RU2541810C2 - Method of treating prostate cancer with using prolonged prodrug of octreotide accompanying surgical or drug-induced castration - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to oncourology, and can be used in the non-surgical treatment of the patients suffering early stages of prostate malignant tumour. A method of treating prostate cancer with using prolonged prodrug of octreotide accompanying surgical or drug-induced castration involves a) measuring pre-therapeutic prostate-specific antigen; b) measuring pre-therapeutic blood plasma chromogranin A; c) selecting the patients having high blood chromogranin A of more than 3 nmol/l; d) conducting a therapy with prolonged prodrug of octreotide in a combination with dexamethasone in the selected patients; e) controlling the prostate-specific antigen variation every month and monitoring a decrease thereof in the patients by measuring it intra-therapeutically according to the stage d); the therapeutic efficacy according to the stage d) is evaluated by a therapeutic response, which is accompanied by maximum decrease of the prostate-specific antigen.

EFFECT: invention enables providing the higher therapeutic efficacy in the patients suffering prostate cancer at the different stages.

3 cl, 1 tbl, 5 ex

Description

The invention relates to medicine, in particular to oncology, and can be used in the conservative treatment of patients with prostate cancer (PCa) at different stages of the tumor process.

PCa is the third leading cause of death from malignant tumors of men of all ages and the most common cause of death from malignant tumors of men over 70 years of age.

In recent years, an increase in the incidence of prostate cancer has continued, which is accompanied by an increase in the volume of studies conducted around the world aimed at finding new effective therapeutic agents and methods for treating the disease.

The choice of optimal treatment for prostate cancer varies depending on the stage of the disease. In the early stages, surgical removal of the prostate and / or radiation therapy is used. With common and metastatic prostate cancer, hormone therapy is used to suppress testosterone production (medical castration) by GnRH analogues (gonadotropin releasing hormone) or testicular removal (surgical castration). With the onset of resistance to hormone therapy, chemotherapy is carried out using drugs such as mitoxantrone, prednisone, estromustine, paclitaxel, docetaxel.

RU 2010128239 A, 01/20/2012, describes a method for treating various cancers, including prostate cancer, using a composition of therapeutic agents containing:

(a) a vascular destroying agent; and

(b) one or more pharmaceutically active substances selected from the group including, for example, dexamethasone, octreotide and mixtures thereof. Moreover, the composition used is intended for simultaneous, joint, separate or sequential use, for the prevention or combined treatment.

So, various methods of treating prostate cancer are known in the art.

A known method of hormonal treatment of prostate cancer using surgical or medical castration by introducing an analogue of GnRH, which is the first line of hormone therapy (see Clinical Oncourology, under the editorship of Matveev BP, M .: Publishing House of the Russian Academy of Medical Sciences, 2011, p. 723).

The disadvantage of this method is the development of hormone resistance in most patients, therefore, the use of hormone therapy does not cure the disease and is temporary. The average duration of the response to primary hormone therapy, as a rule, does not exceed 18-24 months, which leads to the progression of the tumor process (see Yagoda A, Petrylak D. Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. 1993 Feb 1; 71 (3 Suppl ): 1098-1109).

A known method of chemotherapeutic treatment of hormone-resistant prostate cancer (hereinafter - HGRP) using docetaxel and prednisolone, which is currently the standard of treatment. The disadvantage of this method is the restriction of use only for HGRP and that no more than 50% of patients respond to treatment (see Chernyshev I.V., Zhernov A.A., Perepechin D.V. Targeted therapy of hormone-resistant prostate cancer ”, F Experimental and Clinical Urology, No. 1, 2012, pp. 42-46).

The closest analogue of the claimed method of treating prostate cancer (hereinafter referred to as prostate cancer) is the known treatment method described in RU 2411031, C2, 02/10/2011, comprising administering to the patient a pharmaceutical composition comprising a depot form of an somatostatin analog, in particular, a depot form of octreotide, biologically biodegradable polymer (linear or branched lactide-glycolide copolymer) polyethylene glycol dialkyl ether, pharmaceutically acceptable organic solvent. The treatment regimen for this method includes, for example, parenteral administration of the composition at doses of the order of from about 0.2 to about 60 mg per injection per month, or from about 0.03 to about 1.2 mg per 1 kg of body weight per month, administered once or as divided doses. The composition can be entered once a month. Suitable doses for administration once every 2-3 months are from about 1 mg to about 180 mg. The composition is multicomponent and difficult to prepare and does not provide the necessary effectiveness for the treatment of prostate cancer at its various stages, and does not reduce the need for chemotherapy.

