Paclitaxel-Teva concentrate for preparations. solution for infusion 6 mg/ml 5 ml bottle in Moscow

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Manufacturers: Pliva-Lachema (Czech Republic)

Active ingredients

• Paclitaxel

Disease class

• Malignant neoplasm of the esophagus
• Malignant neoplasm of the stomach
• Malignant neoplasm of the bronchi and lungs
• Kaposi's sarcoma
• Malignant neoplasm of the breast
• Malignant neoplasm of the cervix
• Cancer of the triangle of the bladder
• Cancer of the head, face, neck
• Leukemia of unspecified cell type

Clinical and pharmacological group

• Not indicated. See instructions

Pharmacological action

• Antitumor

Pharmacological group

• Antitumor agents of plant origin

Pharmacological properties of the drug Paclitaxel

Antitumor drug of plant origin from the taxane group. Causes irreversible polymerization of microtubule proteins in the cell cytoplasm, as a result of which the dynamic equilibrium of the “polymerization-depolymerization” process, which ensures the normal functioning of intracellular structures throughout the entire life cycle of the cell, is disrupted. Paclitaxel induces the formation and accumulation of abnormal assemblies - microtubule bundles in interphase and numerous microtubule stars during mitosis, which leads to arrest of the cell life cycle in the G2 or M phase. After intravenous administration of paclitaxel, its concentration in the blood plasma is described by a two-phase curve. In vitro, 89–98% of paclitaxel is bound to blood proteins. Metabolism has not been fully studied. Only 1.3–12.6% of paclitaxel is excreted in the urine; It is believed that the main amount of paclitaxel is hydroxylated in the liver. The half-life ranges from 3 to 52.7 hours. The average volume of distribution at steady state varies from 198 to 688 l/m2. With increasing dose during a 3-hour infusion, the pharmacokinetics of paclitaxel becomes nonlinear. When the dose is increased by 30% (from 135 to 175 mg/m2), the maximum concentration and AUC values ​​increase by 75 and 81%, respectively. There was no accumulation of paclitaxel during repeated courses of treatment.

Introduction

Nanobiotechnology, which involves the development of biomedical applications of nanosized systems, is an actively developing area of ​​nanotechnology.
Nanomaterials ranging in size from 1 to 1000 nm provide the opportunity for unique interactions with biological systems at the molecular level. Nanobiotechnology methods can be used in the detection, diagnosis and treatment of cancer, which has led to the formation of a new discipline – nano-oncology [1, 2]. The use of nanoparticles is being developed for in vivo tumor imaging, biomolecular profiling of tumor growth biomarkers, and targeted drug delivery. These nanotechnology-based techniques can be widely used in oncology. It is well known that breast cancer (BC) can express protein biomarkers, such as estrogen and progesterone receptors, based on the presence of which the treatment of the disease is planned. The use of semiconductor fluorescent nanocrystals, used as quantum dots of various sizes and with different emission spectra for the purpose of imaging antibodies, makes it possible to simultaneously classify and accurately determine the amount of these target proteins in one tumor section [3]. The use of gold nanoparticles (eg, Raman probes) provides qualitative and quantitative characterization of multiple proteins in a single tumor section. This makes it possible to plan specific antitumor therapy based on the individual protein profile of a particular patient [4]. The ability to detect multiple molecular targets simultaneously in tumor samples makes it possible to determine the nature of the relationship between gene products and proteins in real time [5]. In addition, the effects of individualized treatment based on the expression of targeted proteins can be tested before and after treatment, allowing rapid assessment of the effectiveness of targeted therapy.

Nanotechnological methods (for example, the use of nanocantilevers and nanoprobes) are being actively studied with the aim of using them to diagnose the tumor process [6], since nanoparticles combined with cancer-specific target ligands can be used for the early detection of tumors, which ensures timely intervention using chemopreventive agent, as well as detection of distant metastases [7]. Promising results have been obtained using supermagnetic nanoparticles with a metal core, bioconjugated with antibodies against HER2/neu with simultaneous tumor imaging and targeted therapeutic effects in vivo [8].

Several nanotechnology approaches are being studied to improve the delivery of chemotherapeutic agents to tumor cells in order to minimize the toxic effects of drugs on healthy tissue while maintaining antitumor efficacy. Doxorubicin was combined with a liposomal delivery system into a complex, the nanoparticles of which retained their effectiveness, but the toxic effect of the drug on the myocardium was reduced [9, 10]. One such delivery system (liposomal doxorubicin with covalently attached polyethylene glycol - pegylated liposomal doxorubicin, PLD) is approved for the treatment of refractory ovarian cancer and Kaposi's sarcoma in the United States. Nanoparticles of albumin-bound paclitaxel (NAB) are also more effective than the traditional form of paclitaxel dissolved in castor oil and are safer to use [11, 12]. The drug is approved in the USA for the treatment of metastatic breast cancer.

Competitive imaging and targeted therapy

As mentioned above, nanoparticles can be coupled to ligands of different affinities and used as contrast agents, allowing the visualization of precellular structures in vivo. Nanoparticles combined with targeted antibodies can simultaneously be used for diagnostics and antitumor treatment. Preliminary studies in vitro and in vivo have demonstrated the great potential of this method [8, 13, 14]. One technique for conjugating target ligands to nanoparticles (anti-HER2/neu antibodies with a modified metal nanoparticle to form a nanoshell) [15] uses biotin and streptavidin as coupling agents. The design consists of a spherical dielectric nanoparticle core made of silicon and surrounded by a thin gold shell. These nanoshells, emitting near-infrared spectrum, convert light into thermal energy and are used for thermal tumor ablation. Thermal induction after exposure to the near-infrared spectrum is almost a million times more effective compared to dye molecules [15].

Ito A. et al. [13] after bioconjugation with anti-HER2 antibodies were able to label the HER2/neupositive breast cancer cell line SK-BR-3 with magnetic nanoparticles. After exposure to the near-infrared spectrum, these nanocharges caused hyperthermia with an average temperature well above the values ​​causing irreversible changes leading to cell death. Thus, targeted nanocharges can be used to achieve localized irreversible photothermal ablation of breast cancer tissue in vivo.

Nanoparticles can also be used for the purpose of tumor-selective delivery of antitumor agents to enhance the effect of damage to tumor cells, provided that healthy tissues are protected from the effects of cytotoxic agents and systemic toxic effects are reduced. Many preclinical studies have been conducted on the use of nanoparticles as targeted therapies in oncology. Some of these ideas have already found clinical application.

Liposomal anthracyclines

Anthracyclines remain one of the most active agents used to treat breast cancer [16] and are widely used in the treatment of all stages of the disease. However, the use of anthracyclines is limited by cardiotoxic effects that occur when a high cumulative dose is reached. Trastuzumab, a monoclonal antibody to HER2/neu, has improved the treatment of aggressive breast cancer [17, 18], but its use is also limited by the risk of cardiotoxicity, which occurs almost exclusively in patients previously treated with anthracyclines [17]. Liposomal forms of anthracyclines were developed to increase the therapeutic index compared to traditional forms while maintaining broad antitumor activity. Three liposomal anthracyclines, represented by nanoparticles about 100 nm in size, are being studied for use in breast cancer: liposomal daunorubicin, approved in the USA for the treatment of Kaposi's sarcoma; liposomal doxorubicin, which in combination with cyclophosphamide is approved for the treatment of metastatic breast cancer in Europe; PLD (polyethylene glycol attached), approved in the United States for the treatment of both Kaposi's sarcoma and refractory ovarian cancer.

Both liposomal doxorubicin and PLD have been compared with standard doxorubicin as first-line therapy in patients with metastatic breast cancer [9, 10]. The study included 297 patients with metastatic breast cancer who had not previously received any chemotherapy treatment. They were randomized to receive 60 mg/m2 of liposomal doxorubicin or 60 mg/m2 of standard doxorubicin in combination with 600 mg/m2 of cyclophosphamide every 3 weeks until disease progression or unacceptable symptoms. toxic effects. The effectiveness of therapy in the two groups did not differ significantly (response to treatment 43 and 43%, median time to progression - 5.1 versus 5.5 months, median survival - 19 versus 16 months) [9]. However, cardiotoxicity was observed in significantly fewer patients receiving liposomal doxorubicin (6 vs. 21%, p = 0.0001) [9]. Thus, the likelihood of a cardiotoxic effect in patients receiving liposomal doxorubicin is 3.5 times lower compared to patients receiving the drug in the standard form.

