Mayo chemotherapy. Chemotherapy of malignant tumors of the female genital organs

MD, prof. Vozny E.K.

GU RONTS im. N.N. Blokhin RAMS

Breast cancer (BC) is the most common oncological diagnosis in women. Per last years Despite the increase in morbidity, a decrease in mortality from tumors of this localization was noted, which is explained, on the one hand, by the identification of an increasing number of patients in the early stages of the neoplasm, and on the other, by the use of systemic drug therapy. The history of the development and progress of drug therapy for oncological diseases is largely the evolution of drug therapy for breast cancer.

Drug therapy for breast cancer

The use of drug therapy is based on the understanding of the fact that breast cancer is already a common process in the early stages of the disease, due to early hematogenous dissemination and distant micrometastases, which cannot be visualized today by technical reasons. It is these subclinical metastases that are the basis of potential progression.

As long-term experience shows, the use of systemic endocrine therapy and chemotherapy in the early stages increases relapse-free and overall survival of patients with breast cancer.

Patients with breast cancer can be divided into 2 groups:

1) patients with locally advanced resectable cancer;

2) patients with distant metastases (disseminated cancer).

Based on this provision, the goals of treatment in each group are different.

For patients of the first group- cure based on the use of all types of treatment: surgery, radiation and drug therapy.

For patients of the second group- achieving clinical remission and its retention for the maximum possible period; increase in life expectancy of patients and improvement of its quality.

From the 50s. 20th century The first studies on adjuvant chemotherapy with individual drugs in mono-regimes began, but positive results were not obtained. In the 60s. studies have been initiated on the use of combination chemotherapy.

In the 70s. 20th century adjuvant polychemotherapy was carried out in patients with metastases to the lymph nodes, and since the 80s. these studies included patients with unaffected lymph nodes.

Received positive results treatments have contributed to an increase in the number clinical research on adjuvant treatment of patients with breast cancer at all stages of the tumor process.

Study Group early stages Breast Cancer (EBCTCG) conducted an international meta-analysis (Oxford reviews) of all randomized trials of adjuvant therapy for certain groups of patients with invasive breast cancer (EBCTCG 1985, 1990, 1995 and 2000). Thus, women younger than 40 years of age have a maximum reduction in the risk of metastases with systemic adjuvant chemotherapy by 37%, and patients aged 60-69 years achieve a statistically significant reduction in the risk of recurrence by 18%.

In recent decades, in all age groups, there has been an increase in the time to death from breast cancer. The highest relative reduction in mortality is observed among women younger than 40 compared with 60-69 years old, 27 versus 8%, respectively /1; 2/. These data are shown in Table 1.

Table 1

Benefits of adjuvant therapy versus observation

Bonadonna in 1976 published the results of a study on classical adjuvant chemotherapy of CMF (cyclophosphamide, methotrexate, fluorouracil) compared with a follow-up group of almost 400 patients with breast cancer metastases to the lymph nodes, where it showed a reduction in the risk of recurrence and death. Its publication 20 years later, in 1995, confirmed these benefits in the same patients /3; four/.

A review of data from EBCTCG randomized trials on the use of adjuvant polychemotherapy conducted in 1998 /2/ stated its significant advantage in increasing disease-free survival and reducing mortality (Table 2).

table 2

Effectiveness of Combination Chemotherapy (2)

At the next stage in the development of adjuvant therapy, the advantage of anthracycline-containing regimens was shown in comparison with CMF /5; 6/.

The use of 6 cycles of CAF (cyclophosphamide, doxorubicin, fluorouracil) gives a 2% increase in survival (p=0.03) compared to CMF /5/. The use of epirubicin in combination with CEF (cyclophosphamide, epirubicin, fluorouracil) also improved relapse-free and overall survival /6/.

In the NSABP B-15 study /6/, when comparing 6 courses of CMF and 4 courses of AS (doxorubicin, cyclophosphamide), no differences in relapse-free and overall survival were obtained between the 2 groups /7/, which currently allows the use of the AC regimen in adjuvant treatment .

The 1998 EBCTCG review analyzed 11 randomized trials, including 5942 patients, directly comparing anthracycline-containing regimens with CMF /2/. Of these, 8 included the use of 3-drug regimens, FEC (fluorouracil, epirubicin, cyclophosphamide) or FAC (fluorouracil, doxorubicin, cyclophosphamide). Overall, there was a proportional reduction in the risk of recurrence by 12% and a reduction in the risk of death by 11%, which corresponds to a statistically significant absolute increase in 5-year survival by 2.7%. The results of three studies using a combination of two drugs AC (doxorubicin, cyclophosphamide) or EC (epirubicin, cyclophosphamide) included more than 50% of all patients. These three studies showed similar results compared to CMF therapy /2/.

Updated in 2000, EBCTCG data including 15 trials comparing anthracycline- and CMF-containing regimens demonstrate a significant benefit of anthracycline-containing regimens, with 3 drugs compared to CMF, and a benefit of 6 cycles of FAC/FEC compared to AC/EC , which may be due to the longer duration of chemotherapy and the addition of fluorouracil to the regimen /8/.

When choosing an anthracycline-based adjuvant treatment regimen, potential late complications such as cardiac dysfunction and leukemia should be taken into account. The risk of developing cardiomyopathy caused by the doses of anthracyclines used in adjuvant therapy is less than 1%. The incidence of myelodysplasia and secondary leukemia increases in patients receiving CMF and correlates with an increase in the total dose of alkylating agents (cyclophosphamide), as well as with radiation. With standard doses and chemotherapy regimens, the risk of developing leukemia is approximately 1.5%/9; ten; eleven/.

There is controversy in the use of regimens containing anthracycline and CMF in patients with oncogene overexpression HER−2/neu. A retrospective analysis of 3 randomized trials on the use of adjuvant therapy, including a doxorubicin treatment regimen, showed that patients with overexpression HER−2/neu have a greater effect on doxorubicin therapy than patients with HER−2/neu(-) tumors /12; 13; fourteen/.

Current research should answer the question of which cytotoxic agents are preferred (if any) to increase the survival of patients with HER−2neu+. While expression HER−2/neu should not influence the choice of adjuvant regimen other than tamoxifen.

Studies are currently underway to clarify the value of taxanes in adjuvant therapy.

The Cancer and Leukemia Study Group (GALGB) in Study 9344, which included patients with lymph node metastases, compared 4 cycles of AC with different doses of doxorubicin (60, 75 and 90 mg/m2) with 4 cycles of AC followed by 4 cycles of monochemotherapy with paclitaxel, at a dose of 175 mg / m 2. All patients with positive hormone receptors subsequently received tamoxifen. At a median follow-up of 60 months, the analysis of the results showed that in patients treated with paclitaxel, there was a 17% (relative) and 5% (absolute) increase in time to progression. The corresponding reduction in the risk of death was 18% and 3%. At the same time, patients with RE (-) received the greatest benefit. In addition, the study showed that an increase in a single dose of doxorubicin does not affect the 5-year disease-free and overall survival rates, but increases toxicity /15/.

In another study conducted at the M.D. Anderson, compared the efficacy of 8 cycles of FAC and 4 cycles of FAC followed by 4 cycles of paclitaxel (250 mg/m 2 for 24 h); a 3% increase in disease-free survival was shown in favor of the paclitaxel group after 60 months of follow-up (P=0.09) (Thomas et al., 2000).

In the NSABP B−28 Adjuvant Breast and Colon Cancer National Study Group study, the treatment regimen was almost identical to that of CALGB, except that the dose of paclitaxel was 225 mg/m 2 . After 67 months of follow-up, NSABP B-28 results showed a 17% reduction in the difference in recurrence between groups with an absolute difference of 4% (p=0.008) with no significant difference in overall survival.

The International Breast Cancer Research Group (BCIRG) 001 study of 1491 patients compared 6 cycles of FAC (fluorouracil 500 mg/m 2 , doxorubicin 50 mg/m 2 , cyclophosphamide 500 mg/m 2 every 3 weeks) and 6 cycles TAC therapy (docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , cyclophosphamide 500 mg/m 2 every 3 weeks). After 55 months of follow-up, receptor-positive (ER/PR+) patients treated with TAC showed a statistically significant increase in time to progression by 28% compared with FAC (p=0.0076), in patients with receptor-negative (ER/ PR-) also revealed an increase in time to progression by 31% (p=0.0297). Overall survival was 89% and 87%, respectively, with a 30% reduction in risk of death (p=0.008) with TAC therapy. Toxic reactions, in the form of grade 3 and 4 neutropenia, were more common with TAC therapy compared with FAC (65 and 49.3%, respectively, p≤0.05), in addition, anemia, stomatitis, and asthenia were more common. The decision on whether to recommend a combination of TACs will be made after the final determination of the effectiveness of docetaxel in this combination on the survival of patients with early stages of breast cancer, which requires a longer follow-up.

