Optimising Hormone Therapy in Localised and Early Disease

Prostate cancer (PCa) is being diagnosed at an earlier age, and at an earlier stage of disease. Increasing numbers of relatively young patients (<60 years) with localised and early disease are receiving radical therapy. The addition of hormonal therapy in an adjuvant and/or neoadjuvant setting is widely used in clinical practice. The key issue when dealing with optimising hormone therapy in localised and early disease is to identify the patients who will benefit from this form of treatment, and optimise the timing of initiation as well as duration of the treatment. The current literature was reviewed to address this issue.Traditionally, most patients diagnosed with localised disease receive radical therapy, either radiation therapy or radical prostatectomy. However, many men have indolent PCa and may not require radical therapy. In contrast, patients with aggressive disease benefit from local therapy. As a consequence, the main clinical challenge is the stratification of patients with localised disease into good risk patients and intermediate-to-high risk patients in order to offer the patient a tailored treatment strategy.Patients diagnosed with good risk disease (stage T1c–T2a, Gleason score ≤6, small volume of disease on biopsy and prostate specific antigen (PSA) ≤10 ng/mL) can be closely monitored with periodic biopsies and measurement of the PSA doubling time (DT).Patients diagnosed with an aggressive form of disease (intermediate-to-high risk disease) need immediate curative therapy. Both radical prostatectomy and radiotherapy are currently used in combination with neoadjuvant and/or adjuvant hormonal therapy.Neoadjuvant therapy prior to radical prostatectomy has failed to demonstrate an improvement in PSA progression in numerous randomised trials. However, one trial showed a benefit in high risk patients (PSA >20 ng/mL) after 3 months of neoadjuvant therapy, based on retrospective stratification analysis. Overall, some practitioners recommend neoadjuvant therapy for patients with high risk localised PCa. Adjuvant hormonal therapy after surgery has not, to date, demonstrated an improvement in overall or disease specific survival, but does delay PSA progression. The significance of this remains uncertain.Neoadjuvant hormonal therapy prior to radiation therapy is recommended for patients with intermediate-to-high risk disease. The optimal duration of neoadjuvant hormone therapy is not yet defined. However, a 3 to 6 month course of neoadjuvant therapy prior to radiation is widely utilised. Adjuvant hormonal therapy after radiotherapy is also widely used in patients with intermediate-to-high risk disease. The optimal duration of adjuvant therapy is between 6 months and 3 years.For patients with biochemical failure, androgen deprivation therapy is appropriate for those whose clinical and pathologic parameters indicate that local recurrence is unlikely. For such patients who are at high risk (Gleason ≥8, or PSA DT <1 year), androgen deprivation should be implemented when the PSA is between 5 and 10 ng/mL. For lower risk patients, or those who have secondary failure after initial attempt at salvage radiation, there is no evidence that early androgen deprivation enhances survival or time to androgen independent progression. These patients should be monitored and treated upon clinical progression or rapid biochemical progression.     

Androgen Deprivation Therapies and Changes in Comorbidity: A Comparison of Gonadotropin-releasing Hormone Agonists and Antiandrogen Monotherapy as Primary Therapy in Men with High-risk Prostate Cancer

Background

Some studies suggest that gonadotropin-releasing hormone (GnRH) agonists are associated with higher risk of adverse events than antiandrogens (AAs) monotherapy. However, it has been unclear whether this is due to indication bias.

更换抗雄药物治疗初始内分泌治疗失效的晚期前列腺癌

目的观察初始内分泌治疗失效的晚期前列腺癌更换抗雄激素药物的二线内分泌治疗疗效。方法 48例晚期前列腺癌,采用药物或手术去势联合比卡鲁胺(50mg,qd)行全雄激素阻断治疗。初始治疗失效后更换抗雄药物为氟他胺(250mg,tid)进行二线内分泌治疗,以血清PSA值是否下降作为疗效评估指标,观察药物不良反应。结果所有患者均耐受氟他胺治疗。29例(60.4%)血清PSA值下降,其中17例(35.4%)下降50%,中位有效时间(10.2±3.5)个月;12例(25.0%)下降50%,中位有效时间(7.4±2.7)个月。19例(39.6%)治疗无效。统计分析显示一线内分泌治疗有效时间长者可获得良好的二线内分泌治疗反应(P0.05),而Gleason评分,一、二线内分泌治疗前PSA及治疗后PSA谷值均与二线内分泌治疗疗效无关。结论晚期前列腺癌初始内分泌治疗失效后,部分患者更换抗雄激素药物仍可取得一定疗效,可作为细胞毒化疗前的有效选择。     

