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Tillyashaykhov Mirza, Yusupov Sherali, Temirov Orif, Khojitoev Sanjar, Tursunova Matluba, Republican Cancer Research Center, Tashkent E-mail: sanjarkh@gmail.com
INTERMITTING HORMONAL THERAPY IN PATIENTS WITH COMMON PROSTATE CANCER
Abstract: Intermittent androgen deprivation can lead to a prolonged decrease in serum testosterone, but the choice of regimens and tactics for this therapy for prostate cancer (PCA) remains relevant for oncologists. The purpose of this study was to improve the treatment outcomes and the quality of life of patients with advanced PCA by choosing the optimal regimen of hormone therapy depending on the prognostic factors. The study included 186 patients with advanced prostate cancer (PCA) treated at the City Cancer Dispensary in Tashkent. It was found that the advanced age of patients with PCa (75.46 ± 0.66 years), the prevalence of the tumor process of stages T2-3, the presence of bone metastases, retroperitoneal and iliac lymph nodes are not limiting factors in the appointment of hormone therapy. In the process of treatment of advanced prostate cancer with criteria for the appointment and withdrawal of hormonal drugs, we determined the dynamics of clinical symptoms of cancer, the level of PSA and testosterone, the severity of complications of hormone therapy from the cardiovascular system and liver.
Resistance of malignant neoplasms of the prostate to hormone therapy remains the main problem when choosing a therapy in such patients. We determined the optimal regimen of hormone therapy, which led to better treatment outcomes and quality of life for patients with advanced PCA.
Keywords: prostate cancer, hormonal therapy, limiting factors, luteinizing releasing hormone agonists.
Introduction. Neoadjuvant therapy for prostate can- results are similar to those obtained in patients with met-cer (PKD) is used to reduce the frequency of the positive astatic prostate cancer [4].
surgical edge and possibly improve the results of radi- Recently, studies have focused on the study of in-
cal prostatectomy. A number of randomized trials have termittent hormonal blockade in order to assess the demonstrated that neoadjuvant therapy reduces the decrease in side effects following androgen deprivation, frequency of the positive surgical margin for a clinically improvement in the quality of life in a common process, localized stage; data for a locally advanced disease are and delay in the development of hormonal refractoriness less convincing [1; 2; 3]. [5]. These studies are based on the assumption that in-
The goal of adjuvant therapy is to act on residual termittent androgen deprivation can lead to a prolonged microscopic cancer foci after local primary treatment. decrease in serum testosterone levels. Patients who received therapy immediately after surgery The purpose of this study was to improve the treat-
showed a significant advantage in all cases and a better ment outcomes and the quality of life of patients with cancer-specific survival rate compared with those who advanced PCa by choosing the optimal regimen of hor-received delayed treatment (62 vs 71%,p <0.001). These mone therapy depending on the prognostic factors.
Material and methods. The study included 186 patients with advanced prostate adenocarcinoma treated at the City Oncology Dispensary in Tashkent. The mean age of patients was 75.46 ± 0.66 years. In 59 patients (31.7 ± 3.41%) the extent of the tumor process was T2NxMx, in 102 (54.8 ± 3.64%) - T3NxMx, in 25 (13.4 ± 2.50) - T3NxMx. In 37 patients (19.9 ± 2.92%) metastases were found in the bones of the skeleton, ret-
roperitoneal and iliac lymph nodes.
All patients received treatment in the mode of intermittent therapy with the agonist LHRH-goserelin acetate 3,6 mg as a depot injection once a month, and with the injection form of anti-androgen cyproterone acetate 300 mg twice a month in combination with bisphos-phonates. Patients who received drugs from the group
of bisphosphonates - zoledronic acid, daily received 500 mg of calcium as a food supplement and vitamin D in tableted form (500 I.U). Admission of these drugs reduced the compensatory increase in the level of parathyroid hormone (PGH) in the serum, which occurs in response to transient hypocalcemia caused by the introduction of a bisphosphonate. The duration of treatment was 12 months. Objective evaluation was performed before the start of treatment and after 6 months. In the evaluation, data from digital rectal examination, PSA level, morphological examination, ultrasound, computed tomography, skeletal scintigraphy, and necessary radiographic and radiological studies were taken into account.
Results and discussion. In Fig. 1 shows the results of the determination of PSA before and after treatment.
