Medical castration in the treatment of common types of prostate cancer. Role of Buserelin

Medical castration in the treatment of common types of prostate cancer.

Role of Buserelin

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

In the last decade in Russia, the incidence of prostate cancer has been growing rapidly. In 2012 more than 29,000 new cases were recorded. In the structure of cancer incidence, prostate cancer took the second place. The index of mortality is high [1].

Despite the tendency to increased identification of patients with localized prostate cancer, in 49.6% of primarily revealed patients locally advanced and metastatic types of cancer [1] are diagnosed, and these patients more often require multicomponent treatment [2].

For many years the main approach in the treatment of the locally advanced and metastatic prostate cancer is hormonal therapy [3]. The principle of androgen blockade underlies any strategy of hormonal therapy, and this blockage can be achieved by stopping the endogenous testosterone production [4] as well as by cessation of androgenic effect due to competitive action of medicinal agents [5].

One of the options of the hormonal therapy is medical castration with the use of agonists of luteinizing hormone-releasing hormone (LHRH) [6]. Numerous studies have shown that this treatment option is as effective as surgical castration, and it has a number of advantages i.e. reversible character of hormonal effect, the possibility of the use of an intermittent scheme of the hormonal therapy with regression of adverse events and reactions against the background of temporary withdrawal of drugs [7, 8].

Buserelin is one of the drugs of this group, and it is widely used in the clinical practice.

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 to stimulation of the synthesis of gonadotrophins for the first several days, and then to desensitization of the pituitary and the blockade of the pituitary-testicle axis. Subsequently, 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 [9, 10, 11].

From the beginning of December 2012 to December 2013 86 patients with prostate cancer at the age of 58 to 69 years who received the treatment with LHRH analogues were observed at the premises of City Hospital 57, Oncologic Dispensary No 3, city of Moscow, and Krasnodar Regional Oncology Center. The mean age of patients was 64.2 years.

Before the treatment all the patients had verified diagnosis of prostate cancer with the help of general clinical and special methods of investigation including the determination of prostate-specific antigen (PSA) levels and histological verification of the oncological process, ultrasound examination of internal organs and transrectal ultrasound examination of prostate, bone scintigraphy, chest X-ray. For indications, magnetic resonance and / or computed tomography was performed in order to define the distribution of the process more precisely.

44 patients had locally advanced prostate cancer, 42 patients were diagnosed with generalized prostate cancer (Table 1).

The patients were divided into two groups with the equal number of patients who had bone metastases. In the first group (n = 45) the patients received the therapy with Buserelin-depo, in the second group (n = 41) the patients were administered one of the other LHRH analogues (goserelin, leuprorelin, triptorelin). The period of the treatment with the drugs was at least 6 months.

Table 1. Distribution of the patients considering stages of the disease

Stages of the disease	Buserelin (n=45)	Other LHRH analogues (n=41)
T2N1Mо	6	6
ТЗNоМо	23	21
T3NоM1	7	6
T3N1M1	3	4
T4N1M1	6	4
Total	45	41

The objective of the study was to evaluate the efficacy of the drug Buserelin-depo at a dose of 3.75 mg with a 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 patients’ performance status and the level of the pain syndrome, to compare with the group of the patients who received the treatment with 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 the hormonal therapy: palliative external beam therapy to bone metastases and the treatment with zoledronic acid.

During histological verification of the diagnosis moderately and poorly differentiated types of prostate cancer predominated (Table 2).

Table 2. Histological types of tumors

Histological type of tumor	Buserelin (n=45)		Other LHRH analogues (n=41)
Histological type of tumor	Abs.	%	Abs.	%
Gleason 2-4	6	13.3	6	14.6
Gleason 5-6	12	26.7	11	26.8
Gleason 7	20	44.4	16	39
Gleason 8-10	7	15.6	8	19.6
Total	45	100	41	100

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 examination.

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 105.2 ng/ml, in the second group it was 94.7 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 in the first 2 months of the treatment followed by a gradual regression and stabilization of indices.

