Watchful waiting (WW) The rationale behind WW is the observation that PCa often progresses slowly, and is diagnosed in older men in whom there is a high incidence of co-morbidity and related high competitive mortality (5). WW can be considered as an option for treating patients with localised PCa in whom life expectancy is limited, or older patients with less aggressive cancers. There have been several attempts to summarise the key papers dealing with deferred treatment in patients with presumed localised PCa (6-10). Most of them present the same results as they analyse roughly the same series, but with a somewhat different methodology. The outcome studies on WW usually include patients whose PSA readings are not always available, and in whom the lesions are predominantly palpable, which would currently be defined as intermediate-risk tumours as described by D’Amico et al. (11). These studies include patients with a follow-up of up to 25 years, having as endpoints overall survival (OS) and disease-specific survival (DSS). Several WW series show a very consistent DSS ratio at 10 years, ranging from 82-87% (6, 12-17). In three studies with data beyond 15 years, the DSS was 80%, 79% and 58%, respectively (14, 16, 17). Two of them reported a 20-year DSS of 57% and 32%, respectively (14, 16). Chodak and co-workers reported a pooled analysis of the original data from 828 patients treated by WW (6). The paper is based on patients from six non-randomised studies (10, 18-23). The results describe cancerspecific survival (CSS) and metastasis-free survival after five and 10 years of follow-up (6) (level of evidence: 2b). Tumour grade is clearly significant, with very low survival rates for grade 3 tumours. Although the 10-year CSS rate is equally good (87%) for grade 1 and 2 tumours, the latter have a significantly higher progression rate, with 42% of these patients developing metastases (Table 8). Table 8: O utcome of deferred treatment in localised PCa in relation to tumour grade (6): percentage of patients (95% confidence interval) surviving at five and 10 years. Grade Disease-specific survival Grade 1 Grade 2 Grade 3 Metastasis-free survival Grade 1 Grade 2 Grade 3
5 years (%)
10 years (%)
98 (96-99) 97 (93-98) 67 (51-79)
87 (81-91) 87 (80-92) 34 (19-50)
93 (90-95) 84 (79-89) 51 (36-64)
81 (75-86) 58 (49-66) 26 (13-41)
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The importance of tumour grade on survival after conservative management of PCa was also underlined in a large register study utilising the Surveillance, Epidemiology and End Results (SEER) database of the National Cancer Institute in the USA (12) (level of evidence: 3). Patients with grade 1, 2 and 3 tumours had 10-year CSS rates of 92%, 76% and 43%, respectively, correlating with the data from the pooled analysis. The paper by Chodak and co-workers also specifically described the outcome for stage T1a patients (6), with cancer-specific 10-year survival rates of 96% and 94%, respectively, for grade 1 and 2 tumours. The metastasis-free survival rate was 92% for patients with grade 1 tumours, but 78% for those with grade 2 tumours, indicating a higher risk of progression in individuals with moderately differentiated tumours. This difference in progression rate correlates with other studies on stage T1a disease (24, 25). In order to stage patients accurately and not overlook the presence of more extensive and/or more poorly differentiated tumours, repeat examinations with PSA measurement, transrectal ultrasound (TRUS) and needle biopsy of the prostate remnant have been advocated, especially in younger males with a long life expectancy (26). The impact of grade on the risk of tumour progression and ultimately death from PCa is also described in a paper by Albertsen and co-workers (27). They re-evaluated all biopsy specimens using the more widely accepted Gleason score, and showed that the risk of PCa death was very high in Gleason 7-10 tumours, intermediate in Gleason 6 tumours, but low in Gleason 2-5 cancers (Table 9) (28, 29) (level of evidence: 3). This paper also showed that Gleason 6-10 tumours carry a continuously increasing risk of ending the patient’s life for up to 15 years of follow-up after conservative management. The CSS curves for this group of patients have been published in a recent discussion article on different methods of assessing outcome in treatment for localised PCa (28). Table 9: The 15-year risk of dying from PCa in relation to Gleason score at diagnosis in patients with localised disease aged 55-74 years (27, 28). Gleason score Risk of cancer death* (%) Cancer-specific mortality† (%) 2-4 4-7 8 5 6-11 14 6 18-30 44 7 42-70 76 8-10 60-87 93 * The figures on the risk of cancer death differ for different age groups and represent the true risk in the studied population (taking actual competing mortality from other causes into consideration). † The cancer-specific mortality compensates for differences in competing mortality and indicates the outcome if the patient actually lived for 15 years. Three randomised clinical trials have reported long-term follow-up of patients randomised to WW or radical prostatectomy (RP): the first was in the pre-PSA screening era (29); the second was at the beginning of PSA screening (30); and the third was a recent study, the results from which are not yet mature (1). The Veterans Administration Cooperative Urological Research Group between 1967 and 1975, randomised 142 patients affected by clinical localised PCa. The study was underpowered to detected treatment differences (31). Between 1989 and 1999, the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) randomised 695 patients with clinical stage T1-T2 to WW (348) or RP (347) (Table 10) (30). This study began after PSA screening was introduced into clinical practice, but only 5% of men were diagnosed by screening. After a median followup of 10.8 years, this study showed a significant decrease in cancer-specific mortality, overall mortality, metastatic risk progression and local progression in patients treated with RP vs WW (level of evidence: 1b).
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Table 10: O utcome of Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) at 10 years of follow-up (median of 8.2 years) (30). RP (n 347) % (n) Disease-specific mortality 9.6 (30) Overall mortality 27 (83) Metastatic progression 15.2 (50) Local progression 19.2 (64)
The results of three more years of follow-up were published recently. At 12 years’ follow-up, the group of patients treated with RP presented a favourably significant difference of 5.4% in PCa-specific mortality and 6.7% in non-metastatic progression (Table 11) (32) (level of evidence: 1b). Table 11: Outcome of Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) at 12 years of follow-up (median of 10.8 years) (32). RP (n 347) % (n) Disease-specific mortality 12.5 (43) Metastatic progression 19.3
The Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT) (1) is an ongoing controlled multicentre randomised clinical trial comparing RP with WW in patients with clinical stage T1-T2 disease. Between 1994 and 2002, 731 patients with a median age of 67 years were enrolled. The median PSA was 7.8 ng/mL (mean 10.2 ng/mL). Three-quarters of the men had clinical stage T1c disease. Using previously developed tumour risk categorisations incorporating PSA levels, Gleason histological grade and tumour stage, approximately 43% had low-risk, 36% had medium-risk and 20% had high-risk PCa. Follow-up is planned for 15 years, and the primary endpoint is the overall mortality. PIVOT enrolees are more representative of men being diagnosed and treated in contemporary clinical practice than were those enrolled in SPCG-4. In summary: • Clinical stage T1c currently represents 40-50% of new cases of PCa (33). The incidence of small, localised, well-differentiated PCa is increasing, mainly as a result of PSA screening and ‘multi-core’ schemes of prostate biopsy. • The SPCG-4 study demonstrated significant advantages for RP over WW, but only 5% of those studied were PSA-screened patients. • During the past 20 years, there has apparently been a shift towards higher Gleason scoring levels (34), even in cases evaluating microscopic foci of PCa. Some tumours previously given a Gleason score of 6 (3 + 3), might be scored as 7 (3 + 4) or more today. • The lead time in PSA screening is about 10 years (35, 36). It is therefore possible that the cancer mortality from untreated, non-screen-detected PCa in patients with contemporary Gleason scores of 6 might be as low as 10% at 20-year follow-up (37). It would seem that many small, localised, well-differentiated PCas will not progress, and radical therapy may lead to substantial overtreatment with consequent problems in terms of quality of life and socio-economic costs. 8.2.2 Active surveillance AS was conceived with the aim of reducing the ratio of overtreatment in patients with clinically confined lowrisk PCa, without giving up radical treatment, as happened with the WW strategy. Only data from non-mature randomised clinical trials of AS with follow-up < 10 years are currently available. A multicentre clinical trial of AS versus immediate treatment was opened in the USA in 2006. Its results are expected in 2025. Choo, Klotz and co-workers were the first to report on a prospective AS protocol (38, 39). They enrolled 331 patients with clinical stage T1c or T2a, PSA ≤ 10 ng/mL and a Gleason score ≤ 6 (PSA ≤ 15 and Gleason score ≤ 7 [3 + 4] in patients above the age of 70 years). At a median follow-up of eight years, the overall survival was
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85%, DSS and metastasis-free survival were 99%. The median value of the PSA doubling time was 7 years; in 42% of patients it was > 10 years, and in 22% < 3 years. Thirty-three per cent of the patients subsequently underwent a radical treatment: 20% for a PSA doubling time < 3 years; 5% for Gleason score progression on repeat biopsies; and 10% because of patient preference. Soloway et al., evaluating 175 patients with a median follow-up of four years, reported no PCa deaths or metastatic disease and a ratio of only 8% having delayed treatment (40). Carter et al., looking at 407 patients with a median follow-up of 3.4 years, reported no PCa deaths (41). All these studies confirm that, in well selected patients with low-risk disease, there is a very low rate of progression and cancer-specific death, and only a few patients require delayed radical intervention. However, another five to seven more years of follow-up will be necessary in order to obtain definitive results. Different series have identified several eligibility criteria for enrollers: • clinically confined PCa (T1-T2) • Gleason score ≤ 7 • PSA < 15-20 ng/mL (5). Moreover, different criteria were applied to define cancer progression (5), although all groups used: • a PSA doubling time with a cut off ranging between ≤ 2 and ≤ 4years • Gleason score progression to ≥ 7 at re-biopsy, at intervals ranging from one to four years. These indicators are poorly validated and, currently, it is impossible to make evidence-based recommendations on when to intervene in patients with a long life expectancy. Data that include PSA and PSA changes over time are relatively sparse in the literature. In a recent review article, it was pointed out that patients with a PSA of < 3 ng/mL had no mortality from PCa within the first 10 years, and that PSA changes over time were relatively unreliable in determining the risk for tumour progression (42). The data above indicate a high risk of tumour progression after conservative treatment for some patients with apparently localised PCa. This has been supported by the results of other studies in which patients with a life expectancy exceeding 10 years have been shown to have a higher mortality rate from PCa when left without curative treatment (43-45). Long-term follow-up of the Johansson series shows the same outcome: there is a higher risk of dying from PCa in patients surviving more than 15 years with well and moderately differentiated tumours at diagnosis (46) (level of evidence: 3). For patients who choose deferred treatment, the risk of delaying hormone therapy until disease progression has occurred appears to be modest, although shorter CSS times have been reported after deferred therapy compared with immediate hormone therapy in presumed localised PCa (not utilising PSA for staging) after 15 years of follow-up (47). In contradiction of Lundgren et al. (47), the report of the Casodex Early Prostate Cancer Trialists’ Group programme showed higher mortality in a group of men with localised PCa treated with bicalutamide 150 mg than in those who received placebo (48). In summary, it seems that hormonal therapy should be withheld until there is definitive proof of disease activity (progression), but it is open to speculation whether there might be some benefit in delivering it before the patient develops metastatic disease (see below).