PLD (50 mg/m2 every 4 weeks) was compared with standard doxorubicin (60 mg/m2 every 3 weeks) in 509 patients with metastatic breast cancer [19]. Both drugs demonstrated similar efficacy with response rates of 33 and 38%, respectively, and time to progression of 6.9 and 7.8 months, respectively [10]. The risk of developing a cardiotoxic effect was significantly lower in patients receiving PLD (in a ratio of 3:16; p < 0.001). Neutropenia and gastrointestinal toxic effects were more common in patients receiving doxorubicin, while hand-foot syndrome was more common with PLD.

Liposomal doxorubicin was studied in combination with trastuzumab in phase I–II clinical trials in patients with metastatic breast cancer. At the same time, the response to treatment reached 59%, despite the fact that patients could have received trastuzumab previously. A cardiotoxic effect occurred in two patients, who had previously received doxorubicin in a standard form [20]. Anthracyclines are highly effective in HER2/neu-positive breast cancer [17], so the use of a combination of liposomal forms of the drug with trastuzumab has great prospects.

NAB-paclitaxel

Taxanes (paclitaxel and docetaxel) are among the most important therapeutic drugs in the treatment of solid tumors and are widely used in all stages of breast cancer. Both drugs have strong hydrophobic properties and therefore require synthetic delivery vehicles (polyethylene castor oil for paclitaxel and polysorbate ethanol for docetaxel). Toxic effects occur with both drugs and are largely associated with synthetic delivery vehicles rather than with the chemotherapeutic agents themselves [21,22]. Several new dosage forms of taxanes have been developed to reduce their toxic effects. NAB-paclitaxel, a nanoparticle with a core containing paclitaxel surrounded by albumin (the most suitable shell for a hydrophobic molecule), has demonstrated high efficacy in the treatment of breast cancer.

Preclinical studies have shown that NAB-paclitaxel is able to penetrate tumor tissue better than standard forms of paclitaxel [23]. In a phase II study that included 63 patients with metastatic breast cancer, response to treatment with NAB-paclitaxel at a dose of 300 mg/m2 every 3 weeks was demonstrated in 48% of cases.

A phase III study [10] compared NAB-paclitaxel with a standard form of this taxane. Four hundred and sixty taxane-naïve patients with metastatic breast cancer were randomized to receive NAB-paclitaxel or castor oil-based paclitaxel every three weeks until signs of progression. The overall response to treatment was significantly higher in patients receiving NAB-paclitaxel, regardless of line of therapy (33 vs. 19%; p = 0.001). Time to progression was significantly longer in the NAB-paclitaxel group (23 vs 17 weeks; P = 0.006) [10], although overall survival was not significantly different (P = 0.374). In the group of patients receiving NAB-paclitaxel, better tolerability of the drug was noted. No hypersensitivity reactions were noted, although patients treated with NAB-paclitaxel had not received any medications prior to enrollment in the study. Grade IV neutropenia was observed significantly less frequently, and grade III neuropathy was significantly more common in patients treated with NAB-paclitaxel compared with patients treated with the standard form of the taxane (p < 0.001).

In another study [24], NAB-paclitaxel was prescribed with a one-week interval to patients with metastatic breast cancer who had previously received multicomponent treatment. Response to treatment was observed in patients previously treated with paclitaxel, docetaxel, or both. With this treatment regimen, the incidence of neuropathy decreased. Thus, paclitaxel in the form of nanoparticles has advantages over the standard form of the drug due to reduced toxic effects, no need for premedication, and higher efficiency.

Fluorouracil (FU) loaded into PEG-PBLG nanoparticles (FU/PEGPBLG) demonstrated improved pharmacokinetic properties, including sustained drug release, extended half-life, and increased affinity for tumor tissue. In vivo, FU/PEG-PBLG nanoparticles showed good antitumor activity against colon cancer xenografts and oral squamous cell carcinoma. The PEGPBLG delivery system can effectively attenuate the side effects of FU and increase its therapeutic index.

Targeted delivery of tamoxifen

Approximately 75% of breast cancer cases show expression of steroid hormone receptors. In approximately 50% of patients with such expression, effective hormone therapy is possible. Tamoxifen remains a drug that is widely used in all stages of breast cancer, both pre- and postmenopausal. The drug is subject to significant metabolic effects that prevent it from entering the tumor tissue, which can neutralize its effect. Shenoy DB and Amiji MM [25] developed a tamoxifen-carrying polymer nanoparticle capable of enhancing the penetration of the drug into tumor tissue. Using a xenograft model of human breast cancer, they demonstrated significantly greater accumulation of tamoxifen in tumor tissue in mice treated with tamoxifen-carrying nanoparticles compared to mice administered the standard drug intravenously. The use of nanoparticles as tamoxifen carriers improves the penetration of the drug into tumor tissues, its more selective effects and, consequently, the weakening of the toxic effects of drugs.

Conclusion

The biological application of nanoparticles is a rapidly developing area of ​​nanotechnology, opening up new opportunities in the diagnosis and treatment of human malignancies. For cancer diagnostics, fluorescent nanoparticles can be used for multicomponent one-time profiling of tumor biomarkers and detection of various genes, as well as matrix RNA using fluorescent in situ hybridization. In the near future, the use of pooled nanoparticles will allow the simultaneous detection of at least 10 oncoproteins in a tiny section of a tumor. This will pave the way for the development of methods for determining the individual proteomic profile of a tumor. Supermagnetic nanoparticles can be effectively used for contrast purposes to detect cancer in vivo, as well as to monitor treatment. Several chemotherapy agents have already been tested in nanoparticle form and have at least equivalent efficacy with less toxicity compared to traditional forms. The use of nanoparticles will soon make it possible to target tumors by delivering drugs in a unique way.

Based on the data obtained using nanoparticles, adequate treatment can be planned. Using nanoparticle tags, it is possible to compare the expression of a gene and the protein it encodes in a tumor. The field of application of nanoparticles for visualizing the tumor process in vivo with simultaneous targeted effects on tumor antigens (targets) is rapidly developing.

The use of nanoparticles is a new method of targeted action that increases the effectiveness and reduces the toxicity of both existing and new anticancer drugs. It is expected that in the near future the introduction of nanotechnology will lead to revolutionary changes not only in oncology, but also in medicine in general.

Indications for use of the drug Paclitaxel

Non-small cell lung cancer in patients for whom radical surgical treatment and/or radiation therapy is not indicated. Common form of ovarian carcinoma (as monotherapy or as part of combination antitumor therapy):

• for primary treatment of ovarian cancer in patients with an advanced form of the disease or with residual tumor (more than 1 cm) after surgical treatment in combination with treatment with cisplatin;
• for the treatment of recurrent ovarian cancer with metastases when standard therapy is ineffective.

Metastatic breast carcinoma when standard therapy is ineffective.

Paclitaxel-LENS 6 mg/ml 50 ml No. 1 bottle + infusion system

Content

Indications Contraindications With caution Use during pregnancy and breastfeeding Side effects Interaction Overdose Special instructions Storage conditions Expiration date

Indications

• ovarian cancer - first-line therapy in patients with an advanced form of the disease or residual tumor (more than 1 cm) after laparotomy (in combination with cisplatin) and second-line therapy for metastases after standard therapy that did not produce a positive result);
• breast cancer in the presence of affected lymph nodes after standard combination therapy (adjuvant treatment); after relapse of the disease, within 6 months after the start of adjuvant therapy - first-line therapy; metastatic breast cancer after ineffective standard therapy - second-line therapy;
• non-small cell lung cancer - first-line therapy in patients who are not planned for surgical treatment and/or radiation therapy (in combination with cisplatin);
• Kaposi's sarcoma in patients with AIDS is second-line therapy after ineffective therapy with liposomal anthracyclines.

Contraindications

• hypersensitivity to the drug, as well as other drugs, the dosage form of which includes polyoxyethylene castor oil;
• pregnancy;
• breastfeeding period;
• initial neutrophil count less than 1500/μl in patients with solid tumors;
• the initial or recorded during treatment neutrophil content is less than 1000/μl in patients with Kaposi's sarcoma in patients with AIDS.

Carefully

• thrombocytopenia (less than 100,000/µl);
• liver failure;
• acute infectious diseases (including herpes zoster, chicken pox, herpes);
• severe course of coronary heart disease;
• history of myocardial infarction;
• arrhythmias.
• The safety and effectiveness of Paclitaxel-LENS® in children has not been established.