Whether the taxanes will be most effective in combination with the old agents or whether they should be used sequentially after the standard combination also remain questions for further study.

Improvement of dose regimens, the sequence of administration of already well-established drugs in adjuvant chemotherapy of breast cancer became the subject of a large randomized trial INT C9741 /16/.

In this study, which included 2 thousand patients, 2 provisions were considered:

1. Administration frequency. The use of drugs with a shortened interval between the introduction of individual doses. Moreover, each of the active drugs is used in the form of multiple cycles, and not by increasing doses. The use of CSF allows the use of 2-week intervals instead of the usual 3 weeks.

2. Sequence of therapy. The drugs are not used simultaneously, but alternately, which is based on the hypothesis of frequent administration of the drug in the treatment of slowly growing tumors, which include breast cancer.

The study examined the use of sequential and simultaneous administration of the same drugs, with 3- or 2-week intervals between courses. All patients were divided into four groups: the first group received sequentially doxorubicin (60 mg/m 2 , IV, every 3 weeks) - 4 cycles, then paclitaxel (175 mg/m 2 , IV, every 3 weeks) - 4 cycles and then (600 mg / m 2, in / in, every 3 weeks) - 4 cycles; the second - the same drugs, in the same doses, but the intervals between cycles were 2 weeks; the third group - simultaneously received the same doses of the same drugs together with filgrastim, every 3 weeks; the fourth - at the same time the same drugs and doses, but with a 2-week interval, plus filgrastim.

As a result, recurrence-free survival with frequent administration regimens was significantly superior to that with chemotherapy regimens administered every 3 weeks. The 4-year relapse-free survival was 82% for frequent dosing and 75% for other regimens. Overall 3-year survival was 92% for frequent dosing and 90% for 3-week interval regimens. The data obtained indicate that the intensification, i.e. shorter cycle intervals improves clinical outcomes and that sequential chemotherapy using frequent dosing has less toxicity and is as effective as a co-administration regimen.

As for trastuzumab (Herceptin), a monoclonal antibody against HER−2/neu receptor, when combined with AC chemotherapy or paclitaxel, an increase in patient survival has been shown /17/. Four randomized trials are currently ongoing to investigate the potential benefit of trastuzumab in combination with adjuvant chemotherapy regimens. For the time being, trastuzumab should not be included in adjuvant therapy outside of clinical trials.

All of the above results of adjuvant treatment demonstrated a significant benefit of additional therapy for all patients - regardless of age, lesion lymph nodes, hormonal status, although the benefit for each patient depends on prognostic factors for the development of the disease and the response of the tumor to the ongoing treatment.

Thus, all patients with operable breast cancer should receive additional treatment.

Each EBCTCG review has repeatedly demonstrated the benefits of systemic adjuvant chemotherapy in all subgroups of patients with aggressive breast cancer, regardless of menopausal status, axillary lymph node involvement, age, or receptor status. The benefit to each patient must be weighed against the potential adverse effects of chemotherapy. The only group of patients for whom the risks of chemotherapy may outweigh the benefits are patients in whom the tumor is ≤1 cm with negative lymph nodes or ≤3 cm with a favorable histological variant (tubular, papillary, mucinous, medullary and adenoid cystic carcinoma) of cancer.

Modern data on the use of adjuvant chemotherapy, incl. and domestic authors /84; 85/, suggest the need for its use in women with or without lymph node metastases, but with a high risk of disease recurrence.

Based on the results obtained in clinical studies /83/, the following effective chemotherapy regimens are currently used in the adjuvant regimen (Table 3).

Table 3

Adjuvant chemotherapy regimens used in practice

* using antibiotics to prevent febrile neutropenia.

Adjuvant hormonal treatment of breast cancer in premenopausal women

Modern data on the use of adjuvant endocrine therapy have shown the possibility of hormonal effects in various clinical situations.

The EBCTCG review (Table 4) published in 1995 shows that women younger than 50 years of age who had their ovaries removed (by surgery or radiation, without chemotherapy) had a significant advantage in recurrence-free and overall survival compared with observation, (25±7) % reduction in annual difference in recurrence and (24±7) % reduction in annual difference in death /69/.

Table 4

Efficacy of Surgical Spaying, Chemotherapy, and Tamoxifen Therapy in Women <50 Years of Age with Early Breast Cancer: An Indirect Comparison

*SD - standard deviation
** In women with EC+ tumors

The ZEBRA (Early Breast Cancer Research Association), an open-label, multicentre, randomized trial of 1,640 patients of reproductive age under 50 years of age showed that, with a median follow-up of 7.3 years, luteinizing gonadotropin-releasing hormone (LHRH)-goserelin and CMF in adjuvant treatment provide the same relapse-free (281 vs 269 cases; HR = 1.05; 95% CI 0.88-1.24; p = 0.597) and overall survival (148 vs 154 deaths; HR = 0.94; 95% CI 0 .75-1.18; p=0.622) in breast cancer patients with affected lymph nodes and positive receptors (ER+). Patients with negative receptors (ER-) had lower relapse-free (89 versus 66 cases; HR=1.83; 95% CI 1.33-2.52; p=0.0001) and overall survival in the LHRH group compared with SMF (66 vs 47 deaths; HR = 1.64; 95% CI 1.13-2.39; p=0.009) /77/.

Side effects after 24 weeks of treatment were typical of chemotherapy (baldness, nausea/vomiting, and infections), and menopausal symptoms (vaginal dryness and hot flashes) were noted in the LHRH group, which became virtually the same compared to CMF after the end of treatment /78/. Thus, in women of reproductive age with (ER+), it is advisable to use LHRH rather than CMF in the adjuvant regimen, and vice versa in women with (ER-).

An IBCSG (International Breast Cancer Research Group) /72/ study comparing LHRH therapy with CMF, as well as sequential use of CMF chemotherapy and goserelin, enrolling 1063 premenopausal patients without lymph node metastases (70% of them had positive ER+ receptors) , with a median follow-up of 5.7 years, showed that premenopausal patients without affected lymph nodes, whose tumors have low or no estrogen receptor (ER-) levels, benefit more from chemotherapy, and patients with ER+ have the same percentage of effect. It also confirmed the position that the sequential use of chemotherapy and LHRH is superior to each of the methods separately. The results of the study are presented in table 5.

Table 5

Thus, in independent studies, identical results were obtained.

Results of the French study FASG 06 /79/ comparing the combination of drug-induced "ovarian removal" LHRH (triptorelin) + tamoxifen with anthracycline-based chemotherapy regimens in premenopausal patients with hormone receptors positive and affected lymph nodes (1-3 nodes), after 54 months of observation showed high relapse-free and overall survival when using both regimens (Table 6).

Table 6

Survival of patients after endocrine and chemotherapy

Chemotherapy and ovarian shutdown alone are highly effective treatments for resectable breast cancer in premenopausal women. The subject of subsequent research was the study of the possibilities of combining these two methods. It should be emphasized that amenorrhea achieved after drug therapy is one of the favorable prognostic factors for the development of the disease.

Turning off ovarian function in premenopausal women in addition to chemotherapy has advantages because chemotherapy does not always induce amenorrhea. Thus, in patients younger than 40 years, the frequency of amenorrhea after 3 months of chemotherapy is 40% (95% CI36-44), in addition, the shutdown of ovarian function is necessary in patients with the restoration of menstruation after chemotherapy /80/.

The results of a study by the international group for the study of breast cancer (IBCSG) confirmed this position. In premenopausal women without lymph node metastases and with ER/PR-, consistent use of LHRH after CMF therapy results in a reduced risk of recurrence compared with chemotherapy alone, especially in younger patients. The relapse-free 5-year survival was 88% and 62%, respectively /72/.

In a treatment analysis of 3,700 premenopausal patients (314 were under 35 years of age) treated with various regimens of CMF, chemotherapy unfortunately does not adequately shut down ovarian function. This may be why younger patients had a higher risk of recurrence and death than older ones, especially in the case of ER+ tumors. Disease-free survival was shortest in those young patients with positive tumor receptors (ER+) who did not achieve amenorrhea (Table 7).

Table 7

Relapse-free survival and risk of recurrence in patients in different age groups

An hazard ratio >1 indicates an increased risk of recurrence for younger (<35 лет) по сравнению со старшими (>35 years old) patients.

Thus, the endocrine effects of chemotherapy alone are not sufficient for young women, and these patients should receive additional endocrine therapy (tamoxifen or ovarian shutdown), especially in the case of ER+.