8.3 Deferred treatment for locally advanced PCa (stage T3-T4, Nx-N0, M0) The literature reporting on deferred treatment for locally advanced PCa is sparse. There are no randomised studies that compare more aggressive treatments, such as radiotherapy or surgery, with or without hormones. Most patients whose disease progresses after deferred treatment of locally advanced PCa will be candidates for hormone therapy. There are reports from non-randomised studies showing that hormone treatment may safely be delayed until metastatic progression occurs, as no survival advantage was noted between patients treated with immediate orchiectomy compared with delayed treatment (49, 50). In a recent prospective randomised clinical phase III trial (EORTC 30981), 985 patients with T0-4 N0-2 M0 prostate cancer were randomly assigned to immediate androgen-deprivation therapy (ADT) or received ADT
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only on symptomatic disease progression or occurrence of serious complications (51, 52). After a median follow-up of 7.8 years, the overall survival hazard ratio was 1.25 (95% CI, 1.05-1.48; non-inferiority p > 0.1) favouring immediate treatment, seemingly due to fewer deaths of non-prostatic cancer causes (p = 0.06). The time from randomisation to progression of hormone refractory disease did not differ significantly, nor did prostate cancer-specific survival. The median time to the start of deferred treatment after study entry was seven years. In this group, 126 patients (25.6%) died without ever needing treatment (44% of the deaths in this arm). The conclusion drawn from this study is that immediate ADT resulted in a modest but statistically significant increase in overall survival but no significant difference in prostate cancer mortality or symptomfree survival. Furthermore, the authors identified significant risk factors associated with a significantly worse outcome: in both arms, patients with a baseline PSA > 50 ng/mL were at a > 3.5-fold higher risk of dying of PCa than patients with a baseline PSA ≤ to 8 ng/mL. If the baseline PSA was between 8 ng/mL and 50 ng/ mL, the risk of PCa death was approximately 7.5-fold higher in patients with a PSA doubling time < 12 months than in patients with a PSA doubling time > 12 months. The time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness. However, when early and delayed treatments were compared in a large randomised trial carried out by the Medical Research Council (MRC), a survival benefit for immediate hormone therapy was demonstrated (53), comparable with the results of the Lundgren et al. study mentioned above (47) (level of evidence: 1b). Also, a comparison of bicalutamide, 150 mg/day, with placebo showed that progression-free survival was better with early treatment in patients with locally advanced PCa (48) (level of evidence: 1b). Fifty selected asymptomatic patients (mean age 71 years) with highly or moderately differentiated stage T3 M0 PCa were followed up for 169 months (54). The five- and 10-year CSS rates were 90% and 74%, respectively, and the likelihood of being without treatment at five and 10 years was 40% and 30%, respectively. The authors concluded that WW might be a treatment option for selected patients with non-poorly differentiated T3 tumours and a life expectancy of less than 10 years (level of evidence: 3).
8.4 Deferred treatment for metastatic PCa (stage M1) There are only very sparse data on this subject. The only candidates for such treatment should be asymptomatic patients with a strong wish to avoid treatment-related side-effects (level of evidence: 4). As the median survival time is about two years, the time without any treatment (before symptoms occur) is very short in most cases. The MRC trial highlighted the risk of developing symptoms (pathological fractures, spinal cord compression), and even death from PCa, without receiving the possible benefit from hormone treatment (53, 55) (level of evidence:1b). If a deferred treatment policy is chosen for a patient with advanced PCa, close follow-up must be possible.
8.5 Summary of deferred treatment 8.5.1 Indications In presumed localised PCa (Nx-N0, M0): • Stage T1a: well and moderately differentiated tumours. In younger patients with a life expectancy of > 10 years, re-evaluation with PSA, TRUS and biopsies of the prostatic remnant is recommended (level of evidence: 2a). • Stage T1b-T2b: well and moderately differentiated tumours. In asymptomatic patients with a life expectancy of < 10 years (level of evidence: 2a). 8.5.2 Options In presumed localised PCa (Nx-N0, M0): • stage T1b-T2b patients who are well informed and have well differentiated (or Gleason 2-4) PCa and a life expectancy of 10-15 years • all patients not willing to accept side-effects of active treatment • well informed, asymptomatic patients with high PSA levels for whom cure is unlikely (level of evidence: 3). In locally advanced disease (stage T3-T4): • asymptomatic patients with well or moderately differentiated cancer, PCa and a short life expectancy (level of evidence: 3) • PSA < 50 ng/mL and PSA doubling time > 12 months (level of evidence: 1).
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In metastatic disease (M1): • a very rare patient without any symptoms and the possibility of close follow-up (level of evidence: 4).
8.6 REFERENCES 1.
Wilt TJ, Brawer MK, Barry MJ, Jones KM, Kwon Y, Gingrich JR, Aronson WJ, Nsouli I, Iyer P, Cartagena R, Snider G, Roehrborn C, Fox S. The Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer. Contemp Clin Trials 2009;30(1):81-7. http://www.ncbi.nlm.nih.gov/pubmed/18783735 Rullis I, Schaeffer JA, Lilien OM. Incidence of prostatic carcinoma in the elderly. Urology 1975;6(3):295-7. http://www.ncbi.nlm.nih.gov/pubmed/1172317 Sakr, WA, Grignon, DJ, Crissman JD, Heilbrun LK, Cassin BJ, Pontes JJ, Haas GP. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases. In Vivo 1994;8(3):439-43. http://www.ncbi.nlm.nih.gov/pubmed/7803731 Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer statistics, 2006. CA Cancer J Clin 2006;56(2):106-30. http://caonline.amcancersoc.org/cgi/content/full/56/2/106 Adolfsson J .Watchful waiting and active surveillance: the current position. BJU Int 2008;102(1):10-4. http://www.ncbi.nlm.nih.gov/pubmed/18422774 Chodak GW, Thisted RA, Gerber GS, Johansson JE, Adolfsson J, Jones GW, Chisholm GD, Moskovitz B, Livne PM, Warner J. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330(4):242-8. http://www.ncbi.nlm.nih.gov/pubmed/8272085 Middleton RG, Thompson IM, Austenfeld MS, Cooner WH, Correa RJ, Gibbons RP, Miller HC, Oesterling JE, Resnick MI, Smalley SR, Wasson JH. Prostate Cancer Clinical Guidelines Panel Summary report on the management of clinically localized prostate cancer. The American Urological Association. J Urol 1995;154(6):2144-8. http://www.ncbi.nlm.nih.gov/pubmed/7500479 Thompson IM. Observation alone in the management of localized prostate cancer: the natural history of untreated disease. Urology 1994;43(2Suppl.):41-6. http://www.ncbi.nlm.nih.gov/pubmed/8272085 Schellhammer PF. Contemporary expectant therapy series: a viewpoint. Urology Symposium 1994;44(6A):47-52. Adolfsson J, Steineck G, Whitmore WF Jr. Recent results of management of palpable clinically localized prostate cancer. Cancer 1993;72(2):310-22. http://4www.ncbi.nlm.nih.gov/pubmed/8319164 D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280(11):969-74. http://jama.ama-assn.org/cgi/content/full/280/11/969 Lu-Yao GL, Yao SL. Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 1997;349(9056):906-10. http://www.ncbi.nlm.nih.gov/pubmed/9093251 Sandblom G, Dufmats M, Varenhorst E. Long-term survival in a Swedish population-based cohort of men with prostate cancer. Urology 2000;56(3):442-7. http://www.ncbi.nlm.nih.gov/pubmed/10962312 Johansson JE, Adami HO, Andersson SO, Bergström R, Krusemo UB, Kraaz W. Natural history of localized prostatic cancer. A population-based study in 223 untreated patients. Lancet 1989;1(8642):799-803. http://www.ncbi.nlm.nih.gov/pubmed/2564901 Bill-Axelson A, Holmberg L, Ruutu M, Häggman M, Andersson SO, Bratell S, Spångberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlén BJ, Johansson JE; for the Scandinavian Prostate Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352(19):1977-84. http://content.nejm.org/cgi/content/full/352/19/1977
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Adolfsson J, Tribukait B, Levitt S. The 20-yr outcome in patients with well- or moderately differentiated clinically localized prostate cancer diagnosed in the pre-PSA era: the prognostic value of tumour ploidy and comorbidity. Eur Urol 2007 Oct;52(4):1028-35. http://www.ncbi.nlm.nih.gov/pubmed/17467883 17. Jonsson E, Sigbjarnarson HP, Tomasson J, Benediktsdottir KR, Tryggvadottir L, Hrafnkelsson J, Olafsdottir EJ, Tulinius H, Jonasson JG. Adenocarcinoma of the prostate in Iceland: a populationbased study of stage, Gleason grade, treatment and long-term survival in males diagnosed between 1983 and 1987. Scand J Urol Nephrol 2006;40(4):265-71. http://www.ncbi.nlm.nih.gov/pubmed/16916765 18. Moskovitz B, Nitecki A, Richter Levin D. Cancer of the prostate: is there a need for aggressive treatment? Urol Int 1987;42(1):49-52. http://www.ncbi.nlm.nih.gov/pubmed/3590404 19. Goodman CM, Busuttil A, Chisholm GD. Age, and size and grade of tumour predict prognosis in incidentally diagnosed carcinoma of the prostate. Br J Urol 1988;62(6):576-80. http://www.ncbi.nlm.nih.gov/pubmed/3219513 20. Jones GW. Prospective, conservative management of localized prostate cancer. Cancer 1992;70(1Suppl.):307-10. http://www.ncbi.nlm.nih.gov/pubmed/1600492 21. Whitmore WF Jr, Warner JA, Thompson IM Jr. Expectant management of localized prostatic cancer. Cancer 1991;67(4):1091-6. http://www.ncbi.nlm.nih.gov/pubmed/1991257 22. Adolfsson J, Carstensen J, Löwhagen T. Deferred treatment in clinically localised prostatic carcinoma. Br J Urol 1992;69(2):183-7. http://www.ncbi.nlm.nih.gov/pubmed/1537031 23. Johansson JE, Adami HO, Andersson SO, Bergström R, Holmberg L, Krusemo UB. High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 1992;267(16):2191-6. http://www.ncbi.nlm.nih.gov/pubmed/1556796 24. Lowe BA. Management of stage T1a Prostate cancer. Semin Urol Oncol 1996;14(3):178-82. http://www.ncbi.nlm.nih.gov/pubmed/8865481 25. Loughlin KR, Renshaw AA, Kumar S. Expectant management of stage A-1 (T1a) prostate cancer utilizing serum PSA levels: a preliminary report. J Surg Oncol 1999;70(1):49-53. http://www.ncbi.nlm.nih.gov/pubmed/9989421 26. Griebling TL, Williams RD. Staging of incidentally detected prostate cancer: role of repeat resection, prostate-specific antigen, needle biopsy, and imaging. Semin Urol Oncol 1996;14(3):156-64. http://www.ncbi.nlm.nih.gov/pubmed/8865478 27. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280(11): 975-80. http://www.ncbi.nlm.nih.gov/pubmed/9749479 28. Albertsen P, Hanley JA, Murphy-Setzko M. Statistical considerations when assessing outcomes following treatment for prostate cancer. J Urol 1999;162(2):439-44. http://www.ncbi.nlm.nih.gov/pubmed/10411053 29. Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K; 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 Nov;172(5Pt1):1871-6. http://www.ncbi.nlm.nih.gov/pubmed/15540741 30. Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Haggman M, Andersson SO, Spangberg A, Busch C, Nordling S, Palmgren J, Adami HO, Johansson JE, Norlen BJ; 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(11):781-9. http://www.ncbi.nlm.nih.gov/pubmed/12226148 31. Iversen P, Madsen PO, Corle DK. Radical prostatectomy versus expectant treatment for early carcinoma of the prostate. Twenty-three year follow-up of a prospective randomized study. Scand J Urol Nephrol Suppl 1995;172:65-72. http://www.ncbi.nlm.nih.gov/pubmed/8578259