The technical task and the achieved technical result of the claimed method is to optimize and increase the effectiveness of treatment of prostate cancer at various stages of the disease, reduce the need for chemotherapy and increase survival.

The task and technical result are achieved by a method of treating prostate cancer against a background of surgical or medical castration, including:

a) determination of PSA in patients prior to treatment;

b) determination in patients of the content of the level of chromogranin A in the blood plasma (hereinafter - XP A). At the same time, patients are sampled on an empty stomach with a further determination of the level of Chr A using an ELISA Kit (EURO DIAGNOSTICA, Sweden). The values of Chr A normal when determined by this method are from 0 to 3 nmol / L (for more details on the determination of Chr A see Appendix 1).

c) selection of patients with a high content of Chr A level of more than 3 nmol / l;

g) the treatment of selected patients with elevated XP And prolonged depot form of octreotide (hereinafter - PDFO) in combination with dexamethasone;

e) the implementation of monthly monitoring of changes in prostate-specific antigen and monitoring its decrease in patients by determining it during the treatment period according to stage (g), while the effectiveness of therapy according to stage (g) is determined by the “response” to treatment, at which the maximum decreased prostate-specific antigen. One example of a prolonged depot of the octreotide form is the octreotide depot (PDFO).

In the method according to the invention, therapy using PDFO in combination with dexamethasone in selected patients with an increased level of Chr A exceeding the upper limit of the normal range is carried out by administering PDFO intramuscularly (hereinafter / m) in doses of 20 or 30 mg once, every 4 weeks, and dexamethasone is administered orally at a dose of 4 mg per day for 1 month, then 2 mg per day for 2 weeks, 1 mg per day (maintenance dose). The indicated therapy is used against the background of surgical or medical castration (analogues of GnRH), both in case of widespread prostate cancer, as well as with GRH and the onset of resistance to chemotherapy.

The following PSA levels are available depending on age and PCa:

- for men of young and middle age, the PSA indicator norm is no more than 2 ng / ml (hereinafter in the text instead of “ng / ml” “units” are indicated),

- for older men, the normal PSA is not more than 4 units,

- PSA can reach up to 100 and higher with the development of prostate cancer.

The effectiveness of prostate cancer therapy is conventionally characterized by a “response” to treatment, which is understood as a decrease in PSA under the influence of the treatment method.

In the existing analogue, PDFO and dexamethasone are administered to all patients with HGRP. The response to treatment is observed in no more than 50% of patients.

The applicant considers it necessary to pay particular attention to the following most important advantage of the claimed method: if you apply the claimed method, then instead of 50% of respondents to treatment, the number of respondents among the selected patients with elevated levels of Chr A increases to 90%.

The selection of optimal therapy is important in terms of increased survival. When applying this or that treatment regimen, the body's response to the treatment of prostate cancer appears only after 2-3 months. Therefore, with an ineffective choice of treatment regimen, the tumor process can grow threateningly fast, which will lead to a decrease in patient survival.

The claimed method allows you to immediately select the optimal therapy that stops the tumor process and increase the survival of patients with prostate cancer.

The following are specific examples of the method, illustrating the invention, but not limiting it.

Example 1 (Control, with a normal level of XP And). Patient S. 81 years old. Diagnosis: prostate cancer T3N1M1c. Morphologically verified, low-differentiated prostate adenocarcinoma (Glisson - 8). Previous treatment: a course of hormone therapy was carried out with an analog of GnRH (Lucrin Depot) and an antiandrogen - Casodex. Status: before treatment, hormone resistance was detected, PSA - 11.5 ng / ml, Chr. A - 0.6 nmol / L. In the treatment process according to the proposed method, intramuscular administration of PDFO was carried out at a dose of 20 mg once every 4 weeks for 1 month and then at a dose of 30 mg once every month, and dexamethasone was administered orally at a dose of 4 mg per day for 1 month, then 2 mg day for 2 weeks, then 1 mg per day (maintenance dose). A monthly PSA determination was made, noting its change. During treatment, a decrease in PSA was not observed; at 2 months of treatment, a rise in PSA to 30 ng / ml was noted. There was a lack of response to treatment.

Example 2. Patient F. 65 years old (with elevated levels of XP And). Diagnosis: prostate cancer pT2cN1M1cG2. Morphologically verified, low-differentiated prostate adenocarcinoma (Glisson - 9). Previous treatment: a course of hormone therapy was carried out with an analog of GnRH (Buserelin-depot). Status: before treatment - hormone resistance detected, PSA - 108 ng / ml, Chr. A - 6.3 nmol / l (higher than the norm by more than 2 times). In the treatment process according to the proposed method, intramuscular administration of PDFO at a dose of 20 mg was administered once every 4 weeks for 2 months and then at a dose of 30 mg once every month, and dexamethasone was administered orally at a dose of 4 mg per day for 1 month, then 2 mg day for 2 weeks, then 1 mg per day (maintenance dose). A monthly PSA determination was made, noting its change. The maximum decrease in PSA to 7.8 ng / ml was obtained after 5 months. A complete response to treatment has been recorded.