Use during pregnancy and breastfeeding

Contraindicated during pregnancy. Breastfeeding should be stopped during treatment.

Side effects

• From the hematopoietic organs: neutropenia, thrombocytopenia, anemia.
• Allergic reactions: decreased blood pressure, chest pain, flushing, skin rashes, generalized urticaria, angioedema.
• From the cardiovascular system: decreased blood pressure, increased blood pressure, bradycardia, tachycardia, atrioventricular block, ECG changes, vascular thrombosis and thrombophlebritis.
• From the nervous system: paresthesia, visual impairment, ataxia, encephalopathy, autonomic neuropathy, manifested by paralytic ileus and orthostatic hypotension.
• From the musculoskeletal system: arthralgia, myalgia.
• From the digestive system: nausea, vomiting, diarrhea, mucositis, anorexia, constipation.
• From the liver: increased activity of “liver” transaminases (usually AST), alkaline phosphatase and bilirubin levels in the blood serum.
• Local reactions: pain, swelling, erythema, induration and pigmentation of the skin at the injection site; extravasation can cause inflammation and necrosis of the subcutaneous tissue.
• From the skin and skin appendages: alopecia, pigmentation disorders or discoloration of the nail bed.
• Other: asthenia and general malaise.

Interaction

Cisplatin reduces the total clearance of paclitaxel by 20% (with more pronounced myelosuppression observed when paclitaxel is administered after cisplatin).

Co-administration with cimetidine, ranitidine, dexamethasone or diphenhydramine does not affect the binding of paclitaxel to plasma proteins.

Inhibitors of microsomal oxidation (including ketoconazole, cimetidine, verapamil, diazepam, quinidine, cyclosporine, etc.) suppress the metabolism of paclitaxel.

Directions for use and doses

Intravenous infusion, as a 3-hour or 24-hour infusion; should be administered through a system with a built-in membrane filter with a pore size of no more than 0.22 microns.

When preparing, storing and administering Paclitaxel-LENS®, you should use equipment that does not contain PVC parts.

To prevent severe hypersensitivity reactions, all patients should be premedicated with corticosteroids, H1-antihistamines and H2-histamine receptor antagonists. For example, 20 mg dexamethasone (or equivalent) orally approximately 12 and 6 hours before administration of Paclitaxel-LENS®, 50 mg diphenhydramine (or equivalent) intravenously, and 300 mg cimetidine or 50 mg ranitidine intravenously 30–60 minutes before administration drug Paclitaxel-LENS®.

When choosing a regimen and doses in each individual case, one should be guided by data from specialized literature.

Paclitaxel-LENS® should be administered intravenously as a 3-hour or 24-hour infusion at a dose of 135–175 mg/m2 with an interval of 3 weeks between courses. The drug is used as monotherapy or in combination with cisplatin (ovarian cancer and non-small cell lung cancer) or doxorubicin (breast cancer).

The recommended dose of Paclitaxel-LENS® for the treatment of Kaposi's sarcoma in patients with AIDS is 100 mg/m2 as a 3-hour infusion every 2 weeks. Administration of Paclitaxel-LENS® should not be repeated until the neutrophil count is at least 1500/μl of blood and the platelet count is at least 100,000/μl of blood. For patients who, after administration of Paclitaxel-LENS®, experienced severe neutropenia (neutrophil count <500/mm3 of blood for 7 days or longer) or severe peripheral neuropathy, during subsequent courses of treatment the dose of Paclitaxel-LENS® should be reduced by 20 %.

The drug solution is prepared immediately before administration by diluting the concentrate with 0.9% sodium chloride solution, or 5% dextrose solution, or 5% dextrose solution in 0.9% sodium chloride injection solution, or 5% dextrose solution in Ringer's solution to the final concentration from 0.3 to 1.2 mg/ml. The prepared solutions may become opalescent due to the carrier base present in the dosage form, and after filtration the opalescence of the solution remains.

Overdose

Symptoms: bone marrow aplasia, peripheral neuropathy, mucositis.

Treatment: There is no known antidote for paclitaxel.

special instructions

The use of Paclitaxel-LENS® should be under the supervision of a physician experienced in working with anticancer chemotherapy drugs.

In case of severe hypersensitivity reactions, the infusion of Paclitaxel-LENS® should be stopped immediately and symptomatic treatment should be started, and the drug should not be re-administered.

Polyoxyethylated castor oil, which is part of the drug Paclitaxel-LENS®, can cause the extraction of DEHP [di-(2-hexyl) phthalate] from plasticized PVC containers, and the degree of leaching of DEHP increases with increasing solution concentration and over time. Therefore, when preparing, storing and administering Paclitaxel-LENS®, you should use equipment that does not contain PVC parts.

During treatment, it is necessary to regularly monitor the picture of peripheral blood, blood pressure, heart rate and the number of respirations (especially during the first hour of infusion), and carry out ECG monitoring (and before the start of treatment).

In cases of development of AV conduction disturbances, continuous cardiac monitoring is necessary during repeated administrations.

If Paclitaxel-LENS® is used in combination with cisplatin, Paclitaxel-LENS® should be administered first and then cisplatin. Patients should use reliable methods of contraception during treatment with Paclitaxel-LENS® and for at least 3 months after the end of therapy.

During the treatment period, it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Paclitaxel-LENS® is a cytotoxic substance, when working with which you must be careful, use gloves and avoid contact with the skin or mucous membranes, which in such cases must be thoroughly washed with soap and water or (eyes) with plenty of water.

Storage conditions

In a place protected from light, at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Best before date

2 years.

Do not use after the expiration date stated on the package.

Use of the drug Paclitaxel

Usually prescribed at a dose of 175 mg/m2 as a 3-hour infusion once every 3 weeks, provided that the number of platelets in the peripheral blood is at least 100,000 per 1 mm3, neutrophil granulocytes - at least 1500 per 1 mm3; otherwise, the next course of treatment is carried out only after normalization of hematological parameters. If, after the previous course of treatment, the patient developed severe neutropenia (the number of neutrophil granulocytes less than 500 per 1 mm3), lasting 7 days or more or accompanied by the development of infectious complications, as well as severe peripheral neuropathy, the dose of paclitaxel for subsequent administrations is reduced by 20%. Before administering paclitaxel, all patients are given premedication to prevent hypersensitivity reactions. Premedication includes the administration of corticosteroids (dexamethasone 20 mg or its equivalent intramuscularly or orally 12 and 6 hours before infusion), antihistamines (diphenhydramine 50 mg IV as a bolus 30 minutes before infusion), H2-receptor blockers (cimetidine 300 mg or ranitidine 50 mg IV 30 minutes before infusion).

Paclitaxel

The use of paclitaxel should be under the supervision of a physician experienced in the use of anticancer chemotherapy drugs. Paclitaxel should be used as a diluted solution.

Before administering Paclitaxel, patients should be premedicated with glucocorticosteroids, H1 and H2 histamine receptor blockers.

If Paclitaxel is used in combination with cisplatin, Paclitaxel should be administered first followed by cisplatin.

Anaphylaxis and serious hypersensitivity reactions

In less than 1% of patients, despite premedication, serious hypersensitivity reactions were observed during treatment with Paclitaxel. The frequency and severity of such reactions did not depend on the dose or schedule of administration of the drug. With the development of severe reactions, the most frequently observed symptoms were suffocation, hot flashes, chest pain, tachycardia, as well as abdominal pain, pain in the extremities, increased sweating, and increased blood pressure (BP).

If severe hypersensitivity reactions develop, administration of Paclitaxel should be stopped immediately and, if necessary, symptomatic treatment should be prescribed; in such cases, repeated courses of treatment with the drug should not be prescribed.

Reactions at the injection site

During intravenous administration of the drug, the following usually mild reactions at the injection site were observed: swelling, pain at the injection site, erythema, tenderness at the injection site, induration at the injection site, hemorrhages, which can lead to the development of cellulite. Such reactions were observed more often with a 24-hour infusion than with a 3-hour infusion. In some cases, the onset of such reactions was observed both during the infusion and 7-10 days after it.

Myelosuppression

Bone marrow suppression (mainly neutropenia) is dose- and dosage-dependent and is the main dose-limiting toxicity. For example, when cisplatin is administered at a dose of 75 mg/m2 and Paclitaxel at a dose of 175 mg/m2 as a 3-hour infusion, severe neurotoxicity is observed more often than when Paclitaxel is administered at a dose of 135 mg/m2 as a 24-hour infusion. , i.e. The duration of infusion has a greater influence on the risk of developing myelosuppression than the dose.

