Chemotherapy regimen ep. Chemotherapy - types, regimens, side effects, cost

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Malignant ovarian tumors

World Health Organization (WHO) And International Association of Obstetricians and Gynecologists (FIGO) A unified morphological classification of malignant ovarian tumors has been adopted, distinguishing epithelial tumors, sex cord stromal tumors and germ cell tumors.

Most malignant tumors (80-90%) are epithelial.

Among them are serous cystadenocarcinoma - 42%, mucinous cystadenocarcinoma - 12%, endometrioid carcinoma - 15%, undifferentiated carcinoma - 17%, clear cell carcinoma - 6%.

The main types include borderline (potentially low-grade) tumors. They make up about 15% of epithelial tumors. In addition to the morphological type of tumor, the most important independent prognostic factor for the effectiveness of treatment and patient survival is the degree of cellular differentiation of epithelial tumors, which determines the degree of its malignancy. The Broders histological assessment system is used, and the I degree of differentiation is more prognostically favorable and the III degree is the least favorable (G1 - highly differentiated, G2 - average, G3 - poorly differentiated).

Of all tumors of stromal origin, including granulosa-, thecacollagen-producing, as well as Sertoli/Leidigo-stromal cells or their embryonic precursors, granulosa cell tumor is the most common.

Germ cell tumors account for less than 5% of all ovarian malignancies, but are important because... occur in young girls and women and require special treatment that is different from other ovarian tumors. The most common among these tumors are dysgerminoma, similar to testicular seminoma (a tumor of endodermal origin), and embryonal cancer, in which there is an increase in the level of tumor markers (serum and α-fetoprotein).

Borderline tumors, or tumors with poor malignant potential, account for approximately 15% of all epithelial ovarian tumors.

Mandatory morphological confirmation of the diagnosis of such a tumor is necessary, since its prognosis and treatment are completely different from other malignant neoplasms.
A review of 22 studies (953 patients) with a mean follow-up of 7 years showed a survival rate of 92% for advanced disease, excluding cases of invasive tumor implants.

The method of treating borderline tumors is an operation, the scope of which is determined by the stage of the process, the age of the patient and her desire to preserve reproductive function. Patients with a widespread process undergo radical operations involving extirpation or supravaginal amputation of the uterus and appendages, removal of the greater omentum and all tumor nodes in the form of so-called aggressive cytoreduction.

Patients with residual borderline tumors are not given chemo- and radiation therapy, since numerous studies (including those at the N.N. Blokhin Russian Cancer Research Center of the Russian Academy of Medical Sciences) have not shown its significance. Patients without residual tumors who do not receive adjuvant treatment have similar or better survival outcomes when compared with the treatment group.

In cases of rapid growth of residual tumors and their repeated removal, some authors use melphalan or cisplatin.

Ovarian cancer

Ovarian cancer is one of the most common malignant gynecological tumors and ranks 5th in mortality from cancer in women. 50% of all cases of the disease occur over the age of 65 years. 5-year survival has improved significantly over time, from 36% in the mid-1970s to 45% in 2002. Approximately 5-10% of ovarian cancer is familial, with the three most common variants being ovarian cancer only, ovarian cancer and cancer breast, ovarian and colon cancer.

First of all, heredity is traced among first-degree relatives (mother, daughter, sister). Women of the second degree (grandmother, aunt) are at lower risk. Genetic studies reveal BRCA1 mutations at the 17q21 locus. The BRCA2 gene, which is also responsible for the occurrence of familial ovarian cancer and breast cancer (BC), located on chromosome 13q12.

In women at increased risk who are over 35 years of age and have children, prophylactic oophorectomy may be considered, but its value has not yet been definitively established. Cases of the disease after prophylactic surgery have been described, starting with peritoneal tumor growths similar to ovarian cancer.

A feature of ovarian cancer is spread into the abdominal cavity through cell implantation and local invasion of the bladder and intestines. The incidence of lymph node involvement is 24% in stage I, 50% in stage II, 74% in stage III and 73% in stage IV. Pelvic lymph nodes are involved as often as para-aortic ones. The tumor, through transdiaphragmatic spread, can block the diaphragmatic lymphatic drainage, which causes ascites and pleurisy.

The most informative prognosis factors for ovarian cancer include the following (Table 9.23).

Table 9.23. Main prognosis factors for ovarian cancer

Note: “+” - favorable; “-” - unfavorable, “±” - intermediate

For patients with stage I, the degree of morphological differentiation of the tumor is most important. Flow cytometric analysis of DNA in stages I and IIA can identify a group at increased risk.

After optimal operations for stage III, the median survival is 52-63 months.

In table Figure 9.24 shows the FIGO classification of ovarian cancer.

Table 9.24. Classification of ovarian cancer (FIGO)

The survival rate of patients directly depends on the stage of the process (Table 9.25).

Table 9.25. Survival of patients according to FIGO stages

To diagnose and monitor the effectiveness of treatment for epithelial tumors, tumor markers such as carcinoembryonic antigen (REA) and tumor-specific antigen CA-125. There is a high correlation of CA-125 levels one month after the 3rd course chemotherapy (XT) at stages III and IV and survival. In cases of normalization of this marker during treatment, its repeated increase determines the activation of the process, although it does not mean the need for immediate treatment.

An elevated CA-125 level indicates a high likelihood of ovarian cancer, while a negative response does not exclude the presence of residual tumor. The level of CA-125 can be elevated both in other malignant tumors and in various diseases of the genital organs, for example, endometriosis.

Treatment methods depend on the stage of the process. The key to treatment is surgery. Unlike other tumors of the female genital organs, the stage of the process for ovarian cancer is established after surgery. Although only a small number of patients can be cured by a single operation, the success of therapy is determined by the extent of the initial intervention. The possibility of subsequently achieving complete remission, confirmed morphologically, depends on the size of the residual tumors.

Radical surgery for ovarian cancer is considered to be bilateral ovariosalpingectomy with extirpation of the uterus and removal of the greater omentum. In young women who insist on preserving reproductive function, at stage I and degree I of malignancy (G1), unilateral oophorectomy is possible.

During the operation, to clarify the stage and morphological variant, a biopsy specimen is taken from the lateral canals, pelvic peritoneum and diaphragm, suspensory ligament, para-aortic, common iliac, external and internal iliac lymph nodes, serosa of the rectum and bladder.

Studies have not shown improved long-term outcomes with neoadjuvant chemotherapy. Currently, aggressive surgical management as initial therapy is considered preferable for the best survival. However, in case of questionable success of the operation in patients with potential complications and concomitant diseases, neoadjuvant XT is possible.

Treatment tactics

Stage I

Patients with tumors in stage IA-IB with a high or moderate degree of differentiation (i.e., grades I-II of malignancy, G1-G2) do not require additional treatment after surgery.

With grade III malignancy (G3) stage 1C, there is a high probability of relapse (up to 20%), which requires additional treatment methods.

Possible options include systemic chemotherapy, intraperitoneal (IP) administration of 32P radioactive phosphorus, or irradiation of the abdominal cavity and pelvis. However, the administration of 32P turned out to be more toxic with the same effectiveness when compared with 6 courses of cisplatin.

Stage II

After surgical treatment, adjuvant XT is performed according to the TC regimen.

Stage III

Extirpation or supravaginal amputation of the uterus and appendages with resection of the greater omentum and removal of all or most tumors. In the absence of visible tumors, multiple biopsies and washings from the abdominal cavity are performed.

Further treatment includes the following:

1. For minimal residual tumors (
Total irradiation of the abdominal cavity and small pelvis is possible (only if there are no macroscopic manifestations of the disease in the abdominal cavity and there are minimal residual tumors less than 0.5 cm in diameter in the pelvic cavity) or intraperitoneal injection of 32R (only if residual tumors are less than 1 cm) or colloidal radioactive gold.

2. For macroscopic residual tumors more than 2 cm in diameter in the pelvic cavity, combination chemotherapy is administered in the TC, TP, CP or CC mode.

The effectiveness of XT is assessed clinically, radiologically and by marker levels. It is becoming increasingly important to confirm complete remission. positron emission tomography (PAT).

Research programs have demonstrated a statistically significant improvement in disease-free survival in patients with minimal residual tumors who received IP cisplatin and IP and IV paclitaxel compared with those who received IV cisplatin plus paclitaxel alone. These data open up prospects for intraperitoneal chemotherapy in patients with minimal residual tumors.

Stages III and IV. Full and cytoreductive operations to remove the largest volume of tumor masses, after which combined XT is performed.

Therapeutic approaches for stages III and IV ovarian cancer are the same, despite the fact that the prognosis for patients with stage IV is worse. In patients with stage IV, the main manifestation is usually large tumors in the abdominal cavity and cytoreductive surgery, if possible, should be performed in order to reduce the volume of tumor masses as much as possible.

The volume of residual tumors is a prognostic factor that significantly influences survival. The median survival of patients after optimal cytoreductive surgery is 39 months, and after suboptimal cytoreduction it is only 17 months. In case of technical impossibility of performing the operation, treatment can be started with chemotherapy in order to re-evaluate the possibility of cytoreductive surgery after 3 courses. The value of repeated cytoreductive operations has not been proven.

Chemotherapy

Platinum derivatives form the basis of first-line XT combinations for advanced ovarian cancer. The standard dose of cisplatin is 75 mg/m2 and carboplatin AUC is 6.0~7.5.

Cisplatin and carboplatin are equivalent in effectiveness in ovarian cancer. Only a few studies have shown the benefit of carboplatin (AUC 7.5) + paclitaxel (175 mg/m2) 3-hour infusion compared with cisplatin (75 mg/m2) + paclitaxel (135 mg/m2) 24-hour infusion.

An alternative to the paclitaxel regimen is the docetaxel and carboplatin regimen, which showed equal efficacy in a comparative study with greater hematological and less neurotoxicity. Survival at 2 years of follow-up remains similar. The TC regimen (paclitaxel and carboplatin) is considered the best for initial XT, taking into account the effectiveness, toxicity and quality of life of the patient. Cisplatin is associated with greater neuro-, nephro-, oto- and gastrointestinal toxicity but less myelosuppression than carboplatin.

Despite anecdotal evidence of equivalent efficacy among TC, ATS, and carboplatin monotherapy (ICON-3) regimens, most authors consider the TC regimen to be preferable.

Docetaxel can replace paclitaxel in cases requiring reduced neurotoxicity. Adding a third agent to such combinations is not justified.

Starting regimen: paclitaxel 175 mg/m2 3-hour infusion and carboplatin AUC 6.0-7.5 (high dose for patients in good general condition) every 3 weeks for a total of 6 cycles. Chemotherapy should be started after 4-6 weeks. after operation.

Intraperitoneal XT in a comparative study demonstrated significant improvement in median progression-free survival (29.8 vs 18.3 months) and overall survival (65.6 vs 49.7 months).

This type of treatment may be considered for patients with minimal residual tumors because It is for this category of patients that it has an advantage: the median survival rate for minimal tumors is 66 months, and for large residual tumors it is 26 months.

The preferred regimen studied is the following: paclitaxel 135 mg/m2 IV 24-hour infusion on day 1. Sequentially cisplatin 100 mg/m2 i.p. on day 2 and paclitaxel 60 mg/m2 i.p. on day 8. A total of six 21-day courses of treatment are carried out.

This approach should be discussed in detail with the patient as is associated with greater toxicity than intravenous XT. In addition to catheter-associated complications (infection, prolapse, blockage), it may be accompanied by grade III-IV fatigue, neutro- and thrombocytopenia, as well as gastrointestinal toxicity, abdominal pain, metabolic disorders, and neuropathy. Intraperitoneal therapy should only be performed in clinics with appropriate experience.

New drugs such as gemcitabine (Gemzar), oxaliplatin, topotecan, and triplet regimens including epirubicin (Farmorubicin) and altretamine continue to be studied with promising results.

Maintenance and consolidation chemotherapy, as well as high-dose chemotherapy, is not justified due to the lack of data on improvement in overall survival.

Recurrence of ovarian cancer. Second line chemotherapy

The most important predictors of recurrence of ovarian cancer are clinical stage and size of residual tumors (Table 9.26).

Table 9.26. Prediction factors for recurrence of ovarian cancer

The age of the patients also matters: 5-year survival rate in women younger and older than 40 years old is 65% and 20%. Other negative factors include clear cell or mucinous histology, poor differentiation, poor performance status, non-platinum first-line XT regimens, and presence of ascites. Overall, the relapse rate is 62%.