Abarelix and other gonadotrophin‐releasing hormone antagonists in prostate cancer

Hormonal therapy is the main recommended treatment for locally advanced and metastatic prostate cancer. Luteinizing hormone‐releasing hormone (LHRH) agonists, such as buserelin, goserelin, leuprorelin and triptorelin, stimulate the pituitary’s gonadotrophin‐releasing hormone (GnRH) receptor, ultimately leading to its de‐sensitization and subsequent reduction of LH and testosterone levels. However, this reduction is accompanied by a well described increase or ‘surge’ in LH and testosterone levels, necessitating the concomitant administration of an antiandrogen to combat the potential effects of transient acceleration in cancer activity. Two pure GnRH antagonists have been developed, abarelix and degarelix, that are devoid of any agonist effect on the GnRH receptor and consequently do not result in testosterone flare. Abarelix was the first GnRH antagonist to be developed and was approved by the USA Food and Drug Administration in 2004 for the initiation of hormonal castration in advanced or metastasizing hormone‐dependent prostate carcinoma, when rapid androgen suppression is necessary. Clinical data on both abarelix and degarelix show that they can produce rapid and sustained decreases in testosterone to castrate levels without the need for co‐administration of an antiandrogen, and with a very low complication rate in the short term.     

Recommended Dose of Flutamide with LH-RH Agonist Therapy in Patients with Advanced Prostate Cancer

Background: In a recent study by the Casodex Combination Study Group, USA, patients in a flutamide (750mg/day) plus LH-RH agonist group showed a high treatment failure rate, mainly due to flutamide-induced diarrhea and hepatotoxicity. Our current study was conducted to determine the optimal dose of flutamide for use in this type of Combination therapy.
Methods: In a randomized, multicenter study, 30 patients (hormone untreated; stage C or D) were divided into 2 groups: flutamide 250mg (125mg × 2; 14 patients) and flutamide 375mg (125mg × 3; 16 patients), and each dose combined with either goserelin acetate (3.6 mg every 4 weeks) or leuprolide acetate (3.75 mg every 4 weeks). Goserelin and leuprolide were administered to patients in a 1:1 ratio. Flutamide monotherapy at a daily dose of 375 mg was determined to be the optimal dose in Japan in our previous phase II study. The endpoints of this pilot study were the objective response and adverse events during the 12-week treatment.
Results: The objective response rate was 83.3% in the flutamide 250mg group and 85.7% in the flutamide 375 mg group according to the Japanese response criteria for prostate cancer. Elevated PSA levels fell to within the normal range in 83.3% of the patients in the former group and in 93.3% of the patients in the latter group. One patient administered 250 mg of flutamide experienced diarrhea, while the serum GOT and/or GPT were elevated in 3 patients administered 250 mg of flutamide and 4 patients administered 375 mg of flutamide.
Conclusions: Based on the findings of this pilot study of maximal androgen-depletion therapy for advanced prostate cancer, 375mg/day of flutamide is recommended in combination with an LH-RH agonist. Assessment of the effects of our recommended regimen on longer term survival, quality of life and antiandrogen withdrawal syndrome of patients treated requires additional patients and time for foIIow-up.     

Activity of ketoconazole after taxane‐based chemotherapy in castration‐resistant prostate cancer

Study Type – Therapy (case series)Level of Evidence 4

OBJECTIVE

To assess the efficacy of the androgen‐synthesis inhibitor ketoconazole as a secondary hormonal therapy in patients with castration‐resistant prostate cancer (CRPC) previously treated with chemotherapy, as persistent androgens appear to play a role in the development and maintenance of CRPC.

PATIENTS AND METHODS

We retrospectively identified 34 patients with CRPC who were treated with ketoconazole as a secondary hormonal therapy after paclitaxel‐ or docetaxel‐based chemotherapy for CRPC. They were treated with ketoconazole 200–400 mg three times daily with or without hydrocortisone. Patients with previous use of ketoconazole were excluded. Half the patients had received estramustine as part of their chemotherapy regimen. The primary endpoint was the proportion of patients with a decline of ≥50% in their prostate‐specific antigen (PSA) level. PSA progression was defined by the PSA Working Group 1 Criteria.

