european urology 50 (2006) 428–439

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Review – Prostate Cancer

Management of the Spectrum of Hormone Refractory Prostate Cancer Noel W. Clarke * Christie Hospital and Salford Royal Hospitals NHS Trusts, Manchester, UK

Article info

Abstract

Article history: Accepted May 12, 2006 Published online ahead of print on June 2, 2006

Introduction: In its advanced stages, hormone refractory prostate cancer (HRPC) is an incurable condition which consists of a spectrum of disease. This requires an integrated multidisciplinary approach by an uro-oncologic team supported by radiologists, skeletal surgeons and palliative care. Aim of this review was to critically evaluate the current and potential approaches to patients affected by HRPC. Materials and Methods: A comprehensive evaluation of available published data included analysis of published full-length papers that were identified with Medline and Cancerlit from January 1981 to January 2006. Official proceedings of internationally known scientific societies held in the same time period were also assessed. Results: Most men with hormone refractory prostate cancer will die of their disease in the absence of intercurrent illness, and the various conditions arising as a consequence of local and distal cancer progression commonly lead to a spectrum of morbidity requiring treatment. Recent data regarding docetaxel-based chemotherapy have shown small but significant improvements in survival and improvement in quality of life in men receiving treatment. However, this therapy may not be suitable for all patients. New agents used alone or in combination with docetaxel currently are under trial in an attempt to provide much needed improvements in outcome. Bone-targeted treatments, particularly late-generation bisphosphonates, have added to the range of options, reducing the incidence of skeletal complications in some men. Further work is needed to target their use more effectively, to explore their efficacy in combination with existing proven therapies and to develop new approaches to treat bone metastases. Complications arising as a consequence of upper and lower tract dysfunction, haematologic, neurologic and psychologic disorders are common. These complications often are amenable to effective treatment, but interventions may engender difficult clinical and ethical decisions. Conclusions: Although HRPC is incurable, it is not untreatable, and that the clinical management embraces not just chemotherapy, but many interventional and supportive therapies. A holistic and supportive approach to patient care is vital for optimal management, and is best provided by a coordinated, multidisciplinary team including urologists and oncologists. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Keywords: Hormone refractory prostate cancer Bone metastases Chemotherapy Anaemia Marrow failure LUTS Obstructive uropathy

* Tel. +44 161 446 3364; Fax: +44 161 446 3365. E-mail address: [email protected]. 0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2006.05.017

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1.

Introduction

In its advanced stages, hormone refractory prostate cancer (HRPC) is an incurable condition. Although use of early hormone manipulation coupled with monitoring of prostate-specific antigen (PSA) has led to ‘‘stage migration’’ and development of the hormone refractory state at an earlier stage of the disease [1,2], when patients have a heavy tumour burden, particularly with bone metastases, the time from progression to death, even in the postchemotherapy era, is only 12–19 months [3]. Despite this outcome, it is important to remember that men with this condition need treatment that does not simply involve the use of chemotherapy. Patients will develop multiple problems as their disease progresses, including lower urinary tract malfunction, ureteric obstruction, skeletal morbidity, marrow failure, lymphoedema, rectal infiltration, pain and psychologic difficulties. This spectrum of disease requires an integrated multidisciplinary approach by a uro-oncologic team supported by radiologists, skeletal surgeons and palliative care. It is important that this team is coordinated centrally to provide support for the patient and to get the best possible outcome for him in the final stages of his life [4]. Treatment options broadly comprise use of cytotoxic chemotherapy/ novel agents, bone-directed therapies [5] and treatment of urologic and general complications.

2.

Cytotoxic chemotherapy/novel agents

The notion that chemotherapy in HRPC has no role [6] has been challenged after the publication of four important randomised controlled trials (RCTs), two involving mitoxantrone and steroids [7,8] and two, docetaxel-based chemotherapy [9,10]. In the first of two parallel studies [7,8], HRPC patients receiving mitoxantrone and steroids had a better quality of life in the final stages of their disease, compared with patients receiving steroids and supportive care only. Mitoxantrone-treated patients showed a response rate of 17% overall (mitoxantrone, 29%; steroids, 12% [7]; mitoxantrone, 64%; steroids, 47% [8]). This effect was seen as an improvement in quality of life (QoL), with no effect on survival. These results led to this regimen being adopted as the ‘‘standard of care’’ in this disease. This ‘‘standard’’ has now shifted to docetaxel after publication of two further RCTs [9,10]. In the first, the ‘‘Tax327’’ study [9], the combination of docetaxel and steroids was compared with the combination of mitoxantrone and steroids, in a randomisation to two docetaxel schedules versus

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mitoxantrone. The most effective treatment was docetaxel 75 mg/m2 three times weekly, producing an improvement of 24% in overall survival, equating to a median survival improvement of 2.5 months (docetaxel, 18.9 months, vs mitoxantrone, 16.5). There were also significant improvements in pain (35% vs 22%), PSA response (45% vs 32%) and QoL. Similar results were obtained in the sister study, SWOG99-16 [9]. This RCT used a lower docetaxel dose (60 mg/m2) combined with estramustine. The main difference in the studies was in toxicity, which was higher in SWOG99-16, probably as a consequence of estramustine. The overall improvement in survival in SWOG 99-16 was 2 months. These two studies were the first to show improvement in survival in HRPC, but it is important to view the results in perspective. The patients were younger than the average in many countries (mean age, 67–68 years [9,10]), particularly those in whom prostate cancer (CaP) screening is limited (e.g., the UK median presenting age is 72 years [11]) and only about one third of patients responded to treatment. The side-effects were also significant. In the study with least toxicity (Tax327), 32% developed neutropaenia (usually reversible) and 5% anaemia. Other effects included alopecia (two thirds of patients), nausea and individual toxicities including gastrointestinal disturbance, myalgia and sensory neuropathy. There has been a stage migration in HRPC attributable to earlier hormone manipulation in recent years, with patients presenting with HRPC at a younger age [1,2]. However, because of the advanced presenting age of many populations with CaP [11], it is possible that the spectrum of sideeffects in these patients may have a higher rate: Of particular note, a further 18–24 months must elapse postmanipulation before refractory disease will manifest. This observation has been demonstrated in a recent study of the final years of life of HRPC patients; their median age was 76 years [12]. It is known that CaP patients in this age group will have a higher incidence of treatment-related comorbidity [13,14]. Another consideration, important in less-affluent countries, is cost. Analysis of mitoxantrone/steroid usage in HRPC shows that, at 1998 prices, total cost was $1700 Canadian dollars (currently, 1200 Euro): This cost was less than the overall cost of steroids only [15]. With regard to docetaxel, at 2004 prices the cost of a cycle (drug only) is 1500 to 1680 Euro [16–18], without factoring in hospital stay and management of complications. It is therefore important to take a balanced view when contemplating use of this therapy, particularly considering the potential cost of additional treatments such as bisphosphonates