During the therapy with Buserelin-depo, a consistent decline in the mean PSA values from 105.2 ng/ml to 36.8 ng/ml after 2 months, up to 27.2 ng/ml after 4 months and up to 3.2 ng/ml after 6 months was revealed in the patients with prostate cancer. In the group of the patients treated with the other LHRH analogues, regression of the mean PSA value was also observed: from 94.7 ng/ml to 23.05 ng/ml after 2 months, up to 12.68 ng/ml after 4 months (-82%,), and up to 3.01 ng/ml after 6 months (Fig. 1).

Figure 1. Dynamics of the PSA values of serum (ng/ml) during the treatment with Buserelin-depo and other LHRH agonists.

With the decrease in PSA levels, the dynamics of the prostate volume correlated. During the therapy with Buserelin-depo, a decrease of prostate volume from 54.5 to 39.6 cm³ was observed after 6 months of the treatment (- 27%) in patients with prostate cancer. The mean prostate volume in the patients of the second group was 62.7 cm³. After 6 months of the treatment, the prostate volume decreased by 30.2% (43.8 cm³). The registered change in the prostate volume during the treatment became a prerequisite for the reduction of the symptoms of inappropriate urination in the vast majority of the patients of the studied groups.

The mean value for testosterone levels in patients of the first group before the treatment was 17.2 ng/ml, the mean value in the second group was 14.19 ng/ml.

During the conducted therapy the reduction of the testosterone level up to post-castration values was achieved in the patients of the both groups. The first group: starting from 17.2 to 2.02 ng/ml after 2 months and 0.43 ng/ml after 4 months of the treatment. The second group: the reduction of the mean value for testosterone was from 14.19 to 1.5 ng/ml after 2 months and up to 0.4 ng/ml after 4 months of the treatment (Figure 2). After 4 months of the treatment, further significant changes in testosterone levels were not observed.

Figure 2. Dynamics of testosterone levels in blood serum (ng/ml) during the treatment with LHRH agonists.

The conducted treatment was of intermittent character. Taking into account the positive results of the 6- month treatment in the "Buserelin" group and in the group of "other LHRH agonists," the 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.

Before the treatment in 59 patients Karnofsky performance status was 80-100%, in 17 patients it was 60-70% and in 10 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 patients with generalized types of prostate cancer. Upon completion of the hormonal therapy the change of the performance status for the better occurred in 4 patients (8.9%) of the first group and in 3 patients (7.3%) in the group of patients treated with LHRH agonists (Table 3).

Table 3. Performance status of the patients in the groups before and after the treatment

Karnofsky performance status, %	Buserelin (n=45)				Other LHRH analogues (n=41)
	Before the treatment		After the treatment		Before the treatment		After the treatment
	Abs.	%	Abs.	%	Abs.	%	Abs.	%
80-100	34	75.6	38	84.4	25	61	28	68.3
60-70	7	15.6	4	8.9	10	24.4	9	21.9
50-60	4	8.8	3	6.7	6	14.6	4	9.8
30-50	-	-	-	-	-	-	-	-

While performing the analysis before the administration of the drugs, it was found that 39 patients (45.3%) had a pain syndrome. 47 patients did not need anesthesia. 13 patients (15.1%) irregularly administered non-opioid analgesics, 9 patients (10.5%) required irregular administration of opioid analgesics to reduce the pain syndrome and 17 patients (19.8%) 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. 4).

Table 4. Dynamics of the pain status of the patients in the groups according to the WHO scale

Scale of pain (WHO), points	Buserelin (n=45)				Other LHRH analogues (n=41)
	Before the treatment		After the treatment		Before the treatment		After the treatment
	Abs.	%	Abs.	%	Abs.	%	Abs.	%
0- analgesics are not required	26	57.8	28	57.8	21	51.2	24	51.2
1- sometimes, non-opioid analgesics	6	13.3	7	13.3	7	17.1	9	17.1
2- regularly, non-opioid analgesics	9	20	6	20	8	19.5	3	19.5
3- sometimes, opioid analgesics	4	8.9	4	8.9	5	12.2	5	12.2
4- regularly, opioid analgesics	-	-	-	-	-	-	-	-

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 a 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 reduced the severity of adverse effects of the hormonal therapy and improved the 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.

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