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Treatment modalities for localised cancer

YASMIN ABU-GHANEM, SUBASH GURU MADHAVAN, ROGER KIRBY AND There are often several suitable treatment options for any individual patient with localised . The authors clarify some of the issues involved when helping men to face the difficult treatment decision of how best to manage their disease.

rostate cancer is the most common Pcancer in men, with about 36000 men diagnosed each year in the UK.1 With increasing awareness of the disease leading to greater uptake of the prostate- specific antigen (PSA) test coupled with a digital rectal examination (DRE), the cohort of patients with localised prostate cancer is growing. Figure 1. The da Vinci surgical system is becoming an increasingly common technique for robotic (courtesy of Intuitive Surgical) Those with a strong family history (multiple first-degree relative involved) or racial predisposition are particularly at risk. African and Caribbean men have a far higher incidence of prostate cancer and often present later in clinical stage with more aggressive disease. In spite of this, in many cases, prostate cancer is slow- growing with no symptoms, and many of Yasmin Abu-Ghanem, MSc, Tel Aviv University Medical School, the patients eventually die of other causes, Israel; Subash Guru Madhavan, MB BS, Clinical Assistant unrelated to the cancer. (), The Clinic; Roger Kirby, MA, MD, FRCS(Urol), FEBU, Director, The Prostate Centre; Ben Challacombe, MS, Unlike with most other solid organ FRCS(Urol), Consultant Urological Surgeon, The Prostate Centre tumours, there are often several suitable and Guy’s and St Thomas’ Hospitals; Honorary Senior Lecturer, treatment options for any individual King’s College London patient with localised prostate cancer, and there is usually enough time to make a

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considered choice. Many men face this PSA Gleason score Clinical stage difficult treatment decision of how best to manage their disease and often turn Low risk <10ng/ml and ≤6 and T1–T2a to their GP or other members of the Intermediate risk 10–20ng/ml or 7 or T2b–T2c primary care team for advice. Individual High risk >20ng/ml or 8–10 or T3–T4* clinicians often offer their own chosen treatment modality first, and patients face *Clinical stage T3–T4 represents locally advanced disease. PSA, prostate-specific antigen. considerable difficulty in weighing up the advantages of each treatment option. Table 1. Risk stratification for men with localised prostate cancer1

DIAGNOSIS OF PROSTATE CANCER MANAGEMENT OF LOCALISED either radical treatments (surgery, radiation As localised prostate cancer is usually an PROSTATE CANCER therapy or brachytherapy) or conservative asymptomatic disease, it is often diagnosed The treatment decision for an individual approaches (watchful waiting or active incidentally by an elevated PSA noticed man with localised prostate cancer surveillance). during a routine check-up. Adenocarcinoma depends on a number of key factors in of the prostate preferentially occurs in each case: RADICAL TREATMENT OPTIONS the peripheral zone of the prostate and • the patient’s overall life expectancy, as Radical treatment options include therefore needs to be of significant size determined by age and comorbidities radical prostatectomy (RP), external to cause symptoms. • the biological characteristics of the beam radiation therapy (EBRT) and tumour, including Gleason grade, number brachytherapy. Occasionally, localised prostate cancer can of biopsy cores positive for cancer, the be symptomatic, often with voiding or actual percentage of core involvement, Radical prostatectomy storage symptoms similar to benign and the clinical and radiological stage The surgical removal of the prostate prostatic hyperplasia, including prolonged • the preferences of the patient for and seminal vesicles is one of the gold- voiding, hesitancy, incomplete emptying, the various treatment options, with standard treatments for intermediate- frequency, nocturia, haematuria and dysuria. consideration of complications, adverse to high-risk disease.3,4 There are now effects, relative efficacy, and quality-of- three common approaches to performing By contrast, advanced prostate cancer life issues RP: retropubic, laparoscopic and robotic. causes general and metastatic • previous surgery or radiotherapy to the Perineal prostatectomy is also still manifestations such as weight loss and abdomen/pelvis performed in some centres. loss of appetite, anaemia, bone marrow • the desire or perceived potential need for suppression, bone pain, pathologic salvage treatments The laparoscopic and robotic techniques fracture, spinal cord compression, • the availability of various treatments in are becoming more frequently adopted, as and oedema caused by obstruction the region. they have the advantages of reduced blood of venous and lymphatic tributaries by loss, reduced pain, shorter inpatient stays nodal metastasis. Localised prostate cancer includes tumours and convalescence when compared to the that are clinically localised and appear to open approach.5 High-volume centres Uraemic symptoms can occur from ureteral be organ confined based on available performing these approaches report obstruction caused by local prostate imaging. These tumours are also referred excellent results with regard to oncological growth or retroperitoneal adenopathy to as T1 and T2 within the TMN staging and functional outcomes, but there is a secondary to nodal metastasis. system,2 but may include some pathological lack of level 1 evidence to support their T3 tumours. use. It is likely that robotic prostatectomy Suspected prostate cancer in patients using the da Vinci surgical system will be who present with elevated PSA levels To aid decision-making, men with localised the most common technique in the UK or abnormal DRE findings is typically prostate cancer are stratified into risk within the next few years (see Figure 1). confirmed by a 12-core transrectal groups according to their risk of recurrence needle biopsy of the prostate. Further and overall survival. A multidisciplinary According to the British Association of tests, such as magnetic resonance imaging team discussion should assign a risk Urological Surgeons, patients selected for (MRI) and bone scans, may be performed category to all newly diagnosed men with surgery should have anaesthetic fitness, to determine whether prostate cancer localised prostate cancer (Table 1). Men at least 10 years’ life expectancy, and has spread. with low-risk disease are managed with preferably be under the age of 70.

