Treatment modalities for localised prostate cancer

Transcription

1 21 Treatment modalities for localised prostate cancer YASMIN ABU-GHANEM, SUBASH GURU MADHAVAN, ROGER KIRBY AND BEN CHALLACOMBE Figure 1. The da Vinci surgical system is becoming an increasingly common technique for robotic prostatectomy (courtesy of Intuitive Surgical) Yasmin Abu-Ghanem, MSc, Tel Aviv University Medical School, Israel; Subash Guru Madhavan, MB BS, Clinical Assistant (Urology), The London Clinic; Roger Kirby, MA, MD, FRCS(Urol), FEBU, Director, The Prostate Centre; Ben Challacombe, MS, FRCS(Urol), Consultant Urological Surgeon, The Prostate Centre and Guy s and St Thomas Hospitals; Honorary Senior Lecturer, King s College London There are often several suitable treatment options for any individual patient with localised prostate cancer. The authors clarify some of the issues involved when helping men to face the difficult treatment decision of how best to manage their disease. Prostate cancer is the most common cancer in men, with about men diagnosed each year in the UK. 1 With increasing awareness of the disease leading to greater uptake of the prostatespecific antigen (PSA) test coupled with a digital rectal examination (DRE), the cohort of patients with localised prostate cancer is growing. 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 slowgrowing with no symptoms, and many of the patients eventually die of other causes, unrelated to the cancer. Unlike with most other solid organ tumours, there are often several suitable treatment options for any individual patient with localised prostate cancer, and there is usually enough time to make a

2 22 considered choice. Many men face this difficult treatment decision of how best to manage their disease and often turn to their GP or other members of the primary care team for advice. Individual clinicians often offer their own chosen treatment modality first, and patients face considerable difficulty in weighing up the advantages of each treatment option. PSA Gleason score Clinical stage Low risk <10ng/ml and 6 and T1 T2a Intermediate risk 10 20ng/ml or 7 or T2b T2c High risk >20ng/ml or 8 10 or T3 T4* *Clinical stage T3 T4 represents locally advanced disease. PSA, prostate-specific antigen. Table 1. Risk stratification for men with localised prostate cancer 1 DIAGNOSIS OF PROSTATE CANCER As localised prostate cancer is usually an asymptomatic disease, it is often diagnosed incidentally by an elevated PSA noticed during a routine check-up. Adenocarcinoma of the prostate preferentially occurs in the peripheral zone of the prostate and therefore needs to be of significant size to cause symptoms. Occasionally, localised prostate cancer can be symptomatic, often with voiding or storage symptoms similar to benign prostatic hyperplasia, including prolonged voiding, hesitancy, incomplete emptying, frequency, nocturia, haematuria and dysuria. By contrast, advanced prostate cancer causes general and metastatic manifestations such as weight loss and loss of appetite, anaemia, bone marrow suppression, bone pain, pathologic fracture, spinal cord compression, and oedema caused by obstruction of venous and lymphatic tributaries by nodal metastasis. Uraemic symptoms can occur from ureteral obstruction caused by local prostate growth or retroperitoneal adenopathy secondary to nodal metastasis. Suspected prostate cancer in patients who present with elevated PSA levels or abnormal DRE findings is typically confirmed by a 12-core transrectal needle biopsy of the prostate. Further tests, such as magnetic resonance imaging (MRI) and bone scans, may be performed to determine whether prostate cancer has spread. MANAGEMENT OF LOCALISED PROSTATE CANCER The treatment decision for an individual man with localised prostate cancer depends on a number of key factors in each case: the patient s overall life expectancy, as determined by age and comorbidities the biological characteristics of the tumour, including Gleason grade, number of biopsy cores positive for cancer, the actual percentage of core involvement, and the clinical and radiological stage the preferences of the patient for the various treatment options, with consideration of complications, adverse effects, relative efficacy, and quality-oflife issues previous surgery or radiotherapy to the abdomen/pelvis the desire or perceived potential need for salvage treatments the availability of various treatments in the region. Localised prostate cancer includes tumours that are clinically localised and appear to be organ confined based on available imaging. These tumours are also referred to as T1 and T2 within the TMN staging system, 2 but may include some pathological T3 tumours. To aid decision-making, men with localised prostate cancer are stratified into risk groups according to their risk of recurrence and overall survival. A multidisciplinary team discussion should assign a risk category to all newly diagnosed men with localised prostate cancer (Table 1). Men with low-risk disease are managed with either radical treatments (surgery, radiation therapy or brachytherapy) or conservative approaches (watchful waiting or active surveillance). RADICAL TREATMENT OPTIONS Radical treatment options include radical prostatectomy (RP), external beam radiation therapy (EBRT) and brachytherapy. Radical prostatectomy The surgical removal of the prostate and seminal vesicles is one of the goldstandard treatments for intermediateto high-risk disease. 