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Keywords:

  • androgen-independent prostate cancer;
  • PSA;
  • estramustine;
  • docetaxel;
  • paclitaxel;
  • calcitriol;
  • thalidomide

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

Of men with metastatic prostate cancer who undergo androgen ablation, 70–80% respond rapidly to therapy, as manifested by a reduction in prostate cancer-related symptoms and declines in serum prostate-specific antigen (PSA) level. Unfortunately, after a median of 18–24 months, nearly all patients with metastatic prostate cancer will progress to androgen independence. Until recently the standard of care for treating hormone-refractory prostate cancer (HRPCa) was the combination of mitoxantrone and prednisone, which palliated bone pain but did not extend survival. Two randomized trials with > 1700 patients showed for the first time a survival benefit for patients with HRPC treated with chemotherapy; when compared with mitoxantrone-based therapy, docetaxel based-therapy reduced the risk of death by 20–24%. Future trials in HRPC are attempting to improve the efficacy of docetaxel by incorporating new agents targeting angiogenesis, apoptosis, and signal transduction pathways; there is promising activity for these novel combinations in phase I and II studies. Concepts are also being refined about definitions of response and progressive disease, patient eligibility criteria, and the validity of surrogate markers of efficacy and survival, as shown by changes in PSA level.


Abbreviations:
(HR)AIPC

(hormone-refractory) androgen-independent prostate cancer

CALGB

Cancer and Leukaemia Group B

SWOG

South-west Oncology Group

VEGF

vascular endothelial growth factor

PSMA

prostate-specific membrane antigen.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

Of men with metastatic prostate cancer, 70–80% respond to androgen-ablative therapy [1,2]; despite the initial high frequency of response, the median response duration is only 18–24 months, with > 90% of patients with metastases developing androgen-independent prostate cancer (AIPC). This form of the disease is both morbid and rapidly progressive, and until recently, no treatment was available that improved survival [1,3]. The previous lack of effective treatments for this group of patients was highlighted in a review of 26 trials conducted between 1987 and 1991, in which the reported median survivals were 9–12 months [4,5], and the complete and partial response rate to chemotherapy was 8.8%.

Recently, two randomized trials showed a reduction in the risk of death by 20–24% in men treated with docetaxel-based therapy. These therapeutic advances are a first step; managing patients with AIPC remains a clinical challenge. Although docetaxel-based therapy improves survival, durable complete remissions have not been reported. New trials are combining docetaxel therapy with therapies that target angiogenesis, apoptotic proteins, and growth factors, with the hope of further extending survival. Second-line chemotherapeutic agents are now, for the first time, being evaluated.

NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

The optimum time to initiate systemic chemotherapy therapy is still controversial (symptomatic treatment vs asymptomatic). Although phase III studies using survival as a primary endpoint remain the ‘gold standard’, the optimum endpoint for assessing the therapeutic response in phase II trials remains controversial. Data from recent randomized trials may support the use of decreases in serum PSA as a surrogate endpoint for survival, and thus reduce the time needed for drug approval.

DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

Data amassed from a trial on the effect of therapy on survival is influenced by the determination of when patients would be considered eligible for therapy. Therefore, it is essential that entry criteria for progressive disease and response criteria for outcome measures be well defined. For most clinical trials, disease progression in castrate patients with metastatic prostate cancer is defined by one of three criteria: (i) rising PSA level; (ii) progression in soft-tissue metastases; or (iii) progression on bone scan. Most patients now present with biochemical progression with no changes in bone scan or CT as their first manifestation of relapse. An increase in PSA level can precede changes in bone scans by 7 months [6]; symptoms from metastases to bone can occur even later. Thus, for clinical trials in prostate cancer, it is important to clearly define the type of progression, as reported survivals will clearly be different. Studies of asymptomatic men treated with mitoxantrone and prednisone whose sole manifestation of progression was a rise in PSA level reported a median survival of 23 months, whereas others have found the median survival in symptomatic men to be 12 months [7,8]. The differences in survival appear to be due to stage migration; whether response rates and survival are truly better in symptomatic or asymptomatic patients is the subject of controversy.

PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

That bone is the predominant site of metastases and disease progression has also caused problems in evaluating response. In solid tumours such as breast and lung cancer, evaluation of the effect of cytotoxic agents is measured by reductions in measurable soft-tissue lesions. However, only 20–30% of patients with prostate cancer have measurable soft-tissue lesions; therefore, relying on this criterion would exclude most patients from treatment trials [2,9]. Changes in lesions on bone scans are difficult to quantify and can be misleading [1,2,10]. The flare phenomenon, which is associated with transient radiographic progression of lesions despite clinical improvement after starting therapy, may further confuse the interpretation of bone scans [1,2,11]. Thus, new isotope uptake on a bone scan may not be progression, but could also be bone repair. Also, it may take months to detect decreased activity on a bone scan, due to the healing of lesions.

The use of decreases in PSA level as an indicator of response to therapy and as a predictor of survival has been controversial [2,10]. The first correlation between PSA decrease and survival was obtained from a landmark analysis of retrospective of data obtained in 110 patients treated on seven clinical trials, where patients who achieved a PSA decline of ≥50% had a longer survival than those who did not have such a decrease [12]. Multivariate analysis identified a ≥ 50% PSA decline and the natural log of lactate dehydrogenase as the two most important predictors of survival [12]. There was a similar relationship in an analysis of PSA decreases in patients treated with estramustine combined with VP-16. A pooled analysis of four Cancer and Leukaemia Group B (CALGB) studies suggests that the reduction in PSA level after chemotherapy is associated with prolonged survival and that the ratio of the PSA slope before and after chemotherapy may be a useful intermediate endpoint in patients with metastatic AIPC [13]. However, a meta-analysis of data obtained in > 2000 patients found that although the association between the PSA level and overall survival was confirmed at the individual level, this relationship was very weak when group data were compared, suggesting that PSA may not be a useful surrogate for survival in phase III trials [14]. The Southwest Oncology Group (SWOG) analysed its PSA data for surrogacy [15] and found that 50% declines do not satisfy the criteria for surrogacy; other levels and duration of PSA declines are currently under analysis.

The evaluation of serum tumour markers as clinical trial endpoints poses several problems. Changes in PSA levels can be a measure of antitumour activity, but changes must be interpreted for the effect of the drug on PSA expression/secretion [3]. Thalidomide and TNP-470, anti-angiogenic agents, often increase PSA expression in vitro[3]. Other drugs, in particular suramin, can induce a PSA decline at doses that are not cytotoxic [16]. Retinoids may increase (e.g. all-trans-retinoic acid) or decrease (e.g. retinol) PSA expression [3]. Thus, although a rapid decline in PSA after administration of a drug with no increase thereafter is the optimum marker response desired, various patterns are possible. Drugs that induce differentiation may initially show increases in PSA followed by declines or stabilization. Treatment with cytostatic agents may stabilize the PSA level or cause a slow decrease in slope. Thus, the search for PSA surrogacy may depend on the mechanism of action of the drug [17].

MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

In a study by Tannock et al.[8] the combination of mitoxantrone 12 mg/m2 and prednisone 5 mg orally twice daily demonstrated superior pain relief to prednisone alone (10 mg daily) in patients with symptomatic hormone-refractory prostate cancer (HRPC). Unfortunately, the median survivals reported were not significantly different when mitoxantrone/prednisone was compared with prednisone alone. Importantly, patients were allowed to cross over at progression from the prednisone arm to the mitoxantrone/prednisone arm, and thus detecting a survival benefit may have been precluded by the crossover. A second study by the CALBG, comparing mitoxantrone 14 mg/m2 hydrocortisone with hydrocortisone failed to detect a survival benefit [18]. On the basis of these two studies, the US Food and Drug Administration approved the combination of mitoxantrone and a corticosteroid for palliation in patients with AIPC.

TAXANE-BASED THERAPY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

The taxanes, docetaxel and paclitaxel, have been extensively investigated in AIPC. Their presumed mechanism is the inhibition of depolymerization of microtubules, but studies suggest that they also promote apoptosis by inhibiting the anti-apoptotic effect of bcl-2. The anti-apoptotic protein bcl-2, which is expressed in ≈ 65% of androgen-independent tumours, may promote both androgen-independent growth and chemoresistance in prostate cancer cells. The common pathway for agents that inhibit depolymerization of tubulin, such as the taxanes, appears to be phosphorylation of bcl-2 [19]. Phosphorylation of bcl-2 is 100 times greater with docetaxel than with paclitaxel. Phase I and II studies with weekly or tri-weekly docetaxel or paclitaxel monotherapy showed PSA decline rates of > 50% in 41–46% and 4–39% of patients, respectively [20–22]. Adding estramustine appeared, in phase I and II studies, to increase the median survival and response rate of patients treated with docetaxel to 20–23 months [9,10,23–25]. The inclusion of a steroid in the regimen does not appear to contribute to the response to combined therapy with estramustine and docetaxel [26].