The choice of second-line chemotherapy is based on tumor sensitivity to first-line XT.

Highlight:

Platinum-sensitive tumors - the first line with platinum derivatives is effective, the relapse-free interval is more than 6 months;
platinum-resistant - disease-free interval is less than 6 months;
refractory cases - patients progress during first-line XT.

Recurrence of ovarian cancer may manifest clinically with the appearance of new symptoms or radiographic findings according to computed tomography (CT), as well as an increase in CA-125 levels, which may precede other symptoms by 6 months. and more.

For women with asymptomatic relapses, the appropriateness of immediate treatment should be carefully considered and discussed.

The goal is palliative treatment with long-term remissions, since a cure in this situation is unlikely. Immediate initiation of treatment is warranted for patients with symptoms of disease, as well as in the presence of a small tumor volume that responds better to chemotherapy. The greatest effectiveness is likely in patients with platinum-sensitive relapse and a relapse-free interval of 12-24 months. and more. It is up to 60% with a median survival rate of 2-4 years. These patients should be treated immediately.

For patients with platinum-resistant relapse and a short disease-free period of time, treatment can be delayed until a certain point (the appearance of symptoms, etc.), and only an increase in the CA-125 marker requires further observation.

For platinum-sensitive relapses, resumption of platinum-containing regimens, primarily TC or TR, is the treatment of choice. The exception is clear cell adenocarcinoma (mesonephroid), which is relatively resistant to these regimens.

Other regimens may include liposomal doxorubicin + carboplatin or carboplatin + gemcitabine. The latter regimen is preferred for patients with residual neurotoxicity after first-line XT.

Combined XT demonstrated better results compared to monotherapy with one of the platinum derivatives. Success depends on the duration of the disease-free interval: if it is 5-12 months. - effect 27%, s pathomorphological complete remission (pCR)- 5%, 13-24 months. - 33% and pPR - 11%, more than 24 months. - 51% and pPR - 22%.

Platinum-resistant relapses

Paclitaxel should be used if it has not been used in first-line chemotherapy.

The drug of choice for platinum- and taxane-resistant relapses is liposomal doxorubicin (Doxil in the USA, Kelix in Europe). Oral etoposide, topotecan, gemcitabine, vinorelbine, 5-fluorouracil (5-FU) with leucovorin and ifosfamide have some effectiveness. Altretamine (Hexalene) and oxaliplatin may also be used.

Tamoxifen gives 9.6% of objective effects.

For second-line XT, weekly regimens of paclitaxel and carboplatin or docetaxel and carboplatin are more effective.

An active and relatively well-tolerated regimen is the combination of gemcitabine 650 mg/m2 on days 1 and 8 and liposomal doxorubicin 30 mg/m2 on day 1. Gemcitabine can be used in combination with cisplatin and oxaliplatin.

Topotecan is used in different dose regimens: standard 5-day dose of 1.5 mg/m2/day (grade IV neutropenia is 70-80% and requires a dose reduction to 1 mg/m2/day). To reduce hematological toxicity, topotecan can be supplemented with amifostine.

A weekly regimen of topotecan 4 mg/m2 on days 1, 8 and 15 of a 28-day cycle is less toxic. In practice, the 15th day of administration should often be skipped. A 24-hour infusion of 8.5 mg/m2 every 3 weeks, as well as oral topotecan 2.3 mg/m2 daily for 5 days every 3 weeks, are being studied. Myelosuppression is lower. There is literature data on the effectiveness of irinotecan in platinum-resistant or refractory patients (250-300 mg/m2 90-minute infusion every 3 weeks).

Efficacy for refractory cancer is: ifosfamide - 12-20%, altretamine (Hexamethylmelamine) - 12-14%, fluorouracil with calcium folinate (Leucovorin) - 10-17%, etoposide (oral) - 6-26%, epirubicin (Farmorubicin) - 16-30%.

The effectiveness of docetaxel is 24-41%, vinorelbine - 15%, topotecan - 14-37%, irinotecan (Campto) - 21%, gemcitabine (Gemzar) - 15-28%, oxaliplatin (Eloxatin) - 29% (46% with potentially platinum-sensitive tumors, 17% - with resistant ones), liposomal doxorubicin - 19.7%.

Some studies have demonstrated the effectiveness of thalidomide and lenalidomide, either alone or in combination with other agents.

A promising new drug is trabectedin (Yondelis), isolated from the marine product Ecteinascidia turbinate and then produced synthetically, which is characterized by a unique mechanism of action.

For platinum-sensitive relapses, trabectedin 1.3 mg/m2 as a 3-hour infusion every 3 weeks. caused an objective effect in 43% of patients with a median time to progression of 7.9 months.

The predominant toxicities were asthenia, neutropenia, and increased aminotransferase activity. Other studies have confirmed an efficacy of 28.3% for the 1.3 mg/m2 3-hour infusion every 3 weeks. and 29.6% for the 1.5 mg/m2 regimen, 24-hour infusion every 3 weeks.

Efficacy, according to 3 phase II studies, was 34% with a median time to progression of 5.8 months. in patients with platinum-sensitive tumors and 8% and 2.1 months. - with platinum-resistant ones. A combination regimen of trabectedin with doxorubicin is considered promising as a second-line treatment for recurrent ovarian cancer.

Bevacizumab (Avastin) 15 mg/kg IV every 3 weeks. showed encouraging results. It can be used in combination with paclitaxel (3-week or weekly regimen) or with endoxan (50 mg/day orally for a long time under monitoring of blood counts). The side effects of bevacizumab should be kept in mind, especially the risk of intestinal perforation if it is involved in the process or after irradiation of the abdominal cavity.

Treatment regimens

Monochemotherapy

Paclitaxel (Taxol) - 175-250 mg/m2 ± granulocyte colony-stimulating factor (G-CSF) 3-hour IV infusion once every 3 weeks. with premedication with corticosteroids, antihistamines and H2-receptor blockers: 20 mg of dexamethasone orally or intramuscularly for 12 and 6 hours, 300 mg of cimetidine or 50 mg of ranitidine and 50 mg of diphenhydramine (diphenylhydraline hydrochloride) intravenously in a stream for 30-60 minutes before introduction. It is necessary to use special infusion systems that do not contain polyvinyl chloride (PVC).

Paclitaxel 70-80 mg/m2 in a solution of 0.9% sodium chloride or 5% glucose to a concentration of 0.3-1.2 mg/ml IV 60-minute infusion weekly for 6 weeks. or on days 1, 8 and 15 every 28 days. Premedication: dexamethasone 20 mg IV bolus over 30 minutes, diphenhydramine 50 mg IV over 30 minutes and ranitidine 50 mg IV in 20-100 ml of 0.9% sodium chloride solution or 5% glucose 30 minutes before administration paclitaxel.

Docetaxel - 75-100 mg/m2 1-hour IV infusion once every 3 weeks. with pre- and post-medication with corticosteroids: 32 mg methylprednisolone or 8 mg dexamethasone orally 13, 7 and 1 hour before administration and then 2 times a day for 3-4 days.

Cisplatin - 75-100 mg/m2 IV drip with hyperhydration and forced diuresis every 3 weeks.

Carboplatin - 400-450 mg/m2 IV drip once every 4 weeks. Given the significant difference in AUC and creatinine clearance in patients with normal and impaired renal function, dose calculation using the Calvert formula is recommended.

Doxorubicin liposomal (Doxil, Kelix) - 40-50 mg/m2 IV infusion in 250 ml of 5% glucose for doses up to 90 mg and in 500 ml for doses over 90 mg every 3-4 weeks. The initial rate of administration is 1 mg/min for 10-15 minutes. If there are no reactions, the speed is increased and the entire dose can be administered in 60 minutes.

Altretamine (Hexamethylmelamine, Hexalene) - 6-8 mg/kg orally daily for 21-28 days, or 65 mg/m2 orally 4 times a day after meals and at night daily for 14 days of a 28-day cycle (total dose per cycle - 3640 mg/m2), or 65 mg/m2 orally 4 times a day after meals and at night every day for 21 days of a 28-day cycle (total dose per cycle - 5460 mg/m2).

Oxaliplatin - 135 mg/m2 IV 2-hour infusion every 3 weeks, diluted in 5% glucose solution.

Vinorelbine (Navelbine) - 25-30 mg/m2 IV weekly for 8-10 weeks.

Gemcitabine (Gemzar) - 800-1250 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle.

Topotecan -1.5 mg/m2/day IV 30-minute infusion for 5 days, or 2.3 mg/m2/day orally for 5 days, or 2.25-4 mg/m2 30-minute infusion in 50-250 ml of 0.9% sodium chloride solution or 5% glucose on days 1, 8 and 15 of a 28-day cycle.

Irinotecan - 250-350 mg/m2 30-minute IV infusion once every 3 weeks; in case of diarrhea, the dose is reduced to no more than 250 mg/m2.

Epirubicin (Farmorubicin) - 75-100 mg/m2 IV once every 3 weeks.

Etoposide (Vepezid, Lasted) - 50 mg/day orally for 21 days every 4 weeks. (total dose per cycle - 1050 mg).

5-FU + LV: leucovorin - 500 mg/m2 in 25-100 ml of 0.9% sodium chloride solution or 5% glucose IV 30-minute infusion daily on days 1-5 of a 21-day cycle. After 1 hour, 5-FU - 375 mg/m2 IV bolus over 3-5 minutes daily on days 1-5 of a 21-day cycle.

Trabectedin (Yondelis) - 1.3 mg/m2 3-hour infusion or 1.5 mg/m2 24-hour infusion every 3 weeks.

Combination chemotherapy TC

Paclitaxel (Taxol) - 175 mg/m2 3-hour IV infusion with premedication.
Carboplatin - AUC 5.0-7.5 IV. Repeat the cycle every 3 weeks.

Paclitaxel (Taxol) - 175 mg/m2 3-hour IV infusion with premedication
Cisplatin - 75 mg/m2 IV drip with hydration. Repeat the cycle every 3 weeks.
Paclitaxel (Taxol) - 135 mg/m2 IV 24-hour infusion on day 1. Cisplatin - 75 mg/m2 IV on the 2nd day.

Docetaxel (Taxotere) - 75 mg/m2 on day 1 with pre- and post-medication.
Carboplatin - AUC 6 IV or cisplatin - 75 mg/m2 IV on day 1. Repeat the cycle after 3 weeks.

Cisplatin - 75 mg/m2 on day 1 or 20 mg/m2/day for 5 days.
Cyclophosphamide - 600-750 mg/m2 on the 1st day. Repeat the cycle after 3 weeks.

Cyclophosphamide - 600 mg/m2 IV on the 1st day.
Carboplatin - AUC 5-6 IV on day 1. Repeat the cycle after 3-4 weeks.

Cisplatin - 75 mg/m2 IV on the 1st day.
Doxorubicin - 40-50 mg/m2 IV on the 1st day.
Cyclophosphamide - 600 mg/m2 IV on the 1st day. Repeat the cycle after 3 weeks.

Ifosfamide - 3000-4000 mg/m2 IV (+ mesna) on day 1 or 1500 mg/m2 IV on days 1-5 (+ mesna).
Cisplatin - 60 mg/m2 IV on the 1st day. Repeat the cycle every 4 weeks.

Gemcitabine (Gemzar) - 1000 mg/m2 IV on days 1, 8 and 15.
Cisplatin - 75 mg/m2 on the 1st or 8th day. Repeat the cycle after 2 weeks.
Gemcitabine - 750 mg/m2 IV on days 1 and 8. Cisplatin - 30 mg/m2 IV on days 1 and 8. Repeat the cycle every 21 days.
Gemcitabine - 650 mg/m2 IV on days 1 and 8.
Liposomal doxorubicin - 30 mg/m2 IV on the 1st day. Repeat the cycle every 21 days.

Vinorelbine (Navelbine) - 25 mg/m2 IV on days 1 and 8.
Cisplatin - 75 mg/m2 IV on days 1 or 8. Repeat the cycle every 21 days.
Liposomal doxorubicin (Doxil, Kelix) - 30 mg/m2 90-minute infusion, then Trabectedin -1.1 mg/m2 3-hour infusion. Repeat the cycle every 3 weeks.