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However, there is no age threshold for BOX 1. Guidelines and recommendations for radical prostatectomy10 RP and a patient should not be denied this procedure on the grounds of INDICATIONS 6 chronological age alone, but on the l In patients with low- and intermediate-risk localised prostate cancer existence of comorbidities, for they may (T1a–T2b and Gleason score 2–7 and PSA ≤20ng/ml) and a life expectancy greatly increase the risk of dying from >10 years non-prostate cancer-related causes.7,8 Relative contraindications include OPTIONAL previous significant abdominal surgery l Patients with stage T1a disease and a life expectancy >15 years or Gleason and bleeding diatheses. score 7 l Selected patients with low-volume high-risk localised prostate cancer The goal of RP by any approach is total (T3a or Gleason score 8–10 or PSA >20ng/ml) eradication of disease, while preserving l Highly selected patients with very-high-risk localised prostate cancer continence and, whenever possible, (T3b–T4 N0 or any T N1) in the context of multimodality treatment potency.9 There is increased interest among the urological community for RECOMMENDATIONS the treatment of high-risk disease with l Short-term (three months) or long-term (nine months) neoadjuvant therapy RP coupled with an extended pelvic with gonadotrophin-releasing hormone analogues is not recommended in the lymphadenectomy. This is partly because of treatment of stage T1–T2 disease the much lower morbidity seen with the l Nerve-sparing surgery may be attempted in preoperatively potent patients current minimally invasive techniques and with low risk for extracapsular disease (T1c, Gleason score <7 and PSA partly as a result of the improvements in <10ng/ml) salvage radiotherapy to the prostatic bed l Unilateral nerve-sparing procedures are an option in stage T2a disease for those in whom cure is not primarily achieved. European Association of Urology (EAU) guidelines and recommendations for addition, EBRT provides a quality of life at small radioactive ‘seeds’ into the prostate RP are summarised in Box 1.10 least as good as that provided by surgery.11 under a general anaesthetic (Figure 2). It may be carried out in one or two stages by External beam radiation therapy In terms of patient selection, EBRT is a combination of urologists and clinical This involves treating the prostate with commonly used in the treatment of older oncologists. After mapping the prostate for around 74Gy of radiation in divided patients (>65 years) who have a greater extent and position, 80–100 seeds of fractions over a six- to seven-week course. likelihood of metastatic disease, or those iodine-125 or caesium-137 are placed, Depending on whether the disease is low, who decide against surgical intervention. ensuring uniform coverage of the prostate intermediate or high risk, neoadjuvant Indications for definitive radiation therapy and a margin around it, with the urethral (three months) or adjuvant (2.5 years) are summarised in the EAU guidelines.10 area generally spared. The seeds are hormonal therapy is given concurrently. permanently placed; early side-effects This usually takes the form of a luteinising External beam radiation therapy may be include , haematuria hormone-releasing hormone agonist or unsuitable for patients with bilateral hip and infection. anti-androgen medication. replacements, previous radiotherapy to the same region (pelvic radiotherapy for There is generally a lower morbidity with Computed tomography and MRI scans are seminoma, or colorectal tumours), severe brachytherapy than with RP or EBRT, but used to define target areas and plan the proctitis or bowel morbidity, including side-effects include worsening of storage administration of radiotherapy. Intensity- ulcerative colitis and diverticular disease, lower urinary tract symptoms, faecal modulated radiation therapy allows for as well as poorly controlled diabetes.12 urgency, rectal symptoms, sexual dysfunction, modulation of the dose intensity to target Patients should ideally be uncatheterised, urethral strictures and treatment failure. the cancer. Recent advances include the able to hold a moderate volume of urine in Overall it is a safe and effective curative use of radio-opaque markers to delineate the bladder and able to lie still. technique that generally requires fewer the extent/location of the cancer. than two days of hospitalisation. It is usually Brachytherapy recommended for: External irradiation offers the same Low-dose transperineal prostate • Gleason score ≤6 long-term survival results as surgery; in brachytherapy involves the placement of • initial PSA level <10ng/ml