RESULTS

Eight of the 32 evaluable patients (25%) had a PSA decline of ≥50%. The median time to progression (TTP) was 3 months (95% confidence interval, 1.2–5.4). A history of previous response to taxane‐based chemotherapy was not associated with the response to ketoconazole. However, previous use of oestrogens for CRPC was significantly associated with a shorter TTP on ketoconazole (1.5 vs 10.2 months; P = 0.03).

CONCLUSIONS

Ketoconazole has moderate activity as secondary hormonal therapy in patients with CRPC previously treated with taxane‐based chemotherapy, although the TTP was short. Previous treatment with oestrogenic therapy is associated with a shorter TTP.     

Intermittent Hormone Therapy: What Is Its Place in Clinical Practice?

ContextIntermittent hormone therapy (IHT) for prostate cancer (PCa) has been garnering interest in the urologic community. IHT aims to minimise treatment-related side-effects, to improve overall quality of life (QoL), to reduce the cost of care, and possibly to delay progression to castration-resistant PCa (CRPC). But questions remain as to whether its use is supported by scientific evidence and how it should be applied in clinical practice.ObjectiveTo discuss the current scientific evidence on IHT and to offer recommendations on how to implement IHT in clinical practice.Evidence acquisitionThis paper was based on a presentation given at a satellite symposium on PCa that was held at the 2009 annual meeting of the European Association of Urology (EAU) in Stockholm, Sweden. Data were retrieved from recent review articles, original articles, and abstracts on IHT.Evidence synthesisSeveral phase 2 and 3 clinical trials have evaluated IHT; however, the phase 2 trials were generally small and used different methodologies, and most of the randomised controlled phase 3 trials are not mature yet. While considering these limitations, it can be concluded that IHT appears to have a beneficial effect on the incidence of side-effects, on QoL, and on cost. Additionally, IHT appears to have no negative impact on overall survival or progression-free survival compared to continuous hormone therapy. It could not yet be demonstrated that IHT prolongs the time to CRPC; therefore, further research is needed, also to provide guidance on how IHT should be applied in clinical practice.ConclusionsIHT appears to have a beneficial effect on treatment-related side-effects and QoL and no negative impact on survival. Final data from phase 3 studies, however, are awaited, also to determine selection criteria for patients.     

Clinical Criteria as Predictive Factors of Response to Primary Hormone Therapy in Locally Advanced Breast Cancer

Abstract:  This study investigates the efficacy of clinical criteria in selecting patients for primary tamoxifen therapy. A total of 60 breast cancer patients with large primary tumors and unknown hormonal receptor status were subjected to primary hormone therapy. Inclusion criteria were age over 60 years old or menopausal status for at least 10 years and no clinical evidence of inflammatory disease and fast tumor growth. The objective response rate was 55%. There was a positive correlation between the lack of clinical response and axillary lymph node metastasis (p = 0.009). Patients with objective response had significantly improved disease-free (p = 0.045) and overall (p = 0.0002) survival over those who did not have response to hormonal therapy. In multivariate analysis, the clinical response to therapy was the most powerful prognostic factor. This analysis demonstrates that clinical criteria were very effective predictor of response to neo-adjuvant hormone therapy in large breast tumors for postmenopausal women. Response to therapy is the major prognostic factor in primary tamoxifen-treated breast cancer.     

Considerations for the use of gonadotropin-releasing hormone agonists and antagonists in patients with prostate cancer

Prostate cancer is the second most common cause of cancer-related deaths in men, representing a major source of morbidity and mortality. Androgen deprivation therapy is the primary treatment for patients with advanced prostate cancer at disease presentation, which can be achieved either with surgical or chemical castration. The development of gonadotropin-releasing hormone agonists revolutionized the treatment of advanced prostate cancer, replacing the need for surgical castration. Agonists downregulate gonadotropin-releasing hormone agonist receptors in the pituitary gland, and thus decrease the release of luteinizing hormone and testosterone. Although agonists are a common therapeutic option to date, their use is associated with testosterone surges, metabolic dysfunction and an increase in the risk of cardiovascular disease; they might contribute to tumor flares and potentially an increase in non-cancer mortality. More recently, gonadotropin-releasing hormone antagonists have entered the prostate cancer treatment landscape. Unlike agonists, antagonists directly inhibit the androgen receptor in the pituitary gland, and thus do not cause initial testosterone surges. In this article, we provide a concise review of the mechanism of actions, safety and efficacy of the approved agonists and antagonists for prostate cancer treatment.     