In patients with a history of previous radiotherapy, neutropenia developed less frequently and to a milder extent, and did not worsen as the drug accumulated in the body.

In patients with ovarian cancer, the risk of renal failure is higher when using the combination drug Paclitaxel + cisplatin compared to cisplatin monotherapy.

Infections were very common and sometimes fatal, including sepsis, pneumonia and peritonitis. Urinary and upper respiratory tract infections were reported as the most common complicated infections. At least one opportunistic infection has been reported in immunosuppressed patients, patients with HIV infection, and patients with AIDS-related Kaposi's sarcoma.

The use of maintenance therapy, including granulocyte colony-stimulating factor, is recommended for patients who have experienced severe neutropenia.

A decrease in the platelet count below 100,000/μl was observed at least once during the entire duration of therapy with Paclitaxel, sometimes the platelet count was below 50,000/μl. There were also cases of bleeding, most of which were local, and the frequency of their occurrence was not associated with the dose of Paclitaxel and the administration schedule.

When using the drug Paclitaxel, it is necessary to regularly monitor your blood count. The drug should not be prescribed to patients with a neutrophil count of less than 1500/μL and less than 1000/μL in patients with Kaposi's sarcoma due to AIDS, and with a platelet count of less than 100,000/μL (75,000/μL in patients with Kaposi's sarcoma due to AIDS).

If severe neutropenia (less than 500/μl) or severe peripheral neuropathy develops during treatment with Paclitaxel, it is recommended to reduce the dose by 20% during subsequent courses of treatment (in patients with AIDS-related Kaposi's sarcoma, by 25%).

Effect on the cardiovascular system

The decrease, increase in blood pressure (BP) and bradycardia observed during the administration of Paclitaxel are usually asymptomatic and in most cases do not require treatment. A decrease in blood pressure (BP) and bradycardia were usually observed during the first 3 hours of infusion. ECG abnormalities were also noted in the form of repolarization disorders such as sinus tachycardia, sinus bradycardia and early extrasystole. In severe cases, treatment with Paclitaxel should be suspended or discontinued.

Monitoring vital signs is recommended, especially during the first hour of drug infusion. If Paclitaxel is used in combination with trastuzumab or doxorubicin for the treatment of metastatic breast cancer, monitoring of cardiac function is recommended.

Cases of severe cardiac conduction disturbances have been reported during treatment with Paclitaxel. If symptoms of cardiac conduction disturbances are detected, patients should be prescribed appropriate therapy along with constant ECG monitoring of the cardiovascular system.

Effect on the nervous system

The incidence and severity of nervous system disorders were generally dose-related. Peripheral neuropathy, usually moderate, was often observed during treatment with Paclitaxel. The incidence of peripheral neuropathy increased as the drug accumulated in the body. Cases of paresthesia were often observed in the form of hyperesthesia.

If severe neuropathy is noted, it is recommended to reduce the dose by 20% in subsequent courses of treatment (in patients with Kaposi's sarcoma due to AIDS - by 25%).

Peripheral neuropathy may be a reason to discontinue therapy with Paclitaxel.

Symptoms of neuropathy decreased or completely disappeared within several months after stopping drug therapy.

The development of neuropathy during previous therapy is not a contraindication for the use of Paclitaxel.

Rarely, abnormal optic nerve evoked potentials have been reported in patients with permanent optic nerve damage.

The possible exposure to ethanol contained in Paclitaxel should be taken into account.

Effect on the gastrointestinal tract

Mild and moderate cases of nausea/vomiting, diarrhea, and mucositis were very common in all patients.

Cases of mucositis depended on the drug administration regimen and were more often observed with a 24-hour infusion than with a 3-hour infusion.

Rare cases of neutropenic enterocolitis (typhlitis), despite co-administration of granulocyte colony-stimulating factor, have been observed in patients using Paclitaxel alone and in combination with other chemotherapy drugs.

Liver failure

Patients with liver failure are at risk for toxic side effects, especially grade 3-4 myelosuppression. Careful monitoring of the patient's condition should be established and, if necessary, consideration should be given to adjusting the dose of the drug.

Radiation pneumonitis has been reported with concomitant radiation therapy.

Patients should use reliable methods of contraception during treatment with Paclitaxel and for at least 3 months after the end of therapy.

Vaccination

When used together, Paclitaxel and live viral vaccines may potentiate the replication of the vaccine virus and/or may increase side effects when using vaccines, since normal protective mechanisms may be inhibited due to the use of Paclitaxel. Vaccination with live viral vaccines in patients using the drug Paclitaxel can lead to the development of severe infections. The patient's immune response to such a vaccine may be reduced.

The use of live vaccines should be avoided in such patients and specialist advice should be obtained.

Fertility

Taking into account the possible mutagenic effect of Paclitaxel, patients of both sexes should be advised to use effective contraception during therapy with Paclitaxel and for 6 months after the end of therapy. Also, due to a possible decrease in fertility in men, cryopreservation of sperm may be recommended for the possibility of conceiving a child in the future.

Side effects of the drug Paclitaxel

Myelosuppression - severe neutropenia (27%), thrombocytopenia (6%), severe thrombocytopenia (1%), anemia (62%), severe anemia (6%); allergic reactions: skin rash (14%), hot flashes (28%), angioedema, bronchospasm, generalized urticaria (2%); arterial hypotension (22%), bradycardia (3%), AV block, ventricular tachycardia, tachycardia in combination with bigeminy (2%), peripheral edema (10%), extremely rarely - myocardial infarction, congestive heart failure (noted during combination chemotherapy, in particular when using anthracyclines); peripheral neuropathy, manifested mainly by paresthesia (64%, and in 4% of patients the symptoms when using the drug in recommended doses were severe), rarely - grand mal attacks and encephalopathy, extremely rarely - muscle weakness, paralytic ileus, optic nerve damage, impairment of visual fields (luminous scotomas), especially with overdose (these effects are usually reversible); reversible alopecia (82%); arthralgia and myalgia (54%, of which in 14% of cases in severe form); nausea and vomiting (44%), diarrhea (25%), anorexia (25%), mucositis (20%), constipation (18%), intestinal obstruction (4%), increased AST activity (18%), alkaline phosphatase ( 18%), hyperbilirubinemia (4%), isolated cases of liver necrosis and hepatic encephalopathy with a fatal outcome, neutropenic and ischemic enterocolitis and intestinal perforation; nail damage and isolated cases of radiation-like dermatitis; local reactions: hyperemia, thrombophlebitis at the injection site (4%). Extravasation with IV administration can lead to the development of edema, tenderness, erythema, infiltration and cellulite; Skin discoloration may occur. Paclitaxel is a potential mutagenic, embryotoxic and fetotoxic agent.

Current aspects of the use of carboplatin in modern chemotherapy of solid tumors

Published in the journal “Effective pharmacotherapy in oncology, hematology and radiology” No. 2/2010

A.Yu. Mashchelueva, M.E. Abramov

Russian Oncology Research Center named after. N.N. Blokhina

Currently, a wide range of antitumor drugs are used in modern oncology. One of the most important and frequently used is carboplatin.

The history of the discovery and development of platinum preparations begins in 1969, when the American chemist Rosenberg, working with platinum electrodes lowered into liquid, saw that the microorganisms in the liquid stopped dividing. He did an analysis and realized that platinum salt, a long-known chemical compound of platinum, had formed there. This is how the idea of ​​developing new antitumor drugs based on platinum arose, which received the opportunity for particularly rapid development in the last 20 years, when various platinum derivatives were created: cisplatin, cycloplatam, carboplatin, oxaliplatin. All these drugs are currently widely used as part of chemotherapy regimens for various nosologies.

Platinum drugs have a similar mechanism of action, based on the formation of covalent bonds with cell DNA, mainly with the nitrogen atom in the seventh position of guanine and adenine. One carboplatin molecule combines with two nucleotides, forming a cross-link, usually within one DNA strand (90%), less often between strands (5%). This leads to disruption of DNA synthesis and functions. The cytotoxicity of carboplatin is also due to binding to nuclear and cytoplasmic proteins. The effect does not depend on the period of the cell cycle [1].