In the treatment of exudative pleurisy and ascites, platinum derivatives are effective, as well as the following drugs administered intraperitoneally or intrapleurally after evacuation of exudate: thiotepa - 20-40 mg, fluorouracil - 0.75-1 g (or a combination thereof), bleomycin - 30-60 mg , mitoxantrone - 25-50 mg. A larger dose of thiotepa can be administered intravenously - 60-100 mg. IP administration of cisplatin (100-200 mg in 200-1000 ml of saline with IV hydration) or carboplatin (600-750 mg), as well as IFN-a2 at 5-50 million units is effective.

Ovarian stromal and germ cell tumors

These tumors account for 5 to 10% of all ovarian malignancies.

They can be divided into three groups:

Ovarian stromal tumors are associated with increased estrogen secretion and concomitant endometrial cancer in 7.8% of patients. 43% of tumors are theca cell, 24% are granulosa cell, and 33% are mixed theca and granulosa cell. The worst prognosis is for granulosa cell tumors with metastases. In the case of residual tumors after surgery, radiation therapy is used at a dose of 50-60 Gy to the pelvic area. For advanced metastases, alkylating agents, doxorubicin, a combination of PVB and combinations used in ovarian cancer are used.

Experience in the treatment of Sertoli/Leydigo cell tumors is limited due to their rarity. The effectiveness of combinations of VAC (vincristine, dactinomycin, cyclophosphamide) and CAP (cyclophosphamide + doxorubicin + cisplatin) has been described.

In malignant mixed ovarian tumors, tumor size and histological structure are the main factors determining the prognosis. The prognosis, as a rule, is poor for large tumors in which more than Y3 are elements of an endodermal sinus tumor, choriocarcinoma or immature teratoma of grade III.

For germ cell tumors, which most often occur in adolescence and adolescence, the operation of choice when one ovary is affected is unilateral ovariosalpingectomy and biopsy of the second ovary. For bilateral lesions, panhysterectomy is performed.

Many tumors produce proteins and enzymes that can be detected in serum as tumor markers: alphafetoprotein (AFP), human chorionic gonadotropin (CG), lactate dehydrogenase (LDH).

5-year survival depends on the stage: for stage 1C - 100%, stage II - 85%, stage III - 79%, stage IV - 71%.

For dysgerminomas less than 10 cm in diameter without capsule disruption or invasion of other organs and without ascites, the 10-year survival rate after conservative surgery was 88.6% in one series; Moreover, many women had one or more normal pregnancies that ended in childbirth after unilateral ovariosalpingectomy. Even in the case of non-radical operations, subsequent chemotherapy with the BEP or PVB regimen may result in good long-term results.

All patients, with the exception of those with stage I and grade I (G1) immature teratoma and stage IA dysgerminoma, require postoperative XT.

Patients after operations with incomplete removal of tumors (cytoreductive) also undergo 3-4 courses of XT according to the BEP or PVB regimen (Table 9.27).

In patients who have multiple extraperitoneal lesions or who are not subject to surgical treatment due to their general condition, chemotherapy is administered at the first stage of treatment. Patients who do not respond to the BEP regimen receive XT as a second line using the VAC or VIP regimen. The issue of subsequent surgery is decided after a thorough examination and monitoring of marker levels.

Combination XT includes a set of drugs and treatment regimens used for testicular germ cell tumors. In order to reduce the pulmonary toxicity of bleomycin for young patients, some modification of treatment regimens according to the PVB and BEP regimens has been proposed.

Can carboplatin replace cisplatin in the combinations used? Carboplatin is associated with less oto- and neurotoxicity. For many tumors, but not all, carboplatin can replace cisplatin without compromising effectiveness. However, this does not apply to testicular germ cell tumors. For ovarian germ cell tumors, carboplatin can be a substitute for cisplatin.

In the treatment of children with extracranial germ cell tumors, 5-year survival and disease-free survival were 91 and 88%, respectively, using a combination of carboplatin, etoposide and bleomycin.

Treatment regimens

First-line chemotherapy regimens

Bleomycin - 30 mg IV or IM once a week for 12 weeks.
Etoposide (VP-16) - 100 mg/m2 IV drip daily on days 1-5.

PVB or UVS

Vinblastine - 3 mg/m2 IV on days 1 and 2.
Bleomycin - 15 mg/m2 (maximum 20 mg) continuous IV 24-hour infusion daily on days 1-3.
Cisplatin - 20 mg/m2 IV drip on days 4-8. Repeat cycles every 3 weeks.

Etoposide (Vepezid) - 100 mg/m2 IV drip on days 1-3.

Cisplatin - 20 mg/m2 IV drip daily on days 1-5. Repeat cycles every 3 weeks.

Etoposide (Vepezid) - 100 mg/m2 IV drip on days 1-3.
Ifosfamide - 1500 mg/m2 IV drip daily on days 1-5 with mesna in the standard regimen.

Vinblastine - 0.11 mg/m2/day IV on days 1 and 2.
Ifosfamide - 1200 mg/m2/day IV on days 1-5.
Cisplatin - 25 mg/m2/day IV on days 1-5.

Paclitaxel (Taxol) - 250 mg/m2 IV 24-hour infusion on day 1
Ifosfamide - 1500 mg/m2/day IV on days 2-6.
Cisplatin - 20 mg/m2/day IV on days 2-6.
Carboplatin - 600 mg/m2 IV on day 2.
Etoposide - 1 20 mg/m2 IV on days 1-3.
Bleomycin - 15 mg/m2 IV on the 3rd day. Repeat cycles every 3-4 weeks.

Second-line chemotherapy regimens

VAC (vincristine, dactinomycin, cyclophosphamide)

For immature teratomas of II and III degrees of malignancy, the VAC regimen or a similar combination with vinblastine is considered the best: Vinblastine - 3 mg/m2 IV on days 1 and 2. Dactinomycin - 0.5 mg/m2 IV on days 1-3. Cyclophosphamide - 800 mg/m2 IV on the 3rd day.

V.A. Gorbunova

(Moscow, 2003) ACCORDING TO THE ASCO CONGRESS 2002 (ORLANDO, USA)

Bychkov M. B.

In the materials of the ASCO-2002 congress, lung cancer took a leading place. On this issue, 314 papers are presented, which discuss various issues of epidemiology, diagnosis, morphology and treatment of both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). One work is devoted separately to bronchioloalveolar cancer and carcinoids. Various schemes and treatment regimens for both first and second lines of treatment of NSCLC and SCLC, the effectiveness of combination chemotherapy using Taxol, Taxotere, gemcitabine, Navelbine and other new cytostatics were studied. Several works address the problems of neoadjuvant chemotherapy and chemoradiation therapy for NSCLC and SCLC.

Particular attention was paid to the problem of molecular biological features of lung cancer and the development of methods of molecularly targeted therapy.

NSCLC is characterized by the presence of expression or overexpression of epidermal growth factor receptor (EGRF), making EGRF a promising target for the treatment of NSCLC. A monoclonal antibody targeting EGRF (IMC-C225) has shown promising results in head and neck tumors in combination with radiation therapy or cisplatin, and therefore a variety of EGRF tyrosine kinase inhibitors are currently in research. Of these, only Iressa, OSI-774, PD-183805 and RK1-166 are undergoing clinical trials. In preclinical studies, these drugs in combination with cytostatics or radiation therapy showed an additive or synergistic effect. This served as the basis for conducting phase III clinical trials including patients with NSCLC. The initial successes achieved in NSCLC by blocking EGRF and interrupting intracellular signaling should lead to the establishment of the first targeted therapy for this disease.

Kris M. et al. (abs. 1166) presented data from several US medical centers on phase II clinical trials of Iressa (ZD1839) for advanced NSCLC in patients with progression after platinum- and Taxotere-containing chemotherapy regimens (Ideal-2 study). Iressa is an oral, selective EGRF tyrosine kinase inhibitor that blocks signaling pathways involved in the proliferation and survival of malignant cells. We treated 216 patients with locally advanced or metastatic NSCLC. 102 patients received Iressa 250 mg per day, and 114 received 500 mg. The effect was achieved in 11.8% and 8.8%, respectively. The effect lasted from 3 to 7+ months. 31% and 27% of patients had stabilization of the process, and 43% and 35% (respectively) showed symptomatic improvement. In 60% of patients, a symptomatic effect was achieved within 2 weeks of treatment. Median survival in both groups was 6.1 and 6.0 months. respectively. Side effects were moderate: diarrhea and skin rash grade I-II. and III-IV Art. toxicities were observed only in 6.9 and 17.5% of patients, respectively. The authors conclude that in this group of patients with a large extent of the process, Iressa showed clinically significant antitumor activity with an acceptable, quite satisfactory side effect profile.

Bissett D. (abs. 1183) with numerous co-authors from the UK, Canada, USA and Germany reported the results of a phase III clinical trial of prinomastat (AG3340), a matrix metallopreinase (MMP) inhibitor, in combination with gemcitabine and cisplatin as first-line treatment for widespread III-B (T4) and IV stage. NSCLC. The patients were randomized: I gr. received prinomastat - 15 mg 2 times a day orally, and II - placebo. Patients in both groups were also treated with gemcitabine - 1250 mg/m2 on days 1 and 8 and cisplatin - 75 mg/m2 on day 1, once every 3 weeks. Toxicity was manifested by a “muscle-bone” (MB) effect, presumably due to MMP inhibition. The second and higher degrees of urinary toxicity were observed in 40% per 1 g. and 16% - in gr. placebo, and were expressed in arthralgia, myalgia, limited joint mobility and swelling. These phenomena lasted 3 weeks or more and subsided after a break in taking the drug and a dose reduction. A break was necessary in 37% of group I. and in 12% - in the II group. Median survival was 11.5 and 10.8 months. (p = 0.82), one-year survival of 43 and 38%, progression-free survival of 6.1 and 5.5 months, and overall effectiveness of 25 and 24%, respectively. The authors concluded that the addition of an MMP inhibitor did not increase the antitumor activity of gemcitabine + cisplatin in patients with advanced NSCLC.

Patel J.D. et al. in the USA (abs. 1218) studied the long-term results of treatment with trastuzumab + either Taxotere or Taxol in patients with advanced NSCLC, depending on the expression of HER-2. A randomized phase II clinical trial was conducted in untreated patients with NSCLC. Fifty-seven patients were treated, of whom 13 (22%) were HER-2 positive and 44 (77%) were HER-2 negative. Overall efficacy and toxicity were similar in the Taxotere or Taxol groups, with no significant differences based on HER-2 stratification. At 12 months During follow-up, the median and 1-year survival rate for HER-2+ was 14 months, and for HER-2 - 19 months. The authors concluded that 1) trastuzumab in combination with weekly taxanes showed excellent median survival and 1-year survival; 2) the contribution of trastuzumab to survival data in each population remains unclear; 3) patients treated with the same regimen with HER-2+ had more unfavorable characteristics and shorter survival. If these differences in survival are confirmed in multivariate analysis, then the presence or absence of HER-2 expression will need to be measured in future randomized trials in NSCLC.

Johnson B. E. et al. (abs. 1171) studied the effectiveness of Gleevec in patients with SCLC. They conducted a phase II clinical study of the drug in 19 patients (9 people received Gleevec as the first line, and 10 people received the second line of treatment, but in sensitive patients with an effect that lasted more than 60 days). The first objective was to evaluate objective improvement with a daily dose of 600 mg. There was no objective effect; six-month survival rate was 68%. The authors conclude that there have been few patients with Kit+ SCLC (CD 117) and that further study of Gleevec as single-agent chemotherapy in SCLC will focus on patients with a Kit+ molecular target (CD 117).

Read W. L et al. (USA) (abs. 1267) provide a large review of the epidemiology of bronchioloalveolar cancer (BAR) over the past 20 years since 1979 every 5 years. Thus, with an increase in the number of patients with NSCLC - from 1979 to 1998. 1.8 times, the number of patients with adenocarcinoma (without bipolar disorder) increased by 6.8% (from 28.6% to 35.4%), and the percentage of patients with bipolar disorder over these years was almost the same (3.3% in 1979 -1983, 2.8% in 1984-1988 and 3.8% in 1994-1998). BD in relation to the total number of patients with NSCLC was 3.4%, while the average age of patients with BD was the same as for all patients with NSCLC (67.1 and 67.2 years), slightly exceeding the age of patients with adenocarcinoma (without BAR) - 65.4 years. Among women with NSCLC, the percentage of patients with squamous cell carcinoma was 36.8%, with adenocarcinoma (without BD) - 44%, and with BD - 53.8%, i.e. almost 2 times more than with squamous cell cancer. 1-year survival rate was the lowest for large cell cancer - 32%, and for bipolar cancer - 64.9%.

