Modern aspects of ovarian cancer diagnosis and treatment

At the beginning of the third millennium, ovarian cancer (OC) remains one of the most severe oncological diseases. Occupying the third place in oncogynecological pathology in terms of incidence, ovarian cancer is the leading cause of death in cancer patients. In the structure of oncological morbidity, ovarian tumors occupy 5-7th place, accounting for 4-6% of malignant tumors in women.

The aim of the literature review was to study modern aspects of diagnosis and treatment of ovarian cancer.

According to the Department of Gynecology of the Russian Cancer Research Center named after N. N. Blokhin, RAMS, the 5-year survival rate of patients with stage I of the disease was 75.2%, with stage II - 41.1%, with III - 35.0%, with IV - 17%. According to the International Federation of Obstetricians and Gynecologists (1998), based on 10,912 observations of ovarian cancer from 100 cancer centers around the world, by the beginning of primary treatment 64% of patients already have late stages of the disease, while the five-year survival rate of patients at all stages does not exceed 69%, and at stages III - IV it fluctuates in different countries from 5 to 24%.

In Ukraine, the incidence of ovarian cancer is 16.4 per 100,000 population, and the mortality rate is 9.8 per 100,000 population.

The age range of people with ovarian cancer fluctuates between 40-60 years and older. The peak incidence in Ukraine is at the age of 60-64 years. The largest group in terms of composition and nature of the lesion is epithelial tumors. These include serous, mucinous, endometrioid, clear cell, mixed epithelial, unclassified epithelial tumors, Brenner tumor and undifferentiated carcinoma.

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What causes ovarian cancer?

There is no longer any doubt that malignant neoplasms (including ovarian cancer) are based on damage to the genetic apparatus in terminal (sex) and somatic cells, making these cells sensitive to the effects of environmental carcinogenic factors that can trigger the process of malignancy. Depending on which cell the initial mutation occurred in - sex or somatic, cancer can be hereditary or sporadic.

Fundamental works devoted to the identification of hereditary forms of ovarian cancer and genetic heterogeneity were the works of H. Lynch, in which he stated that approximately 18% of cancer patients in the family history have relatives affected by cancer of various localizations, especially of the organs of the female reproductive system.

One of the significant achievements of molecular genetic studies of hereditary forms of ovarian and breast cancer was the discovery of the BRCA1 (Brest cancer associated gene) and BRCA2 genes, terminal mutations of which apparently determine hereditary predisposition to these neoplasms. It was assumed that the syndrome of hereditary ovarian cancer is at least partly the result of dominant autosomal inheritance of a recessive gene with high penetrance. In 1990, the first gene, BRCA1, was mapped on the long arm of chromosome 17, which claimed to be a suppressor gene for breast and ovarian cancer. The BRCA1 gene is located in the 17q21 locus. There are versions that BRCA1 is involved in the processes of regulation of cell division transcription, apoptosis induction, DNA reparation and recombination, and maintenance of genome stability. Studies of BRCA1 expression also support the idea that this gene is involved in the regulation of cell growth and/or differentiation.

The association of BRCA1 expression with both cell proliferation and differentiation suggests that BRCA1 is involved in regulating the genetic program that ensures terminal cell differentiation and the ability to maintain phenotype. The region associated with BRCA2 inheritance is physically mapped to 13ql2-13. Frequent loss of heterozygous alleles has been noted in this region of chromosome 13 in sporadic breast and ovarian cancers.

In sporadic ovarian tumors, a high percentage of p53 gene mutations (from 29 to 79%), increased expression of the epidermal growth factor receptor (9-17%), expression of the Her2/neu genes (16-32%) and activation of the Kiras gene were detected.

How is ovarian cancer diagnosed?

Early diagnosis of ovarian cancer is difficult, since at the initial stages the disease has no pathognomonic clinical symptoms. This leads to the fact that in 70% of patients the disease is diagnosed in the late stages. The progression of ovarian cancer occurs mainly due to dissemination through the peritoneum. This explains the low-symptom course of the disease in the early stages.

Examination of primary patients with ovarian cancer is carried out according to the Recommendations of the International Union Against Cancer (UICC) for the refined diagnosis and monitoring of patients with ovarian cancer.

Currently, the determination of the tumor-associated marker CA-125 (Cancer Antigen-12.5) in patients with ovarian tumors is widely used in the clinic for the purpose of early and differential diagnostics. Monoclonal antibodies to this antigen were first obtained and described in 1981 by R. C. Bast et al. The discriminatory level is considered to be 35 U/ml. During embryogenesis, CA-125 is expressed by the epithelial cells of the serous membranes of the fetus and their derivatives, and is also found in the epithelium of the coelom and placental extract. In adults, insignificant expression of the protein is retained in tissues derived from the serous membranes of the fetus - in the mesothelium of the peritoneum and pleural cavities, in the pericardium, endometrium, in the epithelium of the fallopian tubes and endocervix. At the same time, the values of this marker in the blood serum are close to zero.

Increased levels of CA-125 in the blood serum are characteristic not only of ovarian tumors. Cases of positive reactions to this marker have been described in patients with acute hepatitis, pancreatitis, peritonitis, tuberculosis, effusions of various etiologies, endometriosis, and during menstruation.

When examining the blood serum of patients with stage I of the disease, the CA-125 values did not differ from the norm and averaged 28.8 U/ml, which indicates that the use of the test in these patients for early diagnosis is questionable. Starting from stage II of the disease, the marker level increased significantly and averaged 183.2 U/ml. At advanced stages of the disease, the marker level increases even more, sometimes reaching several thousand units. The higher the stage of the disease and the greater the metastatic lesion of the peritoneum, the higher the average CA-125 values.