The multicentre collaborative ECOG/SWOG/CALGB study INT-0101 /74/, evaluating the results of treatment of 1504 patients, compared 6 courses of CAF and 6 courses of CAF followed by goserelin for 5 years, as well as 6 courses of CAF + consecutive goserelin for 5 years + tamoxifen 5 years. Table 8 shows data on 5-year relapse-free and overall survival.

Table 8

Results of the ECOG/SWOG/CALGB study

*CAF + goserelin versus CAF
**CAF + goserelin + tamoxifen versus CAF + goserelin
n.a. - not reliable

As can be seen from the table, the greatest effect is achieved when chemotherapy is used in combination with goserelin and tamoxifen, especially in women under 40 years of age when used sequentially.

In the Mam−1 GOCSI I study /76/, 466 patients with affected lymph nodes, after surgical treatment; The patients were divided into 4 comparison groups:

the first received CMF chemotherapy,

the second is doxorubicin followed by CMF therapy,

the fourth - doxorubicin followed by CMF therapy, then - goserelin + tamoxifen. The results of a 5-year follow-up in the form of a risk ratio are presented in Table 9.

Table 9

Results of the Mam-1 GOCSI I study

The analysis of the results was carried out depending on the size of the tumor, the number of affected lymph nodes and the EC status. When comparing therapy with anthracyclines and no anthracyclines, the hazard ratio was<1 в пользу антрациклинов. При сравнении химиотерапия + эндокринная терапия с одной химиотерапией, отношение рисков было <1 в пользу химиотерапия + эндокринная терапия. Эти данные доказывают необходимость проведения последующей эндокринной терапии после адъювантной химиотерапии для женщин в пременопаузе.

Adjuvant hormonal treatment of breast cancer in postmenopausal women

An analysis of 55 studies including 37,000 postmenopausal women treated with tamoxifen in the adjuvant regimen, published in 1998, showed an increase in disease-free and overall survival of patients treated with tamoxifen for 5 years. In addition, there is a 50% reduction in the risk of developing cancer in the opposite gland, regardless of the hormonal status of the primary tumor.

Important for practice is the increased risk of developing endometrial cancer while taking tamoxifen, which is most pronounced in postmenopausal women /66/.

In the past few years, the attention of researchers has been directed to the study of aromatase inhibitors in the adjuvant treatment of breast cancer. Of particular interest is a recent study of 5187 postmenopausal women, where letrozole was used at a dose of 2.5 mg per day for the next 5 years after the standard 5-year tamoxifen. At the time of publication, the 4-year survival of patients after additional administration of letrozole was 93% compared with 87% in the observation group. During treatment with letrozole, there was no increase in osteoporosis and fractures /67/. Consequently, the answer to the question of what to do with patients after 5 years of taking tamoxifen was given - to give letrozole.

Three regimens were compared in a multicenter randomized trial (ATAC) involving 9366 postmenopausal patients: anastrozole 1 mg for 5 years; tamoxifen - 20 mg for 5 years and a combination of these drugs. The published 4-year results show an advantage over anastrozole therapy compared with tamoxifen in relapse-free survival (86.9 vs 84.5%; HR=0.86; 95% CI 0.76-0.99; p=0.03 ), especially in patients with positive receptors in the tumor (HR=0.82; 95% CI 0.70-0.96; p=0.014); time to progression (HR = 0.83; 95% CI 0.71-0.96; p=0.015); in a lower incidence of cancer in the opposite breast (hazard ratio 0.62 95% CI 0.38-1.02; p = 0.062), especially in patients with positive receptors in the tumor (hazard ratio 0.56; 95% CI 0 .32-0.98; p=0.042). Endometrial cancer (p=0.0007), uterine bleeding (p<0,001), цереброваскулярные осложнения (p<0,001), тромбоз вен (p<0,001) и приливы (p<0,001) встречались реже у пациенток, получавших анастрозол. Проявления осложнений со стороны костно-мышечной системы (p<0,001) и частота переломов (p<0,001) были менее выражены в группе тамоксифена. В группе комбинации обоих препаратов не получено преимуществ /86/. Таким образом, применениеанастрозола в адъювантном режиме на протяжении 4-х лет имеет преимущество перед тамоксифеном.

The results of all conducted studies on adjuvant treatment of breast cancer are regularly discussed at a representative international conference, where, after reaching a common agreement, recommendations are made for the practical use of adjuvant therapy. The last, eighth conference was held in 2003 in St. Galen, where some changes were made to the recommendations /78/. All patients without metastases in the lymph nodes, depending on the prognostic factors, were divided into groups of minimal and medium risk of recurrence. Patients with metastases to the lymph nodes are at high risk (Table 10).

Table 10

Depending on the risk group, i.e. a set of prognostic factors for the development of relapse, recommendations were made on adjuvant treatment for almost every specific patient. At the same time, the regimens and doses of drugs in each country may be different (Table 11).

Table 11

Basic principles of adjuvant drug therapy in patients with locally advanced breast cancer

The conference outlined general approaches to adjuvant endocrine therapy:

Aromatase inhibitors, despite their advantage over tamoxifen in achieving relapse-free and overall survival in postmenopausal patients with EC+/RP+, can be used for intolerance and contraindications to tamoxifen.

The use of tamoxifen and LHRH analogs in premenopausal patients is more effective than the use of an LHRH analog alone.

In patients with RE-/RP- after chemotherapy followed by therapy with an LHRH analogue, higher results were registered.

The use of chemotherapy followed by the use of tamoxifen in premenopausal patients with positive receptors is more effective than chemotherapy alone.

The current standard of adjuvant therapy is the use of oral tamoxifen at a dose of 20 mg for 5 years.

Ovarian suppression is achieved using LHRH analogs (goserelin) s.c. at a dose of 3.6 mg every 28 days for 2 years.

Preoperative systemic drug therapy

Goals of preoperative (induction) systemic therapy in patients with operable breast cancer:

Achieving complete pathomorphological remission;

Reducing the volume of the primary tumor;

Reducing the size and number of affected lymph nodes;

Increasing the proportion of conservative surgical interventions;

Elimination of distant metastases;

Planning for adequate adjuvant treatment based on remission assessment in vivo.

Several randomized trials have examined the effects of preoperative and adjuvant chemotherapy in the same regimens. The largest of these, NSABP B−18 /19/, which included 1523 women who received 4 cycles of AC chemotherapy (doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 every 3 weeks) before or after surgery .

Timing of chemotherapy had no effect on 5-year relapse-free (67.3 and 66.7%) and overall survival (80 and 79.6%) in both groups of patients, although preoperative chemotherapy made it possible to perform a larger number of patients with organ-preserving surgery .

A clear correlation was also found between complete pathomorphological remission of the tumor (absence of tumor cells) and survival /19/. The use of preoperative chemotherapy made it possible to obtain 13% complete pathomorphological remissions, and only in these patients an increase in 5-year disease-free and overall survival was noted.

The second large randomized study with a similar design was conducted by EORTC /22/, which confirmed the results of the NSABP B-18 study: the number of organ-sparing operations after preoperative chemotherapy is increasing. Survival increases only with complete clinical and morphological remission.

At the M.D. hospital Anderson, after preoperative chemotherapy according to the FAC scheme, the same pattern was revealed between the pathomorphological response and survival in the case of the disappearance of the affected lymph nodes /21/.

Complete pathomorphological remission has become the most important criterion in evaluating the effectiveness of preoperative chemotherapy /20; 21; 87/.

When using anthracycline-containing regimens, the achievement of 17% of complete pathomorphological remissions /20-23/ is recorded.

With an increase in the number of chemotherapy courses and the introduction of taxanes into the treatment regimen, the number of complete pathomorphological remissions increases significantly - from 25 to 34% /24-28/

So, in the NSABP B-27 study /25/, the modes were compared:

1. 4 AC cycles + follow-up operation + 4 AC cycles;

2. 4 cycles of AC + follow-up + 4 cycles of docetaxel;

3. 4 AS cycles + 4 docetaxel courses + surgery.

As a result, in the group of patients receiving AC + docetaxel, the number of complete pathomorphological remissions was twice as high as in patients receiving AC (26 compared with 14%, respectively). Longer follow-up is needed to determine the impact of a high pathomorphological remission rate on increased survival after consistent use of taxanes in the preoperative regimen.

Receptor status affects the effectiveness of systemic preoperative chemotherapy. Patients with EC- tumors are more effective than those with EC+. In a comparative analysis of data from more than 1000 patients who received preoperative chemotherapy, complete pathomorphological remission (pCR) was 4 times higher in patients with EC-tumors compared with EC+ patients /29/.