Wirth L.I. et al. (abs. 1293) studied the problem of lung carcinoids and their sensitivity to chemotherapy. 93 patients received chemotherapy according to the EP or CAV regimens. According to the morphological picture, all carcinoids were divided into: I - typical carcinoid, II - atypical carcinoid, III - large cell neuroendocrine carcinoma and IV - small cell carcinoma. The effectiveness of chemotherapy was assessed in the first 2 groups and amounted to 31%. 10-year survival rate was assessed in all 4 groups and was in group I. - more than 80%, in II gr. - 35-56%, a III and IV gr. - less than 10%.

Combination chemotherapy for NSCLC.

Schiller I. H. (USA) presented an analysis of ECOG trials from 1980 to 2000. to compare long-term results and characteristics of patients with advanced NSCLC who received different chemotherapy regimens. The author included 3398 patients in the analysis, divided into 2 groups: in group I. those treated before 1990 (1574 people), and in II - after 1990 (i.e., those who received new cytostatics - taxanes, gemcitabine, navelbine, etc.) - 1824 people. Median survival rate in group I was 5.9 months, and in the 2nd group. - 8.1 months, i.e. increased by 1.4 times. Time until progression to grade I. was 2.7 months, and in the II gr. 3.5, i.e. also increased by 1.3 times. Time interval from the beginning of progression to death in group I. was 2.7 months, and in the II gr. - 4.1 months (also increased by 1.6 times). The author also cites some other characteristics that have undergone changes over the years. Thus, before 1990, 15.4% of patients had weight loss of more than 10 kg, and after 1990, only 11.9%. The number of patients with more than 1 metastasis in group II. decreased by 2 times (45.3 and 22.8%, respectively), and the intervals from the moment of diagnosis to the start of treatment decreased from 1.4 months. up to 1 month

Raftopoulos H. et al. (abs. 1284) conducted a retrospective analysis of randomized clinical trials over 10 years from 1991 to 2001. to determine the role of chemotherapy in advanced NSCLC. 8468 patients were studied. The median survival was the shortest in the group of 783 patients treated with cisplatin alone - 7.2 months, in the group of 509 patients treated with the cisplatin + etoposide regimen, it was 7.8 months, and the longest median survival was in the group of patients receiving cisplatin with new cytostatics - 9.2 months.

Baggstrom M.Q. et al. (USA) (abs. 1222) conducted a meta-analysis of the published literature on the effect of various chemotherapy regimens as 1st line of treatment on the survival of patients at stage III-IV. NSCLC. The authors noted that the third generation of modern chemotherapy - a combination of platinum drugs with taxanes, gemcitabine, Navelbine increases the number of objective effects by 13% (p = 0.001) and median survival by 4% (p = 0.001) compared with the second generation of combination chemotherapy ( combination of platinum drugs with other cytostatics). To conduct this meta-analysis, the authors used 8 large clinical trials that included 3296 patients with NSCLC.

Massarelli E. (abs. 1223) et al. conducted a retrospective analysis of long-term treatment results in various clinics in the US and UK in patients who had previously received 2 chemotherapy regimens, including platinum derivatives and Taxotere for recurrent NSCLC. An objective effect was observed in 21% of patients after 1 line of treatment, 16.3% after 2 lines, and after 3 and 4 lines of treatment, when gemcitabine was used and combinations with other drugs, objective improvement was noted only in 2.3% to 0%. Disease control (OE+ stable) after 1 line was achieved in 62.8% of patients, and after 3 and 4 lines - only in 21.4%. The overall one-year survival rate for all lines of chemotherapy was 81.2%, and the 2-year survival rate was 18.7%. The authors conclude that the 2nd line of treatment for NSCLC is low and the 3rd and 4th lines of treatment are minimally effective, which requires further development of new chemotherapy regimens for the 2nd and other lines of treatment for NSCLC.

Rudd R. M. et al. (abs. 1170) in the UK, a phase III clinical trial was conducted comparing the GC regimen (gemcitabine + carboplatin) with the MIP regimen (mitomycin + ifosfamide + cisplatin). The study included 422 patients with advanced NSCLC. In I gr. gemcitabine was administered at a dose of 1200 mg/m2 on days 1 and 8, and carboplatin AUC-5 on day 1, once every 3 weeks (212 people). In II gr. (210 people), mitomycin was administered at a dose of 6 mg/m2, ifosfamide 3.0 g/m2, cisplatin 50 mg/m2 on 1 day, once every 3 weeks. The number of treatment courses in both groups was 4, the authors did not note a difference in both groups in the number of effects (37% in group I and 40% in group II), however, the median survival rate was statistically significantly higher in group I. - 10 months compared to II gr. - 6.5 months In addition, in I gr. only 14% of courses required hospitalization, and in group II - 89% of courses. Nausea, vomiting and alopecia were also statistically less in group I.

Results of phase II clinical trials of SWOG for the treatment of patients with stage III. NSCLC with a poor prognosis was presented by Davis A. M. et al. (USA) (abs. 1191). They administered concurrent chemotherapy with carboplatin and etoposide and radiation therapy followed by Taxol for consolidation. Carboplatin was administered at 200 mg/m2 on days 1, 3, 29, 31, etoposide 50 mg/m2 on days 1 to 4 and days 29 to 32. Radiation therapy was carried out from the 1st day of treatment with a single dose of 1.8-2 Gy, for a total of 61 Gy. Taxol was administered at a dose of 175 mg/m2 once every 3 weeks, starting from the 11th day of the 3rd chemotherapy cycle. A total of 56 patients were treated. The objective effect after chemoradiotherapy was achieved in 49%, and after treatment with Taxol it increased to 58%. Median survival was 10.3 months, and 2-year survival was 27%. Neutropenia and thrombocytopenia grade III-IV. were present in 45% and 23% of patients, respectively. The authors compared the results of this study with data from their other study, in which Taxol was not administered for consolidation, and noted that although this treatment regimen led to a 2-fold increase in the objective effect (58% and 29%), but the median survival and 2-year survival rate did not increase, which may be due to the high rate of drug-induced mortality (9.2%) in the group receiving Taxol during consolidation therapy.

Kakolyris S. et al. (abs. 1182) conducted a multicenter randomized phase III trial in Greece, where they compared the effectiveness of two chemotherapy regimens: Taxotere + gemcitabine (group A) and Navelbine + cisplatin (group B). A total of 251 patients were treated. 229 patients were assessed. In gr. A (117 people) Taxotere was administered at a dose of 100 mg/m2 on day 8 + gemcitabine 1.0 g/m2 on days 1 and 8, and in gr. B (102 people) - Navelbine 30 mg/m2 on days 1 and 8 + cisplatin 80 g/m2 on day 8, all patients were administered rhG-CSF - 150 μg/m2 on days 9-15. Cycles were repeated every 3 weeks. A total of 917 cycles were performed (median 3 cycles per patient). O.E. in gr. And there was 29%, in gr. B -36%. Duration of effect, time to progression and median survival were 6 months, 8 months. and 9 months in gr. A and 6.5 months, 8.5 months. and 11.5 months. in gr. B. The authors conclude that Taxotere + gemcitabine and Navelbine + cisplatin regimens have comparable activity in patients with advanced NSCLC, but regimen II is more toxic.

Huang C. H. et al. (abs. 1347) conducted a phase III study in the United States comparing the toxicity of two chemotherapy regimens: carboplatin + Taxotere (or + Taxol) in advanced NSCLC. The study included 99 patients; 75 were evaluated at the time of reporting. In I gr. there were significantly fewer neuropathies (14% and 44%, p = 0.002) and myalgias (8% and 31%, p = 0.01), but more neutropenia (61% and 51%, p = 0.390 and anemia (45 % and 38%, p=0.6) grade III-IV OE was comparable (22% and 31%, p=0.23).

Gandara D. R. et al. (abs. 1247) presented a study from the California Cancer Research Consortium that examined the effect of gene level p53 on the results of treatment of patients with NSCLC. 33 patients received chemotherapy according to the regimen: gemcitabine 1000 mg/m2 on days 1 and 8 as the 2nd line of treatment. The median progression-free survival and overall median survival in patients with p53 overexpression was almost 2 times less than in patients without overexpression.

Taxol in combination chemotherapy for NSCLC.

A large number of works are devoted to the role of Taxol in combination chemotherapy for NSCLC. So Lilenbaum R. C. et al. (abs. 2) reported a large randomized study conducted in the United States comparing the effectiveness of Taxol and the combination of Taxol + carboplatin in 584 patients with advanced NSCLC. The objective effect was almost 2 times greater in the combination chemotherapy group (30%) compared to Taxol alone (15%) (the difference is statistically significant). There was also a significant difference in median survival (8.5 months and 6.5 months, respectively).

Belani S. R. et al. (abs. 1245) reported a comparative evaluation of 2 combination chemotherapy regimens with Taxol and gemcitabine in 53 patients with NSCLC. In 1 g. (25 people) Taxol was administered at a dose of 200 mg/m 2 once every 3 weeks, and in 2 g. (28 people) - 100 mg/m2 on days 1 and 8. Gemcitabine in both regimens was administered at 1000 mg/m2 on days 1 and 8. The authors did not note significant differences in both groups in the number of objective effects (52% and 50%), complete remissions (8% and 11%), and the number of stabilizations (36% and 43%, respectively). Neutropenia and thrombocytopenia grade III-IV. was observed significantly more often in group 1 than in group 2 (24% and 12% in group 1 and 14.2% and 3.5% in group 2). Neurotoxicity grade III-IV. was noted only in 2 gr. (3.5%).

Suzuki R. et al. (abs. 1299) studied the effectiveness of 2nd line chemotherapy with Taxol when administered once a week in patients with resistant or relapsed NSCLC previously treated with a combination of Taxotere and carboplatin. The authors treated 32 patients with Taxol at a dose of 80 mg/m 2 once a week for 6 weeks. 70 cycles of chemotherapy were administered. The authors obtained objective improvement in 17% of patients and in another 43% stabilization of the process was noted. Neutropenia and anemia grade III-IV. was present in 41% and 15% of patients, respectively.

Cortes J. et al. (abs. 1297) conducted an interesting study to evaluate the effectiveness of first-line chemotherapy in patients with NSCLC with brain metastases. The authors treated 26 patients according to the following regimen: Taxol 135 mg/m2 on day 1, cisplatin 120 mg/m2 on day 1, + Navelbine 30 mg/m2 on days 1 and 15, or gemcitabine 800 mg/m2 on days 1 and 8 days. In total, the patients received 84 courses of treatment. An objective effect was achieved in 10 out of 26 patients (38.5%), while 1 patient had complete regression of brain metastases. If chemotherapy was ineffective or if there was progression to the brain area, radiation therapy was performed.

And finally, Felip E. et al. (abs. 1217) presented data on a multicenter phase II study studying a new taxane analogue from Bristol-Myers Squibb, the drug BMS-184476 as a 2nd line of chemotherapy. It was administered at a dose of 60 mg/m2 once every 3 weeks to 56 patients with NSCLC, the number of cycles was 262. The authors noted the activity of the drug in 15.6% of patients and stabilization of the process in 59%. Thus, control of tumor growth was achieved in 74% of patients. The authors consider this drug promising for inclusion in various combination chemotherapy regimens for NSCLC.

Taxotere in combination chemotherapy for NSCLC.

Jensen N. V. et al. (abs. 1285) conducted a randomized study in Denmark comparing the effectiveness of Taxotere + carboplatin with carboplatin alone as 1st line treatment for NSCLC. Carboplatin was administered at a dose of AUC-6 at 3-week intervals for a total of 6 cycles (1 g). The same dose of carboplatin 2 g. administered in combination with Taxotere 80 mg/m 2 once every 3 weeks, also 6 cycles. A total of 66 patients were treated (33 in each group). In 1 g. an objective effect was obtained in 12% of patients, and in 2 gr. - in 36%. Median survival and 1-year survival rate in 1 gr. were 6.8 months. and 18%, and in 2 gr. respectively 7.9 months. and 29%. The authors note a significant advantage of combination chemotherapy (OE is 3 times higher, and one-year survival rate is more than 1.5 times higher).