Lifestyle Changes for Improving Disease-specific Quality of Life in Sedentary Men on Long-term Androgen-Deprivation Therapy for Advanced Prostate Cancer: A Randomised Controlled Trial

Background

Prostate cancer is a key driver of cancer-related global disability-adjusted life-years. Androgen-deprivation therapy (ADT) for advanced disease is linked to fatigue, reduced physical function, and quality of life (QoL).

Objective

To evaluate the effect of a lifestyle intervention on disease-specific QoL, diastolic blood pressure, and cancer-related fatigue in sedentary men receiving long-term ADT for advanced prostate cancer.

Design, setting, and participants

A total of 100 hundred sedentary men with locally advanced or metastatic prostate cancer on long-term ADT were randomised to an intervention or usual care group.

Intervention

A 12-wk lifestyle intervention consisting of aerobic and resistance exercise with parallel dietary advice.

Outcome measurements and statistical analysis

Disease-specific QoL was measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaires at 12 wk postintervention and at 6 mo following withdrawal of support. Analysis of covariance and mixed regression were conducted.

Results and limitations

Clinically relevant improvements in FACT-P were seen at 12 wk in the intervention group compared with controls (mean difference: 8.9 points; 95% confidence interval [CI], 3.7–14.2; adjusted p = 0.001). No difference was apparent at 6 mo (mean difference: 3.3 points; 95% CI, −2.6 to 9.3; adjusted p = 0.27). No difference in diastolic blood pressure was seen at either follow-up (all p > 0.05). Clinically relevant improvements in FACT-F were seen at 12 wk (mean difference: 5.3 points; 95% CI, 2.7–7.9; adjusted p < 0.001) and maintained following withdrawal of supervision (mean difference: 3.9 points; 95% CI, 1.1–6.8; adjusted p = 0.007). Improvements in exercise tolerance and behaviour were maintained at 6 mo (adjusted p < 0.001 and 0.038).

Conclusions

A lifestyle intervention resulted in a clinically meaningful improvement in disease-specific QoL that was not maintained postintervention. No effect on blood pressure occurred. Durability of response was seen in fatigue and exercise behaviour. Further evaluation of support structures is essential.

Trial registration

ISRCTN88605738.     

Potential Benefits of Intermittent Androgen Suppression Therapy in the Treatment of Prostate Cancer: A Systematic Review of the Literature

Context

The well-known side-effect profile of androgen-deprivation therapy (ADT) has significant quality-of-life (QoL) implications. Intermittent androgen deprivation (IAD) alternates androgen blockade with treatment cessation to allow hormonal recovery between treatment cycles, thus potentially improving tolerability and QoL.

Objective

To evaluate available evidence regarding the efficacy and tolerability of IAD and assess its value in the treatment of prostate cancer (PCa).

Evidence acquisition

Key phase 2/3 clinical trials of IAD in PCa published within the last 10 yr were identified on Medline using the terms prostatic neoplasms [MeSH], intermittent androgen suppression, intermittent hormonal deprivation, intermittent androgen deprivation, and intermittent hormonal therapy. Abstracts from trials reported at 2008–2009 conferences were also included.

Evidence synthesis

Data from 19 phase 2 studies are discussed with respect to prostate-specific antigen values for treatment suspension/reinitiation, treatment regimens, cycle lengths, testosterone normalisation, and tolerability. Outcome data were promising: Most trials reported an improvement in QoL during the off-therapy periods. Interim data from eight phase 3 trials comparing IAD and continuous androgen deprivation (CAD) support the phase 2 results. IAD generally showed comparable efficacy to CAD with respect to various outcomes, including biochemical progression, progression-free survival, and overall survival. However, IAD was significantly better than CAD with respect to 3-yr risk of progression in one study, and it demonstrated tolerability benefits, particularly with respect to sexual function. Patients most likely to benefit from IAD and factors predictive of poor response are also discussed.

Conclusions

IAD seems to be as effective as CAD while showing tolerability and QoL advantages, especially recovery of sexual potency; however, there are as yet insufficient data to determine whether IAD has the potential to prevent or reverse the long-term complications associated with ADT.