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and radionuclides. For this reason, when chemotherapy cannot be used because of cost or morbidity issues, steroids alone may be effective. Thus, whilst it is true that docetaxel-based chemotherapy is an important new advance in the treatment of HRPC, it also is clear that it is not suitable for all men. Another difficult question in view of the recent stage migration in CaP is when to start the chemotherapy. This uncertainty is compounded by the inability to discriminate ‘‘good and bad prognosis disease clearly’’ [19]. Direction may be provided by new nomograms [1,20], but more trials are needed urgently in this area. In practice, most clinicians avoid using this therapy in asymptomatic men with low rising PSAs, reserving treatment for those with symptoms. For men with progressive HRPC who responded previously, second-treatment cycles with docetaxel can be used, with success in approximately 60%, although haematologic toxicity can occur (A. Heidenreich personal communication: abstract no. 289, Proceedings of EAU annual meeting, 2006).

3.

New therapeutic developments

The search for new therapies continues in the knowledge that current treatment modalities have limited benefits. The targeting of cellular proliferation and survival pathways in drug design is therefore critical [21]. Current strategies are based on phase 1, 2 and 3 trials of new agents, mainly in comparison with docetaxel. There is currently no consensus on the use of second-line chemotherapy, although it has been studied in a number of centres [22]. Oral chemotherapy using agents such as capecitabine [23], satraplatin [24] and epothilones [25] is in development. Satraplatin is an orally available thirdgeneration platinum analogue. Five phase 2 and 3 studies have been initiated, the largest published study being EORTC 30972. Sponsorship difficulties stopped this trial early, but the results provided encouragement, with PSA responses of 39% of treated patients vs 9% in controls, and improvement in survival similar to that for docetaxel (2.7 months) [26]. This study is too small for definitive comment, but further information hopefully will be available through the SPARC trial, studying satraplatin/prednisolone vs placebo/prednisolone. Epothilones are a new class of chemotherapeutic drugs targeting tubulins [27]. Phase 2 studies have shown PSA responses in HRPC patients previously receiving docetaxel [25], suggesting a possible second-line role.

4.

New therapeutic directions

There is considerable activity in the study of new agents in HRPC, which mainly comprises evaluation of ‘‘small molecule’’ transduction inhibitors, combinations of these with chemotherapy (‘‘bio-chemotherapy’’) and treatment with cancer vaccines. Transduction inhibition heralds considerable promise. These small molecules or monoclonal antibodies block cellular-signalling pathways involved in proliferation, migration and apoptosis. Although their use as monotherapy has been disappointing to date [28], there is optimism that they will be beneficial in combination with taxanes and other agents. This topic is reviewed more comprehensively elsewhere [29,30], but examples of studies using these agents include SWOG 0421 (docetaxel/ atrasentan vs docetaxel/placebo) and CALBG 9040 (docetaxel/prednisone  bevacizumab (monoclonal anti-vascular endothelial growth factor). Vaccines also are potentially important. They are administered mainly as autologous dendritic cells (DCs) augmented with specific prostatic antigens (e.g., prostate-specific membrane antigen and recombinant prostate fusion proteins) [31]. An example of a more promising agent is PROVENGE, a DC-based vaccine linking a fusion protein combining prostatic acid phosphatase and granulocyte macrophage-colony stimulating factor antigens. Phase 2 studies showed improved survival (22.3– 30.7 months) in patients with HRPC [32]. A number of these therapies are currently under evaluation in phase 2 and 3 trials.

5.

Bone-directed therapies

These therapies comprise systemic or local therapies directed towards treatment of skeletal-related problems or reduction of morbidity from skeletal infiltration by HRPC. Systemic treatments include radionuclides and bisphosphonates given alone, together or with chemotherapy, or treatment of skeletal complications in specific areas (namely, bone pain, cord compression and pathologic fracture), by surgery and local radiotherapy. Pathologic fracture was perceived as uncommon in CaP, with a reported incidence of 3% [33], contrasting with 9% in malignancies overall and 16% in breast cancer [34,35]. Recent analysis has shown that subclinical pathologic fracture is a more common problem than previously thought. The HRPC fracture rate is now reported as 33%, with approximately two thirds occurring in the vertebral column and one third in the long bones [36]. This risk is exacerbated by long-

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term androgen suppression [37]. Pathologic long bone fracture is treated by rapid orthopaedic fixation/joint replacement. This approach is highly effective in reducing pain and restoring mobility, although such fractures are associated with a significant reduction in survival [38]. Fixation usually is supplemented by local radiotherapy 2–4 weeks after surgery. Prophylactic measures to reduce risk of long bone fracture include bisphosphonates (see Bone pain); when lytic metastases are visible in long bones or the femoral neck, prophylactic irradiation may be considered. It is possible to identify high-risk patients by using estimates of tumour load, bone formation/ breakdown markers and symptom assessment; these patients will develop skeletal complications more frequently and targeted therapy is appropriate [39,40]. This approach may help to minimise side effects and reduce the costs of these treatments.

6.

