Role of buserelin in the treatment of common types of prostate cancer

S.V. Mishugin, А.А. Drobyazko, А.А. Mordovin, А.А. Gritskevich, I.G. Rusakov

Since 1941 after the study published by Huggins and Hodges which demonstrated the dependence of prostatic cells on androgens, the main method in the treatment of locally advanced and metastatic prostate cancer has been hormonal therapy [1]. Any strategy of hormonal therapy is based on the principle of androgen blockade which can be achieved by elimination of endogenous testosterone production [2] as well as by termination of androgenic effect due to competitive action of medicinal agents [3].

Currently, the main method of androgen deprivation is medical castration with the use of LHRH agonists [4]. Today, the preference is given to androgenous drug deprivation instead of surgical castration. This is due to psycho-emotional state of patients after surgery and multiple adverse effects with the same clinical effect, which is shown in several studies. It is also possible to use intermittent regimes of hormonal therapy, which leads to regression of adverse reactions against the background of temporary withdrawal of drugs [5, 6].
Buserelin is one of the drugs of this group which are widely used in the clinical practice.

The drug Buserelin is enclosed in microspheres with a different disintegration period. The basis of these microspheres is biosoluble DL-copolymer of lactic and glycolic acids. The microspheres in the form of aqueous suspension are administered by deep intramuscular injections. After injection the gradual release of the LHRH analogue from the surface of microspheres starts, which leads for the first several days to stimulation of the synthesis of gonadotropins, and then to desensitization of the pituitary and the blockade of the pituitary-testicle axis. Then, microspheres undergoing the biodegradation in tissues slowly release the LHRH analogue contained in them, thus, durably maintaining the concentration of the drug in blood necessary for desensitisation of pituitary [7, 8, 9].

From the beginning of December 2011 to December 2014, we observed 142 patients with prostate cancer at the age of 56 to 70 years who received the treatment with LHRH analogues. The average age of patients was 64.6 years.

All the patients before the treatment underwent medical examination which included an interview, physical check-up, detection of PSA serum levels (at least 7-10 days after transrectal / transurethral manipulations). To assess the local prevalence of tumor processes, in all the cases a digital rectal examination was performed. To determine the location, size and extent of spread of primary tumor, all the patients underwent transrectal US of prostate. After receiving measurement data the volume of the prostate was calculated using the software.
In order to identify regional and distant metastases, in all the cases transabdominal ultrasound examination of the abdominal cavity, retroperitoneal space and pelvis, chest X-ray and bone supersonic scanning were performed. To clarify the extent of the spread of primary tumors and the state of pelvic lymph nodes, the patients underwent computer tomography imaging or magnetic resonance imaging of the pelvis. Clinical and laboratory tests were also performed to all the patients (general blood analysis, biochemical blood test, blood coagulability test, common urine analysis and bacteriological urine test (if indicated), electrocardiography). In order to verify the diagnosis, all patients underwent transrectal biopsy of the prostate gland under control of ultrasound examination.

75 patients had locally advanced prostate cancer, 67 patients had generalized cancer (Table 1). The patients were divided into two groups.
In the first group (n = 55), the patients received the therapy with Buserelin-depo, in the second group (n = 87) the patients were administered one of the other LHRH analogues (goserelin, leuprorelin, triptorelin). The period of the drug treatment was at least 6 months.

Table 1. Distribution of the patients according to the stages of the disease

At the time of enrollment in the study 137 men out of 142 had complaints (96.5%). The main symptoms were inappropriate urination (77.6% of the patients in the group receiving Buserelin and 66.7% of the patients in the group treated with the other LHRH analogues), pains of different localization caused by primary tumors (5.5% of observations in the first group and 13.8% in the second group), bone metastases (30.9% of the patients in the first group and 35.6% of the patients in the second group), and disorder of the outflow of urine from the pelvicalyceal system (23.6% of the patients in the first group and 17.2% of the patients from the second group) (Table 2).

Table 2. Complaints of 142 patients with the advanced prostate cance

The objective of the study was to evaluate the efficacy of the drug Buserelin-depo at a dose of 3.75 mg with the frequency of administration of every 28 days through the investigation of the dynamics of testosterone levels, PSA and prostate volume; to find out the effect of the drug on the performance status of the patients and the level of the pain syndrome and to compare with the group of the patients who received the other LHRH analogues, and to monitor adverse effects.

The patients of the second group received one of the LHRH analogues every 28 days. The patients with bone metastases underwent other methods of special treatment in addition to hormonal therapy: palliative external beam therapy to bone metastases and treatment with zoledronic acid.

During histological verification of the diagnosis moderately and poorly differentiated types of prostate cancer predominated (Table 3)

Table 3. Histological types of tumors

Before the start of the treatment the following indices were evaluated in the patients of the both groups: the levels of PSA and testosterone, Karnofsky performance status, pain status according to the WHO scale and prostate volume measured by means of transrectal US.
Subsequently, every 4 weeks monitoring of PSA and testosterone was performed to all the patients; after 3 months a control determination of prostate volume was carried out; upon completion of the treatment the performance status and the pain status of the patients were redetermined.