Figure 1. Results of the definition of PSA before and after treatment in patients with PCA
As seen from the results of the PSA determination, before the treatment, the marker level in patients with PCA significantly exceeded the concentration of this protein in the norm (<4.0 ng/ml). Conducting therapy for 1 month allowed to reduce this figure to 12.41 ± 1.94 ng/ml. When planning intermittent therapy, we weekly monitored the level of PSA: if it was more than 20 ng/ml and as a result of treatment it decreased to less than 4 ng/ml, a new cycle of hormone therapy was pre-
scribed until the PSA concentration was 10-20 ng/ml, while "biochemical relapse", possible after the 1 stage of treatment, was taken into account.
Six months after the start of treatment, in patients with PCA, the PSA level in the blood averaged 3.81 ± 0.30 ng/ml, which corresponds to the norm for a healthy person. The maximum testosterone concentration was 30 ng/dL, i. e. was less than the castration level of the hormone (50 ng/dL).
In the process of hormone therapy of advanced prostate cancer, the following criteria for the appointment and withdrawal of hormonal drugs were used: the dynamics of clinical symptoms of cancer, the level of PSA and testosterone, the severity of complications of hormone therapy from the cardiovascular system and the liver. At the same time, the important advantage of the chosen treatment tactics was noted: improving the quality of life of patients with PCa by reducing the side effects of hormone therapy.
At the first admission of prescribed drugs, agonists LHRH caused a temporary release of the pituitary latinizing hormone. This was accompanied by an increase in plasma levels of testosterone to concentrations far exceeding the values prior to treatment (flash phenomenon). A similar effect of hormone therapy for PCA was previously noted by researchers for locally advanced PCA [6]. In the case of treatment of advanced prostate cancer, we encountered a significant increase in testosterone
concentrations and conducted a short-term parallel assignment of antiandrogens. On average, after 3-4 weeks, the pituitary LHRH receptors became insensitive, which led to a decrease in serum testosterone concentrations to the castration level of 50 ng/dl. In this regulation, two factors play a key role: (1) constant, and not as in the natural conditions, cyclic, the intake of the LHRH agonist; and (2) hyperstimulation of the receptors with the development of insensitivity due to the stable maintenance of the LHRH agonist concentration in the blood> 100 pg/ml [7].
In (Fig. 2) presents the results of determining the tumor size before and after treatment in patients with advanced PCA. The dynamics of a decrease in tumor volume after hormone therapy shows good results of treatment. One month after the administration of drugs, the tumor volume in patients with prostate cancer decreased by an average of 17.9%. In the next 6 months, the chosen tactics of treating patients allowed.
Figure 2. The results of determining the tumor volume (cm3) before and after treatment in patients with PCA. inhibit the tumor process — the antitumor effect was 67.7%
We attribute these results to a decrease in the syn- to other organs, including the prostate gland. In prosthesis of growth factors due to inhibition of testosterone tate cells, testosterone is converted by 5b-reductase to production. It is known that testosterone produced by dihydrotestosterone (DHT). DHT has a higher affinity Leydig cells circulates through the systemic circulation for the intracellular androgen receptor than testosterone.
After the binding of DHT to the androgen receptor of the cell nucleus, a complex is formed, which eventually leads to protein synthesis of the specific antigen of the prostate (PSA) and growth factors [8].
Thus, the choice of optimal therapy for suppressing the synthesis of testosterone leads to an effective suppression of the production of prostate-specific growth-inducing factors, which demonstrates the results of a decrease in tumor volume in patients with PCA.
The conclusion. The resistance of malignant neoplasms of the prostate to hormone therapy remains the main problem in the choice of therapy in patients with advanced PCA. We determined the ways of choosing the optimal regimen of hormone therapy depending on the prognostic factors, which led to better treatment outcomes and quality of life for patients with advanced PCA. Standard primary treatment of a common disease is based on a decrease in the level of circulating androgens and inhibition of their effect on the tumor. In
patients with advanced prostate cancer, LHRH analogs can be used in monotherapy or in combination with antiandrogens. The use of first-line drugs allows assessing the hormone sensitivity of the tumor. Positive clinical and biochemical (reduction in PSA) dynamics after 3 months of treatment with LHRH analogues confirms the hormonal sensitivity of the tumor. The advanced age of patients with PCA (75.46 ± 0.66 years), the prevalence of the tumor process of stages T2-3, the presence of bone metastases, retroperitoneal and iliac lymph nodes is not a limiting factor in the appointment of the hormone therapy that we have chosen.
In the process of hormone therapy of advanced prostate cancer, the authors defined the following criteria for the appointment and withdrawal of hormonal drugs: the dynamics of clinical symptoms of cancer, the level of PSA and testosterone, the severity of complications of hormone therapy from the cardiovascular system and liver.
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