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PROSTATE DISEASE 35 Management of locally advanced prostate cancer REENA DAVDA, DANNY BLOOMFIELD AND HEATHER PAYNE The management of locally advanced or high-risk prostate cancer is challenging – involving the patient and multidisciplinary team in decision-making is essential so that treatment is tailored to the individual. he management of prostate cancer involves the consideration of a number of clinical, biological and patient factors in order to determine the most appropriate treatment. These include the clinical stage of the tumour, the presence or absence of high-risk features, and individual patient factors such as comorbidities and performance status. There is then careful discussion between the patient and the multidisciplinary team regarding treatment options and their potential risks and benefits (Figure 1). T Clinical stage is defined using the American Joint Committee on Cancer staging system.1 Locally advanced prostate cancer includes T3 and T4 disease (where tumour extends beyond the prostate capsule and may invade Disease stage/risk – appropriate treatment options • Efficacy: overall survival, disease-free survival, progression-free survival • Reduction in symptoms Side-effects • Impact on quality of life • Importance of: sexual, bowel and urinary changes, physical strength, bone strength, level of anxiety local structures) and any tumour that has metastasised to local lymph nodes. However, TNM staging alone does not provide sufficient prognostic information in selecting out patients with apparent organconfined tumours but with significant risk of extraprostatic invasion and undetectable micrometastases. Additional parameters of Gleason score (denoting the degree of differentiation of cancer cells) and pre-treatment prostate-specific antigen (PSA) were used by D’Amico and colleagues to describe three prognostic groups in non-metastatic disease (Box 1).2 The management of patients with locally advanced disease and those with high-risk features often involves local treatment of the primary disease and systemic treatment BOX 1. Prognostic groups for non-metastatic prostate cancer2 LOW RISK If all of the following are met: G T1–T2a primary G PSA <10 G Gleason score ≤6 INTERMEDIATE RISK If any of the following are met: G T2b–c primary G PSA 10–20 G Gleason score 7 HIGH RISK If any of the following are met: G T3 or T4 primary G PSA >20 G Gleason score ≥8 Figure 1. A risk–benefit decision is required for each patient Dr R. Davda, MB BS, MRCP, FRCR, Specialist Registrar in Clinical Oncology, University College Hospital, London; Dr D. Bloomfield, MA, BM BCh, MRCP, FRCR, Specialist Registrar in Clinical Oncology, Royal Surrey County Hospital, Guildford; Dr H. Payne, MB BS, FRCP, FRCR, Consultant in Clinical Oncology, University College Hospital, London TRENDS IN UROLOGY & MEN’S HEALTH OCTOBER/NOVEMBER 2010 www.trendsinurology.com PROSTATE DISEASE 36 for potential micrometastases. The therapeutic options for these patients are discussed below. IMMEDIATE OR DELAYED HORMONE THERAPY ALONE Watchful waiting involves monitoring a patient for symptoms (such as bone pain) and/or a PSA rise, with hormone treatment initiated at the time of progressive disease. This strategy serves to avoid or delay the morbidity of immediate treatment. Hormone therapy may involve castration, which is achieved medically with luteinising hormone-releasing hormone (LHRH) agonists such as goserelin, or surgically with bilateral orchidectomy. Alternatively, antiandrogens such as bicalutamide, which block the effects of endogenous hormones, may be used. ‘ A Medical Research Council study randomised patients with locally advanced or asymptomatic metastatic prostate cancer to immediate castration-based treatment or treatment upon clinical progression.3 Progression from locally advanced to metastatic disease and the development of metastatic pain occurred more rapidly in patients who received deferred hormone therapy. In addition, complications from metastatic disease, such as pathological fractures, spinal cord compression and ureteric obstruction, were twice as common in deferred patients. This study suggested that early hormone therapy reduces disease progression and the complications due to progression. RADICAL PROSTATECTOMY Patients with locally advanced disease or high-risk features have not traditionally been treated with radical surgery, as they are likely to require additional treatment. A proportion of patients