The most common side effects include the following. From the gastrointestinal tract - nausea, vomiting, abdominal pain. Possible complications from the nervous system and sensory organs are peripheral polyneuropathy, asthenia, convulsive syndrome. However, compared to cisplatin, the neurotoxicity of carboplatin is much less pronounced and occurs in 1-6% of cases. From the cardiovascular system and hematopoietic organs - myelosuppression (thrombocytopenia is most often observed, leukopenia, neutropenia, anemia is less common). From the respiratory system - shortness of breath, bronchospasm, cough. From the genitourinary system - impaired renal function. On the part of the skin - in rare cases, the development of alopecia and an allergic reaction in the form of itching and urticaria is possible. On the metabolic side, hypomagnesemia, hypocalcemia, changes in sodium concentration, hypokalemia, increased alkaline phosphatase activity, AST levels, creatinine, total bilirubin, and decreased creatinine clearance occur.

Until recently, the standard chemotherapy for ovarian cancer was the regimen of cisplatin + cyclophosphamide, but based on the results of further studies, it was found that the combination of taxanes and cisplatin is superior to it by increasing the frequency of objective effect (from 64% to 77%), the median time to progression (13 and 18 months) and overall survival (24 and 38 months), respectively [2].

The next step was the replacement of cisplatin with carboplatin due to the pronounced nephro- and neurotoxicity, as well as the emetogenicity of the former. A comparative analysis showed that the use of carboplatin in combination with taxanes did not worsen treatment results, but a decrease in the frequency and intensity of toxic side effects was observed [3,4].

The equal effectiveness of carboplatin and cisplatin in the treatment of epithelial ovarian tumors was confirmed in several randomized studies, such as Alberts (342 patients), Ten Bokkel (339 patients), Edmondson (103 patients).

The above facts have led to the fact that the use of taxol and carboplatin has now become the “gold standard” of drug treatment for ovarian cancer.

Calculating the dose of carboplatin using the Calvert formula (AUC 5-7) allows treatment with minimal toxicity and greatest effectiveness [5,6].

Returning to the topic of scientific monitoring of the use of drugs and their implementation in practice, it should be noted that after the establishment of taxanes and carboplatin as the optimal treatment regimen for ovarian cancer in the treatment of this pathology, there was a certain lull in the treatment of this pathology, which was disrupted by the GOG 182 study, the goal of which was to improve results first-line chemotherapy by adding a third drug to the combination of paclitaxel and carboplatin. However, carboplatin remained an unchanged component of the regimens.

A total of 4312 patients with stage III-IV epithelial ovarian cancer after cytoreductive surgery were included in the study. The study design is presented in Table 1.

Table 1

. GOG Study 182. Chemotherapy regimens.

However, the study showed that the addition of a third drug did not improve treatment outcomes and significantly increased hematological toxicity [7].

table 2

. Preliminary results of the GOG 182 study.

The same conclusion was reached by Italian researchers who, in a randomized study, compared the efficacy and toxicity of the combination of carboplatin and paclitaxel with the combination of topotecan, carboplatin and paclitaxel. The addition of topotecan did not prolong the time to progression, but increased the hematological toxicity of therapy [8].

A study was conducted in Greece in which doxorubicin was added to a combination of cisplatin and paclitaxel. The control group received paclitaxel and carboplatin. The median duration was 44 and 37 months, respectively; the difference was not statistically significant. Regarding toxicity, an increase in the degree and duration of neutropenia was observed. Thus, it was concluded that the triple combination does not lead to a significant improvement in the results of therapy for patients with ovarian tumors compared to the standard one [9].

The next step towards improving the results of chemotherapy for ovarian cancer was the attempt to add bevacizumab, an antibody to VEGF that inhibits the angiogenesis of tumor vessels, to the standard “carboplatin + paclitaxel”. Thus, in a study by Cannistra et al. bevacizumab at a dose of 15 mg/kg IV once every 3 weeks was prescribed to patients with progression after treatment with topotecan and liposomal doxorubicin. The study included 44 patients, of whom 7 (16%) showed an objective effect from the drug. Acute intestinal perforation was noted in 5 (11%) patients, and arterial thromboembolism was noted in another 4 (9%) patients [10].

These data demonstrate the effectiveness of this triple combination, but the reported serious adverse side effects significantly limit the possibility of adding bevacizumab to therapy in treatment-naïve patients. In this regard, the leading role of the combination of carboplatin and taxanes in the first-line treatment of ovarian cancer has been almost completely established.

Undoubtedly, the use of platinum drugs, including Carboplatin-Ebeve, remains fundamentally important in the treatment of ovarian cancer. But regarding the broader discussion of the use of carboplatin, it is possible to consider its use in the treatment of other types of cancer pathologies. In particular, quite good results were obtained when studying combinations of carboplatin with other drugs in the treatment of non-small cell lung cancer.

The combination of platinum derivatives and taxanes is currently recognized as the standard of care for first-line treatment of non-small cell lung cancer. When considering the choice of a specific platinum derivative, cisplatin is usually used in combination with taxanes. However, when analyzing the results of treatment of 1489 patients who received chemotherapy containing cisplatin and 1479 patients who received carboplatin, it was concluded that patients with disseminated NSCLC can be prescribed both cisplatin and carboplatin. The rate of objective effect was significantly higher in the cisplatin group – 30% and 24%, respectively. At the same time, the better immediate efficacy of cisplatin did not lead to an increase in life expectancy compared with carboplatin. When cisplatin was prescribed, patients were more likely to experience nausea, vomiting, and signs of nephrotoxicity, while when carboplatin was prescribed, the only common toxicity was thrombocytopenia. Thus, we can conclude that the inclusion of carboplatin in the treatment regimen for disseminated NSCLC does not worsen long-term results, but is better tolerated, thereby not having a negative impact on the quality of life of patients [11,12].

Another study by Eleni M. Karapanagiotou et al. discussed the combination of carboplatin and pemetrexed in the adjuvant treatment of resectable patients with stage IB, II and IIIA non-small cell lung cancer after surgical treatment. The following regimen was chosen: carboplatin AUC 5 and pemetrexed days 1 and 14 for a total cycle length of 28 days. This study resulted in a time to progression of 26 months with moderate, manageable toxicity. Based on this, it was concluded that the combination of carboplatin and pemetrexed is not inferior in effectiveness to other regimens, but has less toxicity, which contributes to its wider implementation in practice [13].

It is impossible not to note the importance and relevance of discussing the issue of using carboplatin in the treatment of breast cancer. A number of studies have shown that the addition of carboplatin to trastuzumab and paclitaxel therapy in the first line of Her-2-positive disseminated breast cancer is more effective than the combination of trastuzumab and paclitaxel. When comparing the two given regimens, the objective response rate was 53% in the trastuzumab + paclitaxel group and 62% in the trastuzumab + paclitaxel + carboplatin group, respectively [14].

Triple negative breast cancer (ER, PR, HER2-negative) deserves special attention in modern practice. For these patients, chemotherapy alone remains the only treatment option. Currently, evidence has accumulated in the literature that triple negative breast cancer is highly sensitive to platinum agents. Thus, at ASCO 2007, the results of using the combination of taxanes + carboplatin in patients with initially existing metastases, as well as relapses of triple negative breast cancer, were reported. 57% of patients had a partial effect of therapy. The median time to tumor progression was 16 weeks (range, 4 to 28 weeks). These data provided preliminary evidence of the effectiveness of carboplatin-containing chemotherapy regimens in the treatment of triple-negative breast cancer [15].

Quite good results were also shown by a weekly regimen of neoadjuvant chemotherapy for breast cancer with the inclusion of Carboplatin-Ebeve when it was impossible to use anthracyclines [16].

An interesting pilot study was the use of carboplatin in combination with navelbine and interleukin-2 (IL-2). Melanoma is known to be a tumor characterized by low sensitivity to chemotherapy, and patients with advanced metastatic disease have a poor prognosis. There is evidence that platinum preparations and vinca alkaloids have shown some effectiveness in the treatment of disseminated melanoma. Interleukin-2 has been suggested to increase tumor sensitivity to chemotherapy. Twenty-two patients were included in the study, 11 of whom had disseminated cutaneous melanoma, 6 had iris melanoma, and 3 had metastatic melanoma without an identified primary site. As a result of treatment with carboplatin, vinorelbine and interleukin-2, 1 patient had a partial response, 9 patients had stable disease for a median of 6 months (range, 3.0 to 8.6 months). The median time to progression in all patients was 1.8 months (range, 0.7 to 8.6 months), and the median survival was 7.2 months (range, 1.4 to 42.0 months). Toxicity was moderate, quite manageable and manifested mainly by myelosuppression. Thus, it was concluded that the use of carboplatin in combination with vinorelbine and interleukin-2 could be considered as second-line chemotherapy in patients who have progressed after treatment with dacarbazine [17].

