Xeloda, 500 mg, film-coated tablets, 120 pcs.

Release form and composition

Xeloda is produced in the form of film-coated tablets: oblong, biconvex, with the inscription “XELODA” on one side and “150” or “500” on the other:

• 150 mg: 60 pcs. in polyethylene bottles, 1 bottle in a cardboard box; 10 pcs. in blisters, 6 blisters in a cardboard pack;
• 500 mg: 120 pcs. in polyethylene bottles, 1 bottle in a cardboard box; 10 pcs. in blisters, 12 blisters in a cardboard box).

1 tablet contains:

• Active substance: capecitabine – 150 or 500 mg;
• Auxiliary components (respectively): lactose – 15.6 / 52 mg; microcrystalline cellulose – 7.2 / 24 mg; croscarmellose sodium – 6/20 mg; hypromellose (3 mPa.s) – 4.5/15 mg, magnesium stearate – 2.7/9 mg.

Shell composition:

• 150 mg tablets (light milky pink): Opadry pink 03A14309 – 8.5 mg;
• 500 mg tablets (milky pink): Opadry pink 03A14380 – 18 mg.

Indications for use

• Breast cancer: monotherapy for metastatic or locally advanced breast cancer, resistant to chemotherapy with taxanes or anthracycline drugs, or if there are contraindications to them;
• Breast cancer: combination treatment with docetaxel for metastatic or locally advanced breast cancer, when chemotherapy including anthracycline drugs is ineffective;
• Gastric cancer: first-line treatment for advanced gastric cancer;
• Colorectal cancer: adjuvant treatment of stage III colon cancer after surgical treatment;
• Colorectal cancer: treatment of metastatic colorectal cancer.

Contraindications

• Presence of contraindications to one of the combination therapy drugs;
• The initial content of neutrophils is less than 1.5 × 109/L and/or platelets is less than 100 × 109/L;
• Severe renal failure (creatinine clearance below 30 ml per minute);
• Established deficiency of dihydropyrimidine dehydrogenase (DPD);
• Concomitant use with sorivudine and its structural analogues such as brivudine;
• Children's age (the safety and effectiveness of the drug for this age group of patients have not been established);
• Pregnancy and lactation (breastfeeding);
• Hypersensitivity to the components of the drug, as well as to fluorouracil, or with a history of reported cases of severe or unexpected adverse reactions to treatment with fluoropyrimidine derivatives.

Xeloda should be prescribed with caution to patients over 60 years of age, as well as to patients with the following diseases/conditions:

• Liver failure;
• Moderate renal failure;
• Cardiac ischemia;
• Simultaneous use with oral coumarin anticoagulants;
• Hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Directions for use and dosage

Xeloda should be taken orally with water, no later than 30 minutes after meals.

For monotherapy of colorectal cancer, colon cancer and breast cancer, Xeloda is usually prescribed 2 times a day (morning and evening) at 1250 mg/m2 for 14 days, followed by a break for 7 days.

In the treatment of breast cancer, Xeloda as part of combination therapy is prescribed according to the same regimen simultaneously with docetaxel, which is used once every 3 weeks at a dose of 75 mg/m2 as an intravenous infusion for 1 hour. Premedication should be given before docetaxel is administered.

As part of combination therapy for colorectal cancer and gastric cancer, the single dose of Xeloda should be reduced to 800-1000 mg/m2. The drug is used 2 times a day for 14 days, followed by a seven-day break or continuously at 625 mg/m2 2 times a day. The addition of immunobiological drugs to combination therapy does not affect the dose of Xeloda.

Antiemetics and premedication are prescribed before the administration of oxaliplatin and cisplatin according to the instructions for their use.

When carrying out adjuvant therapy for stage III colon cancer, the recommended duration of the treatment course with Xeloda is 6 months (i.e. 8 courses).

Xeloda in combination with cisplatin is usually prescribed 2 times a day at 1000 mg/m2 for 14 days, followed by a break of 7 days. Cisplatin is administered as an intravenous infusion over 2 hours once every 3 weeks at 80 mg/m2 (the first infusion should be carried out on the first day of the cycle).

In combination with bevacizumab and/or oxaliplatin, Xeloda is prescribed 2 times a day at 1000 mg/m2 for 14 days, followed by a seven-day break. The first dose of Xeloda should be taken in the evening on the first day of the therapy cycle, the last dose in the morning on the 15th day. Bevacizumab is administered intravenously by infusion over 30-90 minutes at 7.5 mg/kg once every 3 weeks. The first infusion should be given on the first day of the cycle. After bevacizumab, oxaliplatin is administered intravenously at a dose of 130 mg/m2 within 2 hours.

Simultaneously with epirubicin and a platinum-based drug, Xeloda is prescribed continuously at 625 mg/m2 2 times a day. Starting from the first day of the cycle, epirubicin is administered intravenously as a bolus of 50 mg/m2 once every 3 weeks. A platinum-based drug (oxaliplatin 130 mg/m2 or cisplatin 60 mg/m2) should be administered on the first day of the cycle as an intravenous infusion over 2 hours, then once every 3 weeks.

Xeloda in combination with irinotecan is taken 2 times a day at 1000 mg/m2 for 14 days, followed by a seven-day break. Irinotecan is administered intravenously by infusion over 30 minutes at 250 mg/m2 once every 3 weeks. The first infusion is prescribed on the first day of the cycle.

Xeloda is prescribed simultaneously with bevacizumab and irinotecan 2 times a day at 800 mg/m2 for 14 days, followed by a seven-day break. Irinotecan is administered intravenously by infusion over 30 minutes at a dose of 200 mg/m2 once every 3 weeks. Bevacizumab is also administered intravenously by infusion for 30-90 minutes once every 3 weeks at a dose of 7.5 mg/kg. The first infusion of bevacizumab and irinotecan is prescribed on the first day of the cycle.

The toxic effects of Xeloda can be eliminated by symptomatic treatment and/or dose adjustment (by reducing the dose of the drug or interrupting treatment). After reducing the dose, it cannot be subsequently increased.

If, according to the doctor's assessment, the toxic effect of Xeloda is not serious or life-threatening for the patient, therapy can be continued at the initial dose without reducing it or interrupting therapy.

The patient should immediately inform the doctor about the appearance of undesirable symptoms. If several doses of the drug were missed due to toxic effects, they are not made up.

Therapy should be interrupted if signs of grade 3-4 hematological toxicity appear.

In patients with liver metastases and moderate or mild liver dysfunction, no change in the starting dose of Xeloda is required. However, these patients must be carefully monitored.

Elderly and senile patients do not need to adjust the initial dose during monotherapy.

Instructions for use of the drug Xeloda 500 mg No. 120

Composition Pharmacotherapeutic group Pharmacological properties Pharmacokinetics Indications Contraindications Pregnancy and breastfeeding Method of administration and dosage Side effects Overdose Storage conditions For what diseases is it used?