Bone pain

Most patients with progressive HRPC will develop bone pain at some time [41]. Focal radiotherapy is effective for pain localised to specific metastases or to one skeletal region. Treatment schedules vary, and the optimal treatment is still debated [42]. A typical European regimen might involve 8 gray (G) in 1 fraction or 4 G in 6, whilst a common US schedule would involve 30 G given as 3-G fractions over 10 treatments [43]. ‘‘Single shot’’ radiotherapy is as effective as multifraction in this situation; an RCT showed single-fraction 8 G vs 10 fractions of 3 G was equally effective [44], and single-shot therapy was more cost-effective, particularly when considering the cost of chemotherapy [45]. Whatever the regimen, 90% of patients will respond, and this response will be complete in 40% [46]. If pain recurs at the treatment site, radiotherapy can be repeated [47]. When multiple sites are painful, hemibody irradiation (HBI) or systemic radionuclides are effective. HBI induces response in 91% of patients, (45% complete) within 3–8 days. Fractionated treatment is most effective [48] with two HBI doses of 3 G on consecutive days and is as effective as 3 G over 5 days [49]. Toxicity (nausea, vomiting, diarrhoea and haematologic suppression) is usually transitory. Second treatments with HBI are not recommended [50]. The most common systemic radioisotope is strontium89, although phosphorus32, samarium155 and rhenium86 have been used [51]. The half-life of strontium is 50 days, and various RCTs have confirmed its efficacy. Response rates of 80% are reported, with 33% being complete [52,53].

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Treatment can induce mild haematologic toxicity, manifested as a 30% reduction in platelet count, with a nadir at 6 weeks and recovery by 12 [51]. Therapy can be repeated, with overall efficacy comparing favourably with HBI [54] and with less toxicity. Evidence for use of bisphosphonates in alleviating bone pain from HRPC is uncertain. Open-label studies using earlier, less-potent agents (etidronate, clodronate [55–57] and pamidronate [58]) reported beneficial effects, results supported by positive findings from use of more-powerful later generation drugs. An open-label study of 25 patients using intravenous ibandronate showed bone pain reductions in 92%, with concomitant diminution in analgesic requirements and improved performance [59]. Such findings have not been replicated in larger controlled studies with clodronate [60,61] or pamidronate [62], possibly as a consequence of their lower potency, compared with zoledronate and ibandronate. In a large-scale RCT using zoledronate, the most potent bisphosphonate, pain requirements decreased in those receiving the drug, although QoL and performance were not affected [63].

7. Bisphosphonates and reduction of skeletal-related event Bisphosphonates reduce bone resorption in HRPC [64], but their clinical utility in reducing skeletalrelated events (SREs) had been questioned. Early RCTs using less-potent agents in small-number studies [55] showed no effect from treatment. Latterly, larger studies [40,63,65–68] have shown some differences even with less-potent agents. An RCT allocating 311 patients with HRPC to clodronate or placebo showed a small reduction in time to symptomatic bone progression [65]. A second study of clodronate with mitoxantrone and prednisone reduced moderate to severe bone pain, although the palliative effects were unaffected [66]. A larger RCT using the more potent zoledronic acid produced an 11% reduction in SREs by comparison with controls [63]. This observation raises the question of whether all patients with HRPC should receive late-generation bisphosphonates. Some experts state that the cost-benefit from this therapy is insufficiently great [67]. However, the same authors accept that some patients are likely to benefit from this treatment. These patients include men with heavy skeletal tumour load, particularly in the thoracolumbar spine/femur and those on long-term luteinizing hormone-releasing hormone therapy or maximal androgen blockade. One potential way to focus

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treatment is to utilise serum and urinary markers to predict the ‘‘at risk’’ population. Bone metastases with high markers of bone turnover are known to identify high-risk patients [40,68], and targeting this group may improve outcome.

8.

Novel skeletal therapies

The endothelin-A (ETA) antagonist atrasentan has shown promise in HRPC. It inhibits CaP by blocking the ETA/ET-1 transduction pathway [69], producing a dose-dependent suppression of bone formation markers [70]. This finding has led to RCTs of atrasentan in HRPC. Preliminary analysis suggests improvement in pain and decreased markers of bone progression. Adverse effects include headache (14%), peripheral oedema (21%) and rhinitis (19%) [71]. Further analysis of benefit from this class of drugs in patients with HRPC is awaited before they can be recommended as a definitive treatment. Another approach is the combination of bonedirected therapies with other agents. An innovative but aggressive phase 2 RCT using chemo/hormone therapy and strontium [72] showed that this approach was effective in prolonging survival in a small group of men with HRPC refractory to conventional treatment. Other combination studies such as SWOG 0421 (docetaxel/atrasentan) and the UK ‘‘TRAPEZE’’ study (docetaxel, zoledronate, strontium) are underway.

9.

Cord compression

Prostate cancer is the most common cause of cord compression, a devastating complication, with clinical manifestations occurring in 10–17% of patients [33,73]. It is possible to identify patients at risk by considering simple clinical parameters. In a review of 68 men [39], heavy skeletal tumour load, duration of androgen suppression and low haemoglobin (Hb) identified an at risk population. Subsequent magnetic resonance imaging (MRI) scanning facilitated identification of men whose disease might be treated locally (e.g., with radiotherapy) before development of irreversible neurologic deterioration. Evidence also suggested that addition of bisphosphonates to this group further decreased the risk of damage [33,63]. Unfortunately, many HRPC patients present with acute problems, the risk being greatest in the thoracic spine [74]. Prodromal symptoms manifest as an excruciating ‘‘band-like’’ pain around the lower abdomen (90%), although more subtle

manifestations include peripheral neuropathy/ lower limb weakness or spontaneous loss of normal bladder/bowel function [74]. High-dose dexamethasone and radiotherapy are mainly used to manage the acute situation. Consideration of surgical decompression requires a balance to be struck regarding outcome and survival, because the durability of response to surgery is limited. In a study of 69 patients (52 with HRPC) [75] with cord compression, only 52% had functional improvement in motor power after treatment, mostly within the first week of therapy. Many had multiple levels of compression, and MRI was the most effective means of diagnosing this complication. Patients aged 30 G) or surgical decompression [75]. A further study of 37 patients undergoing surgical decompression showed that only 8 of 19 men with HRPC had recovery of mobility postoperatively. Perioperative mortality was 8%, and a high proportion died within the first year after surgery, notwithstanding the outcome of decompression. The best outcome was predicated on the ability to walk preoperatively and on rapid intervention after the onset of symptoms. Immobility with onset of 80 years, with overall 90day mortality as high as 8.5% [14]. Urinary incontinence in HRPC is a distressing problem and a major constraint on normal social and family life [80]. Urethral catheterisation is often useful, although suprapubic catheters may be less problematic. These are often ineffective when the sphincter is damaged irreparably by tumour infiltration or injudicious TURP. When it is not possible to use a catheter, condom drainage is the usual alternative [14]. Urinary diversion is rarely indicated, except when rectoprostatic fistulation has occurred. Haematuria is a frightening complication for HRPC patients. The presence of a tumour in the prostatic urethra/bladder neck often is complicated by the superadded effect of platelet dysfunction and low-grade disseminated intravascular coagulation (DIC), which is often present [81]. Bleeding usually settles with conservative measures such as discontinuation of antiplatelet drugs/anticoagulants and use of bladder irrigation, supplemented by transurethral resection (TUR) or fulguration of encroaching tumour [81]. Local radiotherapy can be effective in locally advanced CaP [82] and may be worthwhile in refractory cases previously untreated with X-ray therapy. Although this measure may arrest

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bleeding, it will not help with the irritative or obstructive symptoms [83]. 10.2.

