John B. Anderson

A Randomised Comparison of ‘Casodex’TM (Bicalutamide) 150 mg Monotherapy versus Castration in the Treatment of Metastatic and Locally Advanced Prostate Cancer

Objectives: To evaluate the efficacy and tolerability of ‘Casodex’TM monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer. Methods: A total of 1,453 patients with either confirmed metastatic disease (M1), or T3/T4 non-metastatic disease with elevated prostate-specific antigen (M₀) were recruited into one of two identical, multicentre, randomsied studies to compare ‘Casodex’ 150 mg/day with castration. The protocols allowed for combined analysis. Results: At a median follow-up period of approximately 100 weeks for both studies, ‘Casodex’ 150 mg was found to be less effective than castration in patients with metastatic disease (M1) at entry (hazard ratio of 1.30 for time to death) with a difference in median survival of 6 weeks. In symptomatic M1 patients, ‘Casodex’ was associated with a statistically significant improvement in subjective response (70%) compared with castration (58%). Analysis of a validated quality-of-life questionnaire proved an advantage for ‘Casodex’ in sexual interest and physical capacity. ‘Casodex’ had a substantially lower incidence of hot flushes compared to castration (6–13% compared with 39–44%) and the most commonly reported adverse events were those expected for a potent antiandrogen. However, in patients with M₀ disease at entry, the data are still immature with only 13% of M₀ patients having died. An initial analysis of this immature data has suggested that the results in these patients may be different to those obtained in patients with M1 disease. A further survival analysis in patients with M₀ disease is therefore planned when the data are more mature. Conclusions: ‘Casodex’ 150 mg is less effective than castration in patients with M1 disease. However, ‘Casodex’ has shown a benefit in terms of quality of life and subjective response when compared to castration and has an acceptable tolerability profile. Thus ‘Casodex’ 150 mg monotherapy is an option for patients with M1 prostate cancer for whom surgical or medical castration is not indicated or is not acceptable.

The changing pattern of mortality and morbidity from radical cystectomy

Objectives To examine the morbidity and mortality of radical cystectomy as currently practised, and to compare the findings with historical data.

The progression of benign prostatic hyperplasia: examining the evidence and determining the risk.

Background: Benign prostatic hyperplasia (BPH) is often associated with enlargement of the prostate gland, lower urinary tract symptoms, decreased urinary flow and a reduced quality of life. Furthermore, if the symptoms associated with BPH are left untreated, serious complications, such as acute urinary retention, may ensue. Evidence is emerging from long–term clinical studies to suggest that BPH is a progressive disease, with some patients progressing much more rapidly than others. Objective: This article aims to explore the natural history of BPH progression from a molecular, pathological and clinical perspective, with emphasis on the key clinical evidence to support the progressive nature of this disease. How our increased understanding of the disease and of the risk factors for BPH progression might be applied to improve current management practices are also discussed. Conclusion: Strategies to identify patients most at risk and guidelines directed towards long–term management, in addition to short–term treatment, may be useful in helping to prevent BPH progression.

The role of antiandrogen monotherapy in the treatment of prostate cancer

The mainstay of hormonal therapy in prostate cancer has been medical or surgical castration, both of which are associated with loss of libido and impotence, and may not always be acceptable to the patient. Antiandrogen monotherapy is an alternative treatment option to castration. There are two types of antiandrogen, i.e. steroidal (cyproterone acetate, CPA), and nonsteroidal (bicalutamide, flutamide and nilutamide). Data comparing survival outcome with CPA and castration are limited and conflicting. Furthermore, CPA is associated with loss of libido and erectile dysfunction. Large phase III trials have established that monotherapy with bicalutamide 150u2003mg once daily provides a survival outcome that is not significantly different to that after castration in men with locally advanced, non‐metastatic disease, while conferring significant advantages for sexual interest and physical capacity. Current data are inadequate to draw conclusions on the comparative efficacy of flutamide and castration, while nilutamide is not licensed for monotherapy. Recent data reveal that bicalutamide 150u2003mg given once daily in addition to standard care (radical prostatectomy, radiotherapy or ‘watchful waiting’) significantly delays the progression of early (localized or locally advanced) prostate cancer. Bicalutamide has a more favourable side‐effect profile than the other antiandrogens and is more likely to promote compliance.

Early Prostate Cancer: Prevention, Treatment Modalities, and Quality of Life Issues

Our understanding of the screening, prevention and treatment of early prostate cancer is improving. This is a result of new data from clinical trials and the incorporation of efficacy measures based on risk assessment and quality of life (QoL). This review aims to examine completed and ongoing clinical trials that address issues in early prostate cancer, including screening, prevention, treatment, and QoL. Prostate-specific antigen (PSA) testing has a crucial and evolving role in detecting primary prostate cancer, evaluating prevention interventions and assessing the effectiveness of treatment. Questions remain about the optimal PSA parameters appropriate for primary screening and for diagnosing relapse. Emerging and established data provide evidence that early intervention with hormone therapy, either as immediate or adjuvant therapy, delays progression in prostate cancer patients with intermediate or poor prognosis. The impact of therapeutic modality on QoL has become better characterized, as QoL instruments have been developed, validated and applied.

A prospective, randomized, double-blind trial to evaluate the role of a short reducing course of oral corticosteroid therapy in the treatment of chronic prostatitis/chronic pelvic pain syndrome.

To assess the validity of our observational experience that a short course of oral prednisolone therapy might be of value in the management of symptoms of chronic pelvic pain syndrome (CPPS) in men.