Compound

Active substance: capecitabine - 500 mg.
Excipients: lactose - 52.0 mg, microcrystalline cellulose - 24.0 mg, croscarmellose sodium - 20.0 mg, hypromellose (3 mPa.s) - 15.0 mg, magnesium stearate - 9.0 mg.

Shell: Opadry pink 03A14380 (hypromellose (6 mPa.s), talc, titanium dioxide (E171), yellow iron oxide dye (E172), red iron oxide dye (E172)) - 18.0 mg.

Pharmacotherapeutic group

Antitumor agent, antimetabolite

Pharmacological properties

Capecitabine is a fluoropyrimidine carbamate derivative, an oral cytostatic agent that is activated in tumor tissue and has a selective cytotoxic effect on it.

In vitro, capecitabine does not have a cytotoxic effect; in vivo, it is converted to 5-fluorouracil (5-FU), which is further metabolized.

The formation of 5-FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase, which minimizes the systemic effect of 5-FU on healthy tissues of the body.

The sequential enzymatic biotransformation of capecitabine into 5-FU creates higher concentrations of the drug in tumor tissues than in surrounding healthy tissues. After oral administration of capecitabine to colorectal cancer patients (N=8), the concentration of 5-FU in tumor tissue was 3.2 times greater than that in adjacent healthy tissue (range, 0.9 to 8.0).

The ratio of 5-FU concentrations in tumor tissue and plasma is 21.4 (range from 3.9 to 59.9), the ratio of its concentration in healthy tissues and plasma is 8.9 (range from 3.0 to 25.8). Thymidine phosphorylase activity in a primary colorectal tumor is also 4 times higher than in adjacent healthy tissues.

Tumor cells from patients with breast, gastric, colorectal, cervical and ovarian cancer contain higher levels of thymidine phosphorylase, which can convert 5'-DFUR (5'-deoxy-5-fluorouridine) to 5-FU, than in corresponding healthy tissues .

Both healthy and tumor cells metabolize 5-FU into 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites damage cells through two different mechanisms. First, FdUMP and the folate cofactor N5-10-methylenetetrahydrofolate bind to thymidylate synthase (TS) to form a covalently linked tertiary complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is an essential precursor to thymidine triphosphate, which in turn is essential for DNA synthesis, so a deficiency of this substance can lead to inhibition of cell division.

Secondly, during RNA synthesis, nuclear transcription enzymes may mistakenly include FUTP instead of uridine triphosphate (UTP). This metabolic "error" disrupts RNA processing and protein synthesis.

Pharmacokinetics

Suction. After oral administration, capecitabine is absorbed quickly and completely, after which it is transformed into the metabolites 5'-deoxy-5-fluorocytidine (5'-DFCT) and 5'-DFUR. Food reduces the rate of absorption of capecitabine, but has little effect on the area under the concentration-time curve (AUC) of 5'-DFUR and the downstream metabolite 5-FU. When prescribing capecitabine after meals at a dose of 1250 mg/m2; on the 14th day, the maximum plasma concentrations (Cmax) of capecitabine, 5'-DFCT, 5'-DFUR, 5-FU and FBAL were, respectively: 4.47, 3.05, 12.1, 0.95 and 5.46 μg/ml. The time to reach maximum concentration (Tmax) was 1.50, 2.00, 2.00, 2.00 and 3.34 hours. AUC0-∞ was 7.75, 7.24, 24.6, 2.03 and 36.3 μg x h/ml, respectively.

Distribution (protein binding) An in vitro study in human plasma showed that for capecitabine, 5'-DFCT, 5'-DFUR and 5-FU, protein binding (mainly albumin) was 54%, 10%, 62% and 10%, respectively.

Metabolism. It is primarily metabolized in the liver under the influence of carboxylesterase to the metabolite 5'-DFCT, which is then transformed into 5'-DFUR under the action of cytidine deaminase, located mainly in the liver and tumor tissues. Further transformation to the active cytotoxic metabolite 5-FU occurs predominantly in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase.

The AUC for 5-FU in plasma is 6-22 times less than after an intravenous bolus of 5-FU at a dose of 600 mg/m2. Capecitabine metabolites become cytotoxic only after conversion to 5-FU and 5-FU metabolites.

Next, 5-FU is catabolized to form inactive metabolites: dihydro-5-fluorouracil (FUN2), 5-fluororeidopropionic acid (FUPA) and α-fluoro-β-alanine (FBAL); this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), the activity of which limits the rate of the reaction.

Excretion. The body half-life (t1/2) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL is 0.85, 1.11, 0.66, 0.76 and 3.23 hours, respectively. The pharmacokinetics of capecitabine were studied in doses from 502 to 3514 mg/m2 per day. The pharmacokinetic parameters of capecitabine, 5'-DFCT and 5'-DFUR on days 1 and 14 were similar. The AUC of 5-FU increased by 30-35% by day 14 and did not increase further (day 22). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of 5-FU, were dose-dependent.

After oral administration of capecitabine, its metabolites are excreted primarily in the urine. The majority (95%) of the administered dose of capecitabine is excreted in the urine. Excretion in feces is minimal (2.6%). The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose taken is excreted unchanged in the urine.

Indications

Mammary cancer:

• Combination therapy with docetaxel for locally advanced or metastatic breast cancer when chemotherapy that includes an anthracycline drug is ineffective.
• Monotherapy for locally advanced or metastatic breast cancer resistant to chemotherapy with taxanes or anthracyclines or if there are contraindications to them.

Colorectal cancer:

• Adjuvant therapy for stage III colon cancer after surgical treatment.
• Therapy of metastatic colorectal cancer.

Stomach cancer:

• First-line therapy for advanced gastric cancer.

Contraindications

• Hypersensitivity to capecitabine or any other components of the drug.
• Hypersensitivity to fluorouracil or with a history of unexpected or severe adverse reactions to treatment with fluoropyrimidine derivatives.
• Established deficiency of DPD (dihydropyrimidine dehydrogenase), as for other fluoropyrimidines.

• Concomitant use of sorivudine or its structural analogues such as brivudine.
• Severe renal failure (creatinine clearance below 30 ml/min). Initial neutrophil count <1.5 x 109/L and/or platelets <100 x109/L.
• If there are contraindications to one of the combination therapy drugs, it should not be used.

Pregnancy and lactation period

Children's age (efficacy and safety of use have not been established).

With caution: In case of coronary artery disease, moderate renal failure or liver failure, age over 60 years, simultaneous use with oral coumarin anticoagulants, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Directions for use and doses

Orally, with water, no later than 30 minutes after meals.

Standard dosage regimen:

Monotherapy. Colorectal cancer, colon cancer and breast cancer. 1250 mg/m2; 2 times a day - morning and evening (total daily dose 2500 mg/m2;) for two weeks, followed by a seven-day break.