Therefore, preoperative chemotherapy increases the percentage of organ-sparing operations, which has been shown in all studies. Achieving complete pathomorphological remission contributes to an increase in disease-free and overall survival. Thus, the goal of preoperative chemotherapy is to achieve complete pathomorphological remission. Achieving this goal in as many patients as possible requires answers to the following questions:

1. How many courses of chemotherapy should there be?

2. Is it necessary to change the chemotherapy regimen?

3. When should the chemotherapy regimen be changed?

4. When should the final assessment of the antitumor effect be carried out?

5. How should lymph nodes be assessed?

6. What prognostic factors should be used to select patients?

The possibilities of using endocrine therapy in the preoperative treatment of postmenopausal patients with positive receptors are currently being studied /90/. The maximum effect was obtained when using letrozole at a dose of 2.5 mg for 3 months; it was 92%, which allowed all patients to undergo organ-preserving treatment.

Treatment of metastatic breast cancer

Goals of treatment for metastatic breast cancer:

Achieve clinical remission

Its retention for the maximum period,

Increasing life expectancy and improving its quality.

Patients with multiple cancer metastases should be assigned to the group of patients with a chronic course of the disease, because. the disease is characterized by periods of disease progression and periods of remission after successful systemic anticancer drug therapy.

Depending on the type of breast cancer recurrence, goals are also set to achieve which types of treatment are selected: surgery, chemotherapy, endocrine therapy, or a combination of them /85/. In case of relapse, if:

Loco-regional recurrence is not combined with metastases to distant organs and tissues, we can talk about a cure;

Loco-regional recurrence is combined with metastases to distant organs and tissues; we can talk about life extension and, extremely rarely, about a cure;

If there are visceral metastases, then with complete regression it is possible to prolong life, and with partial regression, it can improve its quality.

Chemotherapy for disseminated breast cancer is indicated for patients:

With primary infiltrative-edematous form of breast cancer;

Visceral metastases;

A large number of metastatic tumor foci;

Negative RE/RP receptors;

Lack of overexpression HER−2/neu;

Short remissions after radical surgical treatment or preoperative therapy;

Lack of effect from hormone therapy.

The choice of therapy for each patient depends on a number of clinical and laboratory criteria: receptor status, overexpression HER−2/neu, the duration of the relapse-free period, the localization of metastases and their number. Depending on the presence or absence of each of these factors, it is proposed to divide the risk of further development of the disease into high and low degrees. Table 12 presents the factors that determine the degree of progression of the disease.

Table 12

Factors that determine the degree of disease progression

Unfavorable clinical prognostic factors include:

More than 10% weight loss;

General status ECOG 2 or 3;

previous radiation or chemotherapy;

High levels of alkaline phosphatase;

Low levels of hemoglobin;

generalized metastasis.

Many years of experience in the use of chemotherapy in such situations has shown that polychemotherapy is more effective than monotherapy.

In a published review /34/ based on 15 clinical studies, which included 2442 patients, when comparing the objective effect of mono- and polychemotherapy, it was 34 and 48%, respectively. Also, when using chemotherapy, an 18% reduction in the risk of death was noted.

Comparison of the effects of a single alkylating drug and the CMF regimen showed a 30% increase in treatment efficacy when using a combination of drugs.

When comparing the results of treatment using anthracycline alone and combinations of anthracyclines with other drugs, the effect of polychemotherapy increases by 12%.

The CAF combination showed better efficacy (43-82%) compared to CMF (30-62%), as well as an increase in time to progression and life expectancy /35/.

The possibilities of chemotherapy for disseminated breast cancer have significantly expanded with the introduction of taxanes into practice. In a study comparing the FAC regimen with the combination of doxorubicin + paclitaxel /94/, the response rate to therapy with the combination with taxane was significantly higher than in the FAC group (68% vs. 55%, p = 0.032), disease-free survival (8.3 months compared with 6.2 months, p=0.034) and the median overall survival (22.7 months and 18.3 months, p=0.02) was also longer.

Another study compared the AS regimen with the combination of doxorubicin + docetaxel /36/. The results obtained showed that the inclusion of docetaxel in the regimen allows to obtain a greater number of recorded effects (60 vs. 47%, p=0.012) and increase the time to progression (1-year disease-free survival 28 and 19%, respectively).

In recent years, capecitabine and gemcitabine have entered the practice of treating disseminated breast cancer. In third-line chemotherapy, when used alone, they were effective after therapy with anthracyclines and taxanes in more than 20% of cases. In combination with anthracyclines and taxanes and vinorelbine, the effectiveness of these drugs is significantly increased.

If the patient progressed less than a year after anthracycline therapy, the use of anthracycline regimens is not advisable. In such cases, we can talk about taxanes, vinorelbine, capecitabine and other drugs that have shown high efficiency of non-anthracycline combinations. After anthracycline therapy, the combination of capecitabine with docetaxel increases the median survival of patients to 14.5 months with an effect of 42%, and with paclitaxel - with an effect of 51 to 62% - the median survival was 16.5-29.9 months /95/ .

Currently, there is a strategy to intensify the dose regimen of taxanes.

Weekly administration of taxanes delivers more of the drug to tumor cells per unit of time and, in turn, contributes to the death of more cells and reduces the time for tumor growth to resume. Such an intensification of the dose regimen can enhance the cytostatic effect more than simply increasing the single dose of the drug. In addition, a longer exposure of the cytostatic enhances the anti-angiogenic effect and affects the apoptosis of tumor cells.

A number of studies have examined the efficacy of weekly taxanes. When using paclitaxel at a dose of 80 mg / m 2 as a 1-hour infusion before the onset of progression or toxicity, it leads to 25% of the objective effect in the second line of therapy, and in the first - to 33%. There is a moderate toxicity and a significant reduction in alopecia /37/.

The use of docetaxel 40 mg/m 2 weekly (6 weeks) in the form of a one-hour infusion allows you to get 41% of the total effect, while grade III neutropenia was noted in 28% of patients /38/. Currently, this regimen continues to be studied in combination with other drugs.

Another area that is currently being studied and partially used by practical oncology is the treatment of disseminated breast cancer with monoclonal antibodies, in particular trastuzumab (Herceptin).

The gene plays a key role in the development of drug resistance. HER−2/neu, encoding a transmembrane tyrosine kinase, thereby affecting growth factor receptors. Most often this occurs in patients with poorly differentiated tumors, a negative receptor status and affected axillary lymph nodes. They have a short relapse-free period and low overall survival. overexpression HER−2/neu observed in 25-30% of patients with breast cancer.

The response rate to trastuzumab treatment among HER−2/neu positive (3+) patients who did not receive chemotherapy for advanced breast cancer was 30-40% and 15-20% in previously treated patients /39; 40; 41/.

ASCO (1998) presents the results of treatment with trastuzumab in 222 previously repeatedly treated patients, in whom the effect was 16% with an average duration of remission of 9 months /42/.

Later, trastuzumab was studied in combination with various anticancer drugs. Table 13 presents the design of ongoing trials investigating the efficacy of chemotherapy with trastuzumab in overexpressing women. HER−2/neu.

Table 13

Efficacy of trastuzumab/chemotherapy combinations

Randomized trials compared the use of chemotherapy alone and chemotherapy with trastuzumab in overexpressing patients HER−2/neu/49/. Patients received AS chemotherapy or paclitaxel, depending on adjuvant therapy, or the same chemotherapy with trastuzumab. When using the combination of trastuzumab and chemotherapy, the response rate, time to progression, and overall survival increase. With the combination of AS and trastuzumab, 19% of patients experienced the development of grade 3-4 cardiac complications. Therefore, when prescribing trastuzumab, it is necessary to monitor the ejection fraction of the left ventricle.

Very interesting data come from study M77001, which clearly shows that early initiation of trastuzumab in first-line drug therapy concomitantly with docetaxel significantly increases median survival (24.1 months) and overall effect (61%), compared with docetaxel alone - ( 10.8 months and 36%, respectively), while in the second line the median survival of patients is only 16.4 months /91/.

Usually, trastuzumab is administered weekly, however, given the pharmacokinetic data, the present recommendations support its use every 3 weeks, which is naturally more convenient for practice /50/.

Endocrine therapy for disseminated breast cancer

The scientific rationale for endocrine therapy methods is based on knowledge of the factors that affect the growth and development of breast cells. In particular, these include estrogen and progesterone. Therefore, the main task of endocrine therapy is to interrupt the hormonal effect on tumor cells, leading to a delay and suppression of their growth. Some part of the cells retains the proteins of estrogen and progesterone receptors and, accordingly, their growth and development depend on hormonal influence /51/. Such tumors are hormone-dependent. Tumors that do not have receptors are less dependent on hormonal influences. Thanks to this discovery, we can individualize the approach to endocrine therapy for each specific patient.

The number of ER/RP receptors depends on the age of the patient and the degree of differentiation of tumor cells, which helps the physician navigate the treatment when hormone receptors are unknown. In patients over 70 years of age, estrogen receptors are found in 73%, and progestin receptors in 97% of women, while in 20-40-year-olds, receptors are recorded in 23 and 38.5% of cases, respectively /52/. With a low degree of differentiation of tumor cells, EC was registered in 29.4%, and RP - in 11.8% of cases.