The same combination of Taxotere + carboplatin in advanced NSCLC was studied by Ramalingam S. et al. (USA) (abs. 1263). The objective of the study was to examine the effect of carboplatin dose on survival. The study included 78 patients, 66 of them were evaluated. In both groups, Taxotere was administered at 80 mg/m2, and carboplatin at 1 g. were prescribed at a dose of AUC-6 (28 patients), and at 2 g. - AUC-5 (38 patients). The number of cycles was up to 9 in 1 g. and up to 6 - in 2 gr. The objective effect was 46% and 29%, median survival was 13.1 and 11.4 months. respectively. At the same time, febrile neutropenia in 1 g. was more often - 24.2%, and in 2 gr. - 17.8%. The authors concluded that the dose of carboplatin used in combination with Taxotere influences the effectiveness of the combination.

The role of 2nd line chemotherapy in metastatic NSCLC was presented by van Putten J. W. G. et al. (Holland) (abs. 2667). 57 patients with grade III B-IV. NSCLC that experienced disease progression after 1 line of treatment with gemcitabine in combination with epirubicin or cisplatin were treated with Taxotere at a dose of 75 mg/m2 + carboplatin AUC-6 once every 3 weeks, 5 cycles. An objective effect was achieved in 37% of patients, while in those who had previously received platinum-containing regimens, the OE was 31%, and in those treated with non-platinum-containing regimens - 41%. The median time to progression was 17 weeks and the median survival was 31 weeks. The authors concluded that the Taxotere + carboplatin regimen is an active combination for the 2nd line of treatment of patients with advanced NSCLC who have previously received gemcitabine-containing chemotherapy regimens and is not cross-resistant.

Gemcitabine in combination chemotherapy for NSCLC.

A large number of papers in the ASCO materials on chemotherapy for NSCLC are devoted to gemcitabine.

Sederholm S. (abs. 1162) reported a phase III clinical trial conducted by the Swedish Lung Cancer Study Group. This is a large study that treated 332 patients with advanced NSCLC. Gemcitabine at a dose of 1250 mg/m2 was administered on days 1 and 8 once every 3 weeks (1 g - 170 people) and compared with the same dose of gemcitabine in combination with carboplatin AUC-5 on day 1 (2 g - 162 people). Objective effect in 1 g. was noted in 12%, and in 2 gr. - 30%. Time to progression to 2 degrees. was 6 months old, and at 1 gr. - 4 months, the difference in both indicators is statistically significant. Anemia, leukopenia and thrombocytopenia grade III-IV. were noted only in 2nd grade. and were equal to 1.5%, 12.6% and 15.2%, respectively.

Manegold S. et al. (Germany) (abs. 1273) published the final report of two randomized phase II trials of single-agent chemotherapy with gemcitabine and Taxotere administered sequentially at different doses and schedules as first-line treatment for advanced NSCLC. A total of 380 patients were included in the study, divided into 2 groups. In 1 g. gemcitabine was administered at 1000 mg/m2 on days 1, 8, 15, and Taxotere at 35 mg/m2 on the same days, repeating the cycle every 4 weeks, in 2 g. - gemcitabine 1250 mg/m2 on days 1 and 8, Taxotere 80 mg/m2 on day 1, once every 3 weeks. The authors found no difference in the effect of gemcitabine on median survival, 6 months, 1-year survival, and 2-year survival. Only the effect of the Taxotere administration regimen on median survival was statistically significant (5 months in group 1 and 9.2 months in group 2, p = 0.002).

Kouroussis S. et al. (abs. 1212) reported the results of a multicenter phase II study of 2-line chemotherapy in patients with NSCLC previously treated with taxanes and cisplatin. The study included 135 patients. In 1 g. patients received gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 + irinotecan 300 mg/m2 on day 8 (71 people), and on day 2 (64 people) - only irinotecan at the same dose on 1 day. Objective effect in 1 g. was achieved in 21% of patients, and in 2 gr. - 5.5%. Median time to progression was 8 months. and 5 months Neutropenia, anemia and thrombocytopenia grade III-IV. were more common in 1st group than in 2nd group. 26%, 9%, 9% and 20%, 0%, 3% respectively.

Novakova L. et al. (abs. 1225) reported a phase III clinical trial comparing 2 combinations of gemcitabine with cisplatin and carboplatin. The study included 63 patients with grades IIIB and IV. NSCLC who received 1 line of chemotherapy. Gemcitabine in both groups was administered at a dose of 1200 mg/m2 on days 1 and 8. In 1 g. (29 people) - cisplatin was administered at 80 mg/m2 on day 1, and on day 2. - carboplatin AUC-5 on 1 day. Treatment courses were repeated once every 3 weeks. The authors did not find a difference in both groups either in the number of objective effects (48% and 47%), or in the number of complete remissions and partial remissions (7% and 41% in 1 group, and 6% and 41% in 2 groups. ). Anemia, leukopenia, neutropenia, thrombocytopenia were detected in 23.8%, 27%, 54% and 44.4%, respectively, in both groups combined).

Japanese authors (Hosoe S. et al) (abs. 1259) presented the final report on phase II clinical trials of non-platinum-containing triplets in patients with advanced NSCLC. 44 patients received gemcitabine 1000 mg/m2 and Navelbine 25 mg/m2 on days 1 and 8 (3 cycles), followed by Taxotere 60 mg/m2 once every 3 weeks, also 3 cycles. An objective effect was obtained in 47.7% of patients, the median survival and 1-year survival rate were quite high (15.7 months and 59%, respectively). Leukopenia, neutropenia and thrombocytopenia grade III-IV. were present in 36%, 22% and 2% of patients, respectively. The authors conclude that this non-platinum-containing combination chemotherapy regimen for NSCLC is well tolerated and effective.

Joppet M. et al. (USA) (abs. 2671) reported the use of a new combination for the treatment of advanced NSCLC - gemcitabine + topotecan as 1st line of treatment. The authors treated 53 patients with grades IIIB and IV. NSCLC. Gemcitabine was administered at a dose of 1000 mg/m2 on days 1 and 15, topotecan 1 mg/m2 on days 1-5. An objective effect was obtained in 17% of patients and stabilization in another 23%. Median time to progression was 3.4 months. (from 1 to 15 months, duration of effect - 4.7 months (from 2.1 to 10.8 months). 1-year survival = 37%, and median survival 7.6 months (from 1 to 16 . line of chemotherapy for advanced NSCLC with an acceptable toxic profile.

The combination of gemcitabine with cisplatin and Herceptin as 1st line treatment for patients with advanced NSCLC with HER-2 overexpression was studied by Tran H. T. et al. (USA) (abs. 1226). They presented a final report on the treatment of 19 patients with NSCLC who received gemcitabine 1250 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, and Herceptin 4–2 mg/kg once weekly. In 8 out of 19 patients an objective effect was achieved (42%) and in another 8 - stabilization. Thus, disease control was observed in 84% of patients. Data on median survival and time to progression are not presented.

Ettinger D. S. et al. (abs. 1243) studied a new combination: gemcitabine + Alimta in 54 patients with advanced NSCLC. Gemcitabine was administered at a dose of 1250 mg/m2 on days 1 and 8, and Alimta at a dose of 500 mg/m2 on day 8. 228 treatment cycles were performed. An objective effect was achieved in 17% of patients. The median time to progression was 5.1 months, the median survival was 11.3 months, and the 1-year survival rate was 46%. In 63% of patients, grade III-IV neutropenia was noted, and grade III-IV thrombocytopenia. - in 7%. The authors consider it promising to further study this com-

Induction (neoaljuvant) chemotherapy for NSCLC.

Betticher D.C. et al. (abs. 1231) reported a multicenter, nonrandomized study of the use of induction (preoperative) chemotherapy in patients with IIIA pN2 NSCLC. 77 patients with histologically proven pN2 stage of NSCLC by mediastinoscopy received Taxotere 85 mg/m2 on day 1 + cisplatin 40-50 mg/m2 on days 1 and 2, once every 3 weeks. Three cycles of chemotherapy were administered, followed by radical resection with mediastinal lymphadenectomy on day 22 after cycle 3. An objective effect after chemotherapy was achieved in 67% of patients, with 8% achieving complete regression. Radical resection was possible in 56% of patients, while histologically complete regression was noted in 16%. Patients with non-radical resection received radiation therapy at a dose of 60 Gy. The 2-year survival rate in this group of patients was 41%. Median survival was 28 months, median progression-free survival and overall survival were 12 and 28 months. respectively. The most common metastases (in 13% of radically operated patients) were brain metastases, and local relapses - in 22% of all patients.

The work of Italian authors (Cappuzzo et al) (abs. 1313) presents phase II clinical trials of the gemcitabine + cisplatin + Taxol regimen as neoadjuvant therapy for unresectable stage IIIA (N2) and IIIB. NSCLC. Gemcitabine was administered at a dose of 1000 mg/m2, cisplatin 50 mg/m2 and Taxol 125 mg/m2, all drugs were administered on days 1 and 8 every 3 weeks. Three cycles were performed in 36 patients. The objective effect was very high - 72% (in 21 of 36 patients), with 2% achieving complete remission. Radical surgery was performed in all patients with an objective effect, while in 3 (8%) histologically proven complete regression was noted. 11 patients who did not undergo radical resection received radiation therapy. III-IV Art. Neutropenia and thrombocytopenia occurred in 27% and 3%, respectively. These preliminary data showed that this combination is tolerable in locally advanced NSCLC.

Chemotherapy in combination with radiation therapy for NSCLC.

Kawahara M. et al. (abs. 1262) presented the final report of the Japan Clinical Oncology Group on a complex phase II study of induction chemotherapy with sequential radiotherapy in combination with weekly irinotecan in 68 patients with unresectable stage III. NSCLC. Cisplatin was administered at a dose of 80 mg/m2 on days 1 and 29, irinotecan at a dose of 60 mg/m2 on days 1, 8, 15, 29, 36, 43, and then during radiation therapy at a dose of 30 mg/m2 at 57, 64, 71, 78, 85 and 92 days. Radiation therapy in a single dose of 2 Gy per day began on day 57, the total dose was 60 Gy. Objective effect was achieved in 64.7% of patients, and complete remission in 9%. Median survival was 16.5 months, with a 1-year survival rate of 65.8% and a 2-year survival rate of 33%. Neutropenia and esophagitis grade III-IV. were in 18% and 4%, respectively. The authors concluded that this chemotherapy regimen is effective for locally advanced NSCLC.

Zatloukal P. V. et al. (Czech Republic) (abs. 1159) conducted a randomized trial comparing simultaneous and sequential chemoradiotherapy for NSCLC. The authors compared 2 groups of patients: those who received radiation therapy simultaneously with chemotherapy - 52 patients (1 group) and sequential radiation therapy - 50 patients (2 groups). All patients received chemotherapy according to the following regimen: cisplatin 80 mg/m2 on day 1 and Navelbine 25 mg/m2 on days 1, 8, 15. The interval between courses was 4 weeks; all patients received 4 courses of chemotherapy. Radiation therapy in 1 g. began on day 4 of cycle 2 of chemotherapy (60 Gy in 30 fractions over 6 weeks). In 2 gr. Radiation therapy in the same regimen began 2 weeks after the end of chemotherapy. Objective effect in 1 g. was achieved in 80.4% of patients, and in 2 gr. - in 46.8%. Complete remission was obtained in 21.6% and 17% of patients, respectively. The median survival rate was significantly higher by 1 gram. - 619 days compared to 2 gr. - 396 days (p=0.021). The median time to progression was also statistically significantly longer at 1 g. - 366 days compared to 2 gr. - 288 days (p=0.05). The authors believe that their data confirm the superiority of simultaneous chemoradiation therapy over sequential therapy both in terms of objective effect and life expectancy. The higher toxicity in the concurrent radiotherapy group is acceptable.

Combination chemotherapy for SCLC.

Japanese authors have presented several reports on the effectiveness of irinotecan in SCLC. Thus, Kinoshita A. (abs. 1260) et al. reported the results of phase II of combination chemotherapy of 60 patients with SCLC (26 with localized process and 34 with advanced) irinotecan 50 mg/m2 on days 1, 8 and 15 in combination with carboplatin AUC-5 on day 1 as the first line of treatment. Treatment courses were repeated once every 4 weeks. O.E. was achieved in 51 patients (85%), with a localized process (LP) - in 89%, and with a widespread process (RP) - in 84%. Complete remission was observed in 28.3%, and partial remission in 56.7% of patients. Median survival was 15.7 months. (18.2 months with LP and 9.7 months with RP. 1-year survival rate reached 55% (with LP -88%, and with RP - 26.5%). 2-year survival rate was respectively in 29, 6%, 49.8% and 11%). Leukopenia, neutropenia and thrombocytopenia grade III-IV. was present in 35%, 76% and 42% of patients, respectively.