Combination therapy. Breast cancer: 1250 mg/m2; 2 times a day for two weeks, followed by a seven-day break, in combination with docetaxel at a dose of 75 mg/m2; once every three weeks as an intravenous infusion for 1 hour.

Premedication is carried out before the administration of docetaxel in accordance with the instructions for its use.

Colorectal cancer and stomach cancer: as part of combination therapy, the dose of Xeloda should be reduced to 800-1000 mg/m2 2 times a day for two weeks, followed by a seven-day break, or to 625 mg/m2 2 times a day in a continuous mode. The addition of immunobiological drugs to combination therapy does not affect the dose of Xeloda.

Antiemetics and premedication to ensure adequate hydration are prescribed before the administration of cisplatin and oxaliplatin according to the instructions for use of cisplatin and oxaliplatin when used in combination with Xeloda.

• In the adjuvant treatment of stage III colon cancer, the recommended duration of therapy with Xeloda® is 6 months, i.e. 8 courses.
• In combination with cisplatin: 1000 mg/m2 2 times a day for two weeks, followed by a seven-day break in combination with cisplatin (80 mg/m2 once every 3 weeks, IV infusion over 2 hours, the first infusion is prescribed at first day of the cycle). The first dose of Xeloda® is prescribed in the evening on the first day of the therapy cycle, the last dose in the morning on the 15th day.
• In combination with oxaliplatin and/or bevacizumab: 1000 mg/m2 2 times a day for two weeks, followed by a seven-day break in combination with oxaliplatin and/or bevacizumab. The first dose of Xeloda® is prescribed in the evening on the first day of the therapy cycle, the last dose in the morning on the 15th day. Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, intravenous infusion over 30-90 minutes, the first infusion begins on the first day of the cycle. After bevacizumab, oxaliplatin is administered at a dose of 130 mg/m2, intravenous infusion over 2 hours.
• In combination with epirubicin and a platinum-based drug: 625 mg/m2 2 times a day continuously in combination with epirubicin (50 mg/m2 once every 3 weeks, IV bolus, starting from the first day of the cycle) and the drug platinum based. A platinum-based drug (cisplatin at a dose of 60 mg/m2 or oxaliplatin at a dose of 130 mg/m2) should be administered on the first day of the cycle as an intravenous infusion for 2 hours, then once every 3 weeks.

Side effect

The frequency of adverse reactions is presented in accordance with the following gradation: very often >1/10, often from >1/100 to <1/10, infrequently from ≥1/1000 to <1/100.

Monotherapy with Xeloda:

Metabolic and nutritional disorders: very often - anorexia; often - dehydration, loss of appetite.

Nervous system disorders: often - headache, dizziness (except vertigo), paresthesia, dysgeusia (taste perversion).

Visual disturbances: often - increased lacrimation, conjunctivitis.

Gastrointestinal disorders: very often - diarrhea, vomiting, nausea, stomatitis (including ulcerative), abdominal pain; often - constipation, epigastric pain, dyspepsia.

Disorders of the skin and subcutaneous tissues: very often - hand-foot syndrome (paresthesia, swelling, hyperemia, skin peeling, blistering), dermatitis; often - rash, alopecia, erythema, dry skin. Skin cracks at least thought to be related to Xeloda therapy were reported in less than 2% of patients in 7 completed clinical studies (N=949).

Impact on the results of laboratory and instrumental studies: often - hyperbilirubinemia.

General disorders and disorders at the injection site: very often - fatigue, drowsiness; often - fever, weakness, asthenia.

The following adverse reactions are toxicities known to occur with fluoropyrimidine therapy; At least an indirect association between the development of such reactions and the use of Xeloda was reported in less than 5% of patients participating in 7 completed clinical studies (N=949):

disorders of the gastrointestinal tract: dry mouth, flatulence, adverse reactions associated with inflammation/ulceration of the mucous membranes, such as: esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding;

disorders of the cardiovascular system: edema of the lower extremities, cardialgia, including angina pectoris, cardiomyopathy, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including atrial fibrillation, ventricular extrasystoles;

Nervous system disorders: taste disturbance, insomnia, confusion, encephalopathy, symptoms of cerebellar disorders (ataxia, dysarthria, impaired balance and coordination);

mental disorders: depression;

infectious and parasitic diseases: infectious complications associated with myelosuppression, weakened immunity and/or disorders of the integrity of the mucous membranes, such as local and fatal systemic infections (bacterial, viral or fungal etiology) and sepsis;

disorders of the blood and lymphatic system: anemia, myelosuppression/pancytopenia;

disorders of the skin and subcutaneous tissues: itching, focal peeling of the skin, hyperpigmentation of the skin, changes in the nails, photosensitivity reactions, a syndrome resembling radiation dermatitis;

visual disturbances: eye irritation;

disorders of the respiratory system, chest and mediastinal organs: shortness of breath, cough;

musculoskeletal and connective tissue disorders: arthralgia, myalgia, back pain;

general disorders and disorders at the injection site: asthenia, chest pain (non-cardiac etiology), pain in the extremities, increased drowsiness.

Overdose

Symptoms of acute overdose include nausea, vomiting, diarrhea, inflammation of the mucous membrane (mucositis), gastrointestinal irritation and bleeding, and suppression of bone marrow function.

Treatment of overdose should include a standard set of therapeutic and supportive measures aimed at correcting clinical symptoms and preventing possible complications.

Storage conditions

Store at a temperature not exceeding 30°C. Keep out of the reach of children.

SELF-MEDICATION CAN BE DANGEROUS TO YOUR HEALTH. ALWAYS CONSULT WITH YOUR DOCTOR.

For what diseases is it used?

• Colorectal cancer
• Stomach cancer
• Breast cancer/breast cancer

Side effects

When using Xeloda as monotherapy, the following disorders may develop:

• Nervous system: often - paresthesia, dizziness (except vertigo), headache, dysgeusia (taste perversion);
• Gastrointestinal tract: very often - vomiting, diarrhea, nausea, abdominal pain, stomatitis (including ulcerative); often – epigastric pain, constipation, dyspepsia;
• Organ of vision: often – conjunctivitis, increased lacrimation;
• Metabolism and nutrition: very often – anorexia; often – loss of appetite, dehydration;
• Laboratory indicators: often – hyperbilirubinemia;
• Skin and subcutaneous tissues: very often - dermatitis, hand-foot syndrome (swelling, paresthesia, skin peeling, hyperemia, blistering); often – alopecia, rash, dry skin, erythema; the development of skin cracks is also possible;
• General disorders: very often - drowsiness, fatigue; often – weakness, fever, asthenia.