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Bill-Axelson A, Holmberg L, Filén F, Ruutu M, Garmo H, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Adami HO, Johansson JE; Scandinavian prostate cancer Group Study Number 4. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst 2008;100(16):1144-54. http://jnci.oxfordjournals.org/cgi/content/full/100/16/1144 33. Klotz L. Active surveillance for prostate cancer: trials and tribulations. World J Urol 2008;26(5):437-42. http://www.ncbi.nlm.nih.gov/pubmed/18813934 34. Albertsen PC, Hanley JA, Barrows GH, Penson DF, Kowalczyk PD, Sanders MM, Fine J. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005;97(17):1248-53. http://www.ncbi.nlm.nih.gov/pubmed/16145045 35. Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis RA, Schröder FH, de Koning HJ. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for prostate cancer. J Natl Cancer Inst 2003;95(12):868-78. http://www.ncbi.nlm.nih.gov/pubmed/12813170 36. Törnblom M, Eriksson H, Franzén S, Gustafsson O, Lilja H, Norming U, Hugosson J. Lead time associated with screening for prostate cancer. Int J Cancer 2004;108(1):122-9. http://www.ncbi.nlm.nih.gov/pubmed/14618626 37. Klotz L. Active surveillance for favorable-risk prostate cancer: who, how and why? Nat Clin Pract Oncol 2007;4(12):692-8. http://www.nature.com/ncponc/journal/v4/n12/full/ncponc0966.html 38. Choo R, Klotz L, Danjoux C, Morton GC, DeBoer G, Szumacher E, Fleshner N, Bunting P, Hruby G. 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(4):1664-9. http://www.ncbi.nlm.nih.gov/pubmed/11912384 39. Choo R, DeBoer G, Klotz L, Danjoux C, Morton GC, Rakovitch E, Fleshner N, Bunting P, Kapusta L, Hruby G. PSA doubling time of prostate carcinoma managed with watchful observation alone. Int J Radiat Oncol Biol Phys 2001;50(3):615-20. http://www.ncbi.nlm.nih.gov/pubmed/11395227 40. Soloway MS, Soloway CT, Williams S, Ayyathurai R, Kava B, Manoharan M. Active surveillance; a reasonable management alternative for patients with prostate cancer: the Miami experience. BJU Int 2008;101(2):165-9. http://www.ncbi.nlm.nih.gov/pubmed/17850361 41. Carter HB, Kettermann A, Warlick C, Metter EJ, Landis P, Walsh PC, Epstein JI. Expectant management of prostate cancer with curative intent: an update of the Johns Hopkins experience. J Urol 2007;178(6):2359-64. http://www.ncbi.nlm.nih.gov/pubmed/17936806 42. Schmid HP, Adolfsson J, Aus G. Active monitoring (deferred treatment or watchful waiting) in the treatment of prostate cancer. A review. Eur Urol 2001;40(5):488-94. http://www.ncbi.nlm.nih.gov/pubmed/11752854 43. Aus G, Hugosson J, Norlén L. Long-term survival and mortality in prostate cancer treated with noncurative intent. J Urol 1995;154(2 PT 1):460-5. http://www.ncbi.nlm.nih.gov/pubmed/7541864 44. Hugosson J, Aus G, Bergdahl C, Bergdahl S. Prostate cancer mortality in patients surviving more than 10 years after diagnosis. J Urol 1995;154(6):2115-17. http://www.ncbi.nlm.nih.gov/pubmed/7500471 45. Brasso K, Friis S, Juel K, Jorgensen T, Iversen P. Mortality of patients with clinically localized prostate cancer treated with observation for 10 years or longer: a population based study. J Urol 1999;161(2):524-8. http://www.ncbi.nlm.nih.gov/pubmed/9915440 46. Johansson JE, Andrén O, Andersson SO, Dickman PW, Holmberg L, Magnuson A, Adami HO. Natural history of early, localized prostate cancer. JAMA 2004;291(22):2713-19. http://www.ncbi.nlm.nih.gov/pubmed/15187052 47. Lundgren R, Nordle O, Josefsson K. Immediate estrogen or estramustine phosphate therapy versus deferred endocrine treatment in nonmetastatic prostate cancer: a randomized multicentre study with 15 years of followup. The South Sweden Prostate Cancer Study Group. J Urol 1995;153(5):1580-6. http://www.ncbi.nlm.nih.gov/pubmed/7714978 48. Wirth MP, See WA, McLeod DG, Iversen P, Morris T, Carroll K; Casodex Early Prostate Cancer Trialists’ Group. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at
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median followup of 5.4 years. J Urol 2004;172(5Pt1):1865-70. http://www.ncbi.nlm.nih.gov/pubmed/15540740 Rana A, Chisholm GD, Khan M, Rashwan HM, Elton RA. Conservative management with symptomatic treatment and delayed hormonal manipulation is justified in men with locally advanced carcinoma of the prostate. Br J Urol 1994;74(5):637-41. http://www.ncbi.nlm.nih.gov/pubmed/7827816 Parker MC, Cook A, Riddle PR, Fryatt I, O’Sullivan J, Shearer RJ. Is delayed treatment justified in carcinoma of the prostate? Br J Urol 1985;57(6):724-8. http://www.ncbi.nlm.nih.gov/pubmed/4084734 Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, Loidl W, Isorna S, Sundaram SK, Debois M, Collette L. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 2006;24(12):1868-76. http://www.ncbi.nlm.nih.gov/pubmed/16622261 Studer UE, Collette L, Whelan P, Albrecht W, Casselman J, de Reijke T, Knönagel H, Loidl W, Isorna S, Sundaram SK, Debois M; EORTC Genitourinary Group. Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891). Eur Urol 2008;53(5):941-9. http://www.ncbi.nlm.nih.gov/pubmed/18191322 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(2):235-46. [No authors listed.] http://www.ncbi.nlm.nih.gov/pubmed/9052476 Adolfsson J, Steineck G, Hedlund PO. Deferred treatment of locally advanced non-metastatic prostate cancer: a long-term followup. J Urol 1999;161(2):505-8. http://www.ncbi.nlm.nih.gov/pubmed/9915436 Walsh PC. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. J Urol 1997;158(4):1623-4. http://www.ncbi.nlm.nih.gov/pubmed/9302187
9. TREATMENT: RADICAL PROSTATECTOMY 9.1 Introduction The surgical treatment of prostate cancer (PCa) consists of radical prostatectomy (RP), which is the removal of the entire prostate gland between the urethra and the bladder, with resection of both seminal vesicles. In men with localised PCa and a life expectancy of 10 years or more, the goal of an RP by any approach must be eradication of the disease (1). There is no age threshold for RP. A patient should not be denied this procedure on the grounds of age alone (2). In fact, increasing co-morbidity with age greatly increases the risk of dying from non-PCa related causes (3, 4). Life expectancy estimation is paramount in the counselling of a patient for surgery. Radical prostatectomy was first applied at the beginning of the 20th century by Young (5) using a perineal approach, while Memmelaar and Millin were the first to perform retropubic RP (6). In 1982, Walsh and Donker described the anatomy of the dorsal venous complex and the neurovascular bundles. This resulted in a significant reduction of blood loss and improved continence and potency rates (7). Currently, radical prostatectomy is the only treatment for localised PCa that has shown a cancer-specific survival benefit when compared with conservative management in a prospective, randomised trial (8). Surgical expertise has decreased the complication rates and improved cancer cure (9-12). The retropubic approach is more commonly performed, as it enables simultaneous pelvic lymph node assessment to be carried out, which is an advantage over the perineal approach. It has been suggested that perineal radical prostatectomy might result in positive surgical margins more often than the retropubic approach (13), but this has not been confirmed (14). In the past 5-10 years, several European centres have acquired considerable experience with laparoscopic radical prostatectomy (15-18). More recently, the robotic-assisted laparoscopic RP has been developed. It is
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likely that laparoscopic, robot-assisted and perineal prostatectomies have lower morbidity than the retropubic operation, but randomised studies are as yet unavailable. Functional and short-term oncological outcomes of laparoscopic and robot-assisted RP seem comparable with the open technique in high-volume centres. However, long-term oncological outcomes are still unavailable (19).
Low-risk, localised PCa: cT1-T2a and Gleason score 2-6 and PSA < 10
9.2.1 Stage T1a-T1b PCa Stage T1a PCa is defined as an incidental histological finding of cancer in 5% or less of resected prostatic tissue (transurethral resection of the prostate [TURP] or open adenomectomy). Stage T1b PCa is defined as > 5% cancer. A recent Swedish register-based study in 23,288 men with incidental PCa detected at TURP or open adenoma enucleation showed a 10-year PCa mortality of 26.6%. No details on prostate-specific antigen (PSA) or Gleason score were provided. Neither were details available on the numbers of cases with cT1a or cT1b PCa (20). Although the risk of disease progression of untreated T1a PCa after five years is only 5%, these cancers can progress in about 50% of cases after 10-13 years (21). Thus, in younger patients with a life-expectancy of 15 years or more, the chance of disease progression is real. An RP may also be offered when the Gleason score is > 6. In contrast, most patients with T1b tumours are expected to show disease progression after five years, and aggressive treatment is often warranted (21). Patients with T1b lesions are offered RP when they have a life expectancy of 10 years or more. It is consequently very important to distinguish between T1a and T1b tumours. Systematic prostate biopsies of the remnant prostate may be useful to detect concomitant peripheral zone cancer, or to ascertain a more correct tumour grade. RP may be very difficult after a thorough TURP, when almost no residual prostate is left behind (22). 9.2.2 Stage T1c and T2a PCa Clinically unapparent tumour identified by needle biopsy because of an elevated PSA (cT1c) has become the most prevalent PCa. In an individual patient, it is difficult to differentiate between clinically insignificant and life-threatening PCa. Most reports, however, stress that cT1c tumours are mostly significant and should not be left untreated since up to 30% of cT1c tumours are locally advanced disease at final histopathology (23). The proportion of insignificant tumours varies between 11% and 16% (24, 25). Increasing the number of biopsies might carry the risk of detecting a higher number of insignificant cancers. However, a recent study has shown that increasing the number of biopsies to 12 did not increase the number of insignificant tumours (26). The major problem is how to recognise those tumours that do not need RP. The biopsy findings and the free PSA ratio are helpful in predicting insignificant disease (27). Partin tables may be very helpful in better selecting patients requiring surgical treatment because of their ability to provide an estimation of the final pathological stage (28). Other authors have suggested the incorporation of biopsy information, such as the number of cores or the percentage of cores invaded (29). When only one or a few cores are invaded and the percentage of invasion in one core is limited, the chance of finding an insignificant PCa is more likely, certainly when the lesion is of low Gleason grade (30). It might be reasonable to follow up some patients whose tumours are most likely to be insignificant. In general, however, RP should be advocated for patients with T1c tumours, bearing in mind that significant tumours will be found in most of these individuals. T2a patients with a 10-year life expectancy should be offered RP since 35-55% of them will have disease progression after five years if not treated. If watchful waiting (WW) is proposed for low-grade T2 cancer, it should be remembered that pre-operative assessment of tumour grade by needle biopsy is often unreliable (31). As a rule of thumb, an extended pelvic lymph node dissection (eLND) is not necessary in low-risk, localised PCa, as the risk for positive lymph nodes does not exceed 7% (32). A limited lymph node dissection should no longer be performed, as this will miss at least half of the nodes involved.
9.3 Intermediate-risk, localised PCa: cT2b-T2c or Gleason score = 7 or PSA 10-20 RP is one of the recommended standard treatments for patients with intermediate-risk PCa and a life
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expectancy of more than 10 years (33). The prognosis is excellent when the tumour is confined to the prostate based on pathological examination (34, 35). A policy of WW has been proposed for some patients with intermediate-risk localised tumours (36). However, when the tumour is palpable or visible on imaging and clinically still confined to the prostate, disease progression can be expected in most long-term survivors. The median time to progression of untreated T2 disease is reported to be 6-10 years. T2b cancer still confined to the prostate but involving more than half of a lobe or both lobes will progress in more than 70% of patients within five years (37). These data have been confirmed by a large randomised trial comparing RP and WW that included mostly T2 PCa patients showing a significant reduction in disease-specific mortality in favour of RP (8). Total surgical removal is an excellent option, and, if performed by an experienced surgeon, the patient’s subsequent quality of life should be satisfactory. Lower rates of positive surgical margins for high-volume surgeons suggest that experience and careful attention to surgical details, adjusted for the characteristics of the cancer being treated, can decrease positive surgical margin rates and improve cancer control with RP (38). As a rule of thumb, an eLND should be performed if the estimated risk for positive lymph nodes exceeds 7% (32). In all other cases, an eLND can be omitted, accepting a low risk of missing positive nodes. A limited lymph node dissection should no longer be performed, as this will miss at least half of the nodes involved. 9.3.1 Oncological results of RP in low-and intermediate risk PCa The results achieved in a number of studies involving RP are shown in Table 12. Table 12: Oncological results of RP in organ-confined disease Reference (no.) Han et al. (2001) (39) Catalona and Smith (1994) (40)
Mean follow-up (months) 75* 28
Hull et al. (2002) (41)
Trapasso et al. (1994) (42) Zincke et al. (1994) (43) * = 15-year, 66%.
