Casodex in the treatment of prostate cancer

Casodex in the treatment of prostate cancer

Casodex is effective for prostate tumors

Average life expectancy, especially in developed countries, is steadily increasing, and this is good news. Quiet, calm old age in the family circle, communication with grandchildren and great-grandchildren is, of course, good. But, as usual, there is a fly in the ointment in this barrel of honey.

Treat not only with hormonesThe increase in life expectancy (and, as a result, the aging of the population) also has its drawbacks: the prevalence of diseases that affect people precisely in old age is increasing. For example, in many countries in recent years, very often in older men diagnosed with such a serious disease as Prostate cancer. Most often this disease affects men after 65 years (more than 80% of all cases). This disease in the early stages does not have pronounced symptoms, so very often patients seek medical help when the malignant process has gone too far. Most of these patients have metastases. In such cases, the only effective method of treatment is the use of hormonal agents. But, unfortunately, after one and a half to two years, such therapy becomes ineffective, because the tumor cells become, as doctors say, hormone-resistant - that is, insensitive to hormonal drugs.

Casodex is effective and safeTherefore, modern medicine is actively searching for drugs that can achieve good results when exposed to hormone-resistant prostate tumors. One of these substances is, in particular, bicalutamide, which is part of the Casodex preparation. Bicalutamide belongs to the group of non-steroidal (that is, non-hormonal) antiandrogens - substances that suppress the activity of only male sex hormones, while they do not affect other hormones. The result of suppressing androgen activity is regression (reverse development) of the prostate tumor. Studies have shown that Casodex is effective and is safe when used as monotherapy, that is, treatment with only one drug.

It is produced in the form of tablets, each of them contains an active substance (bicalutamide). A positive feature of this drug is that it has a relatively low toxicity. This was noted even when Casodex was used in high doses for treatment. When taking this drug, there are also side effects, but they most often decrease or completely disappear as treatment continues. Many patients who were previously treated with drugs belonging to the antiandrogen group, not carried out, as a result of the use of Casodex, they feel an improvement in their condition. Activity (both physical and sexual) increases significantly. At the same time, in most patients, the tumor stabilized, and in some it even decreased in size.

ONCOLOGICAL UROLOGY

MONOTHERAPY WITH CASODEX

MONOTHERAPY WITH CASODEX AT A DOSAGE OF 150 MG A NEW METHOD OF HORMONAL TREATMENT OF ADVANCED PROSTATE CANCER

I.G. Rusakov, B.Ya. Alekseev Moscow Research Institute of Oncology named after P. A. Herzen (Director Academician of the Russian Academy of Medical Sciences, Professor V. I. Chissov) prostate cancer (PCa) is currently one of the most common forms of malignant neoplasms in men. per 100 thousand of the male population, and in the structure of the entire cancer incidence, prostate tumors occupy the 3rd place (5.4% of all malignant neoplasms). In terms of the rate of increase in the incidence of PROSTATE CANCER, it is ahead of tumors of other localizations; in 1991-2000, the increase was 64.37% (1). Despite the widespread use in clinical practice of the test to determine the level of prostate specific antigen (PSA) in blood serum, most patients with Prostate Cancer are diagnosed at the stage of locally advanced (39%) and generalized (23.2%) of the tumor process, when radical treatment is already impossible (2). The main method of treatment of patients with prostate tumors at the stages of locally advanced and metastatic process is hormonal therapy aimed at suppressing androgen stimulation of tumor cells sensitive to them. Endocrine effects in prostate cancer consist in the suppression of androgen production (androgen deprivation) or blocking the action of androgens at the level of prostate tumor cells by competitive inhibition with androgen receptors. Surgical or medical (LHRH agonists) castration causes deprivation of testicular androgens and, alone or in combination with antiandrogens (combined or maximal androgen blockade), is currently the standard treatment for disseminated PCa.Given that hormonal therapy for common forms of prostate cancer is palliative in nature, improving the quality of life of patients should be considered along with increasing life expectancy as the most important goal of the treatment. However, a decrease in testosterone to post-castration values leads to the development of a number of pronounced side effects that significantly worsen the quality of life of patients: impotence, decreased libido, osteopeorosis, muscle atrophy, and dyslipidemia. Decreased sexual and physical activity in patients undergoing androgen deprivation is an important negative aspect of treatment, especially given the increasing number of younger patients (3). A number of studies based on interviews with patients have shown that a significant proportion of patients are ready to prefer the preservation of libido and Erectile function, even at the cost of reducing life expectancy. A study published by the University of Chicago Center for Clinical Medical Ethics showed that of 50 patients with PCa (age 45-79 years, mean 58 years), 68% forfeited a 10% advantage in 5-year survival in favor of maintaining sexual activity (4). In another study of 230 PCa patients surveyed (mean age 65 years), 67% preferred to maintain potency by reducing life expectancy by 14% (5).