Toxicity known to occur with fluoropyrimidine therapy includes:

• Nervous system: insomnia, taste disturbance, encephalopathy, confusion, symptoms of cerebellar disorders (dysarthria, ataxia, impaired coordination and balance);
• Cardiovascular system: cardialgia, including angina pectoris, edema of the lower extremities, myocardial ischemia, cardiomyopathy, ventricular extrasystoles, myocardial infarction, tachycardia, heart failure, supraventricular arrhythmias, including atrial fibrillation, sudden death;
• Musculoskeletal system and connective tissue: myalgia, arthralgia, back pain;
• Respiratory system: cough, shortness of breath;
• Gastrointestinal tract: flatulence, dry mouth, adverse reactions associated with inflammation/ulceration of the mucous membranes (colitis, gastritis, esophagitis, duodenitis, gastrointestinal bleeding);
• Parasitic and infectious diseases: infectious complications associated with weakened immunity, myelosuppression and/or violations of the integrity of the mucous membranes (fatal and local systemic infections of fungal, viral or bacterial etiology) and sepsis;
• Mental: depression;
• Lymphatic system and blood: myelosuppression, anemia, pancytopenia;
• Skin and subcutaneous tissues: photosensitivity reactions, focal peeling of the skin, itching, nail changes, skin hyperpigmentation, a syndrome resembling radiation dermatitis;
• Eye organ: eye irritation;
• Disturbances at the injection site and general disorders: chest pain (non-cardiac etiology), pain in the extremities, asthenia, increased drowsiness.

When carrying out combined treatment, the following side effects may additionally occur:

• Cardiovascular system: very often - increased blood pressure, thrombosis/embolism;
• Nervous system: very often - peripheral sensory neuropathy, peripheral neuropathy, dysesthesia;
• Respiratory system: very often – sore throat, pharyngeal dysesthesia; often – dysphonia, nosebleeds, rhinorrhea;
• Infectious diseases: often - oral candidiasis;
• Musculoskeletal system and connective tissues: very often – pain in the jaw;
• Nutrition and metabolism: very often - weight loss;
• Lymphatic system and blood: very often – febrile neutropenia, leukopenia;
• Disturbances at the injection site and general disorders: very often - temperature intolerance; often – fever, pain.

When Xeloda was used concomitantly with other chemotherapeutic drugs, there were frequent reports of cases of hypersensitivity reactions and myocardial ischemia/infarction.

Changes in laboratory parameters during therapy can manifest themselves as a decrease in hemoglobin, the number of granulocytes, neutrophils, platelets and lymphocytes, as well as hyperbilirubinemia, hypercreatininemia, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), hyperglycemia, hyponatremia, hypo -/hypercalcemia, hypokalemia.

During a post-marketing study of Xeloda, the following adverse reactions were identified: very rarely - unspecified lacrimal duct stenosis; very rarely - liver failure and cholestatic hepatitis.

Xeloda®

The following categories are used to describe the frequency of adverse reactions: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10000 and <1/1000), very rarely (<1/10000, including isolated cases). The following adverse reactions are listed in order of clinical significance.

The most common and/or clinically significant adverse reactions during therapy with Xeloda® were gastrointestinal disorders (especially diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome, fatigue, drowsiness, anorexia, manifestations of cardiotoxicity, increasing renal failure in patients with a history of impaired renal function, thrombosis/embolism.

Monotherapy with Xeloda®

Infectious and parasitic diseases

: often - herpes viral infection, nasopharyngitis, lower respiratory tract infection; uncommon - sepsis, urinary tract infection, cellulitis, tonsillitis, pharyngitis, candidiasis of the oral mucosa, influenza, gastroenteritis, fungal infections, infections, tooth abscess.

Benign, malignant and unspecified neoplasms:

infrequently - lipoma.

Blood and lymphatic system disorders

: often - neutropenia; uncommon - febrile neutropenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increase in international normalized ratio, prolongation of prothrombin time.

Immune system disorders

: uncommon - increased sensitivity. Metabolic and nutritional disorders: very often - anorexia; often - dehydration, weight loss; uncommon - diabetes mellitus, hypokalemia, indigestion, hypertriglyceridemia.

Mental disorders

: uncommon - panic attacks, depressed mood, decreased libido.

Nervous system disorders

: often - headache, dizziness (except vertigo), lethargy, paresthesia, dysgeusia (taste perversion); Uncommon: aphasia, memory impairment, fainting, imbalance, loss of sensitivity, peripheral neuropathy.

Visual disorders

: often - increased lacrimation, conjunctivitis; infrequently - decreased visual acuity, diplopia.

Hearing and labyrinth disorders

: uncommon - vertigo, ear pain.

Cardiac disorders:

uncommon - angina, including unstable, arrhythmia, sinus tachycardia, palpitations.

Vascular disorders

: often - thrombophlebitis; uncommon - deep vein thrombosis, increased blood pressure, petechiae, decreased blood pressure, hot flashes, coldness of the distal extremities.

Respiratory, thoracic and mediastinal disorders

: often - nosebleeds, rhinorrhea; uncommon - pneumothorax, hemoptysis, bronchial asthma, shortness of breath on exertion.

Gastrointestinal disorders

: very often - diarrhea, vomiting, nausea, stomatitis (including ulcerative), abdominal pain;
often - constipation, epigastric pain, dyspepsia; uncommon - intestinal obstruction, ascites, enteritis, dysphagia, lower abdominal pain, abdominal discomfort, gastroesophageal reflux disease, blood in the stool. Disorders of the liver and biliary tract :
often - changes in liver function tests; infrequently - jaundice.

Skin and subcutaneous tissue disorders

th: very often - palmar-plantar syndrome (paresthesia, swelling, hyperemia, skin peeling, blistering), dermatitis; often - skin hyperpigmentation, macular rash, rash, alopecia, erythema, dry skin; Uncommon: blisters, skin ulcers, urticaria, palmar erythema, facial edema, purpura.

In less than 2% of patients in 7 completed clinical studies (N=949), skin cracks at least thought to be associated with Xeloda therapy were reported.

Musculoskeletal and connective tissue disorders

: often - pain in the limbs, back pain; Uncommon: joint swelling, bone pain, facial pain, stiffness, muscle weakness.

Renal and urinary tract disorders:

uncommon - hydronephrosis, urinary incontinence, hematuria, nocturia, increased plasma creatinine.

Genital and breast disorders

: uncommon - vaginal bleeding.

General and administration site disorders

: very often - fatigue, drowsiness; often - peripheral edema, malaise, chest pain, fever, weakness, asthenia; infrequently - swelling, chills, flu-like syndrome, trembling, increased body temperature.

Influence on the results of laboratory and instrumental studies

: often - hyperbilirubinemia.

