The Changing Pattern of Management for Hormone-Refractory, Metastatic Prostate Cancer

$The Changing Pattern of Management for Hormone-Refractory, Metastatic Prostate Cancer$

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 castration, 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-refractory 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, neurological dysfunction such as months, usually indicate a particularly grave prognosis. paraesthesia, limb weakness and incontinence, and an PSADT has been evaluated in a range of settings, but increased risk of pathological fractures. Following para- results are reasonably consistent both in androgen- plegia, less than 10% of patients regain the ability to sensitive and androgen-resistant patients.14–18 walk.20 Spinal cord compression has a significant

Prostate Cancer and Prostatic Diseases Management of hormone-refractory, prostate cancer ND James et al deleterious effect on life quality and reduces median to the receptor. However, whereas a randomized trial 223 overall survival to only 4 months.21 Clearly, early found the time to progression and survival periods for detection and treatment are essential. prednisone and flutamide to be equivalent, the steroid therapy significantly improved the overall quality of life and in particular, pain, fatigue, role functioning, appetite loss and gastrointestinal distress.29 Therapeutic options

Surgery for the treatment of urological complications Radiotherapy Obstructive uropathy is the key urological complication Bone pain in patients with locally advanced or metastatic of advancing prostate cancer, and is associated with poor 22 prostate cancer is invariably indicative of bone metas- prognosis. The primary tumour can cause both bladder tases and is one of the most common signs of progression outflow obstruction, from direct urethral pressure, and or recurrence. In patients in whom metastases are limited ureteric obstruction, from tumour infiltration of the to a few sites, single-fraction external-beam radiotherapy trigone and periureteric tissue. It may also cause is an option for palliative pain control.30,31 Approxi- bothersome haematuria. In addition, lymph node me- mately 76% of patients will have effective pain relief tastases can cause supra-vesical ureteric obstruction. from this approach with a median duration of around 6 Bladder outflow obstruction not only causes obstruc- months. In addition to the low cost of localized radio- tive uropathy, but also produces symptoms that have a therapy, the approach also has the advantage that considerable impact on quality of life. Both can be easily subsequent isolated metastases may also be treated in palliated with urethral catheterization. More definitive the same way and, if necessary, the development of pain treatment may be achieved surgically or with radio- over a larger area can be treated by wide-field or hemi- therapy. Transurethral resection of the prostate (TURP) is body radiotherapy. Although this latter approach is often the preferred treatment option and can be performed in accompanied by the typical side effects of radiotherapy this group of patients with significant improvement in including nausea, vomiting and diarrhoea, which may urinary symptoms and low morbidity, although rates of require hospitalization, this is usually avoidable with urinary retention and incontinence are higher than in suitable anti-emetic prophylaxis, and it remains a good patients undergoing TURP for benign prostatic obstruc- 23 treatment option for the frail and elderly in whom tion. Radiotherapy is infrequently used to improve this treatment options are limited. type of obstructive uropathy, although it can improve obstructive symptoms in up to 80% of patients.24 Radio- therapy is, however, particularly good at treating Radionuclides haematuria, which is less well controlled by TURP. Palliation of bone pain arising from widespread bony Supra-vesical obstruction is usually unilateral at first, metastases may be effected by the intravenous adminis- and may not require treatment if asymptomatic with tration of radionuclides that target bone metabolism, for adequate overall renal function. However, bilateral example strontium-89, samarium-153 and phosphorous- ureteric obstruction causes life-threatening, progressive 32. Of these, strontium-89 is the most utilized providing renal failure, which requires urgent attention. Effective pain relief in up to 80% of patients, and complete palliation of renal failure is usually achieved by freedom from pain in approximately 10%, for periods percutaneous nephrostomy, ureteric stent or a combina- that can exceed 3 months.32,33 The combination of tion of both, which are procedures with low morbidity 25 strontium-89 injection and external-beam radiotherapy that can improve quality of life. Expandable metallic improved pain relief, delayed progression and enhanced ureteric stents, extra-anatomic stents and surgical diver- some quality of life measures compared with external- sion are alternative methods of invasive treatment. beam therapy alone.34 However, a phase III study has Radiotherapy can also reduce the obstruction; however, 26 suggested that in some patients, systemic strontium-89 it is neither as immediate nor effective. Such palliation may be inferior to local field radiotherapy in terms of of renal failure raises an ethical dilemma in the hormone- survival (11 vs 7.2 months, P ¼ 0.0457).35 The selection of relapsed patient. These patients generally have a short patients has a significant impact on outcome and life expectancy and their prognosis should be considered response, and duration of response to radionuclide before initiating treatment, so that life is not perpetuated therapy in terms of bone pain palliation is reduced in to allow the development of other problems, without those with widespread metastatic disease or a short life improving the quality of useful life. expectancy.36,37 Consequently, the use of radionuclides appears to be optimal at an early stage in disease management. However, their efficacy is reduced or lost Prednisolone and other steroids with repeated use, and overtreatment can also lead to Patients who have received medical or surgical castration irreversible pancytopenia, which can compromise any will still receive androgen stimulation of their prostate subsequent use of chemotherapy. tumour cells as a result of androgens produced by the adrenal glands. Treatment with steroids such as hydrocortisone reduces adrenal androgen production in a Bisphosphonates subset of patients and there is an additional benefit from The use of bisphosphonates in oncology has increased low-dose corticosteroid therapy in terms of improved over the last decade, although their use remains the anabolism and reduced fatigue.27,28 Anti-androgen ther- subject of controversy in prostate cancer. The bispho- apy will inhibit the stimulation of the prostate cancer sphonates inhibit bone catabolism by reducing the cells by competing with residual testosterone for binding numbers of functioning osteoclasts and have been an