Ureteric obstruction

Progressive renal impairment from upper or lower urinary tract obstruction in HRPC occurs in 3–10% of men [11,84–86] (or higher [87]). Renal impairment usually occurs secondary to bladder base infiltration, but it can occur because of ureteric compression by metastatic nodal masses. It is usually a clinically silent phenomenon, and, although it may be detected early by sonography or contrast imaging, it often presents with biochemical disturbance or overt renal failure. The latter is an adverse prognostic indicator in HRPC [84,86,88]. Some authors have concluded that percutaneous nephrostomy drainage (PCND) is of little benefit and ‘‘should only be used in exceptional circumstances’’ [83]. More recently, there has been acknowledgement that PCND produces effective, if short-term, improvement in renal function, and there is now a lower clinical threshold for intervention. Median survival in hormone-relapsed patients treated with PCND varies from 80–350 days [89–91], although these reports contain a mix of hormonenaı¨ve and refractory men. HRPC patients fall in the lower part of this range. After decompression, renal function (measured by serum creatinine) takes a median 17 days to reach the nadir level [89]. In HRPC the decision to treat by PCND depends on various factors, including the nature and severity of obstruction, condition of the patient, extent of disease and, perhaps most importantly, the individual patient’s wishes. When men present acutely with renal failure, it usually is necessary to undertake emergency PCND to stabilise the clinical situation and diagnose the extent of disease. For most cases, however, clinical decisions need not be taken hurriedly, and, when time is required for deliberation, steroids can be effective [92]. When obstruction is caused by nodal masses or bladder infiltration, local treatments are sometimes possible. Radiotherapy can be effective in up to 70% of men [93], although other authors [94] have not achieved this success rate. This treatment usually takes 4–5 weeks before the full benefit is accrued: It is therefore usually used in association with a ureteric stent or nephrostomy. In milder cases, and when the anatomy and degree of obstruction permit, ureteric stenting is effective. Retrograde placement usually is tried first, which makes it possible to assess the functional state of the bladder/urethra. It is vital that neither of these is badly affected by HRPC, and it is unwise

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to attempt stent insertion if they are in poor condition. The condition of the bladder/urethra is important when considering antegrade stent insertion: ‘‘Blind’’ stenting can result in a combination of poor stent placement and/or function, severe lower urinary tract symptoms and difficulty retrieving or replacing the prosthesis if there is extensive local infiltration [4]. Expanded metal stents have been used to maintain ureteric patency, although wall stents have proven disappointing. Most of those inserted are removed within 6–12 months, and their use in malignant ureteric obstruction has largely discontinued [95]. More recently ‘‘Memokath’’ stents seem better, with preliminary results suggesting 76% are patent and functional at a median 19 months [96]. ‘‘Extraanatomic’’ stents have been tried with encouraging results [97], but wider testing is needed to determine their true efficacy they are recommended. Finally, when a patient presents with severe renal impairment from upper tract obstruction, the urologic team has to address a difficult clinical dilemma. Renal failure from malignant obstruction often induces a painless and dignified terminal event over a short period. By contrast, longer survival may entail prolonged pain, debility, indignity and poor QoL. The questions for doctor and patient are, ‘‘how effective will decompression be in extending survival?’’ and ‘‘what quality of life can be expected following the procedure?’’ [4]. In this scenario, it is important to consider the views of the patient and caregivers fully before a clinical management decision is taken. 10.3.

Marrow failure

Marrow failure arises as a consequence of red marrow infiltration. The most common manifestation is anaemia (an adverse risk factor for cancer survival [98]), although immunologic/platelet malfunction and overt DIC are other sequelae [4]. Anaemia occurs in 77% of men with advanced malignancy [99]. In CaP it is caused by chronic disease and red marrow infiltration [100], although haematuria and/or consumptive coagulopathy can be contributory. Anaemia occurs in 10–13% of patients with HRPC [12,101] and often causes lethargy and shortness of breath when the Hb is 2 g/dl [106]. However, given the life expectancy of the patients and the cost of therapy, the treatment cost–benefit ratio is a consideration; therefore, EPO has not gained wider acceptance in HRPC. 10.4.

Lymphoedema

Lymphoedema usually results from lymphatic obstruction rather than hypoalbuminaemia. The only effective treatment is therapy to induce tumour regression. Without this recourse, treatment is based on physical manoeuvres as pharmacologic agents are of little benefit [107]. Simple limb elevation helps in mild cases, with gradual compression stockings in moderate cases and intermittent pneumatic compression in severe cases [81]. 10.5.

Rectal infiltration

Direct invasion of the rectum/perirectum by HRPC is common [87], but symptomatic manifestation varies. The most common is constipation, which can result in tenesmus, rectal pain and bleeding. Reported therapeutic measures include transanal resection [108] and local radiotherapy, although reported experience with the former technique is very limited. If constipation is intractable or bowel obstruction develops, colostomy is needed. It is better to undertake this in a controlled elective manner rather than as an emergency [80]. Rectoprostatic fistulation fortunately is uncommon and, when present, usually requires urinary and faecal diversion. Pain and tenesmus can cause intractable and distressing symptoms that may be alleviated by sacral nerve ablation using neurolytic caudal injection with alcohol or phenol. This therapy eliminates pelvic pain effectively, but it also impairs bladder and rectal emptying. Colostomy may be required as a prelude to neurolysis, and long-term catheter drainage of the bladder usually is needed after the procedure [4]. 10.6.