When hormone therapy is used in the treatment of metastatic breast cancer, the same patterns can be traced as in adjuvant treatment.

In premenopausal women, ovarian shutdown can be achieved by surgical oophorectomy, radiation, or drug therapy. The latter, due to the reversibility of action, is preferable in young women who want to preserve fertility.

A meta-analysis of 4 studies on the effectiveness of hormonal therapy in premenopausal patients showed that the combination of an LHRH analogue and tamoxifen was superior both in terms of effectiveness to monotherapy with an LHRH analogue (39 and 30%), and in terms of time to progression - 8.7 and 5.4 months, respectively (the difference is significant ).

The sequence of endocrine therapy in patients of reproductive age with positive or unknown RE/RP is as follows:

the first line is the shutdown of ovarian function (surgical, drug, radiation) + tamoxifen.

second line - aromatase inhibitors (anastrozole, letrozole, exemestane)

third line - progestins (medroxyprogesterone, megestrol)

A comparative study of tamoxifen with anastrozole showed the advantage of the latter in relapse-free survival in postmenopausal patients with positive receptors, as well as with a lower incidence of thromboembolism and uterine bleeding. Thus, in two large randomized trials (North American 0030 and European 0027), comparing anastrozole 1 mg per day with tamoxifen 20 mg per day in patients with advanced breast cancer sensitive to endocrine therapy, an increase in the median time to progression in the group receiving anastrozole (11.1 months) compared with the tamoxifen group (5.6 months). The objective effect rate was also significantly higher in the anastrozole group (59.1 vs. 45.6%).

A second similar study comparing anastrozole 1 mg per day and tamoxifen 40 mg per day with the inclusion of 238 patients, conducted in Spain, confirmed the advantage of anastrozole in efficacy (36 and 27%), and overall survival (median 17.4 and 16.0 months). respectively) compared with tamoxifen. In addition, anastrozole has been shown to be well tolerated with less thromboembolism and uterine bleeding than tamoxifen. Therefore, anastrozole may be an alternative to tamoxifen in the first line of therapy in postmenopausal patients with disseminated breast cancer. Currently, aromatase inhibitors are increasingly used in the first line of treatment for advanced breast cancer.

Another aromatase inhibitor, letrozole, is widely used for the treatment of breast cancer at a dose of 2.5 mg and shows an effect of 19 to 23%. Anastrozole and letrozole were compared in the second line of treatment for advanced breast cancer, with the inclusion of 713 postmenopausal patients. The median time to progression in both groups was 5.7 months. The only difference between the groups was the higher frequency of effect with letrozole - 19.2%, compared with anastrozole - 12.3% (p = 0.014) /53/.

Materials have been published on the study of the selective estrogen antagonist faslodex at a dose of 250 mg / m, once a month, in women with advanced postmenopausal breast cancer and positive receptors. The drug has demonstrated efficacy equal to tamoxifen, as well as the ability to overcome resistance to tamoxifen. In terms of clinical efficacy (43.5%), faslodex is at least not inferior to aromatase inhibitors, in particular anastrozole (40.9%), and can be used in the second line of endocrine therapy /68/.

Third-generation steroid aromatase inactivator is exemestane, which showed an effect in the second line of endocrine therapy in 23.4 to 28% of patients, and taking into account stabilization for more than 24 weeks - in 47% / 92; 93/.

The concomitant use of a combination of endocrine treatment and chemotherapy is not recommended because studies have shown that the simultaneous use of both methods does not lead to an increase in survival.

More than 50 years of experience in the use of anticancer drug therapy for metastatic breast cancer has shown that the following points should be taken into account when planning treatment:

Patients treated with adjuvant chemotherapy may have a lower percentage of effective treatment /57; 58/.

First line chemotherapy is always more effective than second and subsequent lines of therapy.

Sequential use of chemotherapy and endocrine treatment is more appropriate than their simultaneous use /59/.

An increase in a single dose of anthracyclines or taxanes does not lead to significant differences in overall survival compared with the standard dose /60; 61/.

Patients with an objective effect have a better survival compared to non-responders /62/.

The objective effect is often accompanied by a symptomatic one, which improves the quality of life of patients /63/.

The use of trastuzumab with chemotherapy in women with HER−2/new(+++) metastatic breast cancer increases survival compared to chemotherapy alone /64/.

The effect of chemotherapy is reduced with such unfavorable prognostic factors as: poor general condition, multiple visceral metastases, short relapse-free period, ineffective previous therapy.

Long-term therapy in responding patients is associated with increased time to progression but not overall survival /65/.

Currently, studies are underway to study angiogenesis inhibitors, drugs that affect cell differentiation, monoclonal antibodies, dendritic cells, predictive markers, etc.

Achievements of modern molecular biology allow us to hope for obtaining targeted drugs, which will increase the antitumor effect and the comfort of the therapy.

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Table 3 14-day PCT option according to the schemeCMF

For patients older than 60 years, the dose of methotrexate is 30 mg / m 2, 5-fluorouracil - 400 mg / m 2.

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.

PCT with anthracycline-containing derivatives (doxorubicin, epirubicin) is recommended for breast cancer patients with a poor prognosis. 4 courses.

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

Conducting PCT according to the scheme cap:

cyclophosphamide 500 mg/m 2 intravenously on day 1;

doxorubicin 50 mg/m 2 intravenously on day 1;

5-fluorouracil 500 mg/m 2 intravenously on the 1st day.

Interval 3 weeks.

Patients with breast cancer with an unfavorable prognosis, who have a pathology of the cardiovascular system, undergo chemotherapy regimens with epirubicin.

Carrying out PCT according to the EU scheme:

- epirubicin 60-90 mg/m 2 intravenously on day 1;

Cyclophosphamide 600 mg/m 2 intravenously on the 1st day.
Interval 3 weeks. 4 courses.

Carrying out PCT according to the AC scheme:

doxorubicin 60 mg/m 2 intravenously on day 1;

cyclophosphamide 600 mg/m 2 intravenously on the 1st day.
Interval 3 weeks. 4 courses.

HORMONOTHERAPY

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

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

All patients with stage III postmenopausal 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, bleeding, undergo a palliative mastectomy for sanitary purposes. Treatment is complemented by chemoradiation. hormone therapy.

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

The appointment of other types of special treatment depends on the localization of metastases.

1. In case of cancer with metastases in the contralateral supraclavicular and cervical lymph nodes:

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

corresponding to the size of the residual tumor of the breast) additional dose increase to SOD. equivalent to 80 Gr.

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

In menopause, hormone therapy (antiestrogens) is added.

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

2. In case of cancer with metastases in other organs, as a rule, systemic therapy (chemohormonal) is carried out.

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

Chemotherapy should be discontinued when the full therapeutic effect is obtained or when treatment is ineffective.

The most acceptable modes of chemotherapeutic effects in 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 predominant localization of 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 / m and 30 mg / m 2 when administered intravenously are equivalent to 60 mg / m "; and 80 mg / m"; when taken orally.

Monotherapy:

Vinorelbine - 25-30 mg / m 2 intravenously or 60-80 mg / m 2
inside once a week.

Epirubicin - 30 mg / m 2 intravenously on days 1, 8, 15.

Interval 3 weeks.

3. Calcium folinate 100 mg/m 2 from days 1 to 5.

5-fluorouracil 425 mg/m 2 intravenously as a bolus from days 1 to 5. Interval 4 weeks.

4. Mitoxantrone 10-14 mg/m 2 intravenously on the 1st day (30-
minute infusion).

Interval 3 weeks.

5. Docetaxel 100 mg/m 2 intravenously on the 1st day (1 hour
infusion).

Interval 4 weeks.

6. Paclitaxel 175 mg/m 2 (3-hour intravenous infusion).

Interval 3 weeks. Polychemotherapy1.CMF

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

methotrexate 40 mg/m 2 on the 1st and 8th days;

5-fluorouracil 600 mg/m 2 on days 1 and 8.
An interval of 3 weeks (the course is repeated on the 28th day).

epirubicin 60-90 mg/m 2 on the 1st day;

cyclophosphamide 600 mg/m 2 (8-15 min infusion) on the 1st day.
Interval 3 weeks.

3. Vinorelbine + mitoxantrone

vinorelbine 25 mg/m 2 on the 1st and 8th days;

mitoxantrone 12 mg/m 2 on the 1st day.
An interval of 3 weeks (the course is repeated on the 29th day).

4. doxorubicin + docetaxel

doxorubicin 60 mg/m on day 1;

docetaxel 75 mg/m 2 on day 1, infusion 1 hour.
Interval 3-4 weeks.