Prostate Cancer and Prostatic Diseases Management of hormone-refractory, prostate cancer ND James et al

224 established treatment for osteoporosis and similar con- Treatment of spinal cord compression ditions for many years, and more recently have been Dexamethasone should be given as immediate therapy to used to manage bone metastases in breast cancer.38 In alleviate oedema. Although surgery or radiotherapy may addition, some bisphosphonates, for example zoledronic be effective for the relief of pain and neurological acid but interestingly not clodronate, arrest cell prolif- complications, a surgical approach is only really a viable eration, induce apoptosis and inhibit the growth factor option for spinal cord compression in patients with stimulation of cultured prostate cancer cells.39 otherwise good performance status and well-controlled In the early 1990s, pamidronate as a single i.v. infusion symptoms. Preliminary data indicate that by combining was shown to reduce bone pain in 30% of patients for radiotherapy with decompressive surgical resection, between 2 and 3 weeks with no tolerability issues.40 A patients retain the ability to walk for a significantly later report presented pooled results from two studies longer period compared with radiotherapy alone (126 vs (INT-05 and CGP 032) in which 378 patients received 35 days, P ¼ 0.006) and are also more likely to maintain placebo or pamidronate as randomized therapy for up to continence.46 This is therefore the preferred approach if 27 weeks.41 The investigators found no significant at all possible if precompression performance status was difference between pamidronate and placebo in terms good. Prompt diagnosis and referral to a centre specia- of pain measurements, analgesic use, skeletal-related lizing in spinal surgery are essential if patients are to events or mobility. Recently a large randomized, placebo have any chance of neurological recovery. controlled study (MRC PR05) reported that clodronate improved the pain-free survival period and overall survival periods for patients with metastatic prostate Summary of bone metastases management cancer compared with placebo, although the benefits did The successful management of bone metastases is a not achieve statistical significance (i.e. P40.05).42 major consideration for patients with HRPC and has the Further, although patients in the clodronate group were potential to make a significant impact on quality of life. significantly less likely to experience a deterioration in The early use of palliative radiotherapy, radiotherapeu- their performance status (HR 0.71, 95% confidence tics and bisphosphonates can control pain, may delay or interval 0.56–0.92, P ¼ 0.008), they reported more gastro- even possibly prevent the development of significant intestinal side effects, increased lactose dehydrogenase skeletal complications and are well tolerated with few and required more trial dose modifications. In the sister toxicity issues. Early detection and aggressive surgery trial (MRC PR04), clodronate was added to standard with concomitant radiotherapy in cases of spinal cord therapy (radiotherapy, hormone therapy or both in compression may preserve good neurological function, 46 490% of patients) for locally advanced, non-metastatic and maintain an acceptable quality of life. However, in prostate cancer with the objectives of determining its late-stage disease, radiotherapy and analgesia are cur- effect on the onset of symptomatic bone metastases or rently the only real options for gross spinal complica- disease-specific death, overall survival and toxicity.43 tions. Over 500 men were randomized to receive placebo or clodronate for 5 years duration and the results from 7 years of follow-up found no evidence for prevention of Chemotherapy bone metastases or prostate cancer death (hazard ratio Mitozantrone. Given that chemotherapy is not nor- 1.29, 95% confidence interval 0.92–1.82, P ¼ 0.13) and no mally used in non-metastatic or early prostate cancer, difference in overall survival (hazard ratio 1.03, 95% one might expect to see substantial responses to the first confidence interval 0.76–1.39, P ¼ 0.86). exposure of cytotoxic drugs in hormone-refractory The more potent bisphosphonate zoledronate has been patients. Historically, this has not been the case, and investigated in HRPC. Zoledronate, given at a dose of despite recent developments many urologists still con- 4 mg as a 5-min infusion every 3 weeks, significantly sider HRPC to be a chemo-insensitive condition. Over reduced the proportion of skeletal-related events by the last two decades, estramustine, vinblastine, etopo- around 11% compared with placebo (P ¼ 0.021) and side, doxorubicin and mitozantrone have all been increased the median time to the first of such events investigated for the treatment of HRPC. The absence of (P ¼ 0.011). However, there was no difference between a consensus on definitive end points has hampered the two groups for disease progression, performance comparative assessments of these agents and mitozan- status or quality of life. A third arm in this trial received trone plus prednisone, is approved (in the USA but not zoledronate at an initial dose of 8 mg, but this was in Europe) on the basis of a significant improvement in associated with progressive renal dysfunction, which palliative end points compared with prednisone necessitated dose reduction, and the results from this alone.11,47 Mitozantrone þ prednisone improved pallia- patient group were difficult to interpret and not tion (defined as a two-point decrease in a six-point pain significantly different from placebo. A 9-month extension scale without an increase in analgesic score) in 29% of to this study in 133 patients found that 4 mg zoledronate patients compared with 12% in the prednisone-only arm reduced the risk of a skeletal-related event by 53% (P ¼ 0.01), and the duration of palliation was also compared with placebo (hazard ratio 0.467; 95% con- significantly longer (43 vs 18 weeks, Po0.0001). There fidence interval 0.243–0.897, P ¼ 0.022).44,45 was no difference in survival between the two groups, In summary, the role of bisphosphonates in the although the trial was not powered on this basis. In adjuvant setting is uncertain although there is some addition, patients in the prednisone-only group who did evidence to support their inclusion in pain management not show a palliative response could cross over to the programmes. Two current randomized trials are addres- combination after 6 weeks. sing the use of zoledronate in prostate cancer in the UK: A retrospective follow-up study in 161 of the Stampede and Trapeze (see below). original patients found that 34% of the patients in the