The effectiveness of carboplatin monotherapy was also shown in a study by Krege et al. for the treatment of stage IIA/B seminoma. The study included 108 patients with the indicated stages of the disease. All patients had not previously received treatment for seminoma. Treatment was with carboplatin AUC 7 mg min/mL every 4 weeks for three cycles in stage IIA (n=51) or four cycles in stage IIB (n=57). Patients with residual tumor greater than 3 cm after treatment were scheduled to undergo surgical treatment. As a result, a complete effect was registered in 88 (81%) patients, partial regression in 17 (16%), 2 (2%) patients had stable disease, and progression was recorded in one case. As for toxicity, the main type was grade III-IV hematological toxicity, the development of nausea and vomiting was noted in only 10% of cases. Despite the fact that during an average follow-up of 28 months, 13% of patients showed progression of the disease (all patients had a partial effect during carboplatin therapy, and subsequent relapse was noted in the retroperitoneal lymph nodes), the use of carboplatin was considered quite effective and safe [18].

A good balance of efficacy and, so to speak, acceptable toxicity of carboplatin in combination with gemcitabine was demonstrated in a multicenter phase II study, which included 50 patients with locally advanced or metastatic pancreatic cancer. The treatment regimen consisted of gemcitabine 800 mg/m2 on days 1 and 8 and carboplatin AUC 4 on day 8 of each three-week cycle. On average, patients received 6 cycles of treatment. Of the 35 patients who responded to treatment, 8 (17%) had partial response, 15 (32%) and 12 (25%) had stabilization and progression, respectively. At the same time, the median time to progression was 4.4 months, the median overall survival was 7.4 months, and the one-year survival rate was 28%. Toxicity of the regimen was minor and predictable (8% anemia, 6% neutropenia, and 13% thrombocytopenia). However, it should be noted that the clinical effect was significantly expressed after 2 cycles of treatment and manifested itself in a decrease in the intensity of the pain syndrome and, as a consequence, a decrease in the amount of painkillers, as well as an increase in body weight. Taking into account the presented results, we can conclude that the use of carboplatin, including Carboplatin-Ebeve, in combination with gemcitabine for the treatment of patients with locally advanced and metastatic pancreatic cancer is advisable and effective. Again, it is worth noting that the described regimen has an acceptable toxicity profile, which, in turn, is also of fundamental importance for its further use in practice [19]. Carboplatin in combination with paclitaxel in the treatment of patients with esophageal cancer [20], in the same combination in the treatment of uterine carcinosarcoma [21], and in combination with raltitrexed in the treatment of metastatic squamous cell carcinoma of the head and neck [22] also demonstrates fairly high efficacy and good tolerability.

In onco-ophthalmological practice, carboplatin has proven itself well in the treatment of retinoblastoma [23].

Thus, to summarize the above, it is necessary to conclude that the experience of using carboplatin, both foreign and domestic, is quite large; the described points are just some examples of successful clinical trials. In addition, we can say that carboplatin, including Carboplatin-Ebeve, as a representative of the “family” of platinum drugs, is currently widely and successfully used to treat various oncological pathologies. Research is ongoing to include carboplatin in new combinations.

Bibliography

1. E. Chu, Vincent T. DeVita, Jr. Chemotherapy drug manual. 2007 by Jones and Bartlett Publishers.
2. McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian Cancer. N Engl J Med. 1996; 334:1-6.
3. Ozols, RF, Bundy BN, Fowler J et al. Randomized phase III study of cisplatin/paclitaxel versus carboplatin/paclitaxel in optimal stage III epithelial ovarian cancer: a Gynecologic Oncology Group Trial (GOG 158). In: Program and abstracts of the American Society of Clinical Oncology 35th Annual Meeting; May 15-18, 1999; Atlanta, Georgia. Abstract 1373.
4. Lokich J, Anderson N. Carboplatin versus cisplatin in solid tumors: An analysis of the literature. Ann. Onc., Jan 1998; 9: 13-21.
5. Alberts DS, Green S, Hannigan EV et al. J Clin Oncol 1992, 10: 716-720.
6. Swenerton K, Jeffrey J, Stuart G et al. J Clin Oncol 1992, 10: 718-722.
7. Bookman MA. GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-lipososomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced- stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. Proc Am Soc Clin Oncol. 2006; 24:256s. Abstract 5002.
8. Scarfone G, Scambia G, Raspagliesi F et al. A multicenter, randomized, phase III study comparing paclitaxel/carboplatin (PC) versus topotecan/paclitaxel/carboplatin (TPC) in patients with stage III (residual tumor > 1 cm after primary surgery) and IV ovarian cancer (OC). Proc Am Soc Clin Oncol. 2006; 24:256s. Abstract 5003.
9. Aravantinos G, Fountzilas G, Kalofonos HP. Carboplatin and paclitaxel versus cisplatin, paclitaxel and doxorubicin for frontline chemotherapy of advanced ovarian carcinoma (AOC): A Hellenic Cooperative Oncology Group Study. Proc Am Soc Clin Oncol. 2006; 24:274s. Abstract 5074.
10. Cannistra SA, Matulonis U, Penson R et al. Bevacizumab in patients with advanced platinum-resistant ovarian cancer. Proc Am Soc Clin Oncol. 2006; 24:257s. Abstract 5006.
11. Ardizzoni A, Tiseo M, Boni L et al. CISCA (cisplatin vs. carboplatin) meta-analysis: an individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer. Proc Am Soc Clin Oncol. 2006; 24:366s. Abstract 7011.
12. Treat JA, Gonin R, Socinski MA, Edelman MJ et al. A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer. Ann. Onc., Mar 2010; 21: 540-547.
13. Eleni M. Karapanagiotou, Paraskevi G. Boura et al. Carboplatin-Pemetrexed Adjuvant Chemotherapy in Resected Non-small Cell Lung Cancer (NSCLC): A Phase II Study. Anticancer Res, Oct 2009; 29: 4297-4301.
14. Edith A. Perez. Carboplatin in Combination Therapy for Metastatic Breast Cancer. Oncologist, Sep 2004; 9: 518-527.-
15. Chia JW, Ang P, See H, Wong Z, Soh L, Yap Y, Wong N. Triple-negative metastatic/recurrent breast cancer: Treatment with paclitaxel/carboplatin combination chemotherapy. ASCO Meeting Abstracts, Jun 2007; 25:1086.
16. Chen XS, Nie XQ, Chen CM, Wu JY, Wu J, Lu JS, Shao ZM, Shen ZZ, Shen KW. Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer. Ann. Onc., May 2010; 21: 961-967.
17. Vuoristo MS, Vihinen P, Skytta T, Tyynela K, Kellokumpu-Lehtinen P. Carboplatin and Vinorelbine Combined with Subcutaneous Interleukin-2 in Metastatic Melanoma with Poor Prognosis. Anticancer Res, May 2009; 29: 1755-1759.
18. Krege S, Boergermann C, Baschek R, Hinke A, Pottek T, Kliesch S, Dieckmann K.-P., Albers P, Knutzen B, Weinknecht S, Schmoll H.-J., Beyer J, Ruebben H. Single agent carboplatin for CS IIA/B testicular seminoma. A phase II study of the German Testicular Cancer Study Group (GTCSG). Ann. Onc., Feb 2006; 17: 276-280.
19. Xiros N, Papacostas P, Economopoulos T, Samelis G, Efstathiou E, Kastritis E, Kalofonos H, Onyenadum A, Skarlos D, Bamias A, Gogas H, Bafaloukos D, Samantas E, Kosmidis P. Carboplatin plus gemcitabine in patients with inoperable or metastatic pancreatic cancer: a phase II multicenter study by the Hellenic Cooperative Oncology Group. Ann. Onc., May 2005; 16: 773-779.
20. El-Rayes BF, Shields A, Zalupski M, Heilbrun LK, Jain V, Terry D, Ferris A, Philip PA. A phase II study of carboplatin and paclitaxel in esophageal cancer. Ann. Onc., Jun 2004; 15: 960-965.
21. Powell MA, Filiaci VL, Rose PG, Mannel RS, Hanjani P, DeGeest K, Miller BE, Susumu N, Ueland FR. Phase II Evaluation of Paclitaxel and Carboplatin in the Treatment of Carcinosarcoma of the Uterus: A Gynecologic Oncology Group Study. J. Clin. Oncol., Jun 2010; 28: 2727-2731.
22. Galetta D, Giotta F et al. Carboplatin in Combination with Raltitrexed in Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma: A Multicentre Phase II Study of the Gruppo Oncologico Dell'Italia Meridionale (GOIM). Anticancer Res Nov 2005; 25: 4445-4449.
23. Leng T, Cebulla CM, Schefler AC, Murray TG. Focal periocular carboplatin chemotherapy avoids systemic chemotherapy for unilateral, progressive retinoblastoma. Retina, Apr 2010; 30(4 Suppl): S66-8.