Example 3. Patient P. 57 years. Diagnosis: prostate cancer T2bNxMo. Morphologically verified, low-differentiated prostate adenocarcinoma (Glisson - 8). Previous treatment: a course of hormone therapy was carried out with an analog of GnRH (Buserelin-depot). Status: before treatment, the proposed method retains hormone sensitivity (stabilization of PSA), PSA - 34.5 ng / ml, Chr. A - 5.1 nmol / L. Therapeutic treatment using octreotide-depot and dexamethasone was carried out similarly to Example 2. In the treatment process of the claimed method: the maximum reduction in PSA to 18.3 ng / ml after 3 months. A partial response to treatment has been recorded.

Example 4. Patient A. 65 years. Diagnosis: prostate cancer T4NxM1b. Morphologically verified, low-differentiated prostate adenocarcinoma (Glisson - 8). Previous treatment: a course of chemotherapy was conducted (Paclitaxel + Mitoxantrone). Status: before treatment revealed resistance to chemotherapy, PSA - 57 ng / ml, Chr. A - 7.9 nmol / L. In the treatment process according to the proposed method, intramuscular administration of PDFO in a dose of 30 mg was carried out once every 4 weeks monthly during the entire observation period, and dexamethasone was prescribed as in Example 1. The maximum decrease in PSA to 21.7 ng / ml after 4 months. A complete response to treatment has been recorded.

Example 5. The proposed method is implemented in 23 patients. The effectiveness of treatment was assessed by the number of respondents to treatment: a complete response (PSA reduction of more than 50% of the initial level), a partial response (PSA decrease of less than 50% of the initial level) and no response to treatment (no decrease or increase in PSA). In order to justify the method, the data are compared with the initial level of Chr A in the blood. It was taken into account that the normal level of Chr A in the blood is less than 3 nmol / L. In group 1, 10 patients had a Chr A level above 3.0; in group 2, 13 patients had a Chr A level of less than 3.0 nmol / L. The number of respondents to treatment (in%) was calculated separately for each group.

Table 1 presents the average data for the groups.

Thus, in accordance with the claimed method of treating prostate cancer, patients with a high content of Chr A exceeding the upper limit of the normal range are prescribed therapy using PDFO with dexamethasone. The answer is fixed in 90% of patients. That is, in 90% of patients, PSA decreases. And in patients with a normal level of Chr A, the response to treatment using PDFO and dexamethasone was noted only in 10% of patients.

The data obtained confirm the novelty and inventive step of the proposed method.

Thus, in contrast to the prior art, the proposed method has the following significant advantages and differences:

- is used in patients with prostate cancer with elevated levels of Chr A in the blood at any stages of the tumor process, which allows to optimize treatment, increase its effectiveness and significantly increase the contingent of patients using the proposed method;

- an increase in efficiency, characterized by an increase in the number of full and partial responses to treatment, due to the selective selection of patients with elevated levels of Chr A in the blood, allows other appropriate types of treatment to be prescribed to other patients initially.

Claims (3)

1. A method of treating prostate cancer using a prolonged depot form of octreotide on the background of surgical or drug castration,
including
a) determination of prostate-specific antigen in patients prior to treatment;
b) determining the level of chromogranin A in the blood plasma of patients before treatment;
c) selection of patients with a high content of chromogranin A in the blood more than 3 nmol / l;
d) therapy with a selected patient with a prolonged depot form of octreotide in combination with dexamethasone;
e) monthly monitoring of changes in prostate-specific antigen and monitoring of its decrease in patients by determining it during the period of therapy according to stage (g), while the effectiveness of therapy according to stage (g) is determined by the "response" to treatment, which is achieved maximum reduction in prostate-specific antigen. 2. The method according to p. 1, characterized in that the prolonged depot therapy with the form of octreotide in combination with dexamethasone is carried out by administering the prolonged depot of the form of octreotide intramuscularly in doses of 20 or 30 mg once, every 4 weeks, and dexamethasone is administered orally at a dose of 4 mg day for 1 month, then 2 mg per day for 2 weeks, then 1 mg per day, as a maintenance dose. 3. The method according to p. 1, characterized in that the treatment is also carried out for patients resistant to chemotherapy.