Prostate Cancer and Prostatic Diseases Management of hormone-refractory, prostate cancer ND James et al mitozantrone plus prednisone group achieved a PSA cope at home, and that this more than offset the cost of 225 response (defined as a decline of X50% relative to chemotherapy. Similar deferred costs have been noted in baseline) compared with 11% in the prednisone-only other active treatments for HRPC, for example stron- group (P ¼ 0.0001).48 Further analyses indicated that a tium-89, where the initial costs were recovered by PSA response was associated with an increased like- savings in other aspects of patient care.53 lihood of a palliative response (P ¼ 0.001) and, in conjunction with better performance score and a high haemoglobin level, was an indicator for increased Docetaxel. The taxanes are a relatively new class of survival (Po0.001). A separate, later study compared drugs that prevent completion of the cell cycle at the G2/ mitozantrone with and without hydrocortisone and M checkpoint by stabilizing the microtubule structures of found similar results; the combination provided a small the nucleus. Preclinical studies indicated that the anti- but significant increase in time to progression compared tumour activity of docetaxel was superior to that of with steroid monotherapy (3.7 vs 2.3 months, respec- mitozantrone in prostate cancer xenograft models.54 tively, P ¼ 0.02) but no difference in overall median Docetaxel or paclitaxel in combination with estramustine survival (12.3 vs 12.6 months, respectively, P ¼ 0.77).49 demonstrated a response rate of 50% in phase II studies Finally, a further study found similar extensions to the and was moderately well tolerated.52 In large, direct progression-free period with the combination, as well as randomized comparative phase III trials, some docetaxel an increase in the number of patients with a PSA combinations have demonstrated increased PSA re- response, but confirmed no survival difference between sponses, progression-free survival, overall survival, mitozantrone plus prednisone and prednisone alone.50 improved palliation and better quality of life compared A follow-up study to the initial investigation by with the clearly active, standard mitozantrone combina- Tannock et al.51 examined the cost implications of tion (Table 1). Varying the dose and administration of introducing mitozantrone for HRPC management. A docetaxel affected the relative efficacy, with, for example, detailed examination was performed of the costs the 75 and 60 mg/m2 three-weekly regimens providing a incurred for 114 patients from three of the largest centres clear increase in survival, relative to mitozantrone, between randomization and death and included hospital whereas the 30 mg/m2 weekly schedule did not (Fig- admissions, outpatient visits, investigations, all therapies ure 3). Adverse event and serious adverse event and palliative care. The mean total cost for a patient who reporting increased in the docetaxel arms of both received mitozantrone with prednisolone from randomi- studies,55,56 although the degree of significance was not zation to death was 27 300 Canadian dollars, which was consistent between studies. Low numbers of treatment- effectively the same as the 29 000 Canadian dollars spent related deaths occurred in both the docetaxel arms and on a patient in the prednisolone-only group. The major mitozantrone control arms with no clear or consistent proportion of cost in both arms was in-patient admis- differences. Generally, the docetaxel regimens were sions (53 vs 66% for the chemotherapy and steroid-only reasonably well tolerated and the adverse event profiles groups, respectively). This dominant role of in-patient were similar to those seen with other cytotoxic regimens costs is evident when the costs for an individual patient and included grade 3 or 4 neutropenia, fatigue, alopecia, are plotted against time (Figure 2). This study indicates diarrhoea and stomatitis. Although such conditions are that by reducing pain and improving function, fewer of obvious concern, they can be managed and docetaxel admissions were required for pain control or failure to therefore offers the patient with HRPC tangible benefits in terms of increased quality of life and overall survival over that provided by the current standard therapy.