5. doxorubicin + paclitaxel

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

paclitaxel 175 mg/m 2 intravenously (infusion 3 hours) in the 1st
day.

Interval 3-4 weeks.

5-fluorouracil 500 mg/m 2 intravenously on day 1;

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

cyclophosphamide 500 mg/m"; intravenously on day 1.
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 / m / day from the 1st to the 5th days.

Interval 3 weeks.

8. Vinorelbine-doxorubicin

Vinorelbine 25 mg/m 2 on the 1st and 8th days;

Doxorubicin 50 mg/m 2 on the 1st day.
Interval 3 weeks.

Treatment of patients in menopause

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

With the appearance of relapses of the disease after previous therapy, treatment is always individual.

Breast cancer in men

Breast cancer in men is treated in the same way as breast cancer in women with a central localization of the tumor. It should be remembered that organ-preserving operations in men are not performed. 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 acceptable to perform a wide central resection with postoperative radiation therapy to the mammary gland (if the woman wants to keep it). At

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

Edematous-infiltrative cancer

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

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

In the future - observation or palliative mastectomy (with the resumption of tumor growth or metastases in the lymph nodes).

OBSERVATION, TERMS AND SCOPE OF THE SURVEY

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

When observed during the first 5 years, a complete blood count is required every six months, and then this study is carried out once a year.

At each visit, an examination by an oncologist, an oncogynecologist is required.

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

CERVICAL CANCER (C 53)

According to the Belarusian Cancer Registry (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 detected in women and 848 in 2002.

In the structure of the incidence of 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 the 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 (stages III-IV) - in 33.2%. In 3.0% of cases, the stage cannot be established.

Early occurrence of metastases in regional lymph nodes is characteristic. Their frequency with tumor sizes within T1 is 10-25%, T2 - 25-45%, T3 - 30-65%. Hematogenous metastasis is most typical for mesonephroid, clear cell and poorly differentiated histological tumor types. When the ovaries are involved in the pathological process, the implantation pathway 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 cricoid-cell;) endometrioid; clear cell; malignant adenoma; glandular-papillary; serous; mesonephroid; Other epithelial tumors:

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

Anatomical regions

Malignant neoplasms of the cervix (C 53).

The interior (C 53.0).

The outer part (C 53.1).

Cervical injury extending beyond one and
more than the above localizations (C 53.8).

Cervix, part unspecified (C 53.9).

Classifications(FIGOandTNM,2002)

Cervical cancer prevalence is currently determined using FIGO and TNM staging. The classification is only applicable to cervical cancer. There should be histological confirmation of the diagnosis.

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

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

* In Tis, cystoscopy is not performed.

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

Regional lymph nodes

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

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

Chemotherapy is a medicinal method for the treatment of malignant tumors, the administration of drugs is carried out intravenously or orally. They spread through the bloodstream and reach cancer cells throughout the body. Therapy is carried out in cycles that alternate with periods of recovery. As a rule, treatment lasts for several months.

The cost of breast cancer chemotherapy in Israel is from $2,700 per course.

The Tlv.Hospital medical service will assist in organizing breast cancer chemotherapy in Israeli clinics. The level of development of medicine in this state will allow for the most effective treatment.

Our company offers the services of a professional provider in Israel. We organize a program of diagnostics and treatment, the choice of a leading doctor and clinic, household support at an affordable cost, and much more.

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Types of chemotherapy for breast cancer

Adjuvant chemotherapy is given after surgery. Such treatment is prescribed for patients without obvious signs of cancer after surgery. The goal of adjuvant therapy is to destroy malignant cells that may have persisted and gone unnoticed. This adjuvant treatment reduces the risk of recurrence.

Even in the initial stages of the disease, cancer cells are able to break away from the primary tumor focus and spread throughout the body through the bloodstream. They do not manifest themselves, are not displayed on the diagnostic results. But if these cells begin to grow, they will cause new tumors to form elsewhere. The goal of adjuvant therapy is to destroy them.

Neoadvantant chemotherapy is given before surgery. Often, the same techniques are used here as in adjuvant, only before, and not after, surgery. The main advantage of neoadvantage chemotherapy is that it can shrink large tumors to a size that can be treated with surgery. Another advantage is that doctors can see how a woman's body reacts to chemotherapy drugs.

The leading specialists in breast cancer therapy in Israel are, and. They have extensive experience in the treatment of breast cancer through chemotherapy, radiotherapy and other new methods.

In some cases, breast cancers are too large to be surgically removed at the time of diagnosis. This type of cancer is called locally advanced. With the help of chemotherapy, the size is reduced in order to be removed surgically.

For advanced breast cancer, chemotherapy may be used as the primary treatment when metastases have spread beyond the breast and axilla. The duration of therapy will depend on the rate at which the tumor decreases, how long and how the woman tolerates the treatment.

After surgical treatment in Israel, the patient is recommended the Oncotype test, through which the potential benefits of chemotherapy are determined.

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Chemotherapy regimens for breast cancer

In most cases, especially in adjuvant and neoadjuvant treatment, combinations of drugs are more effective than any one drug. Various chemotherapy regimens are used, and there is no particular one that is undoubtedly the best.

The most common chemotherapeutic drugs for the treatment of early stages of breast cancer are anthracyclines that inhibit gram-positive bacteria and have antitumor activity (Doxorubicin hydrochloride (Adriamycin), Epirubicin (Epirubicin)), and taxanes (paclitaxel / Taxol ®, Docetaxel / Taxotere ®). They may be given in combination with drugs such as Cyclophosphamide (Cytoxan®), Fluorouracil (5-FU).

Some of the most common breast cancer chemotherapy regimens are:

1. CAF (or FAC): Cyclophosphamide, Doxorubicin (Adriamycin), 5-FU.
2. TAC: Docetaxel/Taxotere, Doxorubicin (Adriamycin) and Cyclophosphamide.
3. AC → T: Doxorubicin (Adriamycin) and Cyclophosphamide followed by Taxol (Paclitaxel) or Taxotere (Docetaxel).
4. FEC: → T: 5-FU, Epirubicin and Cyclophosphamide followed by Taxotere (Docetaxel) or Taxol (Paclitaxel)
5. TC: Taxotere (Docetaxel) and Cyclophosphamide.
6. TCH: Taxotere (Docetaxel), Carboplatin, and Herceptin (Trastuzumab)

The management of world medical protocols, as well as the development of unique chemotherapy protocols, are one of the factors for the high efficiency of cancer treatment in Israel.

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Less commonly used chemotherapy regimens for breast cancer:

1. CMF: Cyclophosphamide (Cytoxan®), Methotrexate* (Methotrexate*) and Fluorouracil (5-FU).
2. → CMF: Doxorubicin (Adriamycin) and then CMF scheme.
3. EU: Epirubicin (Epirubicin) and Cyclophosphamide (Cytoxan®)
4. AC: Doxorubicin (Adriamycin), Cyclophosphamide (Cytoxan®).

Other chemotherapy drugs that are helpful in treating women with breast cancer include:

• Platinum agents (Cisplatin, Carboplatin).
• Vinorelbine (Navelbine®)
• Capecitabine (Xeloda®)
• Liposomal doxorubicin (Doxil®).
• Gemcitabine (Gemzar®).
• Mitoxantrone.
• Ixabepilone (Ixempra®).
• ABRAXANE
• Eribulin (Halaven®)

Doctors give chemotherapy in cycles, with a period of treatment followed by a period of rest to give the body a chance to recover from the effects of the drugs. Therapy begins on the first day of each cycle, but the schedule varies depending on the drugs used. For example, some of them give only on the first day of the cycle, others - every day for 14 days, etc. Cycles are most often 2 or 3 weeks long, but vary depending on the specific medication or combination.

Adjuvant and neoadjuvant chemotherapy is generally carried out for 3-6 months, depending on the drugs used. Treatment may take longer for advanced breast cancer, due to efficacy and side effects.

High-dose chemotherapy for breast cancer

Doctors have found that high-intensity chemotherapy courses can reduce the chance of relapse and improve survival. This means that the same chemotherapy cycles given every three weeks are started every two weeks. A drug (growth factor) can help increase your white blood cell count after chemotherapy to make sure your white blood cell count is back to normal before the next cycle of treatment. This approach is used for neoadjuvant and adjuvant therapy. However, it can lead to more significant side effects, and high-dose chemotherapy is not suitable for everyone.

Side effects of breast cancer chemotherapy

Chemotherapy drugs attack cells that are rapidly dividing, so they are effective against cancer. But there are cells in the body, such as cells in the bone marrow, mucous membranes of the mouth and intestines, and hair follicles, which also divide rapidly. Together with malignant ones, they are affected by chemotherapy. Some women have many side effects, some have several.