3,4 There are now three common approaches to performing RP: retropubic, laparoscopic and robotic. Perineal prostatectomy is also still performed in some centres. The laparoscopic and robotic techniques are becoming more frequently adopted, as they have the advantages of reduced blood loss, reduced pain, shorter inpatient stays and convalescence when compared to the open approach. 5 High-volume centres performing these approaches report excellent results with regard to oncological and functional outcomes, but there is a lack of level 1 evidence to support their use. It is likely that robotic prostatectomy using the da Vinci surgical system will be the most common technique in the UK within the next few years (see Figure 1). According to the British Association of Urological Surgeons, patients selected for surgery should have anaesthetic fitness, at least 10 years life expectancy, and preferably be under the age of TRENDS IN UROLOGY & MEN S HEALTH MARCH/APRIL 2012

3 23 However, there is no age threshold for RP and a patient should not be denied this procedure on the grounds of chronological age alone, 6 but on the existence of comorbidities, for they may greatly increase the risk of dying from non-prostate cancer-related causes. 7,8 Relative contraindications include previous significant abdominal surgery and bleeding diatheses. The goal of RP by any approach is total eradication of disease, while preserving continence and, whenever possible, potency. 9 There is increased interest among the urological community for the treatment of high-risk disease with RP coupled with an extended pelvic lymphadenectomy. This is partly because of the much lower morbidity seen with the current minimally invasive techniques and partly as a result of the improvements in salvage radiotherapy to the prostatic bed for those in whom cure is not primarily achieved. European Association of Urology (EAU) guidelines and recommendations for RP are summarised in Box External beam radiation therapy This involves treating the prostate with around 74Gy of radiation in divided fractions over a six- to seven-week course. Depending on whether the disease is low, intermediate or high risk, neoadjuvant (three months) or adjuvant (2.5 years) hormonal therapy is given concurrently. This usually takes the form of a luteinising hormone-releasing hormone agonist or anti-androgen medication. Computed tomography and MRI scans are used to define target areas and plan the administration of radiotherapy. Intensitymodulated radiation therapy allows for modulation of the dose intensity to target the cancer. Recent advances include the use of radio-opaque markers to delineate the extent/location of the cancer. External irradiation offers the same long-term survival results as surgery; in BOX 1. Guidelines and recommendations for radical prostatectomy 10 INDICATIONS l In patients with low- and intermediate-risk localised prostate cancer (T1a T2b and Gleason score 2 7 and PSA 20ng/ml) and a life expectancy >10 years OPTIONAL l Patients with stage T1a disease and a life expectancy >15 years or Gleason score 7 l Selected patients with low-volume high-risk localised prostate cancer (T3a or Gleason score 8 10 or PSA >20ng/ml) l Highly selected patients with very-high-risk localised prostate cancer (T3b T4 N0 or any T N1) in the context of multimodality treatment RECOMMENDATIONS l Short-term (three months) or long-term (nine months) neoadjuvant therapy with gonadotrophin-releasing hormone analogues is not recommended in the treatment of stage T1 T2 disease l Nerve-sparing surgery may be attempted in preoperatively potent patients with low risk for extracapsular disease (T1c, Gleason score <7 and PSA <10ng/ml) l Unilateral nerve-sparing procedures are an option in stage T2a disease addition, EBRT provides a quality of life at least as good as that provided by surgery. 11 In terms of patient selection, EBRT is commonly used in the treatment of older patients (>65 years) who have a greater likelihood of metastatic disease, or those who decide against surgical intervention. Indications for definitive radiation therapy are summarised in the EAU guidelines. 10 External beam radiation therapy may be unsuitable for patients with bilateral hip replacements, previous radiotherapy to the same region (pelvic radiotherapy for seminoma, or colorectal tumours), severe proctitis or bowel morbidity, including ulcerative colitis and diverticular disease, as well as poorly controlled diabetes. 