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Active surveillance The selection criteria for watchful waiting are: Active surveillance offers close monitoring • asymptomatic clinically localised prostate of men with presumed low-risk prostate cancer cancer. It has the benefit of avoiding any • clinical stage T1−3 of the morbidity of radical treatments, • Gleason score ≤7 but the disadvantage of potentially missing • any PSA level the window of opportunity for cure or • unsuitable for radical treatment (usually effective treatment. It involves regular because of age or comorbidities). monitoring by a specialist prostate team using PSA, DRE, repeat biopsies (often now HORMONAL THERAPIES transperineal) and MRI imaging. The goals of pharmacotherapy for prostate cancer are to induce remission, reduce According to NICE, men with low-risk morbidity and prevent complications. In Figure 2. X-ray of the pelvis after low-dose prostate localised prostate cancer (see Table 1) who localised prostate cancer, hormone therapy is brachytherapy are considered suitable for radical treatment given mainly as a neoadjuvant or adjuvant • <50 per cent of biopsy cores involved should first be offered active surveillance.1 therapy with RP, EBRT or brachytherapy. with cancer Although there are many international and • prostate volume of <50cm3; although institutional criteria for active surveillance, it When given as a neoadjuvant agent, some centres can treat larger glands is particularly suitable for a subgroup of men hormone therapy reduces prostate volume • International Prostatic Symptom Score with very low-risk, localised prostate cancer by 30−40 per cent;13 by reducing the <12 with a reasonable flow rate and low who have the following: tumour size, one can reduce the size of the residual urine volume. • clinical stage T1c/T2a treatment field and as a result the level of • Gleason score ≤6 toxicity experienced. When compared with Brachytherapy is usually contraindicated • PSA <10ng/ml EBRT alone, a significant improvement in following transurethral resection of the • PSA density <0.15ng/ml per ml 10-year disease-specific mortality, distant prostate, in men with moderate to severe • fewer than three out of 10–12 biopsy metastases, disease-free survival and storage symptoms and in those with a cores involved biochemical failure was seen with the history of abdomino-perineal resection • <10mm of any core involved addition of neoadjuvant hormone therapy, and high-dose pelvic radiotherapy. Some • are fit for radical treatment options, age but no differences were observed in the centres also offer high-dose brachytherapy, 50–80 years. risk of fatal cardiac events.14 The role of where radioactive sources are inserted into neoadjuvant hormone therapy with the prostate for a short period of time and The decision to change from active brachytherapy is controversial. It is used to then removed. This technique is often used surveillance to radical treatment should reduce the prostate volume when it for treating high-risk disease. be made in the light of the individual’s exceeds 50ml, to facilitate brachytherapy. personal preferences, comorbidities and life CONSERVATIVE MANAGEMENT expectancy. Oncological reasons to stop To date, evidence suggests that the Many men with low-risk localised prostate active surveillance include increasing PSA, downstaging achieved with neoadjuvant cancer will not benefit from radical upgrading or increasing cancer volume at hormone therapy does not provide a treatment, and may even be overtreated. secondary biopsy. survival advantage for patients with Many of these small, localised tumours pathologically proven localised disease.15 will not progress, and radical therapy Watchful waiting could lead to significant consequent Watchful waiting is the conservative NOVEL THERAPIES morbidity in terms of continence, sexual management of prostate cancer, with Novel therapies include high-intensity function and quality of life. The number PSA tests and symptom observation, until focused ultrasonography (HIFU) and of men diagnosed in this situation the development of local or systemic cryotherapy. is increasing. progression, at which point the patient would be treated for urinary tract High-intensity focused ultrasonography In an effort to avoid overtreatment, symptoms or for palliation of metastatic Using ultrasound waves as a medium for two conservative management schemes lesions. It is particularly suitable for energy transmission to heat tissue, HIFU have emerged: active surveillance and patients aged over 75 years or younger causes coagulative necrosis of the prostate. It watchful waiting. men with significant comorbidities. is used to treat low-volume intracapsular

