Prostate Cancer and Prostatic Diseases (2006) 9, 221–229 & 2006 Nature Publishing Group All rights reserved 1365-7852/06 $30.00 www.nature.com/pcan REVIEW The changing pattern of management for hormone-refractory, metastatic prostate cancer ND James1, D Bloomfield2 and C Luscombe3 1Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, UK; 2Sussex Oncology Centre, Royal Sussex County Hospital, Brighton, UK and 3Department of Urology, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, UK Prostate cancer responds initially to hormonal manipulation by androgen withdrawal and peripheral androgen blockade. The inevitable progression to a hormone-refractory state is accompanied by an exacerbation of local symptoms and metastatic spread, principally to the bones, which has a considerable impact on quality of life and survival. Treatment of hormone- refractory prostate cancer is palliative, and surgery and radiotherapy are used for the relief of lower urinary tract symptoms and localized painful bony metastases. Systemic treatments are not widely accepted in this setting, but clinical trials have demonstrated the potential for bone targeting agents such as strontium-89 and the bisphosphonates to palliate painful bone metastases and to delay progression in certain settings. Chemotherapy with mitozantrone in combination with steroids has previously been shown to have palliative benefits and to delay progression. The additional costs incurred by the use of chemotherapy or bone-targeting therapies may be offset by gains in overall care with fewer in-patient admissions compared with steroid monotherapy . Recent clinical trials have demonstrated that docetaxel significantly improves patient quality of life, and importantly, increases survival. Future studies investigating the timing of chemotherapy, combinations with existing treatments or other novel therapies are underway. Prostate Cancer and Prostatic Diseases (2006) 9, 221–229. doi:10.1038/sj.pcan.4500880; published online 27 June 2006 Keywords: chemotherapy; docetaxel; metastatic; bisphosphonates; radioisotopes; zoledronate Introduction ingly important issue for larger numbers of men and may have significant cost implications for health provi- Prostate cancer ders. Cancer of the prostate is the second most common cause Prostate cancer progresses from its initial subclinical of cancer death in men in Western countries today with manifestation through localized and locally advanced over 200 000 deaths in the year 2000.1 Many patients stages to metastatic disease by a process that is present with asymptomatic early-stage disease and have effectively driven by androgen stimulation. Androgen a diverse choice of treatment options. Younger men in ablation can be achieved by medical or surgical castra- tion, which prevents direct testosterone production, and good general health may be considered for primary 2 curative therapy with surgery or radiotherapy, whereas provides a response in approximately 80% of cases. The median duration of primary hormone therapy is around older patients with a poorer performance status and 3,4 shorter life expectancy may be suitable for active 16–18 months. Second-line hormone therapies include surveillance or watchful waiting (Figure 1). Curative the addition of an anti-androgen to give complete therapy is not an option for men presenting with locally androgen blockade (CAB), with a further effect from advanced or metastatic disease and hormonal therapy subsequent withdrawal, diethylstilbestrol and corticos- involving medical or surgical castration is the standard teroids. With CAB, the addition of an anti-androgen approach. The ongoing increases in life expectancy, blocks the activity of the androgens produced by peripheral tissues, but has only a limited effect on coupled with early detection, predict that the effective 2 management of prostate cancer will become an increas- disease progression. There is laboratory evidence that diethylstilbestrol may be active against hormone-refrac- tory cells5 and this agent is frequently used in this Correspondence: Professor N James, Cancer Research UK Institute for setting. Subsequent withdrawal of anti-androgens from Cancer Studies, Clinical Research Block, Queen Elizabeth Hospital, CAB can elicit a short-lived response (approximately 4 Edgbaston, Birmingham, B15 2TT, UK. months) in around 25% of patients.5 Most, if not all, E-mail: [email protected] Received 6 February 2006; revised 17 March 2006; accepted 19 March patients eventually develop hormone-refractory prostate 2006; published online 27 June 2006 cancer (HRPC) and until recently, at this point would Management of hormone-refractory, prostate cancer ND James et al 222 Prostate cancer stage: Localised (T1, T2, N0, M0) Locally