12 Patients should ideally be uncatheterised, able to hold a moderate volume of urine in the bladder and able to lie still. Brachytherapy Low-dose transperineal prostate brachytherapy involves the placement of small radioactive seeds into the prostate under a general anaesthetic (Figure 2). It may be carried out in one or two stages by a combination of urologists and clinical oncologists. After mapping the prostate for extent and position, seeds of iodine-125 or caesium-137 are placed, ensuring uniform coverage of the prostate and a margin around it, with the urethral area generally spared. The seeds are permanently placed; early side-effects include urinary retention, haematuria and infection. There is generally a lower morbidity with brachytherapy than with RP or EBRT, but side-effects include worsening of storage lower urinary tract symptoms, faecal urgency, rectal symptoms, sexual dysfunction, urethral strictures and treatment failure. Overall it is a safe and effective curative technique that generally requires fewer than two days of hospitalisation. It is usually recommended for: Gleason score 6 initial PSA level <10ng/ml

4 24 Figure 2. X-ray of the pelvis after low-dose prostate brachytherapy <50 per cent of biopsy cores involved with cancer prostate volume of <50cm 3 ; although some centres can treat larger glands International Prostatic Symptom Score <12 with a reasonable flow rate and low residual urine volume. Brachytherapy is usually contraindicated following transurethral resection of the prostate, in men with moderate to severe storage symptoms and in those with a history of abdomino-perineal resection and high-dose pelvic radiotherapy. Some centres also offer high-dose brachytherapy, where radioactive sources are inserted into the prostate for a short period of time and then removed. This technique is often used for treating high-risk disease. CONSERVATIVE MANAGEMENT Many men with low-risk localised prostate cancer will not benefit from radical treatment, and may even be overtreated. Many of these small, localised tumours will not progress, and radical therapy could lead to significant consequent morbidity in terms of continence, sexual function and quality of life. The number of men diagnosed in this situation is increasing. In an effort to avoid overtreatment, two conservative management schemes have emerged: active surveillance and watchful waiting. Active surveillance Active surveillance offers close monitoring of men with presumed low-risk prostate cancer. It has the benefit of avoiding any of the morbidity of radical treatments, but the disadvantage of potentially missing the window of opportunity for cure or effective treatment. It involves regular monitoring by a specialist prostate team using PSA, DRE, repeat biopsies (often now transperineal) and MRI imaging. According to NICE, men with low-risk localised prostate cancer (see Table 1) who are considered suitable for radical treatment should first be offered active surveillance. 1 Although there are many international and institutional criteria for active surveillance, it is particularly suitable for a subgroup of men with very low-risk, localised prostate cancer who have the following: clinical stage T1c/T2a Gleason score 6 PSA <10ng/ml PSA density <0.15ng/ml per ml fewer than three out of biopsy cores involved <10mm of any core involved are fit for radical treatment options, age years. The decision to change from active surveillance to radical treatment should be made in the light of the individual s personal preferences, comorbidities and life expectancy. Oncological reasons to stop active surveillance include increasing PSA, upgrading or increasing cancer volume at secondary biopsy. Watchful waiting Watchful waiting is the conservative management of prostate cancer, with PSA tests and symptom observation, until the development of local or systemic progression, at which point the patient would be treated for urinary tract symptoms or for palliation of metastatic lesions. It is particularly suitable for patients aged over 75 years or younger men with significant comorbidities. The selection criteria for watchful waiting are: asymptomatic clinically localised prostate cancer clinical stage T1 3 Gleason score 7 any PSA level unsuitable for radical treatment (usually because of age or comorbidities). HORMONAL THERAPIES The goals of pharmacotherapy for prostate cancer are to induce remission, reduce morbidity and prevent complications. In localised prostate cancer, hormone therapy is given mainly as a neoadjuvant or adjuvant therapy with RP, EBRT or brachytherapy. When given as a neoadjuvant agent, hormone therapy reduces prostate volume by per cent; 13 by reducing the tumour size, one can reduce the size of the treatment field and as a result the level of toxicity experienced. When compared with EBRT alone, a significant improvement in 10-year disease-specific mortality, distant metastases, disease-free survival and biochemical failure was seen with the addition of neoadjuvant hormone therapy, but no differences were observed in the risk of fatal cardiac events. 