An alternative to castration or combined androgen blockade is monotherapy with non-steroidal antiandrogens. This method of hormone therapy allows blocking the action of testosterone and adrenal androgens at the level of androgen receptors inside tumor cells. At the same time, the concentration of testosterone in plasma does not fall, but even slightly increases compared to the initial level. In this regard, monotherapy with non-steroidal antiandrogens allows maintaining sexual function in the majority of patients with prostate cancer who have potency and libido before the start of treatment. Other advantages of using antiandrogens are the ease of use of drugs, the psychological acceptability of this type of treatment for patients, the reversibility of the therapeutic effect and adverse reactions of the therapy. But when conducting monotherapy with antiandrogens, the question always arises about the comparability of the effectiveness of this type of treatment with standard options for endocrine effects of castration and combined androgen blockade. Bicalutamide (casodex) has the highest efficacy among antiandrogens in monotherapy. The aim of our study was to study the impact on the quality of life of patients with advanced PCa monotherapy with casodex at a dose of 150 mg in comparison with traditional methods of treatment of surgical and medical castration.

Materials and methods.

The study included 38 patients with metastatic prostate cancer. Group 1 included 18 patients who received Casodex monotherapy at a dose of 150 mg, group 2 consisted of patients who underwent bilateral orchidectomy or were treated with LHRH agonists.

The age of patients in group 1 was 51-68 years (mean age 58.7 years). For the first time detected prostate cancer was observed in this group in 14 patients, 2 patients had previously received therapy with LHRH agonists, 2 combined androgen blockade. The interval between the end of treatment with LHRH agonists and the start of Casodex monotherapy was at least 3 months. In 15 patients of group 1, only bone metastases were diagnosed, in 3 patients metastases were in the bones and lymph nodes. The PSA level before the start of Casodex treatment was 23.8-287 ng/ml (mean level 96.4 ng/ml). The overall status of patients according to the WHO scale was: 0 points in 9 patients, 1 point in 7 patients and 2 points in 2 patients. Erectile function before the start of treatment was preserved in all patients of group 1: in 11 patients, potency remained at the same level that was observed before the development of the disease, 7 people noted a decrease in potency. The usual level of sexual desire was described by 13 patients, in 5 patients there was a decrease in libido. After informing about the nature of the treatment and consenting to it, each patient in group 1 received Casodex at a dose of 150 mg (3 tablets of 50 mg at a time) for at least 3 months.

The 2nd (control group) included 20 people aged 54-72 years (mean age 61.2 years). The primary identified tumor process was observed in 18 patients, 2 patients received a history of hormone therapy according to the combined androgen blockade scheme. Bone metastases were diagnosed in 16 patients of group 2, 3 patients had bone and lymph node metastases, and 1 patient had bone and visceral (liver) metastases. The PSA level in this group of patients was 18.2-542.8 ng/ml (mean level 117.3 ng/ml). The status of patients according to the WHO scale was: 0 points for 10 patients, 1 point for 7 patients, 2 points for 3 patients. Preservation of potency at the initial level was noted by 10 patients, 10 patients described a decrease in potency after the development of the disease. Sexual interest at a normal level was noted in 11 patients, decreased libido in 9 patients.

Three months after the start of treatment, all patients underwent a follow-up examination, including a general physical examination, determination of PSA and testosterone levels in the blood serum. In addition, before the start of the study and during treatment, patients were surveyed every 4 weeks using the standard EORTC QLQ-C30 questionnaire and questionnaires, including an assessment of sexual function and side effects of the therapy. Based on the sum of the scores indicated in the questionnaires by the patients, the average score for each parameter for assessing the quality of life and the overall average score were determined.

When analyzing the results of treatment of patients of group 1, a significant decrease in PSA levels was noted in 16 (88.9%) patients, in 2 patients (11.1%), the PSA level decreased by less than 20% of the initial values. The PSA concentration after 3 months of therapy with Casodex at a dose of 150 mg was 1.1-86.7 ng/ml (mean level 13.7 ng/ml). Serum testosterone levels increased in 14 (77.8%) patients, a slight decrease in the hormone was observed in 2 (11.1%) patients, and in 2 (11.1%) patients, the testosterone concentration reached values below the physiological norm (both patients had a history of treated with LHRH agonists). The testosterone level after treatment was 4.7-25.1 ng/ml (mean level 19.7 ng/ml).