Quality of Life Aspects of Treatment Options for Localized and Locally Advanced Prostate Cancer

Quality of life considerations are becoming increasingly important in prostate cancer management, particularly with the trend for patients to be diagnosed at an earlier age and at an earlier stage of disease. A rising serum prostate-specific antigen (PSA) level in the absence of symptoms can cause anxiety to many patients. Patients in this situation must weigh the benefits of treatment, such as delay in time to progression and increased time without pain, against the onset of adverse events that may affect quality of life. Traditionally, the active treatment options for locally advanced disease, following either new diagnosis or failure of treatment of primary curative intent, are radiotherapy and castration (medical or surgical). Radiotherapy may affect sexuality and bowel functioning, and castration is particularly associated with loss of libido and sexual dysfunction. Studies have shown that treatment-associated side effects extending over many years are of great concern to many patients. Therefore, for treatments with similar outcomes in terms of survival or time to progression, there is good reason to consider introducing new measures of efficacy based on quality of life endpoints. Data from two large studies of bicalutamide (‘Casodex’) therapy in patients with locally advanced prostate cancer show that this non-steroidal antiandrogen is not only associated with comparable survival outcomes but significant health-related quality of life benefits, compared with castration. In addition, a large early prostate cancer trial has demonstrated that bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localized or locally advanced prostate cancer. Moreover, bicalutamide treatment was associated with fewer adverse events relating to sexual function. The risk of treatment-related side effects or influence on the total quality of life must be considered carefully for each individual patient in order to assess the most appropriate treatment option.

Early versus Deferred Hormone Therapy

Although hormone therapy is widely used in the management of prostate cancer, the optimal timing of its initiation remains a matter of debate. Immediate hormone treatment has been compared with deferred treatment in randomized studies conducted by the Veterans Administration Cooperative Urological Research Group, the South Sweden Prostate Cancer Study Group and the Medical Research Council. Despite criticism of the design of these studies, the results indicate that early treatment may be associated with advantages in time to progression and survival. It is anticipated that ongoing studies, such as the European Organization for Research and Treatment of Cancer protocols 30846 and 30891, will provide further information on the optimal timing of endocrine treatment. Prognostic and quality of life factors also have an impact on the treatment decision. On the basis of available evidence, early hormone therapy is recommended for younger men with poorly differentiated tumours or advanced disease and for those who are seen infrequently by their physician. Deferred treatment using a strategy of watchful waiting is probably the best option for older men with well differentiated, low volume prostate cancer.

PHARMACODYNAMICS OF A LONG ACTING DEPOT PREPARATION OF AVORELIN IN PATIENTS WITH PROSTATE CANCER

PURPOSEnWe evaluate the pharmacodynamics, pharmacokinetics and tolerability of a sustained release depot formulation of avorelin, a new potent super agonist of luteinizing hormone-releasing hormone receptors, in patients with prostate cancer.nnnMATERIALS AND METHODSnA total of 60 patients were randomized to receive a 10 mg. (31) or 15 mg. (29) avorelin subcutaneous depot. Serum testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and plasma avorelin were measured regularly until depot exhaustion.nnnRESULTSnOf the 10 mg. group patients 3 withdrew from the study after 31 to 35 weeks due to disease progression. Of the 15 mg. group patients 1 did not complete the study for logistical reasons. After the expected flare in serum testosterone, LH and FSH during week 1, medical castration (testosterone concentration less than 1.735 nmol./l.) was achieved within 4 weeks of depot injection. Median duration of testosterone suppression was 40 weeks in the 10 mg. (95% confidence interval 35 to 42) and 39 in the 15 mg. (37 to 43) group. The reduction in serum LH was similar to that of testosterone, while that of FSH was less pronounced. Plasma avorelin was proportional to the dose and correlated with serum testosterone. Normalization of serum prostate specific (4 ng./ml. or less) at 6 months was achieved in 80 and 88% of the 10 and 15 mg. groups, respectively. During the (7 to 20-month) observation period 94 and 86% of the 10 and 15 mg. groups, respectively, complained of adverse events mainly related to androgen suppression (hot flushes, decreased libido and impotence) or the nature of the disease (skeletal pain). In each group 3 patients had serious adverse events requiring hospitalization for reasons unrelated to avorelin treatment. The depot was well tolerated locally.nnnCONCLUSIONSnSubcutaneous depot formulations of avorelin were well tolerated and had protracted inhibitory effects on pituitary gonadotropin secretion in patients with prostate cancer. Testosterone suppression was maintained for more than 6 months in all patients. Avorelin depots could be the first luteinizing hormone-releasing hormone agonist formulation to be administered at 6-month intervals.

Screening for Prostate Cancer

In 2010, 217,730 men will have been diagnosed with prostate cancer (PCa) in the United States of America (USA), and around 32,730 will have died from the disease [1]. Depending on the extent of prostate-specific antigen (PSA) testing, similar ratios of incidence and mortality will be seen throughout Europe; PCa is the second commonest cause of death from cancer in men in the UK, and in the USA, it is estimated that a man aged 40 years has a 16 % chance of being diagnosed and a 3 % lifetime chance of dying from PCa [2]. Once diagnosed, the chance of a man dying from his cancer rather than other causes depends not only on the biological aggressiveness of the tumor and the age and comorbidity of the individual in question but crucially on the stage of the disease at diagnosis and, by definition, how early it has been detected. Screening for disease to allow early detection is now an integral part of modern medicine, and screening for breast, cervical, and colorectal cancer is now standard practice in some countries. Although PCa is an equally important health problem, PSA testing to screen for the disease, allowing earlier detection and thereby reducing the chance of a man dying from PCa, remains controversial with the medical community divided on whether this approach causes more harm than good.