Before the treatment all the patients had a higher than normal PSA level. The mean PSA value in the first group amounted to 107.3 ng/ml, in the second group it was 97.5 ng/ml. After the initiation of the treatment, the majority of the patients had a positive dynamics of PSA which was characterized by its sharp decline during the first 2 months of the treatment followed by a gradual regression and stabilization of indices.
During the therapy with Buserelin-depo the patients with prostate cancer showed a steady decline in the average PSA values from 107.3 ng/ml to 37.8 ng/ml after 2 months, up to 27.9 ng/ml after 4 months, and up to 3.3 ng/ml after 6 months. In the group of the patients treated with the other LHRH analogues, the marked regression of the average PSA value was also observed: from 97.5 ng/ml to 24.05 ng/ml after 2 months, up to 12.35 ng/ml after 4 months, up to 3.1 ng/ml after 6 months.

With the decrease in PSA levels, the dynamics of the prostate volume correlated. During the therapy with Buserelin-depo, a decrease in prostate volume from 55.9 to 39.8 cm3 was noted in the patients with prostate cancer to 6th month of the treatment (- 28.8%). The average prostate volume in the patients of the second group was 63.9 cm3. After 6 months of the treatment, the prostate volume decreased by 33.2% (42.7 cm3). The registered change in the prostate volume during the treatment became a prerequisite for reduction of the symptoms of inappropriate urination in the vast majority of the patients of the studied groups.

The mean value of testosterone levels in patients of the first group before the treatment was 17.7 ng/ml, the mean value in the second group was 14.21 ng/ml.

In the course of the conducted therapy, a decrease in testosterone levels up to the post-castration values was observed in the patients of the both groups a month after the start of the hormonal therapy. In the first group: starting from 17.7 to 2.12 ng/ml after 2 months and 0.41 ng/ml after 4 months of the treatment. In the second group: a decrease in the mean testosterone value from 14.21 to 1.53 ng/ml after 2 months and up to 0.39 ng/ml after 4 months of the treatment was observed. After 4 months of the treatment, further significant changes in testosterone values were not observed.

The conducted treatment was of intermittent character. Considering the positive results of the 6-month therapy in the "buserelin" group and in the group of "the other LHRH agonists," further administration of the drugs was discontinued with the subsequent dynamic monitoring over PSA and testosterone levels.

The dynamics of testosterone levels in the first and in the second group of the patients after discontinuation of the treatment with LHRH analogues was monitored. While analyzing the obtained data, it was revealed that the increase in testosterone levels above the castration values during the administration of Buserelin occurred 1 month after the completion of the treatment, and in the second group of the patients, where other LHRH analogues were used, it was observed upon expiration of 1.8 months. Further observation showed that the recovery of initial testosterone values occurred in the Buserelin group after 2.4 months, and during the administration of the other LHRH analogues after 3.2 months.

Prior to the treatment in 822 patients the Karnofsky performance status was 80-100%, in 35 patients it was 60-70%, and in 25 patients the performance status was 50-60% while evaluating the both groups. It should be noted that the lower index of the status was in the patients with generalized types of prostate cancer. Upon the completion of the hormonal therapy, the change of the performance status for the better occurred in 5 patients (9%) patients of the first group and in 8 patients (9.2%) of the group of patients treated with LHRH agonists (Table. 4)

Table 4. Performance status of the patients in the groups before and after the treatment

Before the administration of the hormonal therapy 66 patients (46.5%) had a pain syndrome. 76 patients did not require anesthesia. 22 patients (15.5%) irregularly administered non-opioid analgesics, 16 patients (11.3%) required irregular administration of opioid analgesics to reduce the pain syndrome and 28 patients (19.7%) continuously administered non-opioid analgesics. After 6 months of the administration of the drugs the number of patients who did not require analgesics increased in the both groups by 5.8%. At the same time, none of the patients could completely refuse the administration of analgesic drugs (tab. 5).

Table 5. Dynamics of the pain status of the patients in the groups according to the WHO scale

During the administration of Buserelin-depo the vast majority of the patients complained of "flushes" and sweating, which was also noted by the patients treated with the other LHRH agonists. There was no single case of urinary retention, muscle weakness in the lower extremities, swelling and lymphostasis. It should be noted that most of the adverse effects were fully reversible after withdrawal of the drugs.

The experience of the administration of Buserelin-depo showed that the drug is highly effective for the treatment of hormone-dependent prostate cancer. The administration of Buserelin-depo leads to a decrease in PSA levels, provides a steady decline in serum testosterone levels up to the post-castration level, reduction of prostate volume, and a decrease in the symptoms of urination disorders in the absence of serious adverse problems. Some patients had an increased performance status as well as reduced demand and doses of analgesics.

After the completion of the course of the treatment with Buserelin-depo earlier restoration of the initial testosterone level compared to the treatment with the other LHRH analogues was observed, which reduces the severity of adverse effects of the hormonal therapy and improves patients’ quality of life.

Buserelin-depo can be recommended for administration as an individual therapy or in combination with other hormonal drugs in patients with prostate cancer.

References

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