Ikuo S. et al (abs. 1223) presented materials from a large randomized phase II study examining the effectiveness of the combination of irinotecan + cisplatin + etoposide administered weekly or once every 4 weeks in 60 patients with SCLC. In group I, irinotecan was administered at a dose of 90 mg/m2 in weeks 1, 3, 5, 7, 9 of treatment, cisplatin was administered at a dose of 25 mg/m2 weekly for 9 weeks, etoposide was administered at a dose of 60 mg/m2 in weeks 1-3. days at 2, 4, 6, 8 weeks of treatment. In group II, irinotecan was administered at 60 mg/m2 on days 1, 8, 15, cisplatin - 60 mg/m2 on day 1, etoposide - 50 mg/m2 on days 1-3. Courses of treatment in the II group. repeated once every 4 weeks. There were 30 patients in each group. O.E. was almost the same: in group I - 84%, and in group II - 87%. However, in II gr. CR was achieved in 17% in group II. and only 7% - in group I. Median survival and 1-year survival were also higher in group II. (13.8 months and 56% compared to 8.9 months and 40% in group I). Neutropenia and thrombocytopenia grade III-IV. were 57% and 27% of patients in group I, and 87% and 10% in group II. Diarrhea III-IV stage. was almost the same in both groups (7% and 10%). The authors conclude that combination chemotherapy regimen II is more effective and plan to use it in further scientific developments.

Niell H. B. et al. (abs. 1169) presented data from a large randomized trial comparing etoposide + cisplatin (EP) with or without Taxol in 587 patients with advanced SCLC. In group I (294 patients), etoposide was administered at a dose of 80 mg/m2 on days 1-3 and cisplatin at the same dose once every 3 weeks. In group II, Taxol -175 mg/m2 on day 1 and G-CSF 5 mcg/kg were added to the same chemotherapy regimen on days 4-18 of each cycle. Median survival and 1-year survival rate in group I. were 9.85 months. and 35.7%, and in group II. - respectively 10.3 months. and 36.2%. Toxicity in groups >grade lll was: neutropenia - 63% and 44%, thrombocytopenia -11 and 21%, anemia - 15 and 18%, neurological - 10 and 25%, and general toxicity in 84% and 77%, grade V toxicity (drug-related death) occurred in 2.7% and 6.4%, respectively. The authors conclude that adding Taxol to an EP regimen as initial therapy for advanced SCLC increases grade V toxicity without affecting survival.

Dunphy F. et al. (abs. 1184) provides data from phase II clinical trials of SWOG-9914 on the effectiveness of the combination Taxol + carboplatin + topotecan (PCT regimen) in advanced SCLC as a first-line treatment. This was a randomized study conducted in the USA, which included 86 patients with SCLC. Treatment regimen: Taxol -175 mg/m2 on day 4, carboplatin AUC-5 on day 4 and topotecan 1.0 mg/m2 days 1-4 with G-CSF 5 mcg/kg from day 5 until the absolute neutrophil count increases > 10000. Treatment was carried out once every 3 weeks, a total of 6 cycles. Median survival was 12 months, median to progression was 7 months, 1-year survival rate was 50%. The authors compared these results (historical control) with two other chemotherapy regimens, PET (Taxol + cisplatin + etoposide) and GE (gemcitabine + cisplatin), with 88 patients in each group. Median survival, median time to progression, and 1-year survival were 11 months, 6 months, and 43% in the PET group and 9 months, 5 months, and 28% in the PET group, respectively. G.E. Toxicity IV degree. in the PCT group it was 33%, PET - 39%, GE - 27%. The authors believe that comparisons of PCT, PET, and GE regimens indicate favorable median survival and median survival to progression of the PCT regimen without increased toxicity, as well as a marked increase in 1-year survival in this group of patients with SCLC, which provides some hope.

A comparison of two combination chemotherapy regimens in patients with SCLC with a poor prognosis was carried out by James L. E. et al. (abs. 1170) in the UK. This was a phase III randomized clinical trial comparing the efficacy of gemcitabine + carboplatin (GC) with the standard PE regimen (etoposide + cisplatin). Treatment was carried out in 241 patients (120 in group I and 121 in group II). GC regimen: gemcitabine 1, 2 g/m2 on days 1 and 8, carboplatin AUC-5 on day 1, once every 3 weeks, 4-6 courses. RE regimen: cisplatin 60 mg/m2 on day 1, etoposide 120 mg/m2 on days 1-3, also once every 3 weeks, 4-6 courses. O.E. in I gr. - 58%, in II group. - 63%, median survival 8.1 months and 8.2 months. respectively. Ill and IV Art. toxicities were as follows: anemia 3% and 1%, leukopenia 5% and 1%, neutropenia 11% and 9%, thrombocytopenia 5% and 1%. The study results confirmed that the GC regimen has greater hematologic but less non-hematologic toxicity than the standard PE regimen and provides good survival.

De Marinis F. et al. (abs. 1219) conducted a multicenter, randomized phase II trial in Italy comparing gemcitabine + cisplatin + etoposide (PEG) with gemcitabine + cisplatin (PG) as first-line treatment for SCLC. PEG regimen: cisplatin 70 mg/m2 on day 2, etoposide 50 mg/m2 on days 1-3, gemcitabine 1.0 mg/m2 on days 1 and 8. The intervals between courses were 3 weeks, 62 patients were treated, the number of treatment cycles was 207 (median 4 cycles). PG regimen: cisplatin 70 mg/m2 on day 2, gemcitabine 1.2 g/m2 on days 1 and 8, intervals of 3 weeks, number of patients - 60, number of cycles - 178 (median 3 cycles). O.E. in gr. PEG was obtained in 69%, and gr. PG - in 70%, while complete remission was observed in 25% and 4%, respectively (p = 0.0001). In localized SCLC O.E. was in 70% and 80%, and with widespread in 68% and 59%, respectively. Toxicity grade III-IV: leukopenia -14% and 4%, neutropenia - 44% and 24%, anemia -16% and 8%, thrombocytopenia - 42% and 26%. The authors note that both PEG and PG regimens are active and well tolerated in the treatment of patients with SCLC. At the same time, the triplet leads to a larger number of III-IV degrees. toxicity (statistically unreliable) and greater patient activity. Despite this, among combinations with “new” drugs, PEG and PG regimens appear to be less toxic and have similar activity.

Jett J.R. et al. (abs. 1301) used oral topotecan in combination with Taxol and G-CSF support in patients with untreated advanced SCLC. 38 patients received topotecan orally at a dose of 1.75 mg/m2 for 5 days in a row, Taxol -175 mg/m2 on day 5, G-CSF starting from day 6, intervals between courses - 28 days, a total of 4-6 treatment cycles . O.E. was achieved in 17 patients (45%), while CR was in 3, and PR in 14 people. Median survival was 8.6 months, median time to progression was 5 months, 1-year survival was 43%. The authors believe that oral topotecan in combination with Taxol is an active regimen for advanced SCLC, but may not improve the results of standard treatment. The toxicity of this regimen was moderate. It is planned to continue studying the oral form of topotecan in combination with other cytostatics.

For localized SCLC, chemoradiation therapy continues to be explored using various combination chemotherapy regimens and various radiation therapy (RT) regimens.

So Gray J.R. et al. (abs. 1189) conducted phase II clinical trials in the USA of the Taxol + carboplatin + topotecan regimen in combination with simultaneous RT in the treatment of localized SCLC (LP SCLC) as the first line of treatment. Treatment regimen: Taxol 135 mg/m2 on day 1, carboplatin AUC-5 on day 1, topotecan 0.75 mg/m2 on days 1-3, intervals between courses were 3 weeks, a total of 4 courses of XT were administered. RT began simultaneously with the third cycle of XT in a single dose of 1.8 Gy. daily 5 times a week, DM = 61.2 Gy. Treatment was carried out in 78 patients, 68 of them completed the full cycle of treatment. Thirty-five of 68 patients achieved complete remission (51%). Within 1 year, 65% of patients were without signs of disease. Median survival was 20 months, and 1-year survival was 64%. III-IV Art. toxicities: leukopenia -60%, thrombocytopenia -42%, hospitalization with neutropenic fever -14%, fatigue -14%, esophagitis 8%, pneumonitis -1%. 3 patients died from drug toxicity (radiation pulmonitis - 2, pneumonia - neutropenia - 1). The authors conclude that the use of this triplet in combination with 61.2 Gy RT is a possible treatment method for patients with good PS in patients with LA SCLC and leads to a high number of complete remissions.

Belderbos J. et al. (abs. 1300) in Holland, they also conducted a study to evaluate the effectiveness of combined CT and early RT in patients with LSCLC.

Treatment regimen: chemotherapy CTE -carboplatin AUC-6 on day 1, Taxol 200 mg/m2 on day 1, etoposide 100 mg/m2 per day on days 1-5, courses of treatment once every 3 weeks, 4 courses in total. RT - 1.8 Gy per day starting from day 3 of the second course of XT, total dose of RT - 45 Gy. When CR was achieved, prophylactic brain irradiation (POI) was performed at SD-30 Gy. Treatment was carried out in 26 patients, the number of XT courses was 98. An objective effect was obtained in 24 people. (92%), CR was achieved in 38% of patients. Median survival was 19.7 months. Brain metastases were detected after treatment in 15% of patients. Toxicity grade III-IV: neutropenia - 70%, thrombocytopenia - 35%, esophagitis -27%. The authors concluded that the STE regimen with early radiotherapy is active in LSCLC, but has significant hematological toxicity. Early irradiation of the primary tumor and regional lymph nodes is safe, but the timing of POM should be clarified.

Mori K. et al. (abs. 1173) reported combination chemoradiation therapy for SCLC followed by irinotecan and cisplatin. The authors treated 31 patients with LSCLC using a regimen of cisplatin 80 mg/m2 on day 1, + etoposide 100 mg/m2 on days 1–3. Radiation therapy was carried out at 1.5 Gy. 2 times a day for 3 weeks at a total dose of 45 Gy. From the 29th day of treatment, patients were administered irinotecan 60 mg/m2 on days 1, 8, 15 in combination with cisplatin 60 mg/m2 once every 4 weeks, for a total of 3 cycles. An objective effect was achieved in 29 of 30 patients who completed treatment (96.6%), while 11 people achieved complete remission (36.6%). The 1-year survival rate was also very high - 79.3% for those treated according to the main protocol (25 people) and 87.5% for those also receiving irinotecan + cisplatin. III-IV Art. toxicities during SR chemotherapy were as follows: leukopenia 48% and 12%, thrombocytopenia - 4% and 0%, anemia - 44% and 0%, diarrhea - 4% and 4%. The authors conclude that CP chemotherapy with concurrent twice daily RT followed by 3 cycles of IP is a safe and active treatment with encouraging 1-year survival. Phase III clinical trials using this treatment regimen are planned.

Roof K. S. et al. (abs. 1303) conducted a retrospective analysis of radiation dose escalation in localized SCLC based on materials from the Massachusetts General Hospital in the USA for the period 1990-2000. The patients were divided into 2 groups: I - those who received 50-54 Gy, II - more than 54 Gy. The median overall survival was 41 months, with 2- and 3-year survival rates of 61% and 50%, respectively. Disease-free survival, local control, and absence of distant metastases at 3 years of follow-up were 47%, 76%, and 69%, respectively. There were no significant differences in these indicators in both dose groups. Toxicity >3 st. was also similar in both groups. There were 5 treatment-related deaths: 3 due to neutropenia, 2 due to pulmonary fibrosis, with 4 cases in group II. Although the authors did not find significant differences in long-term outcomes and toxicity in both groups, they believe that a phase III prospective randomized trial to evaluate dose escalation in localized SCLC is warranted.

An interesting study was reported by Videtic G. M. M. et al. (abs. 1176), who presented materials from clinics in the USA, England and Canada on studying the survival of patients with localized SCLC depending on smoking during chemoradiotherapy.

The authors observed 293 patients with SCLC who received chemotherapy according to the CAV->EP regimen and radiation therapy - 40 Gy. I gr. -186 people - patients who smoked during treatment, and II gr. -107 people - non-smokers, 2-year survival rate in group I was 16%, and in 11-28%, 5-year survival rate - 4% and 8.9%, and the median survival rate was 13.6 months. and 18 months respectively. 2- and 5-year disease-free survival rates were -18% and 5% for smokers, and 32% and 18% for non-smokers. A decrease in survival by 2 or more times among patients who continued to smoke during chemoradiation therapy, compared with non-smokers, was also accompanied by lower disease-free survival rates in patients who smoked (2-year - 18%, 5-year - 7%), according to compared with non-smokers (32% and 18%, respectively). At the same time, the authors note that treatment tolerability was almost identical in both groups.