In the group of patients who underwent surgical or medical castration, a decrease in PSA levels 3 months after the start of treatment was noted in 18 (90%) patients. In 1 (5%) patient, the PSA level did not change, and in 1 (5%) patient, an increase in PSA concentration was noted. The PSA level after treatment in patients of group 2 was 0.7-75.3 ng/ml (mean level 9.6 ng/ml). The testosterone concentration after surgical or medical castration was 0.0-2.7 nmol/l, the average concentration was 1.3 nmol/l.

The results of changes in the average concentration of PSA and testosterone as a result of treatment in both groups are presented in Table 1.

When analyzing the sexual activity of patients of group 1, potency was preserved in 15 (83.3%) patients and libido was preserved in 16 (88.9%) patients. In the group of patients who underwent castration, preservation of erectile function was noted only in 2 (10%) patients, and sexual interest was preserved in 7 (35%) patients. In the analysis of surveys of patients of group 1 in 17 (94.4%) patients after 3 months of therapy with Casodex, physical and social activity remained at the same level that was noted before the start of treatment. In the second group, only 15 (75%) patients noted the preservation of physical activity at the same level, and 14 (70%) patients noted social activity. Changes in quality of life parameters during treatment in both groups are presented in Table. 2 and on 1 and 2.

The incidence and structure of side effects that developed in both study groups are presented in Table 3.

It is now generally accepted that non-steroidal antiandrogens are the method of hormonal therapy for prostate cancer, which allows to maintain sexual activity to the greatest extent and ensure the highest quality of life. Of the drugs in this class, only bicalutamide in large randomized trials showed efficacy equal to standard methods when used as monotherapy. Initial studies investigated the possibility of monotherapy with bicalutamide at a dose of 50 mg (the dosage that would be used when using the regimen of combined androgen blockade). In the work of Chodak G. W. et al. Casodex therapy at a dose of 50 mg (243 patients) is compared with surgical or medical (Zoladex) castration (243 patients). The average duration of therapy was about 10 months, with the progression of the process observed in 53% of patients in the Casodex monotherapy group and in 42% in the castration group. When analyzing survival, it was found that 61% of patients (casodex 50 mg) and 65% (castration) remained alive 1 year after the start of treatment. After 86 weeks of follow-up, the median survival was similar in both groups. The authors note a higher quality of life in patients treated with Casodex (6). A review of 3 randomized trials including 1196 patients with metastatic PCa also compared the efficacy of bicalutamide 50 mg and castration. The average life expectancy of patients who underwent castration was 3 months higher than the survival rate of patients who received Casodex, and the quality of life of patients in the bicalutamide group was higher (7).

Due to the fact that at a dose of 50 mg, bicalutamide is somewhat inferior to castration in terms of effectiveness, but surpasses it in terms of quality of life, further studies were associated with dose escalation. Currently, the higher dose of 150 mg is considered the most acceptable for use as monotherapy (8). In a randomized trial of Boccardo F., including 220 patients with advanced prostate cancer, the effectiveness of casodex monotherapy at a dose of 150 mg was compared with the effectiveness of treatment according to the combined androgen dlocade scheme (zoladex and flucin). The median follow-up was 38 months, during which time there was no statistically significant difference in disease-free and overall survival between groups (9). In a study by French authors (270 patients with prostate cancer), the use of bicalutamide 150 mg in mono mode also showed the same efficacy with maximum androgen blockade (surgical or medical castration and nilutamide) in terms of such indicators as an objective response to treatment for 6 months, the duration of the period before progression and overall survival (10). When analyzing the quality of life and sexual interest of patients in these two studies, the benefit of Casodex treatment was revealed, and the authors conclude that Casodex monotherapy at a dose of 150 mg may be an alternative to combined androgen blockade for patients who wish to maintain sexual activity (9, 10).< /p>