14 The role of neoadjuvant hormone therapy with brachytherapy is controversial. It is used to reduce the prostate volume when it exceeds 50ml, to facilitate brachytherapy. To date, evidence suggests that the downstaging achieved with neoadjuvant hormone therapy does not provide a survival advantage for patients with pathologically proven localised disease. 15 NOVEL THERAPIES Novel therapies include high-intensity focused ultrasonography (HIFU) and cryotherapy. High-intensity focused ultrasonography Using ultrasound waves as a medium for energy transmission to heat tissue, HIFU causes coagulative necrosis of the prostate. It is used to treat low-volume intracapsular TRENDS IN UROLOGY & MEN S HEALTH MARCH/APRIL 2012

5 25 Watchful waiting Treatment option Treatment option Treatment option Active surveillance Preferred treatment Treatment option Not recommended Radical treatments prostate cancer. Certain centres offer targeted HIFU (focal therapy) to specific areas identified by biopsy within the gland. Organised results for this option are yet to be published, hence NICE classifies HIFU as an experimental therapy for use in clinical trials. Cryotherapy Cryotherapy is the application of sub-zero temperatures using liquid argon/nitrogen via hollow needles, which are inserted into the prostate transperineally. It has historically caused severe side-effects such as rectovesical fistulas, incontinence and erectile dysfunction. It is usually recommended as a salvage treatment where brachytherapy or EBRT have failed. NICE also recommends cryotherapy only in the context of a clinical trial. Guidelines on treatment options for localised prostate cancer are summarised in Table 2. Declaration of interests: none declared. Low risk Intermediate risk High risk Prostatectomy Treatment option Preferred treatment Preferred treatment a Brachytherapy Treatment option Treatment option Not recommended Conformal Treatment option Preferred treatment Preferred treatment a radiotherapy b Cryotherapy Not recommended c Not recommended c Not recommended c High-intensity Not recommended c Not recommended c Not recommended c focused ultrasound a Offer if there is a realistic prospect of long-term disease control. b Conformal radiotherapy should be given at a minimum dose of 74Gy (at a maximum of 2Gy per fraction). c Unless as part of a clinical trial comparing use with established interventions. Table 2. Treatment options for men with localised prostate cancer 1 REFERENCES 1. National Institute for Health and Clinical Excellence. Prostate cancer: diagnosis and treatment. London: NICE, Greene FL, Page DL, Fleming ID, et al, eds. AJCC cancer staging manual, 6th edn. New York: Springer-Verlag, Bill-Axelson A, Holmberg L, Filén F, et al. 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: Holmberg L, Bill-Axelson A, Helgesen F, et al. Scandinavian Prostate Cancer Group study number 4. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347: Coelho RF, Palmer KJ, Rocco B, et al. Early complication rates in a single-surgeon series of 2500 robotic-assisted radical prostatectomies: report applying a standardized grading system. Eur Urol 2010;57: Corral DA, Bahnson RR. Survival of men with clinically localized prostate cancer detected in the eighth decade of life. J Urol 1994;151: Albertsen PC, Hanley JA, Gleason DF, et al. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280: Tewari A, Johnson CC, Divine G, et al. Longterm survival probability in men with clinically localized prostate cancer: a case-control, propensity modeling study stratified by race, age, treatment and comorbidities. J Urol 2004;171: 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): Heidenreich A, Bolla M, Joniau S, et al. European Association of Urology. Guidelines on prostate cancer, Cancer%20July%206th.pdf 11. Fowler FJ, Barry MJ, Lu-Yao G, et al. Outcomes of external beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three surveillance epidemiology and end results areas. J Clin Oncol 1996;14: Small W Jr, Woloschak GE, eds. Radiation toxicity: a practical guide, vol New York: Springer, Forman JD, Kumar R, Haas G, et al. Neoadjuvant hormonal downsizing of localized carcinoma of the prostate: effects on the volume of normal tissue irradiation. Cancer Invest 1995;13: Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360: Prayer-Galetti T, Zattoni F, Capizzi A, et al. Disease free survival in patients with pathological C Stage prostate cancer at radical prostatectomy submitted to adjuvant hormonal treatment. Eur Urol 2000;38:504 7.