No. of patients
5-year PSA-free survival (%) 84 78
10-year PSA-free survival (%) 74 65
High-risk localised PCa: cT3a or Gleason score 8-10 or PSA > 20
The widespread use of PSA testing has led to a significant migration of stage and grade of PCa, with > 90% of men in the current era diagnosed with clinically localised disease (44). Despite the trends towards lower risk PCa, 20-35% of patients with newly diagnosed PCa are still classified as high risk, based on either PSA > 20 ng/mL, Gleason score > 8, or an advanced clinical stage (45). There is no consensus regarding the optimal treatment of men with high-risk PCa. 9.4.1 Locally advanced PCa: cT3a T3a cancer is defined as cancer that has perforated the prostate capsule. In the past, locally advanced PCa was seen in about 40% of all clinically diagnosed tumours. This figure is lower today, although its management remains controversial. Surgical treatment of clinical stage T3 PCa has traditionally been discouraged (46), mainly because patients have an increased risk of positive surgical margins and lymph node metastases and/or distant relapse (47, 48). Several randomised studies on radiotherapy with androgen-deprivation therapy (ADT) vs radiotherapy alone showed a clear advantage for the combination treatment. However, no trial has ever shown this approach to be superior to RP (49). Another problem is ‘contamination’ by the additional use of either adjuvant radiotherapy or immediate or delayed hormonal treatment in most of the series reporting the treatment of clinical T3 PCa. In recent years, there has been renewed interest in surgery for locally advanced PCa, and several retrospective case-series have been published. Although still controversial, it is increasingly evident that surgery has a place in treating locally advanced disease (50-55). Overstaging of cT3 PCa is relatively frequent and occurs in 13-27% of cases. These pT2 patients and patients with specimen-confined pT3 disease have similarly good biochemical and clinical PFS (54, 55). In about 33.5-
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66% of patients, positive section margins will be present, and 7.9-49% will have positive lymph nodes (56). Thus, 56-78% of patients primarily treated by surgery eventually require adjuvant or salvage radiotherapy or hormonal therapy (54, 55). Nevertheless, excellent 5-, 10- and 15-year overall survival (OS) and cancer-specific survival (CSS) rates have been published (Table 2). These rates surpass radiotherapy-alone series and are no different from radiotherapy combined with adjuvant hormonal therapy series (49). The problem remains the selection of patients before surgery that have neither lymph node involvement nor seminal vesicle invasion. Nomograms, including PSA level, stage and Gleason score, can be useful in predicting the pathological stage of disease (28, 56). In addition, nodal imaging with computed tomography (CT), and seminal vesicle imaging with magnetic resonance imaging (MRI), or directed specific puncture biopsies of the nodes or seminal vesicles can be helpful in recognising those patients unlikely to benefit from a surgical approach (57). RP for clinical T3 cancer requires sufficient surgical expertise to keep the level of morbidity acceptable. Increased overall surgical experience must contribute to a decreased operative morbidity and to better functional results after RP for clinical T3 cancer (54, 58). Table 13: Overall and cancer-specific survival rates for prostate cancer Survival no. of Median and/ OS (%) CSS (%) BPFS (%) CPFS (%) rate patients or mean 5 y 10 y 15 y 5 y 10 y 15 y 5 y 10 y 15 y 5 y 10 y 15 y survival rate Yamada 57 Median, 5.4 y 91.2 - - 45.5 - 81.4 et al. (77.6 at 7.5 y) (PSA > 0.4) (1994) (50) Gerber 242 Mean, 39 m - 85 57 - - 72 32 et al. Median, 26 m (meta free) (1997) (51) Van den 83 Median, 52 m 75 60 - 85 72 - 29 59 31 Ouden (PSA > 0.1) et al. (1998) (52) Isorna 83 Mean, 68.7 m 97.6 94.8 - 100 - 59.8 - Martinez (cT3a only) (PSA > 0.3) de la Riva et al. (2004) (53) Ward 841 Median, 10.3 y 90 76 53 95 90 79 58 43 38 85 73 67 et al. (PSA > 0.4) (2005) (54) Hsu et al. 200 Mean, 70.6 m 95.9 77 - 98.7 91.6 - 59.5 51.1 - 95.9 85.4 (2007) (55) (cT3a only) (PSA > 0.2) BPFS = biochemical progression-free survival; CSS = cancer-specific survival; CPFS = clinical progression-free survival; OS = overall survival; PSA = prostate-specific antigen. 9.4.2 High-grade PCa: Gleason score 8-10 Although most poorly differentiated tumours extend outside the prostate, the incidence of organconfined disease is between 26% and 31%. Patients with high-grade tumours confined to the prostate at histopathological examination still have a good prognosis after RP. Furthermore, one third of patients with a biopsy Gleason score ≥ 8 may in fact have a specimen Gleason score ≤ 7 with better prognostic characteristics. PSA value and the % of positive prostate biopsies may be helpful in selecting men with highgrade prostate cancer most likely to benefit from RP (59). 9.4.3 PCa with PSA > 20 Yossepowitch et al. reported the results of RP as a monotherapy in men with PSA > 20 ng/mL in a cohort with mostly clinically organ-confined tumours, and found a PSA failure rate of 44% and 53% at five and 10 years, respectively (60). D’Amico et al. found that men with PSA levels > 20 ng/mL had a 50% risk of PSA failure at five years after RP (61). Tiguert and co-workers presented the outcome for an identical cohort of patients who had a disease-free survival of 65% at five years after RP (62). More recently, Inman and co-workers described
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the long-term outcomes of RP with multimodal adjuvant therapy in men with PSA ≥ 50. Systemic progressionfree survival rates at 10 years were 83% and 74% for PSA 50-99 and ≥ 100, respectively, while overall CSS was 87%. These results argue for aggressive management with RP as initial step (63). As a rule of thumb, an eLND should be performed in all high-risk cases, as the estimated risk for positive lymph nodes will be in the range 15-40% (32). A limited lymph node dissection should no longer be performed, as this will miss at least half of the nodes involved.
Very high-risk localised prostate cancer: cT3b-T4 N0 or any T, N1
9.5.1 cT3b-T4 N0 Men with very high-risk PCa generally have a significant risk of disease progression and cancer-related death if left untreated. Very high-risk patients present two specific challenges. There is a need for local control as well as a need to treat any microscopic metastases likely to be present but undetectable until disease progression. The optimal treatment approach will therefore often necessitate multiple modalities. The exact combinations, timing and intensity of treatment continue to be strongly debated. Management decisions should be made after all treatments have been discussed by a multidisciplinary team (including urologists, oncologists, radiologists and pathologists), and after the balance of benefits and side-effects of each therapy modality has been considered by the patient with regard to his own individual circumstances. Provided that the tumour is not fixed to the pelvic wall, or that there is no invasion of the urethral sphincter, RP may be considered a reasonable first step in a selection of patients with low tumour volume. 9.5.2 Any T, N1 The indication for RP in all previously described stages assumes the absence of nodal involvement. Lymph node-positive (N+) disease will mostly be followed by systemic disease progression, and all patients with significant N+ disease will ultimately fail treatment. Nevertheless, the combination of RP and simultaneous hormonal treatment has been shown to achieve a 10-year CSS rate of 80% (64). However, it is questionable whether or not these results could also have been obtained with hormonal treatment alone. Most urologists are reluctant to perform RP for clinical N+ disease, or will cancel surgery if a frozen section shows lymph node invasion. It should also be noted that the definitive pathological examination after RP can show microscopic lymph node invasion. The incidence of tumour progression is lower in patients with fewer positive lymph nodes and in those with microscopic invasion only (65, 66). Clinical N+ patients usually have significant nodal involvement and will be treated with hormonal manipulation only. In patients who prove to be pN+ after RP, adjuvant hormonal treatment can be advocated, but the benefits should be judged against the side-effects of long-term hormonal therapy. PSA follow-up and hormonal treatment in the case of an increase in PSA level is therefore an acceptable option in selected cases. The most accurate staging method for the assessment of lymph node involvement is eLND. This includes removal of al node-bearing tissue from the area bounded by the external iliac vein anteriorly, the lateral pelvic side wall, the bladder wall medially, the floor of the pelvis posteriorly, Cooper’s ligament distally, and the internal iliac artery proximally. During recent years, there has been increasing interest in eLND, but controversy regarding indication and extent of ELND, its therapeutic role and morbidity remain. 184.108.40.206 Indication and extent of extrended pelvic lymph node dissectiori (eLND) Although it is generally accepted that eLND provides important information for prognosis (number of nodes involved, tumour volume, capsular perforation) that cannot be matched by any other current procedures, consensus has not been reached as to when eLND is indicated and to what extent it should be performed. When making such decisions, many physicians rely on nomograms based on pre-operative biochemical markers and biopsies (28). According to these nomograms, patients with a PSA value < 10 ng/mL and a biopsy Gleason score < 7 have a low risk of lymph node metastasis and, therefore, eLND might not be beneficial. However, the fact that most of these nomograms are based on a limited eLND (obturator fossa and external iliac vein) probably results in underestimation of the incidence of patients with positive nodes (32). Lymphography studies have shown that the prostate drains not only to the obturator and external iliac but also to the internal iliac and pre-sacral lymph nodes. Performing an eLND results in removal of all lymph nodes in these particular anatomical regions, producing a higher yield of removed lymph nodes (mean of 20 nodes) compared with limited LND (mean of 8-10 nodes). In patients with a PSA value < 10 and a Gleason score ≥ 7, an incidence of 25% nodal involvement was reported (67). Different reports mention that 19-35% of positive lymph nodes are found exclusively outside the area of the traditionally limited LND (68, 69).
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220.127.116.11 Therapeutic role of eLND Besides being a staging procedure, (extended) pelvic lymph node dissection might be curative, or at least beneficial, in a subset of patients with limited lymph node metastases (70-72). For an eLND to be representative, a mean of 20 lymph nodes should be removed (73). In some series, the number of nodes removed during lymphadenectomy correlated significantly with time to progression (74). At present, however, lymph node metastases are considered to be a sign of systemic disease. Whenever lymph node metastases are found, prognosis worsens and systemic therapy is advised. 18.104.22.168 Morbidity An eLND remains a surgical procedure, which adds morbidity to the treatment of PCa. When comparing limited vs extended LND, threefold higher complication rates were reported by some authors (75). Complications consist of lymphocoeles, lymphoedema, deep venous thrombosis and pulmonary embolism. Other authors, however, reported more acceptable complication rates (76, 77). 22.214.171.124 • • •
Summary of eLND eLND can play a role in the treatment of PCa for a subset of patients. The number of lymph nodes removed correlates with the time to progression. Concomitant morbidity has to be balanced against the therapeutic effects, and a decision will have to be made based on individual cases.
Summary of RP in high-risk localised disease
P is a reasonable treatment option in selected patients with cT3a PCa, Gleason score 8-10 or PSA > R 20. If RP is performed, an extended pelvic lymphadenectomy must be performed, as lymph node involvement is frequent. The patient must be informed about the likelihood of a multimodal approach. In case of adverse tumour characteristics (positive section margin, extracapsular extension, seminal vesicle invasion), adjuvant RT may be reasonably used after recuperation from surgery.
Recently, Thompson and colleagues reported the results of a trial enrolling 431 men with pT3N0M0 PCa treated with RP. Patients were randomised to receive 60-64 Gy adjuvant RT or observation. Metastasis-free survival and OS were significantly better with radiotherapy (78). In cases of positive lymph nodes at final histopathology, adjuvant ADT may be considered. Messing et al. examined the role of immediate ADT vs observation in patients with positive lymph nodes found at initial surgery. At a median follow-up of 11.9 years, those receiving immediate ADT had a significant improvement in OS over those managed with observation (79).