The following adverse reactions are toxicities known to occur with fluoropyrimidine therapy; At least an indirect association between the development of such reactions and the use of Xeloda was reported in less than 5% of patients participating in 7 completed clinical studies (N=949):

Gastrointestinal disorders:

dry mouth, flatulence, adverse reactions associated with inflammation/ulceration of the mucous membranes, such as esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding;

disorders of the cardiovascular system

: edema of the lower extremities, cardialgia, including angina pectoris, cardiomyopathy, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including atrial fibrillation, ventricular extrasystoles;

nervous system disorders

: taste disturbance, insomnia, confusion, encephalopathy, symptoms of cerebellar disorders (ataxia, dysarthria, impaired balance and coordination);

mental disorders

: depression;
infectious and parasitic diseases
: infectious complications associated with myelosuppression, immunosuppression and/or mucositis, such as local and fatal systemic infections (bacterial, viral or fungal etiology) and sepsis; disorders of the blood and lymphatic system: anemia, myelosuppression/pancytopenia;

disorders of the skin and subcutaneous tissues: itching, focal peeling of the skin, hyperpigmentation of the skin, changes in the nails, photosensitivity reactions, radiation dermatitis;

visual disturbances: eye irritation;

disorders of the respiratory system, chest and mediastinal organs: shortness of breath, cough;

musculoskeletal and connective tissue disorders: arthralgia, myalgia, back pain;

general disorders and disorders at the injection site: chest pain (non-cardiac etiology), pain in the extremities.

Use of Xeloda® in combination therapy

The safety profile did not differ when prescribed for different indications and with different combinations, however, the adverse reactions listed in monotherapy may be observed with greater frequency when using Xeloda1′ in combination therapy.

The following are undesirable reactions that were observed in addition to those with monotherapy:

infectious and parasitic diseases

: often - candidiasis of the oral mucosa, herpes zoster, urinary tract infections, upper respiratory tract infections, rhinitis, influenza, infection, oral herpes; disorders of the blood and lymphatic system: very often - neutropenia, anemia, thrombocytopenia, leukopenia, febrile neutropenia; often - myelosuppression; disorders of the immune system, often - hypersensitivity;

metabolic and nutritional disorders

: very often - weight loss, loss of appetite; often - hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia;

mental disorders

: often - sleep disorders, anxiety; Nervous system disorders: very often - paresthesia, dysgeusia, headache, peripheral neuropathy, peripheral sensory neuropathy, dysesthesia; often - neurotoxicity, tremor, neuralgia, hypoesthesia;

visual impairment

: very often - lacrimation; often - visual disturbances, dryness, pain in the eyes, blurred vision;

hearing and labyrinth disorders

: often - ringing in the ears, hearing loss;

heart disorders

: often - atrial fibrillation;

Vascular disorders:

very often - thrombosis/embolism, increased blood pressure (BP), swelling of the lower extremities;
often - hyperemia, decreased blood pressure, hypertensive crisis, hot flashes, phlebitis; disorders of the respiratory system, chest and mediastinal organs
: very often - pharyngeal dysesthesia, sore throat; often - nosebleeds, dysphonia, rhinorrhea, hiccups, pain in the pharynx and larynx;

Gastrointestinal disorders:

very often - constipation, dyspepsia; often - bleeding from the upper gastrointestinal tract, oral ulcers, gastritis, bloating, gastroesophageal reflux disease, oral pain, dysphagia, rectal bleeding, lower abdominal pain, dysesthesia, paresthesia and hypoesthesia in the mouth, abdominal discomfort;

disorders of the liver and biliary tract:

often - liver dysfunction;

disorders of the skin and subcutaneous tissues

: very often - alopecia, changes in nails; often - hyperhidrosis, erythematous rash, urticaria, night sweats; disorders of the musculoskeletal and connective tissue: very often - myalgia, arthralgia, pain in the extremities; often - jaw pain, muscle spasms, trismus, muscle weakness;

kidney and urinary tract disorders

: often - hematuria, proteinuria, decreased creatinine clearance, dysuria;

general disorders and disorders at the injection site

: very often - weakness, lethargy, increased sensitivity to high and low temperatures; often - fever, pain, inflammation of the mucous membrane, chills, chest pain, flu-like syndrome, contusion.

Cases of liver failure and cholestatic hepatitis have been reported in clinical studies and post-marketing. A cause-and-effect relationship with taking Xeloda® has not been established.

When treated with Xeloda in combination with other chemotherapeutic drugs, cases of hypersensitivity reactions (2%) and myocardial ischemia/infarction (3%) were frequently reported (but in less than 5% of patients).

Below is information on individual adverse reactions.

Diarrhea

Diarrhea was observed in 50% of patients during capecitabine therapy. A meta-analysis of 14 clinical trials including more than 4,700 patients treated with capecitabine identified covariates that were statistically associated with an increased risk of diarrhea: increasing the initial dose of capecitabine (in grams), lengthening the study period of therapy (in weeks), increasing age ( every 10 years) and female gender. Covariates statistically associated with a reduced risk of diarrhea: increasing the cumulative dose of capecitabine (0.1 * kg), increasing the relative dose intensity in the first 6 weeks of therapy (see section "Special Instructions").

Cardiotoxicity

As a result of an analysis of the safety profile of seven clinical studies involving 949 patients receiving capecitabine as monotherapy, the following adverse reactions were identified (incidence less than 0.1%): cardiomyopathy, heart failure, sudden cardiac arrest and ventricular premature beats (see section "Special Instructions" ).

Encephalopathy

Encephalopathy has also been associated with capecitabine monotherapy (incidence less than 0.1%).

Adverse reactions in special clinical groups

Elderly patients

In a safety profile analysis, patients aged >60 years who received capecitabine in combination with docetaxel and as monotherapy found an increase in serious adverse reactions and grade 3 and 4 treatment-related adverse reactions compared with patients aged <60 years. Patients aged >60 years who received capecitabine in combination with docetaxel also dropped out of the study earlier due to adverse reactions compared with patients aged <60 years. A meta-analysis of 14 clinical studies involving more than 4,700 patients receiving capecitabine found that as the patient's age increased (every 10 years), the risk of developing hand-foot syndrome and diarrhea increased, while the risk of developing neutropenia, on the contrary, increased , decreased (see section “Method of administration and dosage”).

Floor

A meta-analysis of 14 clinical trials involving more than 4,700 patients treated with capecitabine found that female patients had a higher risk of developing hand-foot syndrome and diarrhea, while the risk of developing neutropenia was reduced.

Patients with kidney failure

(see also sections “Method of administration and dosage”, “Special instructions”)

In a safety profile analysis of patients with renal impairment receiving capecitabine as monotherapy (colorectal cancer), an increased incidence of grade 3 and 4 toxicities was found compared with patients with normal renal function (36% (n=268) of patients with normal renal function compared to 41% (n = 257) of patients with mild renal failure and 54% (n = 59) of patients with moderate renal failure) (see section “Pharmacological properties”). Among patients with moderate renal impairment, capecitabine dose reduction was most common (44%) compared with patients with normal renal function (33%) and patients with mild renal impairment (32%). There was also an increase in the number of patients who dropped out of the study early (21% of patients who dropped out during the first two cycles) compared with patients with normal renal function (5%) and patients with mild renal impairment (8%).