All work used in this review was published in Program/Proceedings ASCO, vol. 21, 2002, links to them are given in the text.

A list of references for this article is provided.
Please, introduce yourself.

Table 3. 14-day version of PCT according to the schemeCMF

	A drug	Single dose	Route of administration	Days of introduction
	Cyclophos-famid			Daily but from 1st to 14th
	Methotrexate
	5-fluorouracil
Courses of treatment are repeated every 4 weeks (the course is repeated on the 29th day, i.e. the interval between courses is 2 weeks). 6 courses.

For patients over 60 years of age, the dose of methotrexate is 30 mg/m2, 5-fluorouracil - 400 mg/m2.

therapy in order to prevent the possible development of post-therapeutic changes.

Before starting treatment, catheterization of a peripheral or central vein is performed. The most rational is hardware infusion.

Patients with breast cancer with an unfavorable prognosis are recommended to undergo PCT with anthracycline-containing derivatives (doxorubicin, epirubicin). 4 courses.

In case of metastatic lesions of 4 or more regional lymph nodes, 4 courses of PCT according to the EC scheme are carried out and then 3 courses of PCT according to the CMF scheme.

Carrying out PCT according to the scheme CAP:

cyclophosphamide 500 mg/m2 intravenously on day 1;

doxorubicin 50 mg/m2 intravenously on day 1;

5-fluorouracil 500 mg/m2 intravenously on the 1st day.

Interval 3 weeks.

Patients with breast cancer with an unfavorable prognosis and who have pathology from the cardiovascular system are treated with PCT regimens with epirubicin.

Conducting PCT according to the EU scheme:

- epirubicin 60-90 mg/m2 intravenously on day 1;

Cyclophosphamide 600 mg/m2 intravenously on the 1st day.
Interval 3 weeks. 4 courses.

Carrying out PCT according to the AS scheme:

doxorubicin 60 mg/m2 intravenously on day 1;

cyclophosphamide 600 mg/m2 intravenously on the 1st day.
Interval 3 weeks. 4 courses.

HORMONE THERAPY

In premenopausal women with 8 or more metastatic lymph nodes after completion of 6 courses of PCT and ongoing menstrual function, bilateral oophorectomy is indicated, followed by the administration of tamoxifen 20 mg per day for 5 years. At

cessation of menstrual function after 6 courses of PCT, tamoxifen 20 mg per day is prescribed for 5 years.

All patients with postmenopausal stage III breast cancer with a positive hormone receptor status of the tumor after combined and complex treatment are recommended to take tamoxifen at a dose of 20 mg per day as adjuvant hormone therapy for 5 years.

IVstage

Treatment of patients with preserved ovarian function.

Patients with breast cancer with an ulcerated tumor complicated by infection and bleeding undergo palliative mastectomy for sanitary purposes. Treatment is supplemented with chemoradiotherapy. hormonal therapy.

Patients with preserved ovarian function undergo bilateral oophorectomy followed by tamoxifen 20 mg per day for 5 years or until progression after treatment. After the effect of tamoxifen ends, second- and third-line hormone therapy (medroxyprogesterone acetate, anastrozole, exemestane, letrozole) is prescribed, and then courses of PCT are prescribed.

The prescription of other types of special treatment depends on the location of the metastases.

1. For cancer with metastases in the contralateral supraclavicular and cervical lymph nodes:

Radiation therapy: the entire mammary gland and all areas of regional metastasis are irradiated (suprasubclavian-axillary and parasternal, and, if necessary, cervical lymph nodes). All zones receive ROD 4 Gy, SOD 28 Gy (equivalent to a dose of 40 Gy with the traditional fractionation regimen). After two to three weeks, radiation therapy continues in the traditional dose fractionation mode (DOD 2 Gy) up to TOD 30 Gy. For the entire course of treatment, SOD is equivalent to 60 Gy. Possibly local (from the aiming field.

corresponding to the size of the residual breast tumor) further increase the dose to SOD. equivalent to 80 Gy.

6 courses of PCT according to the CMF or CAP scheme.

During menopause, hormone therapy (antiestrogens) is added.

Sometimes a palliative mastectomy is performed to
increasing the efficiency of PCT (with significant sizes
tumors).

2. For cancer with metastases in other organs, systemic therapy (chemohormonal) is usually carried out.

Simultaneously with hormonal treatment, in the presence of metastatic bone lesions with severe pain, palliative radiation therapy is performed on the area of ​​metastases.

Chemotherapy should be stopped after the full therapeutic effect is achieved or if treatment is ineffective.

The most acceptable chemotherapy regimens for patients with breast cancer with liver metastases are schemes. involving the use of docetaxel and pacliggaxel alone or in combination with doxorubicin.

When treating patients with breast cancer with predominantly localized metastases in soft tissues, it is advisable to give preference to the vinorelbine - 5-fluorouracil regimen.

The antitumor efficacy of vinorelbine in injection form and for oral administration (capsules) is the same. However, the doses are different: 25 mg/m2 and 30 mg/m2 when administered intravenously are equivalent to 60 mg/m2 and 80 mg/m2; when taken orally.

Monotherapy:

Vinorelbine - 25-30 mg/m2 intravenously or 60-80 mg/m2
orally once a week.

Epirubicin - 30 mg/m2 intravenously on days 1, 8, 15.

Interval 3 weeks.

3. Calcium folinate 100 mg/m2 from days 1 to 5.

5-fluorouracil 425 mg/m2 intravenous bolus from days 1 to 5. Interval 4 weeks.

4. Mitoxantrone 10-14 mg/m2 intravenously on day 1 (30-
minute infusion).

Interval 3 weeks.

5. Docetaxel 100 mg/m2 intravenously on day 1 (1 hour
infusion).

Interval 4 weeks.

6. Paclitaxel 175 mg/m2 (3-hour intravenous infusion).

Interval 3 weeks. Polychemotherapy1.CMF

cyclophosphamide 600 mg/m"; on days 1 and 8;

methotrexate 40 mg/m2 on days 1 and 8;

5-fluorouracil 600 mg/m2 on days 1 and 8.
The interval is 3 weeks (the course is repeated on the 28th day).

epirubicin 60-90 mg/m2 on day 1;

cyclophosphamide 600 mg/m2 (infusion 8-15 min) on day 1.
Interval 3 weeks.

3. Vinorelbine + mitoxantrone

vinorelbine 25 mg/m2 on days 1 and 8;

mitoxantrone 12 mg/m2 on the 1st day.
The interval is 3 weeks (the course is repeated on the 29th day).

4. Doxorubicin + docetaxel

doxorubicin 60 mg/m on day 1;

docetaxel 75 mg/m2 on day 1, infusion 1 hour.
Interval 3-4 weeks.

5. Doxorubicin + paclitaxel

doxorubicin 60 mg/m"; intravenously on day 1;

paclitaxel 175 mg/m2 intravenously (infusion 3 hours) in the 1st
day.

Interval 3-4 weeks.

5-fluorouracil 500 mg/m2 intravenously on day 1;

epirubicin 50-120 mg/m"; intravenously on the 1st day;

cyclophosphamide 500 mg/m"; intravenously on 1 day.
Interval 3-4 weeks.

7. Vinorelbine + 5-fluorouracil

vinorelbine 30 mg/m intravenously on days 1 and 5;

5-fluorouracil - continuous intravenous administration
750 mg/m2/day from days 1 to 5.

Interval 3 weeks.

8. Vinorelbine -doxorubicin

Vinorelbine 25 mg/m2 on days 1 and 8;

Doxorubicin 50 mg/m2 on the 1st day.
Interval 3 weeks.

Treatment of menopausal patients

Treatment of breast cancer patients in menopause begins with the appointment of tamoxifen at a dose of 20 mg daily. A month later, the response of the tumor and metastases to endocrine therapy is assessed. Depending on the type of therapeutic effect, the options for hormonal sensitivity of the tumor are determined and, in accordance with them, either sequential hormone therapy regimens, or chemo-hormonal treatment, or polychemotherapy are carried out. Further treatment is identical to that for patients with stage IV breast cancer with preserved ovarian function.

When relapses of the disease occur after previous therapy, treatment is always individualized.

Breast cancer in men

Breast cancer in men is treated in the same way as breast cancer in women if the tumor is centrally located. It should be remembered that organ-preserving operations are not performed on men. In all cases, a mastectomy is performed.

Paget's cancer.

In the absence of a tumor node in the mammary gland, only surgical treatment is performed (mastectomy according to Madden or Patey). It is permissible to perform a wide central resection with postoperative radiation therapy to the mammary gland (if the woman wishes to preserve it). At

In the presence of a tumor in the mammary gland, Paget's disease is treated as cancer of the appropriate stage.

Edema-infiltrative cancer

1. Radiation therapy according to the radical program (first stage -
4 Gy 7 times to the mammary gland and regional zones, the second -
after 3 weeks, 2 Gy to a total dose of 60-70 Gy). IN
the interval between the first and second stages may be
Bilateral oophorectomy was performed on women in
premenopause (before starting treatment in such patients it is advisable
perform a trephine biopsy to study the hormone receptor
tumor status).

2. For a receptor-positive tumor in menopause (or
premenopausal women after oophorectomy) tamoxifen is prescribed according to
20 mg daily for 5 years and 6 courses of PCT according to CMF regimens
or CAP, for a receptor-negative tumor - 6 courses of PCT
according to the CMF or CAP schemes.

In the future - observation or palliative mastectomy (if tumor growth or metastases in the lymph nodes resumes).

OBSERVATION, DATES AND SCOPE OF THE SURVEY

After completion of special treatment, patients are observed every 3 months for the first two years, every 4 months in the third year, once every six months in the 4th-5th year, then once a year.

During observation during the first 5 years, a general blood test is required every six months; subsequently, this study is carried out once a year.

At each visit, an examination by an oncologist or gynecological oncologist is required.

X-ray examination of the lungs during the first 3 years must be performed once every six months, then once a year.

CERVICAL CANCER (C 53)

According to the Belarusian Cancer Register (Malignant neoplasms in Belarus. Minsk, 2003), the incidence of malignant neoplasms of the cervix in the Republic of Belarus was 14.4 per 100,000 inhabitants in 1993 and 16.1 in 2002

In 1993, 783 new cases of this pathology were identified in women and 848 in 2002.

In the structure of morbidity among the female population in 2002, cervical cancer accounted for 4.9%, occupying the eighth ranking place.

Among patients with cervical cancer, women aged 40-60 years predominate. The average age of patients is 54.5 years. In recent decades, there has been an increase in the incidence of cervical cancer in young women. Early forms of the disease (cervical cancer stages I-II) are diagnosed in 63.8% of cases, advanced forms (stages III-IV) - in 33.2%. In 3.0% of cases the stage cannot be established.

The early occurrence of metastases in regional lymph nodes is characteristic. Their frequency for tumor sizes within T1 is 10-25%, T2 - 25-45%, T3 - 30-65%. Hematogenous metastasis is most typical for meso-nephroid, clear cell and low-grade histological tumor types. If the ovaries are involved in the pathological process, the implantation route of metastasis is possible.

Histological classification of cervical cancer

(WHO, 1992)Squamous cell carcinoma:

keratinizing; non-keratinizing; warty; condylomatous; transitional cell; Lymphoepithelial-like.

Adenocarcinoma a:

mucinous (endocervical, intestinal and signet ring cell;) endometrioid; clear cell; malignant adenoma; glandular-papillary; serous; mesonephroid; Other epithelial tumors:

adenosquamous cell carcinoma; clear cell carcinoma; adenoid cystic cancer; adenoid basal cancer; carcinoid-like tumor; small cell carcinoma; undifferentiated cancer.

Anatomical regions

Malignant neoplasms of the cervix (C 53).

Internal part (C 53.0).

External part (C 53.1).

Damage to the cervix that extends beyond one and
more than the above localizations (C 53.8).

Cervix of the uterus, unspecified part (C 53.9).

Classifications(FIGOAndTNM2002)

Currently, the prevalence of cervical cancer is determined using FIGO and TNM staging. The classification is only applicable to cervical cancer. There must be histological confirmation of the diagnosis.