Special instructions for the use of Paclitaxel

Do not allow the undiluted concentrate to come into contact with polyvinyl chloride containing a plasticizer, from which devices for transfusion of infusion solutions can be made. To minimize the risk of ingestion of plasticizer (di-[2-ethylhexyl] phthalate), which may be extracted from polyvinyl chloride containers or infusion sets, diluted solutions of paclitaxel should be prepared and stored in glass, polypropylene or polyolefin containers and administered through an infusion system with an internal surface made of polyethylene. The paclitaxel infusion system must have a membrane filter with a pore diameter of no more than 0.22 µm. If severe hypersensitivity reactions occur, paclitaxel should be discontinued immediately and not re-administered. When using paclitaxel, regular monitoring of peripheral blood composition, blood pressure, heart rate, and ECG is indicated, especially during the 1st hour of drug infusion. If a patient develops myocardial conduction disturbances during treatment with the drug during repeated administrations, continuous ECG monitoring should be performed. Caution must be exercised when handling paclitaxel; Medical personnel should use protective gloves. If paclitaxel solution gets on the skin or mucous membranes, they should be washed immediately with plenty of running water. Upon local contact with paclitaxel, a tingling, burning sensation, as well as skin hyperemia is noted; Accidental inhalation of paclitaxel vapor may cause shortness of breath, chest pain, burning sensation in the eyes, sore throat and nausea.

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Paclitaxel in chemotherapy of ovarian cancer

N

Despite the significant progress in chemotherapy of ovarian cancer achieved in the last decade of the last century and associated, to a large extent, with the emergence and widespread introduction into clinical practice of new antitumor drugs, the results of treatment of this disease today remain unsatisfactory.
The incidence of ovarian cancer has a steady upward trend
, and already in the first year from the moment of diagnosis, every third patient dies.

The use of only surgical treatment (subject to adequate staging) is possible for stage IAB in patients with a low risk of recurrence. In all other cases, chemotherapy (neoadjuvant and/or adjuvant) is necessarily included in the complex of treatment measures, and in case of stage IV of the disease or progression of the process it becomes the main method of treatment.

Today, in 80% of patients, the disease is diagnosed in late stages, and even with clinically established stage I, relapses and metastases subsequently occur in at least 25% of cases. Thus, the population of patients with ovarian cancer who need modern and adequate chemotherapy is extremely wide.

CP was considered the most active regimen

(cisplatin + cyclophosphamide).
The emergence of taxanes, and primarily paclitaxel
, characterized by a unique mechanism of action, has made it possible to achieve significant results.

The first phase II clinical studies of paclitaxel revealed its high antitumor activity in ovarian cancer [2] (Table 1).

The most impressive results were from the Jon Hopkins Group. The effect was registered in 12 out of 41 patients. The main manifestation of toxicity was leukopenia, which required a dose reduction from 250 mg/m2 to 110 mg/m2 and became increasingly dose-limiting from course to course. Similar results were obtained by GOG and Alb. Einstein Group.

Preclinical tests conducted in vitro

on various human tumor cell lines showed that the suppression of the growth of malignant cells under the influence of paclitaxel is dose- and regimen-dependent [4,21].
However, in in vivo
, the maximum antitumor effect was achieved at doses lower than the maximum tolerated [42]. Taking into account these data and the phase II results establishing the high hematological toxicity of paclitaxel at doses > 200 mg/m2, a study of lower doses of 110–200 mg/m2 was initiated. At the same time, paclitaxel was initially considered as a 2nd-line drug, giving in monochemotherapy a fairly high rate of objective effect in platinum-resistant patients (up to 20–30% for a duration of 3 to 6 months).

Table 2 shows the design of the randomized Euro-Canadian phase III trial in disseminated ovarian cancer, which included 382 patients previously treated with cisplatin [11]. This protocol compared two doses of paclitaxel, 135 mg/m2 and 175 mg/m2, and two administration regimens, a 3-hour and a 24-hour infusion.

The overall effectiveness was independent of the duration of infusion and was slightly higher when using a dose of 175 mg/m2 compared with 135 mg/m2 (20% and 17%, respectively, the differences were not statistically significant). However, the time to disease progression at a dose of 175 mg/m2 in a 3-hour infusion mode (group B) turned out to be significantly longer (19 weeks) than in groups A, C and D (14 weeks each). In addition, longer 24-hour infusions were associated with more severe granulocytopenia compared with 3-hour infusions (74% and 17%, respectively, p < 0.0001).

The results of subsequent studies of paclitaxel alone in platinum-resistant patients are presented in Table 3.

The effectiveness of treatment ranged from 13 to 38%, median survival - from 9.6 to 13.2 months.

Thus, the use of paclitaxel at a dose of 175 mg/m2 as a 3-hour infusion once every 3 weeks was considered optimal for ovarian cancer. This mode is now considered standard and is widely used in practice. Due to the fact that the drug is mainly inactivated in the liver and excreted in the bile, if liver function is impaired, its dose should be reduced to 135 mg/m2 and lower (75–50 mg/m2) [42]. Less than 10% of paclitaxel is excreted by the kidneys, so there is no indication of the need for dose reduction in renal failure [35].

The next stage of clinical research was the study of paclitaxel in first-line combination chemotherapy in patients with disseminated ovarian cancer

. The experiment found that the sequence of administration of cytostatics is very important: paclitaxel infusion should be carried out before cisplatin [20]. This is explained by the fact that platinum derivatives increase the number of cells in the S phase, and the subsequent administration of paclitaxel, which acts in the G2|M phase, is ineffective. In addition, administration of cisplatin before paclitaxel increases the toxicity of the latter by reducing its plasma clearance. This may be due to the modulating effect of cisplatin on cytochrome P450 enzymes [18,28].

The results of four randomized international trials comparing paclitaxel + cisplatin (TP) with the then standard cyclophosphamide + cisplatin (CP) regimen are presented in Table 4.

In the
GOG-111
, 386 patients with stage III–IV ovarian cancer after suboptimal cytoreductive operations received 6 cycles of polychemotherapy in the
TP
(paclitaxel - 135 mg/m2 24 h + cisplatin 75 mg/m2) or
CP
(cyclophosphamide 750 mg/m2 +) cisplatin 75 mg/m2). A significant advantage of the TP regimen over the CP regimen was demonstrated in both immediate and long-term results: the overall effectiveness was 73% and 60%, the median time to progression was 18 months. and 13 months, median survival – 38 months. and 24 months respectively.

In the OV-10

similar results were obtained, confirming the advantage of the combination of paclitaxel + cisplatin as the first line of chemotherapy, after which this regimen was widely introduced into clinical practice.

Next study ( GOG-132

) was aimed at assessing the role of each of the cytostatics and compared the TR regimen with monochemotherapy with paclitaxel and cisplatin (“3 arms”). The data obtained did not reveal any significant differences between the compared groups. Further analysis showed that as patients progressed in subsequent lines of treatment, they received crossover drugs. This, apparently, led to the same long-term results.

In the international study ICON 3

, including 2000 patients, compared 3 chemotherapy regimens: paclitaxel 175 mg/m2 + carboplatin AUC 6; one carboplatin AUC 6 and a combination of CAP (cisplatin 50 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2). The median time to progression and overall survival were approximately the same (16.2–17.7 and 36–38 months, respectively, Table 4). However, as in the previous study, more than 30% of patients who progressed during chemotherapy with carboplatin or SAR subsequently received paclitaxel, which could affect the leveling of indicators in the compared groups. Overall, these reports supported the hypothesis that sequential use of platinum and paclitaxel is equivalent to their simultaneous use.

Attempts to improve treatment results by increasing the total number of courses did not produce the expected results. In the GOG-114

[24] compared the standard TR regimen with a more intensive one: 2 courses of carboplatin AUC 9, then 6 courses of paclitaxel 135 mg/m2 infusion over 24 hours + cisplatin intraperitoneal 100 mg/m2. The standard regimen was slightly inferior in terms of median time to progression, but overall survival was similar.