To reduce the side effects of chemotherapy, Israeli doctors successfully use various modern drugs and methods, for example, colony-stimulating factors with certain schemes of cytostatic agents (against neutropenia, anemia).

The negative effects of chemotherapy are due to the type of drugs, their quantity and duration of administration. The most common side effects:

• hair loss;
• mouth ulcers;
• increase or loss of appetite;
• nausea and vomiting;
• low blood cell count.

Chemotherapy can affect the hematopoietic cells in the bone marrow, causing an increased risk of:

• infections due to insufficient white blood cells;
• bruising and bleeding due to low platelets;
• fatigue will develop due to a low level of red blood cells and other reasons.

These side effects usually do not last long and go away after treatment ends.

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menstrual changes

For young women, changes in the menstrual cycle are a common side effect of chemotherapy. Premature menopause or infertility can be an undesirable consequence of a temporary or permanent nature. The older the woman, the higher the likelihood of negative effects of treatment. When this happens, there is a risk of bone loss and osteoporosis. Medicines are prescribed to treat or prevent bone loss.

Even if periods stop while a woman is on chemotherapy, she is still able to get pregnant. Pregnancy during chemotherapy treatment can lead to birth defects in the baby, as well as interfere with the fight against cancer. Therefore, the possibility of using contraceptives is discussed with the doctor.

If a woman was pregnant when breast cancer was diagnosed, there is a possibility of treatment. Some chemotherapy drugs are safe during the last 2 trimesters.

Also, before starting treatment, the question of the patient's desire to have children in the future is discussed with the doctor.

neuropathy

Many drugs used to treat breast cancer, including taxanes (Docetaxel and Taxol), platinum drugs (Carboplatin, Cisplatin), Vinorelbine, Eribulin, and Ixempra, can damage nerves outside of the brain and spinal cord. Sometimes this leads to symptoms (mostly in the arms and legs) such as numbness, pain, burning or tingling, sensitivity to cold or heat, and weakness. In most cases, they disappear as soon as treatment is stopped, but in some women it can last a long time.

Heart damage

Doxorubicin, Epirubicin, and a number of other drugs can cause permanent damage to the heart, called cardiomyopathy. The risk depends on the amount of the drug and the duration of use, especially at high doses. Doctors keep a close eye on this side effect. They check the patient's heart function with a MUGA test (a nuclear medicine test that evaluates the function of the heart's ventricles) or an echocardiogram before starting one of these drugs. Doctors carefully control doses, monitor symptoms. If heart function begins to decline, treatment with these drugs is stopped. However, in some patients, the damage process takes a long time: signs may not appear for several months or even years after therapy has been stopped.

Palmar-plantar syndrome

Some chemotherapy drugs, such as Capecitabine and Doxorubicin, can irritate the palms of your hands and the soles of your feet. Early symptoms include numbness, tingling, and redness. If the condition worsens, swelling, soreness, rash, focal peeling, itching are possible. There is no specific treatment, but some creams may help. Symptoms gradually disappear when medication is stopped or the dose is reduced. The best way to prevent this syndrome is to tell your doctor about the early signs.

Side Effects of Chemotherapy for Breast Cancer: Effects on the Brain

Many women who are being treated for breast cancer report a slight decrease in mental performance. There are some problems with concentration and memory that can last for a long time. According to studies, these signs most often disappear within a few years.

Side effects of breast cancer chemotherapy: increased risk of leukemia

Very rarely, chemotherapy drugs can damage the bone marrow, leading to the development of myelodysplastic syndrome (MDS) or even acute myeloid leukemia. This occurs mostly within 10 years after the end of treatment.

Poor health and fatigue

After chemotherapy, many women do not feel as healthy as they once did. There is a residual feeling of pain, loss of physical activity.

Fatigue is a very common symptom after this type of treatment for women. It may persist for several years.

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

Chemotherapy summarizes various schemes for the treatment of oncological neoplasms, differing in degree, severity and required dosage. FOLFOX, like other methods, has a toxic effect on the human body, but has a large 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 necessary exposure, 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 the dosages, the substances that make up the drugs, and the nature of the effect.

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

The impact is determined by the properties of the causative agent of the disease and its biological qualities. The action of the weak side of the pathogen can reduce the spread of infection in the human body.

The FOLFOX system is called by 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 disturbed life processes).

The FOLFOX system includes the following preparations:

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

The second element of the system - 5-Fluoruracil is applied in two stages by injection and drip for 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).

Folfox Mode Efficiency

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

• the onset of remission of an oncological disease is detected in 10% of cases;
• the percentage of remission of the disease 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 who are stable 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. Decrease in the number of neutrophilic leukocytes in the blood (neutropenia).
5. 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 the reviews of patients who used this scheme, it was noted that the manifestation of side effects in each case is individual.

Other chemotherapy methods

Chemotherapy has several different systems.

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

Folfox chemotherapy is far from the only one. The appointment of a particular therapy depends on the desired result and the required dosage of drugs during treatment.

AC Chemotherapy

The technique includes the use of drugs:

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

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

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

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

Chemotherapy according to the XELOX scheme (CapeOx)

During the course of therapy, drugs are used:

1. Capecitabine.
2. Oxaliplatin.

The technique is repeated after 3 weeks.

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

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

Lymphoma is a cancer of the lymphatic system.

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 a headache;
• hair loss;
• lowering blood pressure;
• weight loss (anorexia);
• decrease in the level of leukocytes in the blood (leukocytopenia).

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

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.

FAC Chemotherapy

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

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

• inhibition of the function of blood formation;
• violation of the digestive tract;
• hair loss;
• violation of reproductive function, infertility;
• disruption of the liver.

This technique is a mirror image of CAF.

It is used as an addition 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, an interval of 4 weeks was adopted, after switching to the third course - 5 weeks. Substances and their quantity may vary depending on the prescription of the attending physician.

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

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

Anthracycline chemotherapy regimens

Anthracyclines are commonly referred to as substances with antibiotic properties.

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

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

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Malignant tumors of the ovaries

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

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

Borderline (potentially low malignancy) tumors were identified in the main types. They make up about 15% of epithelial tumors. In addition to the morphological type of tumor, the most important independent prognostic factor in the effectiveness of treatment and survival of patients 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 favorable prognostically and the III degree is the least favorable (G1 - highly differentiated, G2 - medium, G3 - low-differentiated).

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

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

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

Obligatory 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 with the exception of invasive tumor implants.

The method of treatment of borderline tumors is an operation, the volume 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 common process perform radical operations in the amount of extirpation or supravaginal amputation of the uterus with appendages, removal of the greater omentum and all tumor nodes in the form of the so-called aggressive cytoreduction.

Patients with residual borderline tumors do not undergo 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) do not show its significance. Patients without residual tumors who do not receive adjuvant treatment have the same or better survival results 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

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

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

A feature of ovarian cancer is spread into the abdominal cavity by cell implantation and local invasion into 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. The pelvic lymph nodes are involved as often as the para-aortic ones. The tumor, by transdiaphragmatic spread, can block diaphragmatic lymphatic drainage, which causes ascites and pleurisy.

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

Table 9.23. Main prognostic factors in 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 an increased risk group.

After optimal operations in 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 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 in epithelial tumors, tumor markers such as cancer embryonic antigenREA) and tumor-specific antigen CA-125. There is a high correlation of the level of CA-125 one month after the 3rd course chemotherapy (XT) at III and IV stages 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 probability of ovarian cancer, while a negative response does not rule out the presence of a residual tumor. The level of CA-125 can be elevated both in other malignant tumors and in various diseases of the genital organs, such as endometriosis.

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

Bilateral ovariosalpingectomy with hysterectomy and removal of the greater omentum is considered a radical operation for ovarian cancer. In young women who insist on preserving reproductive function, with stage I and grade I (G1), unilateral oophorectomy is possible.

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

Studies have not shown improvement in long-term outcomes with neoadjuvant XT. Currently, aggressive operative tactics as initial therapy are considered to be preferred for best survival. However, in case of doubtful success of the operation in patients with potential complications and comorbidities, neoadjuvant XT is possible.

Treatment tactics

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

At III degree of malignancy (G3) stage 1C, the probability of recurrence is high (up to 20%), which requires additional methods of treatment.

Systemic chemotherapy, intraperitoneal (ip) administration of radioactive phosphorus 32P, or irradiation of the abdominal cavity and small pelvis are possible. However, the administration of 32P turned out to be more toxic with the same efficiency when compared with 6 courses of cisplatin.

Stage II

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

Stage III

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

Further treatment includes the following:

1. With minimal residual tumors (
Perhaps total irradiation of the abdominal cavity and small pelvis (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 intravenous administration of 32R (only if residual tumors less than 1 cm) or colloidal radioactive gold.