Mental health

The psychologic well-being of the patient should not be forgotten. Up to 25% of CaP patients develop clinical depression and may benefit from treatment [109]. This phenomenon occurs early and is often present 1 year before CaP death [110]. Urologists should be aware of this complication, and, in patients

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suffering sustained symptoms refractory to standard medication, psychiatric counselling and involvement in support groups should be considered [81,111].

11.

Conclusion

It is important to remember that, although HRPC is incurable, it is not untreatable, and that the clinical management embraces not just chemotherapy, but many interventional and supportive therapies. A multidisciplinary approach is ultimately the best method to achieve optimal treatment for individual patients, with management supervised by a single team providing the patient with a central focus for general supportive care. Above all, therapeutic management must be patient centred, and the pastoral and psychologic needs of the individual must be dealt with appropriately in parallel with addressing the physical needs of men suffering from this disease.

References [1] Svatek R, Karakiewicz PI, Shulman M, et al. Pretreatment nomogram for disease specific survival of patients with chemotherapy-naive androgen independent prostate cancer. Eur Urol 2006;49:666–74. [2] Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005;13:2918–25. [3] Petrylak DP. Chemotherapy for androgen independent prostate cancer. Semin Urol Oncol 2002;20:31–5. [4] Clarke NW. The management of hormone refractory prostate cancer. BJU Int 2003;92:860–8. [5] Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48:546–51. [6] Yagoda A, Petrylak D. Cytotoxic chemotherapy for advanced HRPC. Cancer 1993;71:1098–109. [7] Tannock IF, Osaba D, Stockelev MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone resistant prostate cancer. Clin Oncol 1996;17:1756–64. [8] Kantoff PW, Halabi SC, Conway M. Hydrocortisone with or without mitoxantrone in men with hormone refractory prostate cancer: results of the cancer and leukaemia group B 9182 study. J Clin Oncol 1999;17:2506–13. [9] Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for advanced prostate cancer. N Engl J Med 2004;351:1502–12. [10] Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced prostate cancer. N Engl J Med 2004;351:1513–20.

435

[11] British Association of Urological Surgeons Cancer Registry. Minimum Data Set 2001. London: British Association of Urological Surgeons; 2001. [12] Khafagy R, Shackley D, Samuel J, et al. Complications arising in the final year of life of men dying from prostate cancer. BJU Int 2005. In submission. [13] Thorpe AC, Cleary R, Coles J, et al. Deaths and complications following prostatectomy in 1400 men in the Northern Region of England. Brit J Urol 1994;74:559–65. [14] Wyatt MG, Stower MJ, Smith PJB, Roberts JBM. Prostatectomy in the over 80 year old. Brit J Urol 1989;64: 417–9. [15] Bloomfield D, Krahn M, Neogi T, et al. Economic evaluation of chemotherapy with Mitoxantrone and steroids for symptomatic HRPC: based on Canadian randomised trial with palliative end points. J Clin Oncol 1998;16: 2272–9. [16] National horizon scanning center. Docetaxel for hormone refractory prostate cancer. Birmingham national horizon scanning centre 2003. Available from: http://pcpoh. bham.ac.uk/publichealth.horizon/pdffiles/2003reports/ docetaxel.pdf. [17] Monthly index of medical specialties. Taxotere1. Available from: http://www.emims.net. [18] Clarke NW, Wylie JP. Chemotherapy in hormone refractory prostate cancer: where do we stand? Eur Urol 2004;46:709–11. [19] Ryan CJ, Eisenberger M. Chemotherapy for prostate cancer: now it’s a question of ‘‘when?’’ J Clin Oncol 2005;23:8242–6. [20] Halabi S, Small E, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone refractory prostate cancer. J Clin Oncol 2003;21:1232–7. [21] Uzgare AR, Isaacs JT. Prostate cancer: potential targets of anti-proliferative and apoptotic signalling pathways. Int J Biochem Cell Biol 2005;37:707–14. [22] Odrazka K, Vaculikova M, Dolezel M, et al. Is it reasonable to consider second-line chemotherapy in patients with hormone refractory prostate cancer. Oncol Rep 2005;14:1077–81. [23] Spicer J, Plunkett T, Somaiah N, et al. Phase 2 study of oral capecitabine in patients with hormone refractory prostate cancer. Prostate Cancer Prostatic Dis 2005, Epub. [24] Sternberg CN. Satraplatin in the treatment of hormone refractory prostate cancer. BJU Int 2005;96:990–4. [25] Bandaria MS, Hussain M. Epothilones and the next generation of phase 3 trials for prostate cancer. BJU Int 2005;96:296–302. [26] Sternberg C, Whelan P, Hetherington J, et al. Phase 3 trial of satraplatin, an oral platinum agent plus prednisone vs prednisone alone in patients with hormone refractory prostate cancer. Oncology 2005;68:2–9. [27] Goodin S, Kane MP, Rubin EH. Epothilones: mechanism of action and biological activity. J Clin Oncol 2004;22: 2015–25. [28] Trump DL. Randomised phase II study of two doses of Gefitnib in hormone refractory prostate cancer a trial of the National Cancer Institute of Canada Clinical Trials Group. Urol Oncol 2005;23:378–9.