Considering the nephro-, oto- and neurotoxicity of cisplatin, the next stage of the work was to evaluate the possibilities of replacing cisplatin with carboplatin in combination with paclitaxel. Three international randomized studies (GOG 158, the German-Austrian AGO group and the Danish-Dutch group) compared the regimens of paclitaxel + cisplatin and paclitaxel + carboplatin in the first line of chemotherapy in patients with ovarian cancer (Table 5).

In all three studies, both regimens demonstrated equal efficacy in both immediate and long-term results, with significantly higher toxicity in combination with cisplatin.

Thus, in the USA and European countries, the combination of paclitaxel 175 mg/m2 + carboplatin AUC 5–7

(once every 3 weeks, 6 cycles in total) is currently recognized as
the “gold standard” of first-line chemotherapy for ovarian cancer
.

Randomized trials for the treatment of recurrent ovarian cancer in platinum-sensitive patients also clearly demonstrated the advantages of combinations with paclitaxel compared with platinum derivatives alone in both immediate and long-term results (Table 6).

The ICON4/OVAR2.2 protocol included 802 patients with late relapses of ovarian cancer (6 months after the end of platinum-containing chemotherapy). Treatment was carried out with a combination of paclitaxel with platinum derivatives or platinum derivatives alone. 1-year progression-free survival and 2-year overall survival were significantly better in the paclitaxel group (49% and 59%) compared with cisplatin/carboplatin monotherapy (40% and 50%), p = 0.006 [19].

Similar data on the advantage of the combination of paclitaxel + carboplatin compared with carboplatin alone in the treatment of recurrent ovarian cancer in platinum-sensitive patients were presented by the Spanish group [13]. The overall effectiveness of treatment was significantly higher when using the combination (74.4%; CR - 23.1%) compared with carboplatin alone (52.6%; CR - 21%).

Given the meta-analysis data showing that the addition of anthracyclines to first-line chemotherapy without taxanes significantly improves long-term treatment outcomes [43], a number of randomized studies (EORTC-NSGO-NCIC and German-Franco-Austrian) were conducted comparing the combination of TCb (carboplatin AUC–5+ paclitaxel 175 mg/m2 3 hours) with the triple combination of TECb (carboplatin AUC–5+ paclitaxel 175 mg/m2 3 hours + epirubicin 60 mg/m2 before paclitaxel). When assessing the effectiveness of treatment, a certain advantage of the three-component regimen was noted (PR - 48% and 42%, PR - 38% and 32%, differences are not significant), however, it was characterized by higher myelotoxicity, which required a reduction in doses of cytostatics and an increase in the intervals between courses [9] .

Reports of new two- and three-component paclitaxel-based regimens for advanced ovarian cancer deserve close attention.

of paclitaxel + platinum drugs + topotecan is very promising

. When using the regimen of topotecan 1 mg/m2 on days 1, 2, 3 + paclitaxel 175 mg/m2 3 hours on day 3 + carboplatin AUC–5 on day 3 (6 courses every 3 weeks), the overall effectiveness was 88. 2%, of which pathomorphologically confirmed complete remission is in 23.5% of patients [6]. The main toxicity was hematological (grade 3–4 neutropenia – 40%, grade 3–4 anemia – 45%).

In a study by Engelholn S. et al., 2000 (the regimen featured 6-day oral administration of topotecan), the effectiveness of this combination as a 1st line reached 100%

.

The same 100% effectiveness reported by Herben et. al. (1999), achieved using the combination of paclitaxel 110 mg/m2 24 hours 1st day + cisplatin 75 mg/m2 2nd day + topotecan 0.3 mg/m2 120 hours (days 1–6) as the first line in patients with stage III–IV ovarian cancer, but the regimen required the administration of hematohormones.

A phase III multicenter randomized trial comparing the combination of paclitaxel/carboplatin and topotecan/paclitaxel/carboplatin in patients with stage III (suboptimal) and stage IV ovarian cancer is currently underway [37]. Group A receives paclitaxel 175 mg/m2 + carboplatin AUC–5 once every 3 weeks; group B – topotecan 1 mg/m2 on days 1, 2, 3 + paclitaxel 175 mg/m2 on day 3 + carboplatin AUC–5 on day 3 once every 3 weeks.

The results of the combination paclitaxel + carboplatin + altretamine, developed in the chemotherapy department of the Russian Cancer Research Center named after. N.N. Blokhin, as 2–3rd lines of treatment: 70.4% overall effectiveness and 29.6% complete regressions [1].

An important direction is the development of modes for the sequential use of various combinations. Table 7 presents the results of such studies.

In addition to the standard regimen, since the mid-90s, the interest of researchers in short infusions of paclitaxel, carried out once a week, has increased significantly. The fact is that paclitaxel is a phase-specific cytostatic agent that acts on tumor cells in the G2|M phase of the cell cycle. Repeated administration of the drug once a week leads to an increase in the number of dividing cells exposed to paclitaxel in the G2|M phase and, accordingly, their death increases [23].

In addition, longer exposure to the cytostatic agent resulting from its weekly administration may enhance the effect by enhancing the antiangiogenic effect and increasing tumor cell apoptosis [27].

Studies by European scientists have shown that for ovarian cancer, short weekly infusions of low doses (60–90 mg/m2) are as effective as standard treatment regimens. The randomized Swedish-Finnish study included 208 patients with ovarian cancer who had previously received platinum-based therapy [3,36]. Group I received paclitaxel by 3-hour infusion once every 3 weeks. 200 mg/m2. Group II also received paclitaxel for 3 hours, but weekly, at an average dose of 67 mg/m2, while the course dose for 3 weeks was almost 210 mg/m2. The effectiveness of treatment was approximately the same (37% and 35%, respectively) with a median overall survival of 14.7 and 13.6 months. The toxicity of the standard regimen was significantly higher: grade 3–4 neutropenia 45% versus 18%, grade 3 neuropathy 29% versus 11%, alopecia 79% versus 46%.

Kern J. et al. (2000) used weekly administrations of paclitaxel 80 mg/m2 as a 1-hour infusion in 31 patients. The overall effectiveness was 55%, stabilization was achieved in another 20%.

At the 14th International Congress on Anticancer Therapy in Paris in 2003 [32], it was emphasized that paclitaxel

in a weekly regimen, it is currently
the most active drug for second-line monochemotherapy in platinum-resistant patients
(overall effectiveness - 33-47%), significantly superior to gemcitabine (19%), oral etoposide (27%), liposomal doxorubicin (10%) and topotecan (10%).

At the State Scientific Research Center named after. N.N. Blokhin RAMS, GUN Research Institute of Oncology named after. prof. N.N. Petrov Ministry of Health of the Russian Federation and the Sverdlovsk Regional Oncology Center of the Oncology Scientific and Practical Center are conducting a clinical trial of paclitaxel, manufactured by Dr. Reddy's Laboratories Ltd. called Mitotax

®
.
Its structure is identical to the antitumor drug paclitaxel and has similar activity. The drug is available in convenient packaging in bottles of 30 mg/5 ml, 100 mg/16.7 ml and 250 mg/41.7 ml. Composition: active substance: paclitaxel, 1 ml of concentrate contains 6 mg of active substance. Excipients: polyoxyl 35, castor oil, absolute alcohol. In a preliminary analysis of the experience of using Mitotax in patients with ovarian cancer, the spectrum of antitumor activity and toxicity is completely similar to paclitaxel, which allows us to recommend the drug for widespread use in clinical practice [1]. The premedication regimen used for weekly infusions is noteworthy. Before the first injection, 8–10 mg of dexamethasone is used, then its dose is progressively reduced to 8, 6 and 4 mg. In some cases, if no hypersensitivity reactions were observed, dexamethasone was even discontinued.

In conclusion, it should be noted that the combination of paclitaxel 175 mg/m2 + carboplatin AUC 5–7 (once every 3 weeks, 6 cycles in total) is the “gold standard” of first-line chemotherapy for ovarian cancer, and paclitaxel in a weekly regimen is currently day is the most active drug for second-line monotherapy for resistance to platinum derivatives.
The inclusion of paclitaxel in a second-line combination during progression of ovarian cancer should be mandatory for both platinum-sensitive and platinum-resistant patients. Use of Mitotax® (paclitaxel) manufactured by Dr. Reddy's Laboratories Ltd. allows you to make treatment economically accessible without compromising its quality. Literature:
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