Neoadjuvant hormonal therapy and RP
Generally, neoadjuvant or up-front therapy is defined as therapy given prior to definitive local curative treatment (e.g. surgery or radiation therapy). As PCa is an androgen-dependent tumour, neoadjuvant hormonal therapy (NHT) is an appealing concept. Attempts to decrease the size of the prostate before RP were first reported by Vallett as early as 1944 (80). In a recent Cochrane review and meta-analysis, the role of neoadjuvant and adjuvant hormonal therapy and prostatectomy were studied (81). Patients had predominantly localised T1 and T2 disease, low- and intermediate-grade, with Gleason scores < 7, and PSA < 20 ng/mL in most patients. The Cochrane review made the following observations: • Neoadjuvant hormonal therapy before RP does not provide a significant OS advantage over prostatectomy alone (pooled odds ratio [OR] 1.11; 95% confidence interval [CI] 0.67-1.85). • Neoadjuvant hormonal therapy before RP does not provide a significant advantage in disease-free survival over prostatectomy alone (pooled OR 1.24; 95% CI 0.97-1.57). • Neoadjuvant hormonal therapy before RP does substantially improve local pathological variables such as organ-confined rates, pathological down-staging, positive surgical margins and rate of lymph node involvement. • Adjuvant hormonal therapy following RP: the pooled data for five-year OS showed an OR of 1.50 and 95% CI 0.79-2.84. This was not statistically significant, although there was a trend favouring adjuvant hormonal therapy. Similarly, there was no survival advantage at 10 years. • Adjuvant hormonal therapy following RP: the pooled data for disease-free survival gave an overall OR of 3.73 and 95% CI 2.3-6.03. The overall effect estimate was highly statistically significant (p < 0.00001) in favour of the hormonal arm. • It is noteworthy that the Early Prostate Cancer Trialists’ Group (EPC) trial was not included in the
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9.7.1 • • •
Cochrane review. The third update from this large randomised trial of bicalutamide, 150 mg once daily, in addition to standard care in localised and locally advanced, non-metastatic PCa was published in November 2005 (82). Median follow-up was 7.2 years. There was a significant improvement in objective progression-free survival (PFS) in the RP group. This improvement was only statistically significant in the locally advanced disease group (HR 0.75; 95% CI 0.61-0.91). There was no significant improvement in OS in the RP group, both the localised and locally advanced disease groups. In the WW group, there was an OS trend in favour of WW alone in the localised disease group (HR 1.16; 95% CI 0.99-1.37). Summary of neoadjuvant and adjuvant hormonal treatment and RP Neoadjuvant hormonal therapy before RP does not provide a significant OS advantage over prostatectomy alone. Neoadjuvant hormonal therapy before RP does not provide a significant advantage in disease-free survival over prostatectomy alone. Neoadjuvant hormonal therapy before RP does substantially improve local pathological variables such as organ-confined rates, pathological down-staging, positive surgical margins and rate of lymph node involvement. Adjuvant hormonal therapy following RP shows no survival advantage at 10 years. Adjuvant hormonal therapy following RP: the overall effect estimate was highly statistically significant (p < 0.00001) in favour of the hormonal arm.
Complications and functional outcome
The post-operative complications of RP are listed in Table 14. The mortality rate is 0-1.5% (75); urinary fistulas are seen in 1.2-4% of patients (83); and urinary incontinence persists after one year in 7.7% (84). In men undergoing prostatectomy, the rates of post-operative and late urinary complications are significantly reduced if the procedure is performed in a high-volume hospital and by a surgeon who performs a large number of such procedures (85-87). Erectile dysfunction used to occur in nearly all patients, but nerve-sparing techniques can be applied in early-stage disease (88). Patients who benefit from nerve-sparing RP may have a higher chance of local disease recurrence and should therefore be selected carefully. Table 14: Complications of RP Complication Incidence (%) • Peri-operative death 0.0-2.1 • Major bleeding 1.0-11.5 • Rectal injury 0.0-5.4 • Deep venous thrombosis 0.0-8.3 • Pulmonary embolism 0.8-7.7 • Lymphocoele 1.0-3.0 • Urine leak, fistula 0.3-15.4 • Slight stress incontinence 4.0-50.0 • Severe stress incontinence 0.0-15.4 • Impotence 29.0-100.0 • Bladder neck obstruction 0.5-14.6 • Ureteral obstruction 0.0-0.7 • Urethral stricture 2.0-9.0 9.9 Summary of indications for nerve-sparing surgery* Reference name Pre-operative selection criteria Stage > T2 PSA > 10 Biopsy Gleason score 7 Biopsy Gleason score 8-10 Partin tables Side with > 50% tumour in biopsy Side with peri-neural invasion
Sofer (89) Walsh (90) + +
Alsikafi (91) Graefen (92) +
Bianco (93) +
+ + +/-
+ + +
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Intra-operative selection criteria Side of palpable tumour + Side of positive biopsy Induration of lateral pelvic fascia + Adherent to neurovascular bundles + Positive section margins 24% 5% 11% *Clinical criteria used by different authors when NOT to perform a nerve-sparing RP.
+ + + 5%
erve-sparing RP can be performed safely in most men undergoing RP (94, 95). In the past decade, a dramatic N shift towards lower-stage tumours has become evident. More importantly, men are younger at the time of diagnosis and more interested in preserving sexual function. Nevertheless, clear contraindications are those patients in whom there is a high risk of extracapsular disease, such as any cT3 PCa, cT2c, any Gleason score > 7 on biopsy, or more than one biopsy > 6 at the ipsilateral side. Partin tables will help guide decision-making (28). If any doubt remains regarding residual tumour, the surgeon should remove the neurovascular bundle. Alternatively, the use of intra-operative frozen-section analysis can help guide these decisions. The patient must be informed before surgery about the risks of nerve-sparing surgery, the potency rates of the surgeon, and the possibility that, to ensure adequate cancer control, the nerves may be sacrificed despite any pre-operative optimism favouring the potential for their salvage. The early administration of intracavernous injection therapy could improve the definitive potency rates (96, 97) and the significance of sural nerve transplant needs further multicentre study (98). Finally, the early use of PDE-5 inhibitors in penile rehabilitation remains controversial. A recent study showed no benefit of daily early administration of vardenafil versus on-demand vardenafil in the postoperative period (99).
9.10 Guidelines and recommendations for RP LE Indications • In patients with low and intermediate risk localised PCa (cT1b-T2 and Gleason score 2-7 and PSA < 20) and a life expectancy > 10 years. Optional • Patients with stage T1a disease and a life expectancy > 15 years or Gleason score 7. • Selected patients with low-volume high-risk localised PCa (cT3a or Gleason score 8-10 or PSA > 20). • Highly selected patients with very high-risk localised PCa (cT3b-T4 N0 or any T N1) in the context of multimodality treatment. Recommendations • Short-term (three months) neoadjuvant therapy with gonadotrophin releasing-hormone analogues is not recommended in the treatment of stage T1-T2 disease. • Nerve-sparing surgery may be attempted in pre-operatively potent patients with low risk for extracapsular disease (T1c, Gleason score < 7 and PSA < 10 ng/mL or see Partin tables/ nomograms). • Unilateral nerve-sparing procedures are an option in stage T2a disease
3 3 3
LE = level of evidence
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Andrèn O, Garmo H, Mucci L, Andersson SO, Johansson JE, Fall K. Incidence and mortality of incidental prostate cancer: a Swedish register-based study. Br J Cancer 2009;100(1):170-3. http://www.ncbi.nlm.nih.gov/pubmed/19088721 Lowe BA, Listrom MB. Incidental carcinoma of the prostate: an analysis of the predictors of progression. J Urol 1988;140(6):1340-4. http://www.ncbi.nlm.nih.gov/pubmed/3193495 Van Poppel H, Ameye F, Oyen R, Van de Voorde W, Baert L. Radical prostatectomy for localized prostate cancer. Eur J Surg Oncol 1992;18(5):456-62. http://www.ncbi.nlm.nih.gov/pubmed/1426296 Elgamal AA, Van Poppel HP, Van de Voorde WM, Van Dorpe JA, Oyen RH, Baert LV. Impalpable invisible stage T1c prostate cancer: characteristics and clinical relevance in 100 radical prostatectomy specimens – a different view. J Urol 1997;157(1):244-50. http://www.ncbi.nlm.nih.gov/pubmed/8976263 Oesterling JE, Suman VJ, Zincke H, Bostwick DG. PSA-detected (clinical stage T1c or B0) prostate cancer. Pathologically significant tumours. Urol Clin North Am 1993;20(4):687-93. http://www.ncbi.nlm.nih.gov/pubmed/7505977 Epstein JI, Walsh PC, Brendler CB. Radical prostatectomy for impalpable prostate cancer: the Johns Hopkins experience with tumours found on transurethral resection (stages T1A and T1B) and on needle biopsy (stage T1C). J Urol 1994;152(5 Pt 2):1721-9. http://www.ncbi.nlm.nih.gov/pubmed/7523719 Singh H, Canto EI, Shariat SF, Kadmon D, Miles BJ, Wheeler TM, Slawin KM. Improved detection of clinically significant, curable prostate cancer with systematic 12-core biopsy. J Urol 2004;171(3): 1089-92. http://www.ncbi.nlm.nih.gov/pubmed/14767277 Epstein JI, Chan DW, Sokoll LJ, Walsh PC, Cox JL, Rittenhouse H, Wolfert R, Carter HB. Nonpalpable stage T1c prostate cancer: prediction of insignificant disease using free/total prostate specific antigen levels and needle biopsy findings. J Urol 1998;160(6 Pt 2): 2407-11. http://www.ncbi.nlm.nih.gov/pubmed/9817393 Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001;58(6):843-8. http://www.ncbi.nlm.nih.gov/pubmed/11744442 D’Amico AV, Whittington R, Malkowicz SB, Wu YH, Chen M, Art M, Tomaszewski JE, Wein A. Combination of preoperative PSA level, biopsy Gleason score, percentage of positive biopsies and MRI T-stage to predict early failure in men with clinically localized prostate cancer. Urology 2000;55(4):572-7. http://www.ncbi.nlm.nih.gov/pubmed/10736506 Epstein JI. Gleason score 2-4 adenocarcinoma of the prostate on needle biopsy: a diagnosis that should not be made. Am J Surg Pathol 2000;24(4):477-8. http://www.ncbi.nlm.nih.gov/pubmed/10757394 Epstein JI, Steinberg GD. The significance of low grade prostate cancer on needle biopsy. A radical prostatectomy study of tumour grade, volume, and stage of the biopsied and multifocal tumour. Cancer 1990;66(9):1927-32. http://www.ncbi.nlm.nih.gov:/pubmed/1699655 Briganti A, Chun FK, Salonia A, Gallina A, Farina E, Da Pozzo LF, Rigatti P, Montorsi F, Karakiewicz PI. Validation of a nomogram predicting the probability of lymph node invasion based on the extent of pelvic lymphadenectomy in patients with clinically localized prostate cancer. BJU Int 2006;98(4): 788-93. http://www.ncbi.nlm.nih.gov/pubmed/16796698 Schroder FH, Van den Ouden D, Davidson P. The role of surgery in the cure of prostatic carcinoma. Eur Urol Update Series 1992;1:18-23. Gibbons RP. Total prostatectomy for clinically localized prostatic cancer: long-term surgical results and current morbidity. NCI Monogr 1988;(7):123-6. http://www.ncbi.nlm.nih.gov/pubmed/3173498 Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997;24(2):395-406. http://www.ncbi.nlm.nih.gov/pubmed/9126237 Johansson JE, Andersson SO. Deferred treatment in localized prostatic cancer. Acta Oncol 1991;30(2):221-3. http://www.ncbi.nlm.nih.gov/pubmed/2029410