The phase I and II data previously cited provided the scientific rationale for two randomized trials that established docetaxel-based therapy as the standard of care for AIPC. The SWOG study 99–16 randomized 770 men to either the combination of docetaxel/estramustine or mitoxantrone/prednisone [27]. Patients treated with docetaxel/estramustine had a 20% improvement in overall survival compared with those treated with mitoxantrone/prednisone. The median survival time was 17.5 months in the first and 15.6 months in the second group (P = 0.02). The median time to progression was also significantly longer for docetaxel/estramustine (6.3 months) than for mitoxantrone/prednisone (3.2 months) (P < 0.001). Although docetaxel/estramustine was associated with higher incidences of gastrointestinal and cardiovascular side-effects, there was no difference between the groups in the number of toxicity-related death. The TAX 327 multicentre, randomized study compared mitoxantrone given every 3 weeks with docetaxel given either weekly and/or every 3 weeks in 1006 men with metastatic AIPC [28]. All men received daily prednisone 5 mg orally, twice daily. The median survival was significantly better with the docetaxel regimen given every 3 weeks (18.9 months) than with the mitoxantrone regimen (16.5 months; P = 0.009), but there was no survival advantage for the weekly docetaxel regimen (17.4 months; P = 0.36). When compared with mitoxantrone and prednisone, there was a 24% reduction in the risk of death for patients treated with the tri-weekly regimen. The pain responses, and improvements in quality of life indices, were also significantly better in both docetaxel arms than in the mitoxantrone arm.

THE ROLE OF ESTRAMUSTINE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

Estramustine phosphate, a nornitrogen mustard 17β-oestradiol conjugate, which was previously thought to have alkylating agent activity, inhibits microtubule function and mitosis. Its oestrogenic metabolites induce castrate levels of testosterone [1,29]. Estramustine has minimal to modest activity in AIPC [29,30]. In six randomized trials from the National Prostatic Cancer Project, only 14 patients (4.6%) showed an objective response [31,32]. However, there is now interest in the potential synergistic effects of agents that have different mechanisms or that act on microtubule proteins at different loci. Estramustine has been investigated in combination with vinblastine (another microtubule inhibitor) taxanes, and etoposide.

A study from the Hoosier Oncology Group found that the median survival in patients treated with the combination of estramustine and vinblastine was 11.9 months, compared with 9.2 months for vinblastine alone [33]. There were only ≈ 100 patients in each treatment arm, and when data were analysed for the potential influence of prognostic factors such as haemoglobin, lactate dehydrogenase, and alkaline phosphatase, the survival difference was not significant. Although combined estramustine/vinblastine therapy did not significantly improve survival, the combined therapy was better than vinblastine monotherapy for time to progression (median 3.7 vs 2.2 months, P < 0.001) and for sustained PSA decline (25.2% vs 3.2%, P < 0.001). A randomized phase II study showed better survival with paclitaxel/estramustine than with paclitaxel alone. Results from SWOG 99–16 and TAX 327 will not resolve the issue of estramustine use. Only a properly designed randomized trial comparing docetaxel with docetaxel/estramustine will answer this question. However, because of the toxicity found with estramustine and docetaxel, cooperative groups have selected docetaxel/prednisone as the control arm for phase III studies.

NOVEL THERAPEUTIC OPTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

Many potentially useful drugs that are being considered for use in combination with taxanes have many mechanisms of action. Calcitriol, the active metabolite of vitamin D3, has anti-proliferative effects, promotes apoptosis in association with down-regulation of bcl-2 in LNCaP cells, and enhances the antitumour activity of cytotoxic agents such as paclitaxel [34,35]. Artificial overexpression of bcl-2 in LNCaP cells blocked calcitriol-induced apoptosis [35]. In a study by Hershberger et al.[34], pretreatment of human prostatic adenocarcinoma (PC-3) cells with calcitriol reduced the expression of p21 and enhanced paclitaxel-induced cytotoxicity without influencing paclitaxel's effects on bcl-2. Bernardi et al.[36] showed that calcitriol inhibited the proliferation of tumour-derived endothelial cells but was less active against normal endothelial cells, suggesting that calcitriol has anti-angiogenic activity.