with clinically organ-confined disease preoperatively are found to have more extensive or aggressive disease at the time of surgery, with pathological T3 cancer, positive surgical margins, a high Gleason score or even lymph node metastases. Adjuvant treatments for these patients www.trendsinurology.com include radiotherapy, hormonal therapy or both combined. Studies investigating the timing of postoperative radiotherapy in patients found to have T3 disease suggest radiotherapy can reduce the risk of PSA and clinical failure,4,5 and possibly increase metastases-free and overall survival. The optimal timing of radiotherapy and duration of concomitant hormone therapy in postoperative patients is being investigated in the RADICALS study.6 RADIOTHERAPY Radiotherapy entails targeted delivery of high-energy X-rays, which cause doublestrand DNA breaks and subsequent tumour cell death. Individualised radiotherapy plans deliver a high dose to the tumour volume while minimising irradiation of normal tissues such as the bladder and rectum. The benefit of the addition of radiotherapy to hormonal treatment has also been investigated ’ Technological advances in radiotherapy planning have enabled a shift from twodimensional to three-dimensional CT-based conformal planning, and more recently sophisticated dose distributions can be achieved with intensity-modulated radiotherapy. More precise delivery of radiotherapy to the target volume has allowed dose escalation to the tumour while ensuring normal structures are within tolerance levels. This has been shown to improve local tumour control. A UK study found an improved five-year biochemical progression-free survival rate of 71 per cent when treating to an increased radiotherapy dose of 74Gy, compared with 60 per cent in men randomised to receive 64Gy.7 This dose of 74Gy has been adopted as standard UK practice. Radiotherapy is currently delivered in small daily fractions, Monday to Friday, continuously for 7.5 weeks. Early side-effects include cystitis, faecal frequency and urgency, proctitis and rectal bleeding. Late complications occurring three months or later after treatment include erectile dysfunction, bleeding, proctitis and diarrhoea. The dose may be further escalated with high-dose-rate brachytherapy, which entails insertion of a radioactive iridium source temporarily into the prostate gland. This may be used in combination with external beam radiotherapy. RADIOTHERAPY WITH CONCOMITANT HORMONE THERAPY Patients with locally advanced or high-risk disease carry a risk of micrometastases, which needs to be addressed for optimal treatment. Neoadjuvant hormone therapy commenced before radiotherapy reduces tumour bulk and prostate volume, reducing the size of the required radiotherapy fields and potential toxicity to the surrounding normal tissues. Hormone therapy may also sensitise tumour cells to the radiotherapy treatment. An early study, which randomised patients between radical radiotherapy with or without four months of neoadjuvant hormone therapy (goserelin and flutamide), has demonstrated significant improvements with combined treatments. The 10-year disease-specific mortality was significantly lower in the hormone-treated group (23 versus 36 per cent), as was distant metastasis (35 versus 47 per cent), disease-free survival (11 versus 3 per cent) and biochemical failure (65 versus 80 per cent).8 Adjuvant hormone treatment immediately after radical radiotherapy has shown a significant improvement in overall survival, progression-free survival, local control and risk of distant metastases in several large, international, phase 3 randomised trials. In one such study, Bolla and colleagues randomised high-risk patients between TRENDS IN UROLOGY & MEN’S HEALTH OCTOBER/NOVEMBER 2010 PROSTATE DISEASE 37 radiotherapy alone with hormones on progression and radiotherapy with three years of adjuvant goserelin.9 At five-year follow-up, overall survival in those treated with immediate hormones was significantly superior (78 versus 62 per cent), as was disease-free survival (74 versus 40 per cent; Figure 2). Further benefit in overall survival was seen at 10 years (39.8 versus 58.1 per cent).10 There were similar very significant improvements in progression-free survival and clinical or PSA relapse. The large, Early Prostate Cancer study included a subgroup of patients with locally advanced disease treated with radiotherapy, who were randomised between additional adjuvant bicalutamide 150mg once daily and placebo.11 