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Graversen PH, Nielsen KT, Gasser TC, Corle DK, Madsen PO. Radical prostatectomy versus expectant primary treatment in stages I and II prostatic cancer. A fifteen-year follow-up. Urology 1990;36(6):493-8. http://www.ncbi.nlm.nih.gov/pubmed/2247914 38. Eastham JA, Kattan MW, Riedel E, Begg CB, Wheeler TM, Gerigk C, Gonen M, Reuter V, Scardino PT. Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J Urol 2003;170(6 Pt 1):2292-5. http://www.ncbi.nlm.nih.gov/pubmed/14634399 39. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-free and cancerspecific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001;28(3):555-65. http://www.ncbi.nlm.nih.gov/pubmed/11590814 40. Catalona WJ, Smith DJ. 5-year tumour recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152 (5 Pt 2):1837-42. http://www.ncbi.nlm.nih.gov/pubmed/7523731 41. Hull GW, Rabbani F, Abbas F, Wheeler TM, Kattan MW, Scardino PT. Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol 2002;167(2 Pt 1):528-34. http://www.ncbi.nlm.nih.gov/pubmed/11792912 42. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 1994;152(5 Pt 2):1821-5. http://www.ncbi.nlm.nih.gov/pubmed/7523728 43. Zincke H, Oesterling JE, Blute ML, Bergstralh EJ, Myers RP, Barrett DM. Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J Urol 1994;152(5Pt2):1850-7. http://www.ncbi.nlm.nih.gov/pubmed/7523733 44. Makarov DV, Trock BJ, Humphreys EB, Mangold LA, Walsh PC, Epstein JI, Partin AW. Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005. Urology 2007 Jun;69(6):1095-101. http://www.ncbi.nlm.nih.gov/pubmed/17572194 45. Cooperberg MR, Lubeck DP, Mehta SS, Carroll PR; CaPSURE. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE). J Urol 2003;170(6 Pt 2): S21-S25; discussion S26-27. http://www.ncbi.nlm.nih.gov/pubmed/14610406 46. Hodgson D, Warde P, Gospodarowicz M. The management of locally advanced prostate cancer. Urol Oncol 1998;4:3-12. 47. Fallon B, Williams RD. Current options in the management of clinical stage C prostatic carcinoma. Urol Clin North Am 1990;17(4):853-66. http://www.ncbi.nlm.nih.gov/pubmed/2219582 48. Boccon-Gibod L, Bertaccini A, Bono AV, Dev Sarmah B, Höltl W, Mottet N, Tunn U, Zamboglou N. Management of locally advanced prostate cancer: a European Consensus. Int J Clin Pract 2003;57(3):187-94. http://www.ncbi.nlm.nih.gov/pubmed/12723722 49. Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A, Pierart M. 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(9327):103-6. http://www.ncbi.nlm.nih.gov/pubmed/12126818 50. Yamada AH, Lieskovsky G, Petrovich Z, Chen SC, Groshen S, Skinner DG. Results of radical prostatectomy and adjuvant therapy in the management of locally advanced, clinical stage TC, prostate cancer. Am J Clin Oncol 1994;17(4):277-85. http://www.ncbi.nlm.nih.gov/pubmed/8048388 51. Gerber GS, Thisted RA, Chodak GW, Schroder FH, Frohmuller HG, Scardino PT, Paulson DF, Middleton AW Jr, Rukstalis DB, Smith JA Jr, Ohori M, Theiss M, Schellhammer PF. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. Eur Urol 1997;32(4):385-90. http://www.ncbi.nlm.nih.gov/pubmed/9412793
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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(4):1392-7. http://www.ncbi.nlm.nih.gov/pubmed/9751362 53. Isorna Martinez de la Riva S, Belón López-Tomasety J, Marrero Dominguez R, Alvarez Cruz E, Santamaria Blanco P. [Radical prostatectomy as monotherapy for locally advanced prostate cancer (T3a): 12 years follow-up]. Arch Esp Urol 2004;57(7):679-92. [article in Spanish] http://www.ncbi.nlm.nih.gov/pubmed/15536949 54. Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int 2005;95(6):751-6. http://www.ncbi.nlm.nih.gov/pubmed/15794776 55. 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(1):121-8; discussion 128-9. http://www.ncbi.nlm.nih.gov/pubmed/16797831 56. Joniau S, Hsu CY, Lerut E, Van Baelen A, Haustermans K, Roskams T, Oyen R, Van Poppel H. A pretreatment table for the prediction of final histopathology after radical prostatectomy in clinical unilateral T3a prostate cancer. Eur Urol 2007;51(2):388-96. http://www.ncbi.nlm.nih.gov/pubmed/16901622 57. Van Poppel H, Ameye F, Oyen R, Van de Voorde W, Baert L. Accuracy of combined computerized tomography and fine needle aspiration cytology in lymph node staging of localized prostatic carcinoma. J Urol 1994;151(5):1310-14. http://www.ncbi.nlm.nih.gov/pubmed/8158777 58. Van Poppel H, Vekemans K, Da Pozzo L, Bono A, Kliment J, Montironi R, Debois M, Collette L. Radical prostatectomy for locally advanced prostate cancer: results of a feasibility study (EORTC 30001). Eur J Cancer 2006;42(8):1062-7. http://www.ncbi.nlm.nih.gov/pubmed/16624554 59. Van Poppel H, Joniau S. An analysis of radical prostatectomy in advanced stage and high-grade prostate cancer. Eur Urol 2008;53(2):253-9. http://www.ncbi.nlm.nih.gov/pubmed/17949893 60. Yossepowitch O, Eggener SE, Bianco FJ Jr, Carver BS, Serio A, Scardino PT, Eastham JA. Radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. J Urol 2007;178(2):493-9;discussion 499. http://www.ncbi.nlm.nih.gov/pubmed/17561152 61. D’Amico AV, Whittington R, Malkowicz SB, Fondurulia J, Chen MH, Kaplan I, Beard CJ, Tomaszewski JE, Renshaw AA, Wein A, Coleman CN. Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol 1999;17(1):168-72. http://www.ncbi.nlm.nih.gov/pubmed/10458230 62. Tiguert LL, Harrel F, Fradet Y. Disease outcome of patients with a PSA > 20 treated by radical prostatectomy: analysis of 177 patients. J Urol 2006;175:311A. 63. Inman BA, Davies JD, Rangel LJ, Bergstralh EJ, Kwon ED, Blute ML, Karnes RJ, Leibovich BC. Longterm outcomes of radical prostatectomy with multimodal adjuvant therapy in men with a preoperative serum prostate-specific antigen level > or = 50 ng/mL. Cancer 2008;113(7):1544-51. http://www.ncbi.nlm.nih.gov/pubmed/18680171 64. Ghavamian R, Bergstralh EJ, Blute ML, Slezak J, Zincke H. Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. J Urol 1999;161(4):1223-7; discussion 1277-8. http://www.ncbi.nlm.nih.gov/pubmed/10081874 65. Briganti A, Karnes JR, Da Pozzo LF, Cozzarini C, Gallina A, Suardi N, Bianchi M, Freschi M, Doglioni C, Fazio F, Rigatti P, Montorsi F, Blute ML. Specific survival in patients with node positive prostate cancer. a new proposal based on a two-institution experience on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node dissection and adjuvant therapy. Eur Urol 2008. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18838212 66. Schumacher MC, Burkhard FC, Thalmann GN, Fleischmann A, Studer UE. Good outcome for patients with few lymph node metastases after radical retropubic prostatectomy. Eur Urol 2008;54(2):344-52. http://www.ncbi.nlm.nih.gov/pubmed/18511183
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Schumacher MC, Burkhard FC, Thalmann GN, Fleischmann A, Studer UE. Is pelvic lymph node dissection necessary in patients with a serum PSA<10ng/mL undergoing radical prostatectomy for prostate cancer? Eur Urol 2006;50(2):272-9. http://www.ncbi.nlm.nih.gov/pubmed/16632187 68. 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(4):1681-6. http://www.ncbi.nlm.nih.gov/pubmed/11912387 69. Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure? J Urol 2003;169(3): 849-54. http://www.ncbi.nlm.nih.gov/pubmed/12576797 70. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281(17):1591-7. http://www.ncbi.nlm.nih.gov/pubmed/10235151 71. Aus G, Nordenskjöld K, Robinson D, Rosell J, Varenhorst E. Prognostic factors and survival in nodepositive (N1) prostate cancer – a prospective study based on data from a Swedish population-based cohort. Eur Urol 2003;43(6):627-31. http://www.ncbi.nlm.nih.gov/pubmed/12767363 72. Cheng L, Zincke H, Blute ML, Bergstrahl EJ, Scherer B, Bostwick DG. Risk of prostate carcinoma death in patients with lymph node metastasis. Cancer 2001;91(1):66-73. http://www.ncbi.nlm.nih.gov/pubmed/11148561 73. Weingärtner K, Ramaswamy A, Bittinger A, Gerharz EW, Vöge D, Riedmiller H. Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J Urol 1996;156(6):1969-71. http://www.ncbi.nlm.nih.gov/pubmed/8911367 74. Bader P, Burkhard FC, Markwalder R, Studer UE. Is a limited lymph node dissection an adequate staging procedure for prostate cancer? J Urol 2002;168(2):514-8;discussion 518. http://www.ncbi.nlm.nih.gov/pubmed/12131300 75. Briganti A, Chun FK, Salonia A, Suardi N, Gallina A, Da Pozzo LF, Roscigno M, Zanni G, Valiquette L, Rigatti P, Montorsi F, Karakiewicz PI. Complications and other surgical outcomes associated with extended pelvic lymphadenectomy in men with localized prostate cancer. Eur Urol 2006;50(5): 1006-13. http://www.ncbi.nlm.nih.gov/pubmed/16959399 76. Heidenreich A et al. Extended pelvic lymphadenectomy in men undergoing radical retropubic prostatectomy (RRP) – an update on > 300 cases. J Urol 2004;171:a312. 77. Burkhard FC, Schumacher M, Studer UE. The role of lymphadenectomy in prostate cancer. Nat Clin Pract Urol 2005;2(7):336-42. http://www.ncbi.nlm.nih.gov/pubmed/16474786 78. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, Messing E, Forman J, Chin J, Swanson G, Canby-Hagino E, Crawford ED. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/19167731 79. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di’SantAgnese PA, Trump D; Eastern Cooperative Oncology Group study EST 3886. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006;7(6):472-9. http://www.ncbi.nlm.nih.gov/pubmed/16750497 80. Vallett BS. Radical perineal prostatectomy subsequent to bilateral orchiectomy. Delaware Med J 1944;16:19-20. 81. Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neoadjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. Cochrane Database Syst Rev 2006;(4):CD006019. http://www.ncbi.nlm.nih.gov/pubmed/17054269 82. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP; Casodex Early Prostate Cancer Trialists’ Group. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006;97(2):247-54. http://www.ncbi.nlm.nih.gov/pubmed/16430622