436

european urology 50 (2006) 428–439

[29] Kantoff P. Recent progress in the management of advanced prostate cancer. Oncology 2005;19:631–6. [30] Armstrong AJ, Carducci MA. Novel therapeutic approaches to advanced prostate cancer. Clin Adv Hematol Oncol 2005;3:271–82. [31] Totterman TH, Loskog A, Essand M. The immunotherapy of prostate and bladder cancer. BJU Int 2005;96:728–35. [32] Birch PA, Croghan GA, Gastineau DA, et al. Immunotherapy (APC8015) targeting prostatic acid phosphatase can induce durable remission of androgen independent prostate cancer: a phase 2 trial. Prostate 2004;60: 197–204. [33] Soerdjbalie-Maikoev. Pelger RE, Lycklama A, et al. Strontium-89 (Metastron) and the bisphosphonate olpadronate reduce the incidence of spinal cord compression in patients with hormone refractory prostate cancer metastatic to the skeleton. Eur J Nucl Med Mol Imaging 2002;29:494–8. [34] Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Brit J Cancer 1987;55:61–6. [35] Neville–Webbe HC, Holden I, Coleman RE. The antitumour activity of bisphosphonates. Cancer Treat Rev 2002;28:305–19. [36] Berrutti A, Dogliotti L, Tucci M, et al. Metabolic bone disease induced by prostate cancer: rationale for the use of bisphosphonates. J Urol 2001;166:2023–31. [37] Townsend MF, Sanders WH, Northway RU, et al. Bone fractures associated with LHRH agonists used in the treatment of prostate cancer. Cancer 1997;79:545–50. [38] Oefelein MG, Ricchiuti V, Conrad W, et al. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 2002;168:1005–7. [39] Bayley A, Milosevic M, Bland R, et al. A prospective study of factors predicting clinically occult spinal cord compression in patients with metastatic prostate carcinoma. Cancer 2001;92:303–10. [40] Berrutti A, Tucci M, Mosca A, et al. Predictive factors for skeletal complications in HRPC patients with metastatic bone disease. Brit J Cancer 2005;93:633–8. [41] Tofe AJ, Francis MD, Harvey WJ. Correlation of neoplasms with incidence and localisation of skeletal metastases. An analysis of 1355 diphosphonate bone scans. J Nucl Med 1975;986–9. [42] Rose MR, Kagan AR. The final report on the expert panel for the Radiation Oncology Bone Metastasis working group of the American College of Radiology. Int J Radiat Oncol Biol Phys 1998;40:117–24. [43] Staniland E, Leir J. The effect of single fraction compound to multiple fractions in painful bone metastases in prostate cancer. Radiother Oncol 1999;52:101–9. [44] Price P, Hoskin PJ, Easton D, et al. Prospective randomised trial of single and multi–fractional radiotherapy schedules in the treatment of painful bony metastases. Radiother Oncol 1986;65:247–55. [45] Konski A. Radiotherapy is a cost effective treatment for patients with bone metastases from prostate cancer. Int J Radiat Oncol Biol Phys 2004;60:1373–8. [46] Hosking PJ. Scientific and clinical aspects of radiotherapy in the relief of bone pain. Cancer Surviv 1988;7:69–86.

[47] Tong D, Gillick L, Hendrickson FR. The palliation of symptomatic osseous metastases. Final results of the Radiation Therapy Oncology Group. Cancer 1982;50: 893–9. [48] Zelefsky MJ, Scher H, Forman JD, et al. Palliative hemi–skeletal irradiation for widespread metastatic prostate cancer: a comparison of single dose and fractionated regimens. Int J Rad Oncolol Biophys 1989; 17:1281–5. [49] Salazar OM, Sandhu T, La Matta NW, et al. Fractional half body irradiation (HBI) for the rapid palliation of widespread symptomatic, metastatic bone disease: a randomised phase III trial of the IAEA. Int J Radiat Oncol Biol Phys 2001;50:765–75. [50] Friedland J. Local and systemic radiation for palliation of metastatic disease. Urol Clin N Am 1999;76:391–402. [51] Jagar PL, Kuoistia A, Piers DA. Treatment with 89radioactive strontium for patients with bone metastases from prostate cancer. BJU Int 2000;86:929–34. [52] Lang AH, Ackery DM, Bayley RJ, et al. Strontium89 chloride for pain palliation in prostatic skeletal malignancy. Brit J Radiol 1991;64:816–72. [53] Lewington VJ, McEwan AJ, Ackery DM, et al. A prospective randomised double-blind cross-over study to examine the efficacy of strontium89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 1991;27:954–8. [54] Quilty PM, Kirk D, Bolger JJ, et al. Compression of the palliative effects of strontium89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 1994;31:33–40. [55] Smith JA. Palliation of painful bone metastases from prostate cancer using sodium etidronate: results of a randomised, prospective placebo controlled study. J Urol 1989;141:85–7. [56] Lycklama T, Tammela TL, Lincholm TS, Seppanen J. The effect of combined intravenous and oral Clodronate treatment on bone pain in patients with metastatic prostate cancer. Ann Chir Gynaecol 1994;83:316–9. [57] Cresswell SM, English PJ, Hall RR, et al. Pain relief and quality of life assessment following intravenous and oral Clodronate in hormone escape metastatic prostate cancer. Brit J Urol 1995;76:360–5. [58] Purohit OP, Anthony C, Radstone CR, et al. High dose intravenous pamidronate for metastatic bone pain. Brit J Cancer 1994;70:554–8. [59] Heidenreich A, Elert A, Hoffmann R. Ibandronate in the treatment of prostate cancer associated with painful osseous metastases. Prost Can Prost 2002;2: 231–5. [60] Ernst DS, Brasher P, Hagan N, et al. A randomised controlled trail of intravenous Clodronate in patients with metastatic bone disease and pain. J Pain Symptoms Manage 1997;13:319–26. [61] Kylmala T, Taube T, Tammela, et al. Concomitant intravenous and oral Clodronate in the relief of bone pain—a double-blinded placebo controlled cross-over study in patients with prostate cancer. Brit J Cancer 1997;76: 939–42.