Weekly high-dose calcitriol (0.5 µg/kg on day 1) and docetaxel (36 mg/m2 i.v. on day 2) for 6 weeks was associated with a PSA response (>50% decline) in 30 (81%) of 37 patients with metastatic AIPC [37]. Of the 15 patients with measurable disease, eight (53%) had a partial response. The median time to progression was 11.4 months, and median survival was 19.5 months. These results are comparable to those seen with combined estramustine/docetaxel [10,25]. Dexamethasone was also a part of the treatment regimen, although its role in the therapeutic response is unclear [37]. The toxicity profile was similar to that seen in studies of docetaxel monotherapy, except for a somewhat higher than expected incidence of gastric and duodenal ulceration [37]. The phase II/III AIPC Study of Calcitriol Enhancing Taxofere (ASCENT) trial, which has completed patient enrolment, will examine the effect of docetaxel monotherapy compared with combined docetaxel/calcitriol therapy in men with AIPC. The PSA response is the primary endpoint, and survival is a secondary endpoint [38].

Thalidomide, an anti-angiogenic agent, is known to be active in HRPC. In a small, open-label, randomized, phase II trial, low-dose thalidomide (200 mg/day) was associated with a PSA decline of ≥ 50% in 18% of patients; there was a PSA decline of > 40% in 28% of patients. None of the patients in the high-dose arm (1200 mg/day) had a PSA response [39]. These findings generated interest in the potential of the combination of weekly docetaxel and daily thalidomide, which was compared with docetaxel monotherapy in 75 chemotherapy-naive patients with AIPC. The PSA response rate was higher in the combined therapy group (51%) than in the docetaxel monotherapy group (37%) [40]. Although this trial was not designed to detect a survival difference, with further follow-up the median survival of patients treated with docetaxel/thalidomide was better (25.9 months) than docetaxel alone (14.7 months, P = 0.04) [41]. Pleural effusions also occurred in both groups, but thrombotic events occurred only in the combined therapy group [40].

Drugs that target vascular endothelial growth factor (VEGF) also are of interest because plasma VEGF levels are elevated in patients with AIPC. George et al.[42] reported that the plasma VEGF level was inversely correlated with survival time in patients. A CALBG study [43] investigated the effect of adding bevacizumab, a monoclonal antibody to VEGF, to the combination of docetaxel and estramustine in patients with progressive metastatic HRPC. The docetaxel regimen was administered every 3 weeks. There was a PSA response in 79% of patients and 42% with measurable disease had a partial response. There was one treatment-related death, due to a pulmonary embolism. These results have justified a phase III study comparing docetaxel 75 mg/m2, prednisone and bevacizumab to docetaxel and prednisone. This 1020-patient trial is designed to detect an improvement in median survival from 19 to 24 months with 90% power [44].

The findings obtained in studies combining docetaxel with thalidomide or bevacizumab suggest that we can safely combine anti-angiogenic agents with taxanes and that such combinations may enhance cytotoxicity. Newer, more potent thalidomide derivatives are under investigation in combination with docetaxel in phase I studies.

An additional therapeutic option is atrasentan, an endothelin-1 antagonist that has improved the time to progression and quality of life in patients with AIPC [45–47]; another endothelin receptor antagonist (YM598), which has shown high in vitro and in vivo activity against the endothelin ETA receptor [48], is being investigated as treatment and palliation for advanced prostate cancer. A phase III study is being planned by the SWOG, comparing docetaxel 75 mg/m2 for 3 weeks combined with prednisone 5 mg orally twice daily to docetaxel 75 mg/m2, prednisone 5 mg orally twice daily and atresentan. Although the primary endpoint in this trial is to detect an improvement in time to progression, it is also powered to detect a survival difference.

Prostate-specific membrane antigen (PSMA) is a highly prostate-restricted transmembrane glycoprotein expressed in prostate cancer epithelial cells, and in the vascular endothelium of multiple tumour types [49]. The expression of PSMA appears to be increased in poorly differentiated, metastatic and hormone-refractory cancers. A human monoclonal antibody (HuJ591) that recognises PSMA has been linked to isotopes such as 90yttrium [50] and 177lutetium [51], and showed activity in phase I trials in men with AIPC.