Future directions In demonstrating an increase in survival and quality of life, docetaxel has demonstrated an improvement in the treatment of what was previously thought of as a chemo- insensitive disease. The challenge for the immediate future will be to consolidate these findings and maximize the potential for existing drugs in this setting. This may be achieved by manipulating the regimens already in use, exploring the efficacy of new combinations and by investigating earlier or aggressive treatment in suitable patients. For example, a modified vinca alkaloid, vinorelbine, appears to be as effective as mitozantrone in combination with steroid therapy.57 Another new possibility is the oral platinum analogue satraplatin, which has shown encouraging activity in HRPC and is undergoing phase III evaluation in the second-line chemotherapy setting vs best supportive care.58,59 This trial is set to be closed in early 2006. If positive, it will Figure 2 Cumulative costs from the mitoxantrone economic study further extend the indications for chemotherapy in for an individual patient from study randomization to death.52 The prostate cancer and open the way to further combination steep parts of the curve coincide with periods of in-patient care. therapy trials.

Prostate Cancer and Prostatic Diseases Management of hormone-refractory, prostate cancer ND James et al 226 Table 1 Phase III randomized study data comparing docetaxel chemotherapy with mitozantrone in hormone-refractory prostate cancer Tannock et al53 Petrylak et al54

End point Tax 75 mg+ Tax 30 mg+ Mito 12 mg+ Tax 60 mg+ Mito 12 mg+ prednisonea prednisoneb prednisonec estramustined prednisonec

PSA response (%) 45 48 32 50 27 (Statistical analysis) (o0.001) (o0.001) (nae)(o0.001) (nae) Duration (months) 7.7 8.2 7.8 nr nr Tumour response (%) 12 8 7 17 11 (Statistical analysis) (0.11) (0.59) (nae) (0.30) (nae) Pain response (%) 35 31 22 nr nr (Statistical analysis) (0.01) (0.08) (nae) Duration (months) 3.1 5.6 4.8 Median survival (months) 18.9 17.4 16.5 17.5 15.6 (Statistical analysis) (0.009) (0.36) (nae) (0.02) (nae) Improved QoL (%) 22 23 13 nr nr (Statistical analysis) (0.009) (0.005) (nae) Progression-free (months) nr nr nr 6.3 3.2 (Statistical analysis) (o0.001) (nae)

aDocetaxel 75 mg/m2 every 21 days plus prednisone 5 mg twice daily. bDocetaxel 30 mg/m2 every week for 5 weeks followed by a 1 week rest, plus prednisone 5 mg twice daily. cMitozantrone 12 mg/m2 every 21 days, plus prednisone 5 mg twice daily. dDocetaxel 60 mg/m2 every 21 days plus estramustine 280 mg three times daily for first 5 days of the 21-day cycle. eNot applicable (na), P-values for comparison of docetaxel regimen with standard mitozantrone regimen. Abbreviation: nr, not recorded/reported; QoL, quality of life.