european urology 50 (2006) 428–439

[62] Lipton A, Glover. Garvey H, et al. Pamidronate in the treatment of bone metastases: results of 2 dose ranging trials in patients with breast or prostate cancer. Ann Oncol 1994;5:35–53. [63] Saad F, Gleason DM, Murray R, et al. Of randomised placebo controlled trial of Zoledronic Acid in patients with hormone refractory metastatic prostate cancer. J Nat Cancer Inst 2002;94:1458–68. [64] Clarke NW, McClure J, George NJR. Disodium Pamidronate identifies differential osteoclastic bone resorption in metastatic prostate cancer. Br J Urol 1992;69:64–70. [65] Dearnaley DP, Sydes MR. Preliminary evidence that oral clodronate delays symptomatic progression of bone metastases from prostate cancer. First results of the MRC PRO5 trail. ASCO annual meeting. 2001; (abstract no. 1693). [66] Ernst DS, Tannock I, Winquist EW, et al. Randomised double blind controlled trial of mitoxantrone and clodronate vs mitoxantrone and prednisone and placebo in patients with HRPC. J Clin Oncol 2003;2:3335–42. [67] Canil CM, Tannock IF. Should bisphosphonates be used routinely in patients with prostate cancer metastatic to bone. J Nat Cancer Inst 2002;94:1422–3. [68] Coleman RE. Metastatic bone disease and the role of biochemical markers of bone metabolism in benign and malignant diseases. Cancer Treat Rev 2001;27: 133–5. [69] Lassiter LK, Carducci MA. Endothelin receptor antagonists in the treatment of prostate cancer. Semin Oncol 2003;30:678–88. [70] Nelson J, Nabusi A, Vogelsang N, et al. Suppression of prostate cancer induced bone remodelling by the endothelin A antagonist, atrasentan. J Urol 2003;169: 1143–9. [71] Carducci M, Nelson JB, Saad F, et al. Effects of atrasentan on disease progression and biological markers in men with metastatic hormone-refractory prostate cancer: Phase 3 study. Proc Am Soc Clin Oncol 2004;23:383, (abstract no. 4508). [72] Ellerhorst JA, Tu SM, Amato RJ, et al. Phase 2 trial of alternating weekly chemohormonal therapy for patients with androgen independent prostate cancer. Clin Cancer Res 1997;3:2371–6. [73] Osborne J, Getzenberg RH, Trump DL, et al. Spinal cord compression in prostate cancer. J Neurol Oncol 1995;23:135–47. [74] Kuban DA, El–Mahid AM, Siegred SV. Characteristics of spinal cord compression in adenocarcinoma of the prostate. Urology 1986;28:364–9. [75] Huddart RA, Rajan B, Lau M, et al. Spinal cord compression in prostate cancer: treatment outcome and prognostic factors. Radiother Oncol 1997;44:229–36. [76] Iacovou J, Marks JC, Abrams PH, et al. Cord compression and carcinoma prostate: is laminectomy justified? Brit J Urol 1985;57:733–6. [77] Mazur AW, Thompson IM. Efficacy and morbidity of ‘‘channel’’ TURP. Urology 1991;38:562–628. [78] Crain DS, Amling CL, Kane CJ. Palliative transurethral prostate resection for bladder outlet obstruction in

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

437

patients with locally advanced prostate cancer. J Urol 2004;171:668–71. Thorpe AC, Cleary R, Coles J, et al. Deaths and complications following prostatectomy in 1400 men in the Northern Region of England. Brit J Urol 1994;74:559–65. Esper P, Redman GR. Supportive care, pain management and quality of life in advanced prostate cancer. Urol Clin North Am 1999;26:375–89. Pergamen MC, Swain WR, Blackard CE. Disseminated intravascular coagulation in the urological patient. J Urol 1976;116:1–6. Dearnaley DP. Radiotherapy of prostate cancer: established results and new developments. Semin Surg Oncol 1995;11:50–9. Fossa SD. Palliative pelvic radiotherapy in patients with hormone resistant prostate cancer. Prog Clin Biol Res 1987;243B:479. Paul AB, Love C, Chisholm GD. The management of bilateral ureteric obstruction and renal failure in advanced prostate cancer. BJU Int 1994;5:642–5. Honnens de Lichtenberg M, Miskowiak J, Rolff H. Treament of obstructed kidneys in patients with prostate cancer. BJU Int 1993;71:313–6. Oefelein MG. Prognostic significance of obstructive uropathy in advanced prostate cancer. Urology 2004;63: 1117–21. Villavicencio H. Quality of life of patients with advanced and metastatic prostatic carcinoma. Eur Urol 1993;24: 118–21. Romero F, Broglio M, Pires S, et al. Indications for percutaneous nephrostomy in patients with obstructive uropathy due to malignant urogenital neoplasms. Int Braz J Urol 2005;31:117–24. Wilson JR, Urwin GH, Stower MJ. The role of percutaneous nephrostomy in malignant ureteric obstruction. Ann R Coll Surg Engl 2005;87:21–4. Chiou W, Chang Y, Horan JJ. Ureteral obstruction associated with prostate cancer: the outcome after percutaneous nephrostomy. J Urol 1990;143:957–9. Dowling RA, Carrasco CH, Babaian RJ. Percutaneous urinary diversion in patients with hormone–refractory prostate cancer. Urology 1991;37:89–91. Hamdy FC, Williams JL. Use of dexamethasone for ureteric obstruction in advanced prostate cancer: percutaneous nephrostomies can be avoided. BJU Int 1995;75: 782–5. Megalli MR, Gursel CD, Demirag H, et al. External beam radiotherapy in ureteral obstruction secondary to locally invasive prostate cancer. Urology 1974;5:562–4. Michigan S, Catalona WJ. Ureteral obstruction from prostatic carcinoma: response to endocrine and radiation therapy. J Urol 1977;177:733–8. Pollak JS, Rosenblatt M, Egglin T, et al. Initial experience with ureteral obstructions with the wall stent endoprosthesis. J Vasc Interv Radiol 1995;6:417–25. Kulkarni R, Bellamy E. Nickel titanium shape memory alloy Memokath OSI ureteral stent for managing longterm ureteral obstruction: 4 year experience. J Urol 2001;166:1750–4.

438

european urology 50 (2006) 428–439

[97] Jabour ME, Desgrandchamps F, Angelscu E, et al. Percutaneous implantation of subcutaneous prosthetic ureters: long term outcome. J Endo Urol 2001;15:611–4. [98] Caro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 2001;91: 2214–21. [99] Dunn A. Anaemia at the end of life: prevalence, significance, and causes in patients receiving palliative care. J Pain Symptoms Manage 2003;26:1132–9. [100] Berlin N. Anemia of cancer. Ann NY Acad Sci 1974; 230:209–11. [101] Smith Jr JA, Soloway MS, Young RJ. Complications of advanced prostate cancer. Urology 1999;54:8–14. [102] Gobel BH. Bleeding disorders. In: Groenwald S, Frogge M, Goodman M, Yarbro C, editors. Cancer nursing— principles and practice. 3rd ed. Boston: MA Jones Bartlett; 1993. p. 575–607. [103] Esper P, Pienta KJ. Supportive care in the patient with hormone refractory prostate cancer. Semin Urol Oncol 1997;15:56–64. [104] Albers P, Cappell R, Schwaibold H, et al. Erythropoietin in urologic oncology. Eur Urol 2001;39:1–8.