The most representative and well-documented study on the efficacy and effect on sexual activity of patients with prostate cancer of casodex monotherapy at a dose of 150 mg was conducted by Iversen P. et al (11). The study included 1453 patients, of which 480 were diagnosed with locally advanced (T3/T4) tumor process, the remaining patients had metastatic prostate cancer. Patients were randomized into 2 groups: in group 1, patients received monotherapy with Casodex 150 mg, in group 2, bilateral orchidectomy or treatment with Zoladex was performed. The follow-up period for patients with non-metastatic prostate cancer was 6.3 years. During this period, 56% of patients died. The mean survival of patients in the Casodex 150 mg monotherapy group and in the castration group was the same. Also, there were no statistically significant differences in time to progression in both study groups. When analyzing the quality of life of patients, the advantage of Casodex monotherapy in relation to sexual interest and physical activity of patients was noted. 12 months after the start of treatment, a decrease in sexual activity compared with the baseline was noted by 47% of patients in the group of surgical and medical castration and only 23% of patients who received Casodex 150 mg. When analyzing the side effects of treatment, a significant predominance of hot flashes was revealed in patients in the castration group (50.0%) compared with patients who received Casodex (13.1%). Gynecomastia and breast tenderness were more frequently observed in the Casodex 150 mg monotherapy group (49.4% and 40.1%, respectively) compared with standard therapy (4.4% and 1.9%). In the subgroup of patients with metastatic prostate cancer, the life expectancy of patients who underwent castration was higher than in patients who received casodex 150 mg, but the survival advantage was 6 weeks. In addition, when analyzing the results of treatment of patients with generalized PCa with a favorable prognosis, there were no significant differences in the survival of patients in both groups.

Casodex monotherapy at a dose of 150 mg is an effective treatment for patients with advanced PCa, which allows patients to provide patients with a higher quality of life than surgical or medical castration. At the same time, the overall and specific survival of patients, the duration of remission during therapy with Casodex 150 mg do not differ from those during castration or combined androgen blockade. Hormone therapy with casodex 150 mg provides a pronounced decrease in PSA levels and an increase in the concentration of testosterone in the serum of patients. The quality of life advantage of patients receiving casodex at a dose of 150 mg is provided mainly due to higher sexual and physical activity.

V. I. Chissov, V. V. 12-23. V. I. Chissov, V. V. p. 28. Kirby R. Treatment options for early prostate cancer. Urology 1998 Dec;52(6):948-62. Singer PA, Tasch ES, Stocking C. Sex or survival: trade-offs between quality and quantity of life J Clin Oncol 1991 Feb;9(2): 328-34. Mazur DJ, Hickman DH. Patient preferences: survival vs quality-of-life considerations J Gen Intern Med 1993 Jul;8(7): 374-7 Chodak GW, Sharifi R, Rfsimis B et al. Single-agent therapy with bicalutamide a comparison with medical or surgical castration in the treatment of advanced prostate carcinoma. Urology 1995; 46 (6); pp: 849-855. Bales GT, Chodak GW. A controlled trial of bicalutamide versus castration in patients with advanced prostate cfnctr. Urology 1996; 47(1A) Suppl. pp. 38-43. Kolvenbag GJ, Nash A. Bicalutamide dosages used in the treatment of prostate cancer. Prostate 39; 47, 1999. Boccardo F., Rubagotti A., Barichello M. et al. Bicalutamide monotherapy versus flutamide plus gosereline in prostate cancer patients: results of an Italian Prostate Cancer Project study. J Clin Oncol? 17:2027, 1999. Chatelain C., Fourcade R. O., Delshambre J.Bicalutamide (Casodex) versus combined androgen blocade (CAB): open French multicentre study in patients with metastatic prostate cancer. Br J Urol, suppl., 80: 283, abstract 1111, 1997. Tyrrell CJ., Kaisary AV., Iversen P et al. A randomized comparison of Casodex (Bicalutamide) 150 mg monotherapy versus castration in thr treatment of metastatic and locally advanced prostate cancer/ Eur Urol 1998; 33 (5): 447-456.

Casodex in the treatment of prostate cancer

Multicenter clinical studies have been conducted on the effectiveness of the use of the releasing hormone Zoladex and the antiandrogenic nonsteroidal agent Casodex in the treatment of prostate cancer in patients with various stages of the disease. A comparative analysis of the results of using various methods of hormone therapy was also carried out.

Prostate cancer is a hormone-dependent tumor that grows in size rather slowly, not relentlessly. In terms of the number of deaths from cancer in men, it ranks second after lung carcinoma. The dependence of the androgenic nature of prostate cancer was established back in the middle of the last century, when Professor Huggins put forward a theory, later confirmed by practical research, about the androgenic effect on the tumor, which can reduce symptoms in 80% of cases of diagnosed prostate cancer. Over the past decades, there have been no significant changes in the treatment of prostate cancer, only drugs have become less toxic thanks to modern technologies.

Methods of hormone therapy for prostate cancer The main methods of hormone therapy for prostate cancer are aimed at lowering the level of testosterone, as the most active androgen. Testosterone is lowered by methods of inhibiting its production in the adrenal cortex and testicles.