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83. Hautmann RE, Sauter TW, Wenderoth UK. Radical retropubic prostatectomy: morbidity and urinary continence in 418 consecutive cases. Urology 1994;43(2 Suppl.):47-51. http://www.ncbi.nlm.nih.gov/pubmed/8116133 84. Murphy GP, Mettlin C, Menck H, Winchester DP, Davidson AM. National patterns of prostate cancer treatment by radical prostatectomy: results of a survey by the American College of Surgeons Commission on Cancer. J Urol 1994;152(5 Pt 2):1817-9. http://www.ncbi.nlm.nih.gov/pubmed/7523727 85. Begg CB, Riedel ER, Bach PB, Kattan MW, Schrag D, Warren JL, Scardino PT. Variations in morbidity after radical prostatectomy. N Engl J Med 2002;346(15):1138-44. http://www.ncbi.nlm.nih.gov/pubmed/11948274 86. Potosky AL, Legler J, Albertsen PC, Stanford JL, Gilliland FD, Hamilton AS, Eley JW, Stephenson RA, Harlan LC. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcome Study. J Natl Cancer Inst 2000;92(19):1582-92. http://www.ncbi.nlm.nih.gov/pubmed/11018094 87. Van Poppel H, Collette L, Kirkali Z, Brausi M, Hoekstra W, Newling DW, Decoster M, EORTC GU Group. Quality control of radical prostatectomy: a feasibility study. Eur J Cancer 2001;37(7):884-91. http://www.ncbi.nlm.nih.gov/pubmed/11313177 88. Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 1994;152(5Pt2):1831-6. http://www.ncbi.nlm.nih.gov/pubmed/7523730 89. Sofer M, Savoie M, Kim SS, Civantos F, Soloway MS. Biochemical and pathological predictors of the recurrence of prostatic adenocarcinoma with seminal vesicle invasion. J Urol 2003;169(1):153-6. http://www.ncbi.nlm.nih.gov/pubmed/12478125 90. Walsh RM, Thompson IM. Prostate cancer screening and disease management: how screening may have an unintended effect on survival and mortality-the camel’s nose effect. J Urol 2007;177(4): 1303-6. http://www.ncbi.nlm.nih.gov/pubmed/17382719 91. Alsikafi NF, Brendler CB. Surgical modifications of radical retropubic prostatectomy to decrease incidence of positive surgical margins. J Urol 1998;159(4):1281-5. http://www.ncbi.nlm.nih.gov/pubmed/9507853 92. Graefen M. Is the open retropubic radical prostatectomy dead? Eur Urol 2007 Nov;52(5):1281-3. http://www.ncbi.nlm.nih.gov/pubmed/17764828 93. Bianco FJ Jr, Scardino PT, Eastham JA. Radical prostatectomy: long-term cancer control and recovery of sexual and urinary function (‘trifecta’). Urology 2005; 66(5 Suppl.):83-94. http://www.ncbi.nlm.nih.gov/pubmed/16194712 94. Gontero P, Kirby RS. Nerve-sparing radical retropubic prostatectomy: techniques and clinical considerations. Prostate Cancer Prostatic Dis 2005;8(2):133-9. http://www.ncbi.nlm.nih.gov/pubmed/15711608 95. Sokoloff MH, Brendler CB. Indications and contraindications for nerve-sparing radical prostatectomy. Urol Clin North Am 2001;28(3):535-43. http://www.ncbi.nlm.nih.gov/pubmed/11590812 96. Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, Nava L, Barbieri L, Rigatti P, Pizzini G, Miani A. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 1997;158(4):1408-10. http://www.ncbi.nlm.nih.gov/pubmed/9302132 97. Nandipati K, Raina R, Agarwal A, Zippe CD. Early combination therapy: intracavernosal injections and sildenafil following radical prostatectomy increases sexual activity and the return of natural erections. Int J Impot Res 2006;18(5):446-51. http://www.ncbi.nlm.nih.gov/pubmed/16482200 98. Secin FP, Koppie TM, Scardino PT, Eastham JA, Patel M, Bianco FJ, Tal R, Mulhall J, Disa JJ, Cordeiro PG, Rabbani F. Bilateral cavernous nerve interposition grafting during radical retropubic prostatectomy: Memorial Sloan-Kettering Cancer Center experience. J Urol 2007;177(2):664-8. http://www.ncbi.nlm.nih.gov/pubmed/17222654 99. Montorsi F, Brock G, Lee J, Shapiro J, Van Poppel H, Graefen M, Stief C. Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 2008 Oct;54(4):924-31. http://www.ncbi.nlm.nih.gov/pubmed/18640769
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10. TREATMENT: DEFINITIVE RADIATION THERAPY 10.1 Introduction There are no randomised studies comparing radical prostatectomy with either external beam therapy or brachytherapy for localised prostate cancer, but the National Institutes of Health (NIH) consensus set up in 1988 (1) remains available: external irradiation offers the same long-term survival results as surgery; moreover, external irradiation provides a quality of life at least as good as that provided by surgery (2). Three-dimensional conformal radiotherapy (3D-CRT) is the gold standard and, at the beginning of the third millennium, intensity modulated radiotherapy (IMRT), an optimised form of 3D-CRT, is gradually gaining ground in centres of excellence. In addition to external irradiation, there has been continued and growing interest in transperineal low dose or high dose brachytherapy. In localised and locally advanced prostate cancer, several randomised phase III trials conducted by radiation therapy scientific societies, such as the Radiation Therapy Oncology Group (RTOG) and European Organisation for Research and Treatment of Cancer (EORTC), have established the indications for the combination of external irradiation and androgen deprivation treatment (ADT). Whatever the technique, the choice of treatment after the appropriate assessment of tumour extension must be based on a multidisciplinary approach taking account of: • the 2002 tumour node metastasis (TNM) classification • the Gleason score defined on a sufficient number of core biopsies (at least 12) • the baseline prostate-specific antigen (PSA) • the age of the patient • his co-morbidity, life expectancy and quality of life • d’Amico’s prognostic factor classification. Obtaining a patient’s consent is essential after giving full information regarding diagnosis, the therapeutic modalities and morbidity. Additional information on the various aspects of radiotherapy in the treatment of prostate cancer is available in a newly published extensive overview (3).
Technical aspects: three dimensional conformal radiotherapy and intensity modulated external beam radiotherapy
Anatomical data acquired by scanning the patient in a treatment position, are transferred to the 3D treatment planning system where the clinical target volume is visualised, following which a (surrounding) safety margin is added. At the time of irradiation, a multileaf collimator automatically and, in the case of IMRT, continuously, adapts to the contours of the target volume seen by each beam. Real-time verification of the irradiation field by means of portal imaging allows for comparison of the treated and simulated fields, and correction of deviations where displacement is more than 5 mm. Three-dimensional CRT improves local control through dose escalation without increasing the risk of morbidity. The use of IMRT is possible with linear accelerators equipped with the latest multileaf collimators and specific software. Movement of the leaves during the course of the irradiation allows for a more complex distribution of the dose to be delivered within the treatment field, and provides concave isodose curves, which are particularly useful as a means to spare the rectum. Whatever the techniques and their sophistication, quality assurance plays a major role in the management of radiotherapy, mandating the involvement of physicians, physicists, dosimetrists, radiographers, radiologists and computer scientists.
Localised prostate cancer T1-2c N0, M0
10.3.1 T1a-T2a, N0, M0 and Gleason score ≤ 6 and PSA < 10 ng/mL (low-risk group) Retrospective, non-randomised studies have shown that biochemical disease-free survival is significantly higher with a radiation dose ≥ 72 Gy compared with < 72 Gy (p = 0.04) (4). Two randomised trials focusing on clinical stages T1-3 N0 M0 paved the way for dose escalation: • The MD Anderson study compared 78 Gy with 70 Gy conventional radiotherapy: it included 305 stage T1-3 patients with a pre-treatment PSA level of more than 10 ng/mL and, with a median follow-up of
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8.7 years, showed a significant increase in freedom from biochemical and/or clinical failure for low-risk patients (p = 0.04) (5). The PROG 95-09 evaluated 393 T1b-T2b patients, of whom 75% had a Gleason score ≤ 6 and a PSA < 15 ng/mL. Patients were randomised to receive an initial boost to the prostate alone, using conformal protons of either 19.8 Gy or 28.8 Gy, and then 50.4 Gy to a larger volume. With a median follow-up of 5.5 years, there was a significant increase in five-year freedom from biochemical failure (p < 0.001) in favour of low-risk patients, who were given a higher dose (79.2 Gy), compared with those receiving a conventional dose (70.2 Gy) (6).
In daily practice, a minimum dose of 74 Gy is recommended. 10.3.2 T2b or PSA 10-20 ng/mL, or Gleason score 7 (intermediate-risk group) Many non-randomised studies have shown dose escalation to have a significant impact on five-year survival without biochemical relapse for patients classified as cT1c-T3, with a dose ranging from 76-81 Gy (4, 7, 8). A Dutch randomised phase III trial comparing 68 Gy with 78 Gy showed a significant increase in five-year freedom from clinical or biochemical failure for patients in an intermediate-risk group (9). The phase III trial of the French Federation of Cancer Centres compared 70 Gy with 80 Gy in 306 patients with a pelvic lymph node involvement risk of < 10% (Partin) or pN0, with no hormonal therapy allowed before, during or after radiotherapy. With a median follow-up of 59 months, high dose should provide a better five-year biological outcome in intermediate-risk patients, especially if the initial PSA > 15ng/mL (10). Patients who are reluctant to accept short-term hormonal treatment (11) can receive definitive radiotherapy alone provided that a dose escalation up to 78-80 Gy is proposed. 10.3.3 T2c or Gleason score > 7 or PSA > 20 ng/mL (high-risk group) External irradiation with dose escalation is mandatory since it improves the five-year biochemical disease-free survival, as shown in several phase III randomised trials. • The Dutch study comparing 68 Gy with 78 Gy showed a 10% increase in the five-year freedom from clinical or biochemical failure (p = 0.02) (9). • The MRC study comparing 64 Gy with 74 Gy, with neoadjuvant hormonal therapy, has shown an 11% difference in five-year biochemical disease-free survival (12). • The PROG 95-09 study, with a significant increase in five-year freedom from biochemical failure (p < 0.02) in favour of high-risk patients given a higher dose (79.2 Gy) vs those receiving a conventional dose (70.2 Gy) (9). • The MD Anderson study showed a significant increase in freedom from biochemical and/or clinical failure for high-risk patients (p = 0.004) (5). • The EORTC trial 22991, comparing 3D-CRT +/- IMRT with a choice of three levels of dose (70 Gy, 74 Gy and 78 Gy), with or without six months of neoadjuvant and concomitant hormonal therapy, was closed in April 2008 after recruiting 800 patients, and its results are awaited (13). In daily practice, a combination of external irradiation with short-term androgen deprivation is recommended, based on the results of a phase III randomised trial. This trial, which included 206 patients with a PSA of at least 10 ng/mL (maximum 40 ng/mL), a Gleason score of at least 7 (range 5-10), or radiographic evidence of extra-prostatic disease, compared 3D-CRT alone or in combination with six months of ADT. After a median follow-up of 7.6 years, intermediate- or high-risk patients without moderate or severe co-morbidity randomised to receive 3D-CRT plus ADT had a 13% improvement in overall survival rate (p < 0.001) (11). 10.3.4 Prophylactic irradiation of pelvic lymph nodes in high-risk localised prostate cancer Invasion of the pelvic lymph nodes is a poor prognostic factor and mandates systemic medical treatment because radiotherapy alone is insufficient (14). Prophylactic whole pelvis irradiation has been abandoned since randomised trials failed to show that patients benefited from prophylactic irradiation of the pelvic lymph nodes in high-risk cases (46-50 Gy). Such studies include the RTOG study with 484 T1b-T2 patients (15), the Standford study with only 91 patients (16), and the GETUG-01 trial, which included 444 T1b-T3 N0 pNx M0 patients (17). In order better to select patients who might benefit from pelvic lymph node irradiation, and to supplement the use of Partin’s tables (18) and/or the Roach formula (19), pelvic lymphadenectomy might be required, particularly for young patients, because its results will enable radiation oncologists to tailor both the planning target volume and the duration of ADT: specifically, no pelvic irradiation for pN0 patients, but pelvic irradiation for pN1 patients with long term ADT.