Changes in laboratory parameters

Decreased neutrophil count, decreased granulocyte count, decreased lymphocyte count, decreased platelet count, decreased hemoglobin, hyperbilirubinemia, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, hypercreatininemia, hyperglycemia, hypo-/hypercalcemia, hyponatremia, hypokalemia.

Post-registration surveillance

During post-marketing use of Xeloda®, the following adverse reactions were detected:

special instructions

It is necessary to carefully monitor manifestations of toxicity in patients using Xeloda.

As a rule, most adverse events are reversible and do not require complete discontinuation of the drug, although dose adjustment or temporary discontinuation of the drug may be required.

Diarrhea, sometimes severe, may occur during therapy. Standard antidiarrheal medications should be prescribed as early as medically indicated. If necessary, it is possible to reduce the dose of Xeloda.

Dehydration should be prevented or corrected at the first sign of its occurrence. Most often it occurs in patients with asthenia, anorexia, nausea, diarrhea or vomiting. If dehydration of grade 2 or higher develops, treatment is immediately interrupted and rehydration is carried out.

The spectrum of cardiotoxicity with Xeloda is similar to that with other fluoropyrimidines. Symptoms are more common in patients with a history of coronary artery disease and include cardiac arrest, myocardial infarction, arrhythmias, angina, heart failure, and ECG changes.

A manifestation of Xeloda's skin toxicity is hand-foot syndrome. If it develops to grade 2-3, therapy should be interrupted until symptoms disappear or until they decrease to grade 1. In combination treatment with cisplatin, vitamin B6 is not recommended for symptomatic or secondary preventive treatment of hand-foot syndrome.

Treatment should be interrupted in cases of development of hyperbilirubinemia greater than 3 × ULN or increased activity of hepatic aminotransferases (ALT, AST) more than 2.5 × ULN. Therapy can be resumed if bilirubin levels and hepatic aminotransferase activity decrease below the specified limits.

When using Xeloda simultaneously with oral anticoagulants - coumarin derivatives, it is necessary to monitor coagulation parameters and, based on this, select the dose of the anticoagulant.

Patients who experience undesirable effects such as weakness, dizziness or nausea should refrain from driving vehicles or other machinery.

New drugs in the treatment of solid tumors

IN

Recently, significant progress has been made in the treatment of patients with malignant tumors due to the introduction of new drugs into oncological practice. A huge number of drugs are approved for use or are under investigation, both cytostatics and drugs based on the latest discoveries of fundamental science (angiogenesis inhibitors, growth factor receptor blockers, etc.).

This review presents the most effective drugs that have entered everyday practice in the last 2–3 years.

Alimta

Alimta (MTA, Eli Lilly) is a multi-purpose antifolate. The mechanism of action is a disruption of folic acid metabolism by blocking several enzymes involved in it - thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This disrupts the synthesis of purine and thymidine, which are necessary for DNA synthesis. Alimta penetrates the cell membrane and, in the form of polyglutamates, remains in the cell for a long time, which, along with enzyme inhibition, determines selectivity and antitumor activity.

In phase I studies, the optimal treatment regimen was considered to be administration of the drug at a dose of 600 mg/m2 once every 21 days as a 10-minute intravenous infusion. The main toxic manifestations are neutro- and thrombocytopenia (dose-limiting toxicity) and changes in liver function tests (transient and did not require dose adjustment). Other toxic manifestations - weakness, skin rash, mucositis, diarrhea, nausea, are usually moderate (grade I-II).

Objective antitumor activity of Alimta in monotherapy was detected in non-small cell lung cancer (16–23%), colorectal cancer (15–17%), head and neck tumors (26%), breast cancer (18–31%), colon cancer ( 15–17%), pancreas (6%), cervix (25%), bladder (27%). Currently, combinations of Alimta with platinum drugs, Gemcitabine, taxanes, antimetabolites, topoisomerase I inhibitors, alkaloids, as well as with radiation therapy are being studied.

In phase II studies in monotherapy for non-small cell lung cancer, Alimta (500 mg/m2 every 28 days) in the first line induced partial regression in 23% of 30 patients (Canadian group) and in 18% of 51 patients (research centers of Australia and South Africa ). In the second line, in 45 patients who had previously received platinum drugs, the effect of Alimta was achieved in 9% of patients; in those who did not receive platinum drugs (33 patients), the effect was achieved in 15% of cases.

In phase II studies, the combination of Alimta (500 mg/m2 day 1) + Cisplatin (75 mg/m2 day 1, every 3 weeks) was effective (partial regression + disease stabilization) from 39% (36 patients) to 45% (29 patients ). Dose-limiting toxicity was grade III – IV granulocytopenia. Prescribing folic acid before starting chemotherapy with Alimta can significantly minimize its toxicity

Gemcitabine

Gemcitabine (Gemzar, Eli Lilly) is a deoxycytidine analogue that has activity in a number of solid tumors.

Currently, Gemzar is recommended for use in doses of 1000–1250 mg/m2 IV, 30 minute infusion, days 1, 8 and 15 of each 28-day cycle.

The most common side effects are granulocytopenia (II-III) - 46%, influenza-like syndrome (II) - 20%, increased body temperature (I-II) - 53%, peripheral edema (II) - 30%, anemia (I- II) – 61%, increased levels of liver enzymes (I–II) – 40–60%, shortness of breath (I–II) – 10%. Dose-limiting toxicity is neutropenia.

Pancreas cancer

– the first nosology in which Gemcitabine was approved for use, given its pronounced symptomatic effect (in 30% of cases) and a significant increase in overall survival. The combination of Gemcitabine + Cisplatin, according to various authors, induces an objective response from 22% to 36% with a median survival of 8 to 10 months. In combination with 5-fluorouracil, the effect was observed in 17–19% with an average survival of 6 to 8 months. The regimen of Gemcitabine + 5-fluorouracil + Epirubicin, according to preliminary data (26 patients), was effective in 69% with a median survival of 8 months.

Lung cancer.

In monotherapy in phase II studies, the overall effectiveness was 22% with a median survival of 12 months, which places Gemcitabine among the most active drugs in non-small cell lung cancer. In a number of studies, the combination of Gemcitabine (1000–1250 mg/m2, days 1, 8 ± 15) with Cisplatin (80–100 mg/m2, day 1) showed an overall response rate of 50% with an acceptable toxicity profile. When comparing the Gemcitabine + Cisplatin regimen with the standard treatment Etoposide + Cisplatin in 135 patients who had not previously received chemotherapy, the effectiveness in the first case was significantly higher - 41% versus 22%, without significant differences in survival time. The results obtained provide the basis for the use of the combination of Gemcitabine + Cisplatin in the first line of chemotherapy for advanced lung cancer. Combinations of Gemcitabine + Cisplatin are being studied as adjuvant treatment for non-small cell lung cancer, as well as 3-component regimens including Gemcitabine, Cisplatin, Navelbine and taxanes. Despite the encouraging results, the two-component combination is still considered the standard treatment approach (until the results of a phase III clinical trial comparing 2- and 3-component regimens are published).