100 possibly as a result of androgen ablation, and clinical 90 studies show promising results with significant effects 80 not only on the tumour cells, but also on bone metastases.62 Atrasentan is well tolerated and no dose 70 limiting toxicities were seen in phase I studies. However, 60 in common with other targeted therapies, and unlike 50 Docetaxel cytotoxic therapies such as docetaxel, phase II data for 40 Weekly every 3 wk atrasentan are consistent with cytostasis, leading to 30 docetaxel delays in progression rather than a reduction in tumour 20 burden.63 For the time being, the role of these agents 10 Mitoxantrone remains in doubt as the results of phase III trials mature. 0 Probability of Overall Survival (%) Nonetheless, the eventual introduction of the new 0 3 6 9 12 15 18 21 24 27 30 33 targeted therapies that are now in clinical development Months will be an important step in the management of HRPC. No. at Risk Although the activity of targeted therapies as mono- Docetaxel every 335 296 217 104 37 5 therapy may be limited, their good tolerability means 3 wk that they can be combined with established combinations Weekly docetaxel 334 297 200 105 29 4 with minimal impact in terms of safety. Clearly, the Mitoxantrone 337 297 192 95 29 3 options for chemotherapy in the treatment of HRPC are Figure 3 Effect of docetaxel on overall survival in HRPC. set to increase over the coming years. Finally, there is a growing literature on the use of cell- based or immunotherapeutic approaches to prostate The new generation of targeted anticancer drugs such cancer. In particular, a phase III trial of a dendritic cell as those directed against the epidermal growth factor therapy called Provenge is underway in the USA and receptors (e.g. gefitinib, cetuximab and trastuzumab) are definitive results are eagerly awaited for this study. well tolerated and have improved the treatment of certain solid human tumours like lung, breast, colorectal and head and neck. However, their use in HRPC has yet to progress past phase II and this is unlikely given that Forthcoming trials in the UK the available data suggest that the epidermal growth factor receptor family is not a viable target for the The improved quality of life and overall survival seen treatment of HRPC.60 Other therapies with activity with docetaxel may be enhanced further by introducing against specific targets in HRPC are being developed. this drug at an earlier stage in the natural history of For example, atrasentan is a small molecule inhibitor of prostate cancer. The STAMPEDE study (www.stampe- the endothelin-A receptor. Blocking the binding of the de.bham.ac.uk) commenced in September 2005 and will natural ligand endothlin-1 prevents autocrine stimula- randomize patients with advanced or metastatic prostate tion and inhibits several cellular processes including cancer to one of six arms containing hormone therapy hormone production, mitogenesis and cell migration.61 only or hormone therapy plus docetaxel, zoledronate, the The endothelin autocrine loop is upregulated in HRPC, COX 2 inhibitor celecoxib, celecoxib and zoledronate, or

Prostate Cancer and Prostatic Diseases Management of hormone-refractory, prostate cancer ND James et al 227 docetaxel and zoledronate. The study design includes 9 Fossa SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hether- initial assessments of safety and failure-free survival, so ington JW et al. Flutamide versus prednisone in patients with that only those arms with an acceptable safety profile prostate cancer symptomatically progressing after androgen- and potential efficacy will be followed for survival. ablative therapy: a phase III study of the European organization A further four-arm, phase II pilot study, TRAPEZE, for research and treatment of cancer genitourinary group. J Clin will randomize patients with HRPC to receive docetaxel Oncol 2001; 19: 62–71. 10 Yagoda A, Petrylak D. Cytotoxic chemotherapy for advanced and prednisolone only, or plus zoledronate, or plus hormone-resistant prostate cancer. Cancer 1993; 71: 1098–1109. strontium-89, or plus zoledronate and strontium-89. The 11 Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore rationale of this study is to augment the benefits seen MJ et al. Chemotherapy with mitoxantrone plus prednisone or with docetaxel and prednisolone on survival and quality prednisone alone for symptomatic hormone-resistant prostate of life, with the palliative effects of bone-targeting cancer: a Canadian randomized trial with palliative end points therapies. Promising activity has already been noted [see comments]. J Clin Oncol 1996; 14: 1756–1764. with docetaxel and zoledronate in a phase I study.64 12 Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–1512. Conclusions 13 Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr, Jones JA et al. Docetaxel and estramustine compared with mitoxantrone The use of chemotherapy now has the potential to and prednisone for advanced refractory prostate cancer. N Engl J improve the quality of life and extend survival in Med 2004; 351: 1513–1520. patients with HRPC. Patients with a good performance 14 Stewart AJ, Scher HI, Chen MH, McLeod DG, Carroll PR, Moul status will be more suitable for chemotherapy and so it is JW et al. Prostate-specific antigen nadir and cancer-specific important that patients are referred at an early point in mortality following hormonal therapy for prostate-specific the development of their disease. A multidisciplinary antigen failure. J Clin Oncol 2005; 23: 6556–6560. 15 Slovin SF, Wilton AS, Heller G, Scher HI. Time to detectable approach involving urologists, oncologists and radiolo- metastatic disease in patients with rising prostate-specific gists will enable a tailored strategy that is ideally suited antigen values following surgery or radiation therapy. 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