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10.4 Innovative techniques 10.4.1 Intensity modulated radiotherapy IMRT enables radiation oncologists to increase radiation doses homogeneously up to as much as 86 Gy within the target volume, while respecting the tolerance doses in organs at risk. Certainly, for dose escalation beyond 80 Gy, using conventional 2 Gy fraction sizes, or for dose escalation using hypofractionated radiotherapy, in which there has been renewed interest, IMRT is the only safe means of treatment delivery, although both treatment scenarios should be performed only within the confines of a properly designed clinical trial. The Memorial Sloan-Kettering Cancer Center has the largest experience with this technique, and its results have now been updated, reporting on disease control and toxicity in two cohorts of patients. In the first, 561 patients with organ-confined disease were treated with a dose of 81 Gy. The eight-year actuarial PSA relapse-free survival rates for patients in favourable, intermediate and unfavourable risk groups were 85%, 76% and 72%, respectively, according to the then-current American Society for Radiation Oncology (ASTRO) definition (20). In the second cohort, 478 patients with organ-confined disease were treated with a dose of 86.4 Gy. The fiveyear actuarial PSA relapse-free survival according to the nadir plus 2 ng/mL definition was 98%, 85% and 70% for the low-, intermediate-, and high-risk groups, respectively (21). To date, no randomised trials have been published comparing dose escalation using IMRT and 3D-CRT. However, several such trials are ongoing (UK NCRI, MD Anderson, Fox Chase, and Ottawa Health Research Institute), although one (Ottawa) is studying helical tomotherapy (see below), and two (NCRI and MD Anderson) are studying hypofractionated, doseescalated radiotherapy. With dose escalation using IMRT, organ movement becomes a critical issue, in terms of both tumour control and treatment toxicity, and evolving techniques will combine IMRT with some form of image-guided radiotherapy (IGRT), in which organ movement can be visualised and corrected for in real time, although the optimum means of achieving this is still unclear (22). Another evolving technique for the delivery of IMRT is tomotherapy, which uses a linear accelerator mounted on a ring gantry that rotates as the patient is delivered through the centre of the ring, analogous to spiral computed tomography (CT) scanning. Preliminary data suggest that this technique is feasible in prostate cancer treatment (23). 10.4.2 Proton beam and carbon ion beam therapy In theory, proton beams are an attractive alternative to photon beam radiotherapy for prostate cancer because they deposit almost all their radiation dose at the end of the particle’s path in tissue (the Bragg peak), in contrast to photons, which deposit radiation along their path. Additionally, there is a very sharp fall-off for proton beams beyond their deposition depth, meaning that critical normal tissues beyond this depth could be effectively spared, in contrast to photon beams, which will continue to deposit energy up to and including an exit dose as they leave the body. In practice, however, this has the disadvantage that dose distributions from protons are highly sensitive to changes in internal anatomy, such as might occur with bladder or rectal filling, and prostate proton therapy is usually delivered with lateral beams. It is also possible that high linear energy transfer (LET) radiation therapy using protons or carbon ions offers inherent biological advantages over photons, having more capacity for DNA damage dose-for-dose. Only one randomised trial has incorporated proton therapy in one arm: the Loma Linda/Massachusetts General Hospital trial discussed above compared standard-dose conformal radiotherapy with dose-escalated radiotherapy using protons for the boost dose (6). This trial cannot, however, be used as evidence for the superiority of proton therapy per se, as its use here could be viewed merely as a sophisticated method for dose escalation. In order to compare the efficacy of protons versus photons, a randomised trial using equivalent doses, comparing proton beam therapy with IMRT, would be needed, and such a study is under consideration by the RTOG. Two recent planning studies comparing conformal proton therapy with IMRT have yielded conflicting results, one suggesting that the two are equivalent in terms of rectal dose sparing, but IMRT is actually superior in terms of bladder sparing (24), and the other suggesting a clearer advantage to protons (25). Further studies are clearly needed, and in the interim, proton therapy must be regarded as a promising but experimental alternative to photon beam therapy. Theoretically, proton therapy might be associated with a lower risk of secondary
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cancers compared with IMRT, because of the lower integral dose of radiation, but there are no data in patients treated for prostate cancer to support this. Carbon ions offer similar theoretical advantages as protons as an alternative to photon beam therapy. In a phase II study, 175 patients with T1-3, N0-1, M0 prostate cancer were treated with carbon ions in a dose equivalent to 66 Gy in 20 fractions over five weeks (26). Treatment appeared to be well tolerated, with no RTOG grade 3 or 4 bowel or genitourinary toxicity, and an overall four-year biochemical disease-free rate of 88% (25). As with protons, a randomised trial comparing carbon ions with IMRT and using equivalent doses is required.
Transperineal brachytherapy is a safe and effective technique that generally requires fewer than two days of hospitalisation. There is consensus on the following eligibility criteria: • stage cT1b- T2a N0, M0, • a Gleason score ≤ 6 assessed on a sufficient number of random biopsies • an initial PSA level of≤ 10 ng/mL • ≤ 50% of biopsy cores involved with cancer • a prostate volume of < 50 cm3 • a good International Prostatic Symptom Score (IPSS) (27). Patients with low-risk prostate cancer are the most suitable candidates for low-dose rate (LDR) brachytherapy. Further guidelines on technical aspects of brachytherapy have been published recently, and are strongly recommended (28). In 1983, Holm et al. described the transperineal method with endorectal sonography in which the patient is positioned in a dorsal decubitus gynaecological position (29). Implantation is undertaken under general anaesthesia or spinal block, and involves a learning curve for the whole team: the surgeon for the delineation of the prostate and the placement of the needles, the physicist for real-time dosimetry, and the radiation oncologist for source loading. The sonography probe introduced into the rectum is fixed in a stable position. No randomised trials have been performed comparing brachytherapy with other curative treatment modalities, and outcomes are based on unrandomised case series. Results of permanent implants have been reported from different institutions, with a median follow-up ranging between 36 and 120 months (30). Recurrence-free survival after five and 10 years was reported to range from 71-93% and from 65-85%, respectively (31-38). A significant correlation has been shown between the implanted dose and recurrence rates (39). Patients receiving a D90 of > 140 Gy demonstrated a significantly higher biochemical control rate (PSA < 1.0 ng/mL) at four years than patients receiving less than 140 Gy (92% vs 68%). There is no benefit from adding neoadjuvant or adjuvant androgen deprivation to LDR brachytherapy (30). Some patients experience significant urinary complications following implantation, such as urinary retention (1.5-22%), post-implant transurethral resection of the prostate (TURP) (up to 8.7%), and incontinence (0-19%). A small randomised trial has suggested that prophylactic tamsulosin does not reduce the rates of acute urinary retention, but may improve urinary morbidity (40). This observation could usefully be further studied in a larger number of patients. Chronic urinary morbidity can occur in up to 20% of patients, depending on the severity of symptoms prior to brachytherapy. Previous TURP for benign prostatic hyperplasia increases the risk of postimplant incontinence and urinary morbidity. Brachytherapy-induced rectal morbidity with grade II/III proctitis occurs in 5-21% of patients. Erectile dysfunction develops in about 40% of patients after three to five years. In a recent retrospective analysis of 5621 men who had undergone LDR brachytherapy (41), urinary, bowel and erectile morbidity rates were 33.8%, 21% and 16.7%, respectively, with invasive procedure rates of 10.3%, 0.8% and 4%, respectively. In cases of permanent implants, iodine-125 in granular form is the radio-element of reference, while palladium-103 may be used for less differentiated tumours with a high doubling time. The dose delivered to the planning target volume is 160 Gy for iodine-125, and 120 Gy for palladium-103. A Gleason score of 7 remains a ‘grey area’, but patients with a Gleason score of 4 + 3 show no difference in outcome (42). A small randomised trial has suggested that, as one might expect, the use of stranded rather than loose seeds is associated with better seed retention and less seed migration, and this should be the standard choice (43).
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In cases of intermediate or high-risk localised prostate cancer, its combination with supplemental external irradiation (44) or neoadjuvant hormonal treatment (45) may be considered. The optimum dose of supplemental external beam radiation therapy (EBRT) is unclear. A randomised trial comparing 44 Gy with 20 Gy of EBRT plus palladium-103 brachytherapy closed early, showing no difference in biochemical outcomes (46). Non-permanent transperineal interstitial prostate brachytherapy using a high-dose rate iridium-192 stepping source and a remote afterloading technique can be applied with a total dose of 12-20 Gy in two to four fractions combined with fractionated external radiotherapy of 45 Gy (47). Higher doses of supplemental EBRT than this may best be delivered with IMRT, and a report from Memorial Sloan-Kettering indicates that such an approach is safe and feasible (48). Recent data suggest an equivalent outcome in terms of biochemical disease-free survival compared with high-dose EBRT (HD EBRT) (49). In a retrospective analysis of modern series (50, 51), biochemical diseasefree survival rates of 85.8%, 80.3% and 67.8% in men with low-, intermediate- and high-risk prostate cancer, respectively, are reported after a mean follow-up of 9.43 years. Quality-of-life changes are similar between HD EBRT and high-dose rate (HDR) brachytherapy in terms of diarrhoea and insomnia (52). However, the frequency of erectile dysfunction is significantly increased with HDR brachytherapy (86% vs 34%). A single randomised trial of EBRT versus EBRT plus HDR brachytherapy has been reported (53). A total of 220 patients with organ-confined prostate cancer were randomised to EBRT alone with a dose of 55 Gy in 20 fractions, or EBRT with a dose of 35.75 Gy in 13 fractions, followed by HDR brachytherapy with a dose of 17 Gy in two fractions over 24 hours. A significant improvement in biochemical relapse-free survival was seen in favour of the combined brachytherapy schedule (p = 0.03). There were no differences in the rates of late toxicity. Patients randomised to brachytherapy had significantly better quality of life as measured by their Functional Assessment of Cancer Therapy-prostate (FACT-P) score at 12 weeks (53). There is still a need to compare dose escalated EBRT plus hormone therapy, with the same plus a brachytherapy boost, in intermediate- and high-risk patients. For T1-2 N0 M0 disease, the five-year biochemical failure rates are similar for permanent seed implantation, high-dose (> 72 Gy) external radiation, combination seed/external irradiation, and radical prostatectomy. These were the results from a study that included 2991 patients diagnosed with T1-2 consecutive localised prostate cancer treated between 1990 and 1998 at the Cleveland Clinic Foundation and Memorial Sloan-Kettering Cancer Center with a minimum of one-year follow-up (49).
Patients must be informed about the potential late genitourinary or gastrointestinal toxicity that may occur, as well as the impact of irradiation on erectile function. Late toxicity was analysed using a dose of 70 Gy in the prospective EORTC randomised trial 22863 (1987-1995) (54), in which 90% of patients were diagnosed as stage T3-4. A total of 377 patients (91%) out of 415 enrolled were evaluable for long-term toxicity, graded according to a modified RTOG scale. Eighty-six (22.8%) patients had grade ≥ 2 urinary or intestinal complications or leg oedema, of which 72 had grade 2 (moderate) toxicity, 10 had grade 3 (severe) toxicity, and four died due to grade 4 (fatal) toxicity. Although four (1%) late treatment-related deaths occurred, longterm toxicity was limited, with fewer than 5% grade 3 or 4 late complications being reported (Table 15). These data can be used as a baseline for comparison with irradiation techniques currently in use, such as 3D-CRT or IMRT. Table 15: Incidence of late toxicity by RTOG grade (from EORTC trial 22863) Toxicity
Chronic diarrhoea Small bowel obstruction Overall GI toxicity Leg oedema Overall toxicity*
14 1 36 6 72
3.7 0.2 9.5 1.5 19.0
0 1 1 0 10
0.2 0.2 0 2.7
0 0 0 0 4
0 0 0 0 1
14 2 37 6 86
3.7 0.5 9.8 1.5 22.8
GU = genitourinary; GI = gastrointestinal. * Overall toxicity included genitourinary and gastrointestinal toxicity and leg oedema. As most patients had more than one type of toxicity, the overall toxicity does not result from simple addition. † Two of the grade 4 patients were irradiated with cobalt-60. Note: there was no other significant (≥ grade 2) toxicity among patients irradiated with cobalt-60 (n = 15) except for two patients with grade 4 genitourinary toxicity (stated above) and only one patient with grade 2 gastrointestinal toxicity. Radiotherapy affects erectile function to a lesser degree than surgery according to retrospective surveys of patients (2). A recent meta-analysis has shown that the one-year rate of probability for maintaining erectile function was 0.76 after brachytherapy, 0.60 after brachytherapy plus external irradiation, 0.55 after external irradiation, 0.34 after nerve-sparing radical prostatectomy, and 0.25 after standard radical prostatectomy. When studies with more than two years of follow-up were selected (i.e. excluding brachytherapy), the rates became 0.60, 0.52, 0.25, and 0.25, respectively, with a greater spread between the radiation techniques and surgical approaches (55). Recent studies have demonstrated a significantly increased risk of developing secondary malignancies of the rectum and bladder following EBRT (56, 57). In a retrospective evaluation of 30,552 and 55,263 men who had undergone either EBRT or radical prostatecto