Bladder cancer.

Gemcitabine monotherapy is effective in 23–28%. In combination with Cisplatin, the objective response ranges from 24% to 66%. The currently recommended regimen is: Gemcitabine 1000 mg/m2 on days 1, 8 and 15 and Cisplatin 70 mg/m2 on day 2 of each 28-day course.

Three-component regimens are being studied, in particular, data have been published on an 82% overall effect (29 patients) when treated with the Gemcitabine + Cisplatin + Paclitaxel regimen.

Research is being conducted on the effectiveness of combination therapy with the inclusion of Gemcitabine for breast cancer, ovarian cancer, and head and neck tumors.

Herceptin

Herceptin (Trastuzumab, F. Hoffmann–La Roche) is a drug with a fundamentally new mechanism of action. It is a recombinant humanized monoclonal antibody that binds to the HER-2/neu receptor. Currently, studies have been conducted on the use of Herceptin in breast cancer with overexpression of HER-2/neu

, which is detected in 25–30% of tumors and causes a poor prognosis.

Herceptin is administered intravenously, the first dose is 4 mg/kg, then 2 mg/kg weekly. Chills and fever were noted in 40% of patients after the first administration; with subsequent administrations, these phenomena occurred in 5% of patients. The main side effect when using the drug was cardiotoxicity in 2.6% of patients who had not previously received anthracyclines, and in 8.5% after using anthracyclines. When Herceptin is used simultaneously with anthracyclines - in 28% of cases, in 19% of them - grades III-IV.

When Herceptin was used independently in previously untreated patients positive for HER-2/neu, an objective response was obtained in 23% of cases, and long-term stabilization of the disease was noted in 15% of patients. In the II–III line of treatment, an objective response was obtained in 16%.

A randomized study was completed that included 469 patients with metastatic breast cancer. Patients who did not receive anthracyclines in adjuvant treatment were randomized into 2 groups: chemotherapy in the AC regimen (Doxorubicin + Cyclophosphamide) + Herceptin; AC chemotherapy without Herceptin. Patients receiving anthracyclines in adjuvant treatment received Taxol monotherapy or Taxol + Herceptin (Table 1).

It was noted that with HER–2/neu 2+, according to immunohistochemical studies (IHC), complete and partial regression was observed in 26% of patients, with HER–2/neu 3+ in 35%, and with positive HER–2/neu with fluorescent
in situ
hybridization (FISH) method - in 41% of cases. All HER-2/neu 2+ patients who had an effect were positive according to FISH.

Taking into account the research results, recommendations for the use of Herceptin have been developed: the drug is indicated for all patients with HER-2/neu 3+ according to IHC data; in case of HER-2/neu 2+, additional FISH should be performed.

Preclinical studies have shown increased effectiveness when combining Herceptin with Taxol, Doxorubicin, Carboplatin, Cisplatin, Cyclophosphamide, Etoposide, Methotrexate, 5-fluorouracil. Effective regimens have been developed, including Herceptin and Taxol, Herceptin and Navelbine. Combinations of Herceptin with various chemotherapy drugs and endocrine therapy for disseminated breast cancer, as well as in pre- and postoperative treatment, are being studied.

Overexpression of HER-2/neu and the effectiveness of Herceptin, according to experimental data, were detected in lung adenocarcinoma, pancreatic, stomach, and ovarian cancer.

Campto

Campto (Irinotecan, Aventis) is a semi-synthetic soluble derivative of camptothecin that hydrolyzes in vivo

into the active metabolite SN-38. Campto stabilizes the topoisomerase-I complex with DNA, preventing its dissociation and the joining of DNA strands. Campto is a phase-specific drug, causing maximum damage to cells in the S phase.

Side effects: gastrointestinal and myelotoxicity, acute cholinergic syndrome, alopecia. Dose-limiting complications are diarrhea and myelotoxicity. Diarrhea is observed in 87% of patients (severe in 38.5%), usually develops on days 4–8 and is well controlled by taking loperamide. Cholinergic syndrome is observed in 85% and requires premedication with atropine in subsequent courses. Neutropenia occurs in 55%, of which 47% are grade III–IV. Anemia occurs in 20–25% of patients, usually grade III, thrombocytopenia – in 5% of cases. Alopecia – in 50%.

The drug is most widely used in advanced colorectal cancer.

. In patients who had not previously received chemotherapy, the objective response ranged from 18.8 to 36%, with a duration of effect from 6.5 to 9.1 months. The effectiveness of Campto in monotherapy in the II–III line of therapy ranges from 14 to 40%. The duration of the effect is from 3 to 9.1 months.

Currently, Campto is recommended in the United States as a first-line drug for the treatment of colorectal cancer at a dose of 350 mg/m2 every 3 weeks. Considerable research has been conducted on the combination of Campto with 5-fluorouracil/Leucovorin. In a study of the comparative effectiveness of the combination Campto + 5-fluorouracil + Leucovorin; The standard regimen of 5-fluorouracil + Leucovorin and Campto in monotherapy included 666 patients with metastatic colorectal cancer who had not previously received chemotherapy. The best results were obtained in the Campto/5-fluorouracil/Leucovorin group: the objective response was significantly higher - 33% versus 18% and 17%, the median time to progression and life expectancy was 2 months longer than in the other two groups.

Campto + Tomudex regimens are currently being studied; Campto + Oxaliplatin, etc. Research is also being conducted on the effectiveness of Campto in the postoperative period in patients with Dukes' B and C stage colorectal cancer.

Campto monotherapy for non-small cell lung cancer

effective in 21% with 44% average one-year survival rate. The effectiveness of the combination of Campto and Cisplatin is 43–50%. The combination of Campto and Carboplatin is effective in 40%, and in 40% of cases long-term stabilization of the disease is noted.

The combination of Campto and Cisplatin (Cisplatin 80 mg/m2 1 day and Campto 60 mg/m2 1, 8, 15 days every 3 weeks) is effective in 43% of patients, average time to progression 21 weeks, 1-year survival 49%, average life expectancy – 52 weeks. This regimen is one of the most effective in the first line of treatment for non-small cell lung cancer.

For small cell lung cancer

The effectiveness of Campto in patients who had previously received chemotherapy ranged from 26.6% to 50%. The combination of Campto with other drugs is more effective, especially in the first line of chemotherapy. The Campto 60 mg/m2 regimen on days 1, 8 and 15 + Cisplatin 60 mg/m2 on day 1 was effective in 78% of cases, and in combination with Etoposide (Campto 60 mg/m2 on days 1, 8 and 15, Etoposide 80 mg /m2 on days 2, 3 and 4) – in 66% of cases, of which 10% of patients achieved complete remission.