Because many patients are treated with radiation and do not undergo surgery, all patients with cervical cancer undergo clinical staging. When assessing stages, physical examination, imaging techniques, and morphological examination of tissue obtained from cervical biopsy (including conical biopsy) are used.

To determine the T, N and M categories, the following procedures are required:

* In Tis cystoscopy is not performed.

FIGO staging is based on surgical staging. This includes histological examination of the removed conus or amputated portion of the cervix (TNM stages are based on clinical and/or pathological classification).

Regional lymph nodes

Regional lymph nodes are the pelvic lymph nodes: paracervical, parametrical, hypogastric (internal iliac, obturator), common iliac, external iliac, presacral, lateral sacral.

Involvement of other lymph nodes, such as the para-aortic ones, is classified as distant metastases.

	A drug	Single dose, mg/m2	Route of administration	Days of introduction
	Cyclophosphamide			daily from 1st to 14th
	Methotrexate		intravenous stream
	Fluorouracil		intravenous stream
Courses of treatment are repeated every 4 weeks (the course is repeated on day 29, i.e. the interval between courses is 2 weeks) 6 courses.

For patients over 60 years of age, the dose of methotrexate is 30 mg/m2, fluorouracil - 400 mg/m2.

Before starting treatment, catheterization of a peripheral or central vein is performed. The most rational is hardware infusion.

cyclophosphamide 500 mg/m2 intravenously over 20-30 minutes on day 1;

fluorouracil 500 mg/m2 intravenous bolus on the 1st day.

Interval 3 weeks (6 courses).

201.10. 3. A–CMF:

201.10. 4. AT–CMF:

doxorubicin 50 mg/m2 intravenously over 20-30 minutes on day 1;

paclitaxel 200 mg/m2 intravenously on day 1 during pre-post-medication;

Interval 3 weeks (4 courses); then

CMF 4 courses (14-day option) interval 2 weeks;

201.10. 5. AS–T weekly:

doxorubicin 60 mg/m2 intravenously for 20-30 minutes on day 1;

Interval 3 weeks (4 courses); then

paclitaxel 80 mg/m2 intravenously on day 1;

Interval 1 week (12 courses);

201.10. 6. ddAC–ddT (G–СSF):

doxorubicin 60 mg/m2 intravenously for 20-30 minutes on day 1;

cyclophosphamide 600 mg/m2 intravenously on day 1;

Interval 2 weeks (4 courses); then

paclitaxel 175 mg/m2 intravenously on day 1;

filgrastim 5 mcg/kg per day subcutaneously from days 3 to 10;

Interval 2 weeks (4 courses);

201.10. 7.CRBPDOCETRAS:

docetaxel 75 mg/m2 Intravenously on day 1;

carboplatin AUC6 intravenously on day 1;

trastuzumab 8 mg/kg (first administration 90-minute infusion), subsequent administrations 6 mg/kg (30-minute infusion) intravenously on day 1;

Interval 3 weeks (6 courses);

201.10.8. Trastuzumab for adjuvant purposes in the presence of a combination of the following signs: with Her2/neu 3+ (or Her2/neu 2+ and a positive Fish reaction), involvement of 4 or more lymph nodes, high proliferative activity of the tumor (Ki-67 expression level more than 15% ). Trastuzumab administration regimens: first administration (required in a hospital setting) at a dose of 4 mg/kg, subsequent administrations of 2 mg/kg weekly or first administration (required in a hospital setting) 8 mg/kg, subsequent administrations of 6 mg/kg at intervals of 3 weeks. The duration of adjuvant therapy with trastuzumab is 1 year.

When administering trastuzumab, it is necessary to monitor the ejection fraction of the left ventricle of the heart.

201.11. Stage IV.

At this stage of the process, breast cancer is incurable. In some cases, treatment can result in long-term survival and preserve the quality of life of patients.

For stage IV breast cancer, patients receive systemic therapy. Radiation therapy may be used for symptomatic purposes.

Patients with breast cancer with an ulcerated tumor complicated by infection or bleeding undergo palliative mastectomy or amputation of the mammary gland for sanitary purposes. Treatment is complemented by chemoradiotherapy and hormonal therapy.

If surgical treatment is not planned, then at the first stage a trephine biopsy of the tumor or a biopsy of the metastatic lymph node is performed. The hormone receptor, HER2/neu status of the tumor, and the level of proliferative activity of the Ki-67 tumor are determined. In accordance with the results of the study, either sequential hormone therapy regimens, or chemohormonal treatment, or polychemotherapy, or treatment with trastuzumab are carried out. Radiation therapy is performed according to indications.

With a positive hormone receptor status of the tumor, and the presence of metastases in the bones and (or) soft tissues (provided there are no metastases in the visceral organs), the first line of endocrine therapy is performed in menopausal patients - tamoxifen 20 mg orally for a long time until progression. If signs of disease progression appear while taking tamoxifen, the latter is discontinued, the 2nd line of endocrine therapy is prescribed - aromatase inhibitors, then the 3rd line - progestins).

If hormone therapy has no effect, successive lines of monochemotherapy are prescribed.

After the end of remission from sequential monochemotherapy regimens, polychemotherapy is carried out.

In premenopausal patients with the above localization of metastases and with a positive hormone receptor status of the tumor, castration is performed: surgical or pharmacological (goserelin). Then anti-estrogen therapy is carried out with tamoxifen, after which aromatase inhibitors are prescribed. 3rd line of hormone therapy – progestins. If there is no effect from hormone therapy, sequential monochemotherapy regimens are prescribed. After the end of remission from sequential monochemotherapy regimens, polychemotherapy is carried out.

If the tumor's hormone receptor status is negative, systemic chemotherapy is performed. In this case, in patients with overexpression/amplification of HER2/neu, trastuzumab is prescribed in combination with or without PCT.

Chemotherapy regimens are the same as for the treatment of relapses and metastases of breast cancer after previous treatment.

For hypercalcemia and lytic metastases in the bones, bisphosphonates are prescribed for a long time.

Folfox chemotherapy regimen is a widely used technique for treating and prolonging the period of remission of malignant neoplasms of the colon.

Chemotherapy summarizes various regimens for the treatment of oncological tumors, differing in degree, severity and required dosage. FOLFOX, like other methods, has a toxic effect on the human body, but has a higher percentage of treatment effectiveness compared to similar methods.

Chemotherapy is a course of strong drugs used during severe bacterial diseases, as well as oncology. The drug administration system is developed for each patient individually, taking into account the required effect, form and stage of the disease.

The name of the chemotherapy system comes from the first letters of the drugs used during the course. Also, the order of the letters in the name determines the order in which the drugs are taken in this system.

The most significant differences among drug systems are dosages, substances included in the drugs, and the nature of the effect.

Each of these forms has a general toxic effect, but different forms of exposure make it possible to identify and destroy disease agents.

The impact is determined by the properties of the pathogen and its biological qualities. The action of the weak side of the pathogen reduces the spread of infection in the human body.

The “FOLFOX” system is named after the first letters of the cytostatic drugs included in the method.

Cytostatics are drugs whose main function is to slow down growth, development, and disrupt the process of cell division in the body. The most exposed tumor cells reduce their activity due to the development of apoptosis (programmed cell death due to disrupted life processes).

The FOLFOX system includes the following drugs:

1. Folinsäure (folinic acid).
2. 5-Fluoruracil.
3. Oxaliplatin.

The second element of the system, 5-Fluoruracil, is applied in two stages using injection and drip administration over two days.

This system is most often used to treat colorectal cancer (a severe form of oncology, the most common example is colon cancer and carcinomatosis).

Efficiency of Folfox mode

The effect and speed of treatment using the Folfox method depends on the stage at which the disease was detected.

Statistics show that:

• the onset of remission of cancer is detected in 10% of cases;
• the percentage of disease remission during the course is almost 8 times higher than the positive result in comparison with the passage of such methods as fluorouracil and calcium folinate, oxaliplatin.

This technique is used to treat patients in a stable condition and in general good health.

The folfox chemotherapy regimen is a system of strong drugs that have a toxic effect on the entire body.

Due to the nature of the substances used, the technique has pronounced side effects:

1. Diarrhea.
2. Nausea.
3. The appearance of stomatitis in the oral cavity.
4. Decreased number of neutrophil leukocytes in the blood (neutropenia).
5. A decrease in the number of platelets in the blood (thrombocytopenia).

The main consequence is a decrease in the body's defenses, which makes a person more susceptible to infectious diseases (including stomatitis when the oral epithelium is damaged).

From reviews of patients who used this regimen, it was noted that the manifestation of side effects in each case is individual.

Other chemotherapy techniques

Chemotherapy has several different systems.

These include:

1. ABVD.
2. XELOX.
3. BEACOPP escalated.
4. Mayo.
5. Anthracyclines.

Chemotherapy using the Folfox method is far from the only one. The prescription of a particular therapy depends on the desired result and the required dosage of drugs during treatment.

Chemotherapy according to the AC regimen

The technique includes the use of drugs:

1. Cyclophosphamide - 1 dose every 21 days.
2. Adriamycin - 1 dose every 21 days.

The latter has an analogue, Doxorubicin, which is used quite often.

Side effects of the technique:

• severe nausea and vomiting;
• hair loss;
• decrease in the level of neutrophil leukocytes in the blood.

Before starting the course, you must familiarize yourself with the list of contraindications. This therapy method is used to initiate remission and treat breast cancer.

Chemotherapy according to the XELOX (CapeOx) scheme

During the course of therapy the following drugs are used:

1. Capecitabine.
2. Oxaliplatin.

The technique is repeated after 3 weeks.

Side effects of the technique:

• severe diarrhea;
• severe nausea, vomiting;
• decrease in the level of neutrophil leukocytes in the blood;
• signs of irritated palms and soles of the feet.

Like chemotherapy according to the folfox regimen, it is prescribed for the treatment of malignant neoplasms of the esophagus and intestines.

Lymphoma is a cancer of the lymphatic system.

To treat this disease, a complex of ABVD drugs is used, including:

1. Adriamycin.
2. Bleomycin.
3. Vinblastine.
4. Dacarbazine.

Injections of drugs are used on the first and 15 days.

Possible side effects of the technique:

• the appearance of headache;
• hair loss;
• decreased blood pressure levels;
• weight loss (anorexia);
• decrease in the level of leukocytes in the blood (leukocytopenia).

The BEACOPP escalated technique is also used to treat this disease.

This regimen includes the following drugs:

1. Bleomycin.
2. Etoposide.
3. Adriamycin.
4. Cyclophosphamide.
5. Vincristine.
6. Procarbazine.
7. Prednisolone.

This complex increases the likelihood of a successful outcome of treatment, but the elements of therapy themselves are also toxic.

Chemotherapy according to the FAC regimen

The FAC technique is used to treat breast cancer in the early stages.

The scheme includes:

1. Fluorouracil on days 1 and 8 (intravenously).
2. Adriamycin for 1 day (intravenously).
3. Cyclophosphamide for 1 day.

Side effects of the technique include:

• inhibition of blood formation function;
• disruption of the gastrointestinal tract;
• hair loss;
• impaired reproductive function, infertility;
• liver dysfunction.

This technique is a mirror image of CAF.

Used as a supplement during the main course of treatment.

The scheme includes:

1. Leucovorin from 1 to 5 days.
2. 5-fluorouracil from 1 to 5 days.

Between courses of therapy, a gap of 4 weeks is accepted, after the transition to the third course - 5 weeks. Substances and their quantities may vary depending on the prescription of the attending physician.

Possible side effects of therapy:

• diarrhea;
• the appearance of signs of stomatitis;
• inhibition of hematopoiesis;
• formation of dermatitis.

An additional method is used for the treatment of oncological tumors in various clinics due to its obvious properties.

Anthracycline chemotherapy regimens

Anthracyclines are commonly called substances with antibiotic properties.

These include:

1. Doxorubicin.
2. Daunorubicin.
3. Idarubicin.
4. Epirubicin.

The main effect of this series of drugs is inhibition of the DNA isomerase enzyme and activation of oxidation. Anthracyclines have a strong toxic effect on the circulatory system and gastrointestinal tract, and the injection sites are affected by dermatonecrosis.

Both doctors and patients should be aware of all possible side effects and complications during therapy.

Chemotherapy is an effective technique often used in the treatment of cancer. This method is prescribed only taking into account possible improvements, side effects and consequences of treatment. Before starting therapy, the patient is given the opportunity to refuse the proposed method.