Classic Methods Hormone therapy, which is the classic conventional treatment option, is a bilateral orchiectomy or the use of estrogenic drugs. An orchiectomy is an operation to remove the testicles. This surgical intervention is aimed at reducing the level of testosterone, since most of it is produced by Leydig cells. But this method is not effective in relation to the adrenal cortex, which, as you know, is also an apparatus for the synthesis of the hormone testosterone. Estrogen therapy is aimed at suppressing the synthesis of androgen production by slowing down the production of gonadotropins, but does not affect the production of adrenal androgens. In addition, estrogen-type drugs increase the concentration of prolactin in the blood, which, in turn, activates the transition of androgens to prostate tumor cells. In addition, estrogen therapy has serious risks of causing side effects such as cardiovascular and thromboembolic complications. That is why a number of leading experts have put forward completely new, alternative methods of treating prostate cancer.

Alternative methods According to the presented modern data, based on numerous laboratory studies, a direct dependence of cell division of normal and tumor tissues of the prostate gland on the complex effect of androgens produced by the testicles and adrenal cortex was revealed. The biosynthesis of these androgens is stimulated by a pituitary hormone called LHRH (Luteinizing Hormone-Releasing Hormone). As a result, there is a significant decrease in testosterone in the blood plasma to a level corresponding to the post-castration state.

Zoladex The most used medication in this group of hormonal drugs is Zoladex, produced by the well-known pharmaceutical company Astra-Zeneca, UK. The drug is a complete analogue of LHRH synthetic production. To date, Zoladex is recognized as one of the most effective hormonal drugs for the treatment of prostate cancer. The drug is well tolerated and has no contraindications, with the exception of individual hypersensitivity. It is used in the form of a depot (long-acting), injection form for injection under the skin at a therapeutic dose of 3.6 mg every 4 weeks or 10.8 mg every 12 weeks. Conducted multilevel studies have shown the high efficiency of the hormonal preparation. A group of 292 men diagnosed with hormone-dependent advanced prostate cancer was divided into two subgroups. One (subgroup A) received a therapeutic dose of Zoladex, the second (subgroup B) underwent an orchiectomy. The indications were approximately the same, in both subgroups the median survival was two years, and the percentage of the onset of regression of the primary tumor reached 71-72%.Thus, the survival rate and the presence of subjective effects in both methods of prostate cancer treatment were approximately the same, but the patient's quality of life improved significantly with hormonal therapy. When using Zoladex:

• operational risks are eliminated;
• chemical castration is reversible.

In addition, therapy was compared in two groups of 230 patients with Zoladex (group A) and steroid antiandrogen drugs (group B). Just like in the previous comparison, the results of the studies were about the same. But in terms of the number of side effects, steroids are significantly ahead of hormonal drugs, since Zoladex has practically no serious side effects. But in addition to steroidal antiandrogens, modern medicine uses non-steroidal antiandrogen drugs such as Casodex (bicalutamide) to treat prostate cancer.

Casodex Nonsteroidal antiandrogenic drugs have a number of advantages over their steroidal counterparts. And first of all, this concerns selective binding to androgens in malignant and normal tissues of the prostate gland. While steroid drugs bind to various hormone receptors. The most highly effective non-steroidal drug is Casodex, which belongs to the pharmacological group of antiandrogens, antitumor hormonal agents, and hormone antagonists. The active ingredient of the drug is Bicalutamide, produced at the Astra-Zeneca pharmaceutical factory in the UK. The drug was created as a more assimilable means of tolerance, with fewer contraindications and side effects. The release form of the drug Casodex 50 mg in tablets taken once a day, which greatly facilitates therapy. The drug was specially developed with a long half-life for a single daily use. The composition of the tablet contains the active ingredient Bicalutamide 50 mg and a film coating. The medicine is used without restrictions on diet and age categories, it is not contraindicated in case of renal failure or other violations of their functions. It has low hepatoxicity compared to flutamide due to the simplest metabolism.

The largest practical study was conducted with two groups of volunteers diagnosed with hormone-dependent prostate cancer. In group A, patients received Casodex + Zoladex, in group B, flutamide + Zoladex or another LHRH analogue. Patients in both groups were followed up for 160 weeks. The study showed a greater number of further progression of the disease and mortality (by 13%) in group B, while in group A there was an improvement in the condition in the next 3 months after therapy in 70% of patients (for comparison, after orchiectomy, similar improvements occurred in 3 months in 3 %.

Conclusions The conducted studies give grounds to assert the use of maximum androgen blockade with the use of drugs Casodex + Zoladex as the most effective in the treatment of prostate cancer in the early stages. Also, these medicines are recommended as first-line drugs for the treatment of disseminated and locally advanced PCa.