The effectiveness of Campto in ovarian cancer

fluctuates between 21–23%. Combinations of Campto with other drugs are being studied in the first and second line of chemotherapy for ovarian cancer.

For stomach cancer

the effectiveness of Campto in monotherapy was 17.6%, with 40% having a symptomatic effect.

In 25 previously treated patients with advanced gastric cancer, the combination of Campto 65 mg/m2 and Cisplatin 30 mg/m2 weekly was 51% effective. The combination of Campto and Mitomycin is being studied.

Xeloda

Xeloda (Capecitabine, F. Hoffmann–La Roche) is a new class of antitumor drug that is converted into an active form directly in the tumor, which ensures high efficiency and low toxicity. Xeloda, when taken orally, is well absorbed in the intestine, undergoes a series of transformations in the liver, and the final product (5-fluorouracil) is formed in tumor tissue under the action of the enzyme thymidine phosphorylase, which, unlike normal tissue, is found in much greater quantities in breast tumors, colon, stomach, ovaries, cervix, kidney, bladder.

2 regimens of taking the drug are recommended: daily continuously at 1330 mg/m2/day (in 2 doses), or for 2 weeks at 2500 mg/m2/day with a break of 1 week. Most authors prefer the second regimen; some believe that reducing the dose to 2000 mg/m2/day improves tolerability of the drug while maintaining the same effect.

Main side effects: diarrhea, mucositis, nausea/vomiting, hand-foot syndrome. Severe reactions (grades III–IV) are rare. Adjusting the doses of Xeloda allows you to continue treatment effectively and safely while maintaining a good quality of life.

The synergism of Xeloda with various cytostatics - Cyclophosphamide, Adriamycin, taxanes, Methotrexate, Mitomycin C - has been experimentally shown. One of the mechanisms for potentiating the effect is stimulation of the synthesis of thymidine phosphorylase in the tumor.

A comparative study of Xeloda monotherapy and the combination of CMF (Cyclophosphamide, Methotrexate, 5-fluorouracil) was conducted in previously untreated patients with metastatic breast cancer

. The effect was noted in 30% of patients receiving Xeloda (the CMF regimen was effective in 16% of patients).

In patients with anthracycline-resistant breast cancer, Xeloda was more effective than Taxol, and the objective effect was 36% and 21%, respectively. At the same time, neutropenia was observed significantly less often during treatment with Xeloda than during chemotherapy with Taxol or in the CMF regimen.

The high effectiveness of Xeloda has been shown in lines II–III of treatment of metastatic breast cancer, with 100% of patients previously receiving taxanes and 91% receiving anthracyclines. An objective effect was achieved in 20% of patients, stabilization in 41%. Median survival was 12.8 months.

Currently, combinations of Xeloda with anthracyclines, taxanes, platinum drugs, and Herceptin have been developed and are being studied.

The high effectiveness of Xeloda is shown in metastatic colorectal cancer

. In a randomized trial of 1207 patients, Xeloda was more effective than the standard Mayo regimen (5-fluorouracil + leucovorin). The objective effect was 22.4% and 13.2%, respectively. A large study has been opened to compare Xeloda and the Mayo regimen in adjuvant use. Combinations of Xeloda with Campto, Oxaliplatin, and radiation therapy are being developed.

Oxaliplatin

One of the new and promising drugs - platinum derivatives is Oxaliplatin (Eloxatin, Sanofi-Synthelabo) - a platinum-containing drug of the third generation.

Based on the results of phase I studies, Oxaliplatin was recommended for subsequent study at a dose of 130 mg/m2, once every 3 weeks or 85 mg/m2 every 2 weeks, in the form of infusions lasting from 2 to 6 hours.

The toxicity of the drug is the development of specific neuropathy, moderate myelotoxicity, and rarely gastrointestinal. Unlike Cisplatin, Oxaliplatin does not cause renal or ototoxicity.

Specific neuropathy is cumulative and becomes pronounced when a dose of 1200 mg/m2 is reached. After discontinuation of the drug, these disorders usually disappear. Also one of the manifestations of neurotoxicity is laryngospasm. Gastrointestinal and myelotoxicity are usually moderate (grade I–II).

Objective effect of Oxaliplatin in the first line of advanced colorectal cancer

ranged from 20 to 24%. The combination of Oxaliplatin + 5-fluorouracil/Leucovorin (5FU/LV), based on data on drug synergy, achieved a significant increase in efficiency. In a large comparative study that included 207 patients, the objective response rate was 50.7% versus 16% in those receiving standard 5-FU/LV therapy.

When using Oxaliplatin in the second line, an objective effect was noted in 10–11%, long-term stabilization in 31–42%.

Also shown is a 13–40% effectiveness of treatment with Oxaliplatin + 5FU/LV in patients with progression after 5-fluorouracil.

Combinations of Oxaliplatin and Campto, Tomudex, Xeloda and other drugs are currently being studied.

Another tumor for which Oxaliplatin has shown high effectiveness is ovarian cancer

. The effectiveness of Oxaliplatin/Cyclophosphamide in first-line therapy was comparable to Cisplatin/Cyclophosphamide (33% and 42%, respectively), with the same time to progression (13 months) and similar average survival (36 and 25 months).

In the second line of therapy in patients who responded to Cisplatin-containing regimens, the objective response was 42%, while in those resistant to Cisplatin it was 14%.

Combinations of Oxaliplatin and Taxol, Oxaliplatin and Cisplatin are being studied in the second line of treatment of patients resistant to Cisplatin. The effectiveness of treatment reaches 40–73%.

Extensive research is being conducted to study the effectiveness of Oxaliplatin in monotherapy and in combination for other tumors, such as breast cancer, prostate cancer, malignant mesothelioma, small cell and non-small cell lung cancer, etc.

Advances in the study of the fundamental mechanisms of carcinogenesis have made it possible to create highly effective targeted antitumor drugs.
The use of new antitumor drugs in daily clinical practice has significantly increased the effectiveness of therapy and improved the quality of life of cancer patients. Currently, many antitumor drugs are being studied that selectively act on the processes of tumor growth and progression, which in the near future will be able to fundamentally change the results of treatment. Literature:
1. New antitumor drugs in the treatment of cancer. Collection of works of the European School of Oncology. Moscow, 1999.

2. Oxaliplatin. // Drugs, 2000; 60(4): 895–924.

3. Treatment of Solid Tumors: A Clinical Update of Gemzar and MTA. Ely Lilly ONCOLOGY. 2000.

4. Seminars in Oncology Vol 26, N 4, Suppl 12, 1999.

5. Campto. Official abstracts from the 23rd European Society for Medical Oncology Congress. Athens, November 6–10, 1998.