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6. Corral DA, Bahnson RR. Survival of men Low risk Intermediate risk High risk with clinically localized prostate cancer Watchful waiting Treatment option Treatment option Treatment option detected in the eighth decade of life. J Urol 1994;151:1326–9. Active surveillance Preferred treatment Treatment option Not recommended 7. Albertsen PC, Hanley JA, Gleason DF, et al. Competing risk analysis of men aged 55 Radical treatments to 74 years at diagnosis managed conservatively for clinically localized Prostatectomy Treatment option Preferred treatment Preferred treatmenta prostate cancer. JAMA 1998;280:975–80. 8. Tewari A, Johnson CC, Divine G, et al. Long- Brachytherapy Treatment option Treatment option Not recommended term survival probability in men with clinically localized prostate cancer: a Conformal Treatment option Preferred treatment Preferred treatmenta case-control, propensity modeling study radiotherapyb stratified by race, age, treatment and comorbidities. J Urol 2004;171:1513–19. Cryotherapy Not recommendedc Not recommendedc Not recommendedc 9. Bianco FJ Jr, Scardino PT, Eastham JA. Radical prostatectomy: long-term cancer High-intensity Not recommendedc Not recommendedc Not recommendedc control and recovery of sexual and urinary focused ultrasound function (`trifecta’). Urology 2005;66 (5 Suppl):83–94. aOffer if there is a realistic prospect of long-term disease control. 10. Heidenreich A, Bolla M, Joniau S, et al. bConformal radiotherapy should be given at a minimum dose of 74Gy (at a maximum of European Association of Urology. 2Gy per fraction). Guidelines on prostate cancer, 2011. cUnless as part of a clinical trial comparing use with established interventions. www.uroweb.org/gls/pdf/08_Prostate_ Cancer%20July%206th.pdf 1 Table 2. Treatment options for men with localised prostate cancer 11. Fowler FJ, Barry MJ, Lu-Yao G, et al. prostate cancer. Certain centres offer REFERENCES Outcomes of external beam radiation targeted HIFU (focal therapy) to specific 1. National Institute for Health and Clinical therapy for prostate cancer: a study of areas identified by biopsy within the gland. Excellence. Prostate cancer: diagnosis and Medicare beneficiaries in three surveillance Organised results for this option are yet to be treatment. London: NICE, 2008. epidemiology and end results areas. J Clin published, hence NICE classifies HIFU as an 2. Greene FL, Page DL, Fleming ID, et al, eds. Oncol 1996;14:2258–65. experimental therapy for use in clinical trials. AJCC cancer staging manual, 6th edn. New 12. Small W Jr, Woloschak GE, eds. Radiation York: Springer-Verlag, 2002. toxicity: a practical guide, vol. 128. New Cryotherapy 3. Bill-Axelson A, Holmberg L, Filén F, et al. York: Springer, 2006. Cryotherapy is the application of sub-zero Scandinavian Prostate Cancer Group study 13. Forman JD, Kumar R, Haas G, et al. temperatures using liquid argon/nitrogen number 4. Radical prostatectomy versus Neoadjuvant hormonal downsizing of via hollow needles, which are inserted watchful waiting in localized prostate localized carcinoma of the prostate: effects into the prostate transperineally. It has cancer: the Scandinavian prostate cancer on the volume of normal tissue irradiation. historically caused severe side-effects group-4 randomized trial. J Natl Cancer Inst Cancer Invest 1995;13:8−15. such as rectovesical fistulas, incontinence 2008;100:1144–54. 14. Bolla M, Collette L, Blank L, et al. Long-term and erectile dysfunction. It is usually 4. Holmberg L, Bill-Axelson A, Helgesen F, et al. results with immediate androgen recommended as a salvage treatment Scandinavian Prostate Cancer Group study suppression and external irradiation in where brachytherapy or EBRT have failed. number 4. A randomized trial comparing patients with locally advanced prostate NICE also recommends cryotherapy only radical prostatectomy with watchful cancer (an EORTC study): a phase III in the context of a clinical trial. waiting in early prostate cancer. N Engl J randomised trial. Lancet 2002;360:103−6. Med 2002;347:781–9. 15. Prayer-Galetti T, Zattoni F, Capizzi A, et al. Guidelines on treatment options for 5. Coelho RF, Palmer KJ, Rocco B, et al. Early Disease free survival in patients with localised prostate cancer are summarised complication rates in a single-surgeon series of pathological “C Stage” prostate cancer in Table 2. 2500 robotic-assisted radical : at radical prostatectomy submitted to report applying a standardized grading system. adjuvant hormonal treatment. Eur Urol Declaration of interests: none declared. Eur Urol 2010;57:945–52. 2000;38:504−7.

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