Editorial Comment George Thalmann [email protected] The review on the management spectrum of hormone refractory prostate cancer by Noel Clarke provides an excellent overview of the current armamentarium at hand in the treatment of patients with hormone refractory disease. Clearly there is need for a multidisciplinary approach. In times of patients requesting more and more a holistic approach, however, we as urologists should remain the primary manager of these patients, as we are mostly already involved early on in diagnosis and treatment of their prostate cancer and follow up these patients for many years until they develop androgen-independent disease. In contrast to the oncologist and radio oncologist we know the patient’s history and personality. Because, as this review shows, treatment algorithms are almost impossible to set up, treatment has to be adapted individually and is dependent on close knowledge of the patient’s situation.

Editorial Comment Pierre Karakiewicz [email protected] This article represents an excellent review of this timely topic, as the face of hormone refractory

[105] Beshara S, Letochka H, Linde T, et al. Anaemia associated with advanced prostatic adenocarcinoma: effects of recombinant human erythropoietin. Prostate 1997;31:153–60. [106] Johannsson JE, Wersall P, Brandberg Y, et al. Efficacy of epoeitin beta on haemoglobin, quality of life and transfusion needs in patients with anaemia due to HRPC—a randomised study. Scand J Nephrol 2001;35:288–94. [107] Brennan MJ. Lymphoedema following the surgical management of breast cancer. J Pain Symptoms Manage 1992;2:110–6. [108] Chen TF, Eardley I, Doyle PT, et al. Rectal obstruction secondary to carcinoma of the prostate treated by trans-anal resection of the prostate. BJU Int 1992; 70:613–7. [109] Tiernan E. Palliative care in urological cancer. UroOncology 2000;1:7–10. [110] Roth AJ, Holland JC. Psychiatric complications in cancer patients. In: Braum MC, Carbone PP, editors. Current therapy in haematology–oncology. 5th ed. St Louis: Mosby Yearbook; 1995. p. 609–18. [111] Litwin MS, Lubeck DP, Stoddard MC, et al. Quality of life before death for men with prostate cancer: results from the CAPSURE database. J Urol 2001;165:871–5.

Another problem this review points out is that for many new treatment forms the optimal time point of treatment remains to be determined. We now know that taxotere based chemotherapy is effective. But should we give it early on or wait until the patient develops symptoms? Will every patient profit from therapy? We know that bisphosphonates can reduce skeletal related events. As our experience with these compounds increases, we are learning that they also cause morbidity and we do not know their long term toxicity. Can bone turnover be inhibited for ever or do we risk pathological fractures due to bone growing brittle and frail from treatment? Despite many open questions we must bear in mind that although hormone refractory prostate cancer may not be cured, many treatment options exist and long term survival is often possible with good quality of life. Even though many options exist, palliative treatment should be given when necessary and with involvement of the patient in decision making.

prostate cancer (HRPCa) is changing. HRPCa no longer represents a disease with median survival well below 20 months, as previously reported by Smaletz et al. and Halabi et al. [1,2]. Instead, median survival of 53 or 54 months should be expected, as indicated by the contemporary series

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of Oefelein et al. and Svatek et al. [3,4]. These drastic median survival differences relate to changes in the definition of HRPCa. Contemporary PCa patients are qualified as hormone-refractory early in their castrate PSA recurrence stages. Oefelein used a backdated series of castrate PSA elevations above 0.3 ng/ml to define HRPCa [3]. In Svatek’s series, HRPCa was also backdated and defined as two consecutive increases in PSA values above the nadir value, each of which was >25% of the nadir value [3]. These definitions cannot be compared to those used by Smaletz et al. or Halabi et al., where virtually all included subjects had failed one or several HRPCa protocols [1,2]. Due to increasing awareness of effective chemotherapeutic regimens medical and urologic oncologists are faced with ‘early stages’ of HRPCa. This in turn raises the question of when and in whom taxoterebased chemotherapy should be initiated. Measurable disease represents a sine qua non for treatment. However, the fraction of patients with bony metastases, who are given taxotere-based chemotherapy progressively, decreases. This brings in the question when to initiate chemotherapy. Clearly, not all men with castrate rising serum PSA values need immediate treatment. HRPCa may take months to achieve exponential growth, which usually parallels exponential increases in serum PSA. Therefore, PSA doubling time, as shown in Svatek’s nomogram, is the single most important indicator of prognosis and also the most important indicator of possible need for taxotere-based chemotherapy [4]. However, change in disease kinetics, is better shown when the combined effect of all of Svatek’s nomogram predictors is used. Once the treatment decision is made, the magnitude of the treatment may represent an issue. The host’s ability to tolerate chemotherapy can be determined by patient’s age, comorbidity, performance status and symptom classification. Despite the advanced age of virtually all patients, who present for taxotere-based chemotherapy, dose reductions are rarely needed. Virtually all

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men tolerate a full induction dose. Some require neupogen due to presence of hematological side effects, but dose reductions are rarely required. Febrile neutropenia is exceedingly rare and the great majority of patients tolerate the usual 10 cycles of q3weeks chemotherapy very well. Many respond and after several months present for second or subsequent line chemotherapy. Again, many demonstrate favorable radiographic, scintigraphic and biochemical responses. The same or similar criteria for initiation of second or third line chemotherapy can be used, as for induction chemotherapy. Excellent responses to taxotere have narrowed the indications for mitoxantrone– prednisone chemotherapy. Conversely, the palliative effect of zoledronic acid, as well as its potential synergy with taxotere should prompt the use of both agents. Nonetheless, the ideal timing and the length of treatment with zoledronate remain to be further elucidated. Despite the stage migration of HRPCa, this category of patients virtually invariably succumbs to terminal complications of this incurable stage of prostate cancer.

References [1] Smaletz O, Scher HI, Small EJ, Verbel DA, McMillan A, Regan K, et al. Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. J Clin Oncol 2002;20:3972–82. [2] Halabi S, Small EJ, Kantoff PW, Kattan MW, Kaplan EB, Dawson NA, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 2003;21:1232–7. [3] Oefelein MG, Agarwal PK, Resnick MI. Survival of patients with hormone refractory prostate cancer in the prostate specific antigen era. J Urol 2004;171:1525–8. [4] Svatek R, Karakiewicz PI, Shulman M, Karam J, Perrotte P, Benaim E. Pre-treatment nomogram for diseasespecific survival of patients with chemotherapy-naive androgen independent prostate cancer. Eur Urol 2006; 49:666–74.