advanced (T3, T4, N+, Advanced/metastatic hormone dependent M0) or Metastatic (M1) hormone refractory Established treatments Curative radiotherapy Androgen ablation/CAB: Second line hormonal therapy Curative prostatectomy goserelin +/- flutamide or Steroid therapy: prednisolone Watchful waiting/active bicalutamide Palliative radiotherapy monitoring Radiotherapy (radical or Radionulides: Sr-89, Sm-150 palliative depending on extent Chemotherapy: estramustine, of disease) mitozantrone Figure 1 Changes in systemic therapy for prostate cancer. expect a median survival period in the order of 12 Symptoms of HRPC months.6–9 The majority of advanced prostate cancer patients will In addition to a decrease in life expectancy, the develop symptomatic bony metastases and may exhibit development of HRPC is often associated with progres- an initial good palliative response to hormonal manip- sive bone metastases, substantial comorbidity, pain and ulation before the inevitable loss of hormone sensitivity. decreased physical function. The treatment options at During the period of progressive hormone-refractory this point are essentially palliative and recent years have disease, bone metastases produce the debilitating effects seen the development of new strategies. Bisphospho- of diffuse bone pain, pathological fractures and spinal nates and radiotherapy are being explored in conjunction cord compression that are the only too familiar hallmarks with more traditional palliative measures to control of the disease. These comorbidities will have a major symptoms and improve both the quality and the impact on the patients’ quality of life. duration of life. Historically, chemotherapy has been Involvement of the pelvic lymph nodes can be an early regarded as ineffective in the management of HRPC, and common event in the progression of prostate cancer with a review of clinical trials carried out between 1987 and is often followed by spread to more distal nodes. The and 1991 reporting an overall response rate of only involvement of the nodes, and in particular those of the 8.7%.10 Since then, the widespread adoption of mitoxan- pelvis, may cause obstruction of the pelvic lymphatic trone into chemotherapy regimens has been shown to system with concomitant oedema, often resulting in reduce pain, improve quality of life measures and reduce discomfort and pain. prostate-specific antigen (PSA) levels in patients with A number of lower urinary tract symptoms can be HRPC.11 The role of chemotherapy in the treatment of evident at presentation or occur on local progression, and HRPC is becoming increasingly established and the usually result from enlargement of the prostate alone, inclusion of taxanes to chemotherapy regimens has been but also in some instances from accompanying tumour shown to provide improved symptom control and invasion into the surrounding tissues. Blood in the urine increased median survival compared with mitoxan- or semen (uncommon of course in androgen ablated trone.12,13 patients), increased urinary frequency, incontinence and The initial manifestation of HRPC is a rise in the serum impotence are common, cause discomfort for the patient PSA despite appropriate hormone manipulation. and can be a source of great distress. Although PSA as a screening test is controversial, its The risk of spinal comorbidities in prostate cancer use as a disease marker is much less so. In general, rises arises from both a reduction in bone mineral density, as a in PSA will indicate a worsening of disease, and a fall in consequence of androgen ablation therapy, and by the PSA the reverse. There is no good correlation between prevalence of spinal metastases that occur in around 85% absolute PSA levels and disease, thus one patient with a of patients.19 Risk factors include prolonged androgen rising PSA in low double figures may have severe ablation and low serum 25-hydroxyvitamin D levels.19 symptoms, whereas another with PSA values in the Initial neuropathological symptoms, such as tingling or hundreds or even thousands may be asymptomatic. altered gait, are common, as are indications of progres- Thus, PSA values must always be interpreted in the light sive disease such as rising levels of PSA and these, of the underlying trend. A useful measure of severity is especially in conjunction with back pain, require in- the PSA doubling time (PSADT). Once PSA is rising, it vestigation by bone scan or scintigraphy. Left unchecked, usually does so in an exponential manner. The doubling growth of the metastases can cause compression of the time is then easily estimated. Doubling times signifi- spinal cord leading to further pain, marrow crowding, cantly less than a year, and in particular less than 6 decreased motility,