The addition of bicalutamide significantly improved overall survival (hazard ratio 0.65) and reduced the risk of prostate-cancer-related death compared with placebo. Given this demonstrated efficacy of hormones, the benefit of the addition of radiotherapy to hormonal treatment has also been investigated.12 Patients treated with hormones alone were found to have a 10-year prostate-cancer-specific mortality of 23.9 per cent compared with 11.9 per cent in those who received hormones plus KEY POINTS • Factors considered in selecting the appropriate management of non-metastatic prostate cancer include clinical TNM stage, presenting PSA, Gleason sum score, patient comorbid factors and patient preference • Current treatment options for locally advanced disease include immediate or delayed hormone monotherapy, radical radiotherapy in combination with hormone therapy, or radical prostatectomy with or without further adjuvant treatments • Several studies have demonstrated a significant improvement in overall survival when radiotherapy is combined with hormonal therapy • Standard UK practice for locally advanced or high-risk prostate cancer is treatment with hormonal therapy both before and after radiotherapy, for a total of two to three years • Luteinising hormone-releasing hormone agonists and the antiandrogen bicalutamide 150mg have both shown positive results in this setting with different side-effect profiles, allowing patients a choice in hormone therapies radiotherapy. There was an acceptable risk of side-effects in the radiotherapy group. Although trials of radiotherapy and hormone therapy have used different hormone agents, varying the timing and duration, there is strong evidence for benefits in overall and disease-free survival when radiotherapy is used in combination with hormonal treatment. This combined modality approach is therefore standard to achieve optimal outcomes in locally advanced and high-risk prostate cancer. 100 Radiotherapy + androgen deprivation therapy Overall survival (%) 80 60 40 Radiotherapy alone 20 Log-rank test p<0.001 HR = 0.51 (95% Cl 0.36–0.73) 0 0 1 2 3 4 5 6 Time since randomisation (years) 7 8 HR: hazard ratio; CI: confidence interval. Figure 2. Kaplan–Meier estimates of overall survival by treatment group in EORTC trial 22863 by Bolla et al.9 TRENDS IN UROLOGY & MEN’S HEALTH OCTOBER/NOVEMBER 2010 CONCLUSION The management of locally advanced or high-risk prostate cancer is challenging. Optimal patient care is dependent upon discussion and collaboration between radiologists, pathologists, oncologists, urologists and specialist nurses to recommend the most appropriate options for an individual patient. Declaration of interests Heather Payne has received honoraria and expenses for consultancy and involvement in educational projects for Astra Zeneca. REFERENCES 1 American Joint Committee on Cancer. Prostate. AJCC Cancer Staging Manual. New York: Springer, 2006;293–301. 2 D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–74. 3 Medical Research Council. 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. Br J Urol 1997;79:235–46. www.trendsinurology.com PROSTATE DISEASE 38 4 Bolla M, van Poppel H, Collette L, et al. European Organization for Research and Treatment of Cancer. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005;366:572–8. 5 Thompson IM Jr, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006;296:2329–35. 6 Parker C, Sydes MR, Catton C, et al. Radiotherapy and androgen deprivation in combination after local surgery (RADICALS): a new Medical Research Council/National Cancer Institute of Canada phase III trial of adjuvant treatment after radical prostatectomy. BJU Int 2007;99:1376–9. 7 Dearnaley DP, Sydes MR, Graham JD, et al. RT01 collaborators. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;8:475–87. 8 Roach M, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol 2008;26:585–91. 9 Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360:103–6. 10 Bolla M, Collette L, Van Tienhoven G, et al. Ten year results of long term adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy: a phase III EORTC study. Int J Radiat Oncol Biol Phys 2008;72(Suppl 1):S30-1. 11 McLeod DG, Iversen P, See WA, et al. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006;97:247–54. 12 Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (Scandinavian Prostate Cancer Group Study 7; Swedish Association for Urological Oncology 3): an open randomised phase III trial. Lancet 2009;373:301–8. www.trendsinurology.com