2. In case of macroscopic residual tumors more than 2 cm in diameter in the pelvic cavity, combined chemotherapy is performed in the TC, TP, CP or CC mode.

The effectiveness of XT is assessed clinically, radiologically and by marker level. Increasingly important for confirmation of complete remission is positron emission tomography (PAT).

Research programs have demonstrated a statistically significant improvement in relapse-free survival in patients with minimal residual tumors treated with ip cisplatin and ip and iv paclitaxel compared to those who received only iv cisplatin with paclitaxel. These data open up prospects for intraperitoneal chemotherapy in patients with minimal residual tumors.

Stages III and IV. Operations in full and cytoreductive to remove the largest volume of tumor masses, after which a combined XT is performed.

Therapeutic approaches for stage 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 carried out in order to minimize the volume of tumor masses as much as possible.

The volume of residual tumors is a prognostic factor that significantly affects survival. Median survival in patients after optimal cytoreductive surgery is 39 months, and after suboptimal cytoreduction - 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

Cisplatin and carboplatin are equivalent in efficacy in ovarian cancer. Few studies have shown superiority of carboplatin (AUC 7.5) + paclitaxel (175 mg/m2) 3-hour infusion over cisplatin (75 mg/m2) + paclitaxel (135 mg/m2) 24-hour infusion.

An alternative to the paclitaxel regimen is the docetaxel and carboplatin regimen, which has shown similar efficacy in a comparative study with greater hematologic and lower neurotoxicity. Survival at 2 years of follow-up remains the same. The TC regimen (paclitaxel and carboplatin) is considered to be the best for initial XT in terms of efficacy, toxicity, and patient quality of life. Cisplatin is associated with greater neuro-, nephro-, oto-, and gastrointestinal toxicity but less myelosuppression than carboplatin.

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

Docetaxel may replace paclitaxel in cases where neurotoxicity needs to be reduced. 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 showed a 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, as It is for this category of patients that it has an advantage: the median survival for minimal tumors is 66 months, and for large residual tumors - 26 months.

The preferred regimen studied is as follows: 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. There are six 21-day courses of treatment in total.

This approach should be discussed in detail with the patient as is associated with more significant toxicity than intravenous XT. In addition to catheter-related 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 be carried out only in clinics with relevant experience.

New drugs such as gemcitabine (Gemzar), oxaliplatin, topotecan, and triple regimens including epirubicin (Pharmorubicin) and altretamine continue to be studied with encouraging results.

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

Relapses of ovarian cancer. Second line chemotherapy

Table 9.26. Predictive factors for ovarian cancer recurrence

The age of patients also matters: 5-year survival in women younger and older than 40 years correlates as 65 and 20%. Other negative factors include clear cell or mucinous histology, poor differentiation, poor general condition, non-platinum first line XT regimens, presence of ascites. The overall recurrence rate is 62%.

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

Allocate:

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

Recurrent ovarian cancer may be clinically manifested by new symptoms or radiographic findings. computed tomography (CT), as well as an increase in the level of CA-125, which may precede other symptoms for 6 months. and more.

For women with asymptomatic relapses, the advisability of starting treatment immediately 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 justified for patients with symptoms of the disease, as well as in the presence of a small tumor volume that responds better to chemotherapy. The greatest efficacy is likely in patients with a platinum-sensitive relapse and a relapse-free interval of 12-24 months. and more. It is up to 60% with a median survival of up to 2-4 years. These patients are subject to immediate treatment.

For patients with platinum-resistant recurrence and a short relapse-free period, treatment can be delayed until a certain point (appearance of symptoms, etc.), and only the growth of the CA-125 marker requires further monitoring.

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 be: liposomal doxorubicin + carboplatin or carboplatin + gemcitabine. The latter regimen is preferred for patients with residual neurotoxicity after first line XT.

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

Platinum-resistant relapses

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

Tamoxifen gives 9.6% objective effects.

For the 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 dose reduction to 1 mg/m2/day). To reduce haematological toxicity, topotecan may 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 must often be skipped. A 24-hour infusion of 8.5 mg/m2 every 3 weeks is being studied, as well as an oral form of topotecan 2.3 mg/m2 daily for 5 days every 3 weeks. Myelosuppression is lower. There are literature data on the effectiveness of irinotecan in platinum-resistant or refractory patients (250-300 mg / m2 90-minute infusion every 3 weeks.).

Efficacy in refractory cancer is: ifosfamide - 12-20%, altretamine (Hexamethylmelamine) - 12-14%, fluorouracil with calcium folinate (Leucovorin) - 10-17%, etoposide (oral) - 6-26%, epirubicin (Pharmorubicin) - 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% - at potentially platinum-sensitive tumors, 17% - with resistant ones), liposomal doxorubicin - 19.7%.

Several 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 to progression of 7.9 months.

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

Efficacy, according to 3 phase II studies, was 34% with a median to progression of 5.8 months. in patients with platinum-sensitive tumors and 8% and 2.1 months. - with platinum-resistant. The combination regimen of trabectedin with doxorubicin is considered promising as a second line XT 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 on a long-term basis with blood counts monitored). The side effects of bevacizumab should be borne in mind, especially the risk of intestinal perforation when it is involved in the process or after irradiation of the abdominal cavity.

Therapy regimens

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 by 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 1 time in 3 weeks. with pre- and postmedication with corticosteroids: 32 mg of methylprednisolone or 8 mg of 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, it is recommended to calculate the dose using the Calvert formula.

Doxorubicin liposomal (Doxil, Kelix) - 40-50 mg / m2 IV infusion in 250 ml of 5% glucose for a dose of up to 90 mg and in 500 ml - for a dose of more than 90 mg every 3-4 weeks. The initial rate of administration is 1 mg / min for 10-15 minutes. In the absence of reactions, the rate is increased and the entire dose can be administered in 60 minutes.

Altretamine (Hexamethylmelamine, Hexalene) 6-8 mg/kg po daily for 21-28 days, or 65 mg/m2 po 4 times a day after meals and at bedtime 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 daily 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 (Navelbin) - 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, reduce the dose to no more than 250 mg/m2.

Epirubicin (Farmorubicin) - 75-100 mg / m2 IV 1 time in 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 i.v.

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

Combination chemotherapy TS

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

Paclitaxel (Taxol) 175 mg/m2 3-hour IV infusion with premedication
Cisplatin - 75 mg/m2 intravenously with hydration. Repeat 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 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 cycle after 3 weeks.

Cyclophosphamide - 600 mg / m2 IV on the 1st day.
Carboplatin - AUC 5-6 IV on day 1. Repetition of 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 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 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 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 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 cycle every 21 days.

Vinorelbine (Navelbin) - 25 mg/m2 IV on days 1 and 8.
Cisplatin - 75 mg/m2 IV on days 1 or 8. Repeat cycle every 21 days.
Liposomal doxorubicin (Doxil, Kelix) - 30 mg / m2 90-minute infusion, then Trabectedin - 1.1 mg / m2 3-hour infusion. Repeat 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 exudate evacuation: thiotepa - 20-40 mg, fluorouracil - 0.75-1 g (or a combination thereof), bleomycin - 30-60 mg , mitoxantrone - 25-50 mg. A large dose of thiotepa, 60-100 mg, can also be administered intramuscularly. Effective intravenous administration of cisplatin (100-200 mg in 200-1000 ml of saline with intravenous hydration) or carboplatin (600-750 mg), as well as IFN-a2, 5-50 million units.

Stromal and germ cell tumors of the ovaries

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 thecacellular, 24% are granulosa cells, and 33% are mixed theca and granulosa cells. The worst prognosis 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 widespread 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 efficacy 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 that determine the prognosis. The prognosis is generally poor in large tumors in which more than Y3 are elements of an endodermal sinus tumor, choriocarcinoma, or grade III immature teratoma.

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

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

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

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

All patients, except 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 scheme (Table 9.27).

In patients with multiple extraperitoneal lesions or who are not subject to surgical treatment due to their general condition, chemotherapy is performed at the first stage of treatment. Patients who do not respond to the BEP regimen receive XT as a second line under the VAC or VIP regimen. The issue of a subsequent operation is decided after a thorough examination and control of the level of markers.

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 the 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 efficacy. However, this does not apply to testicular germ cell tumors. In ovarian germ cell tumors, carboplatin may be a substitute for cisplatin.

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

Therapy 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 intravenously 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 intravenously daily on the 1-5th day with mass in the standard mode.

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 the 2nd day.
Etoposide - 1 20 mg/m2 IV on days 1-3.
Bleomycin - 15 mg/m2 IV on the 3rd day. Repetition of cycles every 3-4 weeks.

Second line chemotherapy regimens

VAC (vincristine, dactinomycin, cyclophosphamide)

For immature grade II and III teratomas, a VAC regimen or similar combination with vinblastine is considered 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