NF-κB is a transcription factor that regulates angiogenesis, metastases, cell proliferation and apoptosis [52], and activates the PSA-core enhancer independently of androgen [53]. It was proposed that NF-κB inhibitors may enhance the effectiveness of taxane therapy [54]. Bortezomib (formerly PS-341), a dipeptide that reduces NF-κB levels in vitro, is under investigation in patients with AIPC [55]. Single-agent activity was shown when bortezomib was administered as a single agent [56] or combined with docetaxel [57].

WHO SHOULD BE TREATED AND WHEN?

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES

One of the most important issues for using chemotherapy in prostate cancer is identifying the proper timing of administration in patients with metastatic disease. Mitoxantrone was approved for patients with symptomatic HRPC, and docetaxel for patients with HRPC. Thus, there is no clear indication for the proper time to initiate treatment with docetaxel. Theoretically, earlier treatment affords the chance to administer chemotherapy at lower volumes of disease. However, with no clear survival advantage to earlier therapy, deferring treatment until objective progression or the development of symptoms delays the side-effects. Although the hazard ratios and the ≈ 2-month difference in median survivals observed in symptomatic and asymptomatic patients treated with tri-weekly docetaxel on TAX 327 appear to be similar, this observation was a subset analysis and not part of the original trial design. A randomized trial is needed to define the role of early vs delayed therapy in the state of HRPC. Unfortunately, The Eastern Cooperative Oncology Group (ECOG) 1899, a trial designed to compare early docetaxel therapy to a secondary hormonal manipulation with nizoral and hydrocortisone in men with biochemical relapse after androgen blockade, closed due to lack of accrual. Thus, the answer to the question of when to administer chemotherapy in a patient with HRPC will remain unanswered for the foreseeable future.

It was shown in breast cancer, lung cancer, and colorectal cancer that early administration of chemotherapy to high-risk patients prolongs survival. Some of the pretreatment characteristics that indicate high risk in patients with prostate cancer have already been described: a Gleason score of ≥ 8, higher clinical stage, and high PSA levels before prostatectomy [58]. These are the types of patients who might benefit from early chemotherapy. Partin et al.[59] updated their staging nomograms for prostate cancer, with increased stratification of the Gleason score and PSA level allowing better differentiation of patients.

Small studies have provided some evidence that early use of chemotherapy improves survival. For example, a study of adjuvant mitoxantrone in patients with locally advanced prostate cancer receiving hormone therapy was associated with an 84-month survival compared with 36-month survival in patients who did not receive mitoxantrone. There was no survival difference in patients with established metastases [60]. These results imply that early chemotherapy might have a role in managing high-risk prostate cancer after local therapy. The SWOG is currently evaluating this concept in a randomized trial comparing 2 years of combined androgen blockade to 2 years of androgen blockade combined with six cycles of mitoxantrone 12 mg/m2 and prednisone 5 mg orally twice daily. A phase II study investigated adjuvant weekly docetaxel therapy in high-risk patients, with high risk defined as a relative risk of relapse of > 2.84, according to Partin nomograms (or a minimum 50% risk of recurrence at 3 years) in 70 patients. The regimen consists of i.v. docetaxel 35 mg/m2 on days 1, 8, and 15 of a 28-day cycle, by six cycles. Only moderate and reversible toxicity was reported, suggesting that the weekly docetaxel regimen is feasible [61]. No comparative survival data are available. Patients with rising PSA levels after local therapy are another subgroup who might be appropriate candidates for chemotherapy. PSA doubling times were prognostic in this group of patients [2,62].

In conclusion, the standard of care for AIPC is docetaxel combined with prednisone. Although studies are underway evaluating the earlier use of chemotherapy in high-risk prostate cancer, there is at present no evidence for the routine use of chemotherapy outside a clinical trial in these patients. New phase III trials will evaluate the role of anti-angiogenic agents and anti-endothelins in combination with docetaxel.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NEW QUESTIONS ON THE ROLE OF CHEMOTHERAPY IN PROSTATE CANCER
  5. DEFINING PROGRESSION OF DISEASE AFTER ANDROGEN ABLATION
  6. PSA DECLINE AS A MEASURE OF THERAPEUTIC ACTIVITY
  7. MITOXANTRONE THERAPY: PALLLIATION OF BONE PAIN
  8. TAXANE-BASED THERAPY
  9. THE ROLE OF ESTRAMUSTINE
  10. NOVEL THERAPEUTIC OPTIONS
  11. WHO SHOULD BE TREATED AND WHEN?
  12. REFERENCES
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