The CA-125 marker can be used to monitor the effectiveness of the treatment. To do this, its level must be determined after each course of chemotherapy.

The use of CA-125 is possible for early detection of disease relapses. If a patient in remission had a "positive" CA-125 level, then this meant with almost 100% probability the presence of a hidden relapse.

Research is currently underway to use carcinoembryonic antigen (CEA) and CA-19-9 to diagnose ovarian cancer.

Malignant epithelial ovarian tumors are characterized predominantly by implantation metastasis, which occurs both along the length and by exfoliation of tumor cells from the surface of the affected ovarian tissue with the flow of intraperitoneal fluid.

How is ovarian cancer treated?

In the treatment of patients with ovarian cancer, 3 main methods are used: surgery, medication and radiation.

Surgical intervention is currently given primary importance as an independent method and the most important stage in a complex of treatment measures. In almost all ovarian tumors, a median laparotomy should be performed. It allows for a thorough revision of the abdominal organs and retroperitoneal space.

The radicality of the operation is assessed by the size of the residual tumor: optimal cytoreductive surgery - there is no residual tumor, but the CA-125 level remains elevated, sometimes ascites or pleurisy is observed; subtotal - residual tumor up to 2 cm in greatest dimension or small dissemination along the peritoneum; non-optimal - residual tumor more than 2 cm.

Organ-preserving operations cannot be performed in the case of moderate or low tumor differentiation or the presence of intraoperative findings that change the stage of the disease. In this case, extirpation of the uterus with appendages is performed.

Literature data indicate that even in patients with ovarian cancer stages I-II, which are considered by clinicians as "early", metastases to retroperitoneal lymph nodes of various localizations are diagnosed with targeted examination. According to a large cooperative study, laparotomy turned out to be the most accurate method for determining the stage of ovarian cancer. At the same time, out of 100 patients with ovarian cancer stages I-II, 28% with presumed I and 43% with presumed II stage of the disease were diagnosed with later stages of the process. There is a difficulty in palpation and visual diagnosis of metastases to retroperitoneal lymph nodes, which is explained by the fact that even lymph nodes affected by the tumor are not enlarged, have a dense elastic consistency, freely or relatively displaceable. In addition, there are from 80 to 120 retroperitoneal lymph nodes in the paraaortic zone alone, and almost each of them can be affected by metastases.

In case of metastatic lesions of retroperitoneal lymph nodes and absence of residual tumor in the abdominal cavity after standard surgery, extended operations are performed (standard volume and lymph node dissection). In this case, iliac, paraaortic, and, if necessary, inguinal lymph nodes are removed.

In the presence of a tumor affecting neighboring organs, a combined operation is performed. When performing combined operations on patients with ovarian cancer, they mainly perform resection of part of the intestine, urinary tract, liver, and removal of the spleen.

It should be noted that the expansion of the standard scope of surgical intervention, i.e. the performance of combined operations, is considered appropriate by many authors in the case of performing an optimal operation. In cases where, when performing a combined operation, there is a residual tumor of more than 2 cm, the long-term treatment results do not improve.

Depending on the size of the residual tumor, operations are divided into the following types:

1. Primary cytoreductive surgery: removal of as much of the tumor and metastases as possible before starting subsequent therapy. Its goal should be complete or as much of the tumor as possible.
2. Intermediate cytoreductive surgery: performed in patients after a short course of induction chemotherapy (usually 2-3 courses).
3. The "Second look" operation is a diagnostic laparotomy that is performed to assess the residual tumor in the absence of clinical manifestations of the disease after courses of chemotherapy.
4. Secondary cytoreductive surgery: Most secondary cytoreductive surgeries are performed for localized recurrences that occur after combination therapy.
5. Palliative surgeries: are mainly performed to alleviate the patient’s condition, for example, in cases of intestinal obstruction due to adhesions or disease progression.

Surgery can rapidly and effectively shrink a tumor, but it cannot completely eliminate all viable tumor cells. Thus, the biological significance of surgery should not be overestimated. Surgical reduction of a kilogram tumor to a residual one weighing 1 g will reduce the number of cells from only 1012 to 109. This effort is clearly useless without additional treatments, but is essential for the successful implementation of chemotherapy.

Chemotherapy, along with surgery, is considered an important component in the treatment of ovarian cancer patients. Most clinicians recognize the need for chemotherapy at all stages of the disease.

Preoperative chemotherapy is recommended for massive tumor lesions of the peritoneum and greater omentum with signs of ingrowth into the anterior abdominal wall; infiltrative growth of ovarian tumors (as evidenced by confluent dissemination along the peritoneum of the small pelvis, with significant displacement of intestinal loops, changes in the topography of the pelvic organs, retroperitoneal location of the tumor with signs of ingrowth into the main vessels); severe exudation - pleurisy/ascites.

After assessing the effect of chemotherapy, cytoreductive surgery is performed.

Radiation therapy for ovarian cancer, used since the beginning of the 20th century, has undergone an extremely complex history of development. Over the years, attempts have been made to use all available types and methods of radiation therapy for malignant ovarian tumors: from deep X-ray therapy, hand-held cobalt and radium applicators, intravenous and intracavitary administration of radioactive drugs to distant gamma therapy. Distant radiation therapy varied from local irradiation of individual tumor foci to irradiation of the pelvic organs and abdominal cavity; in static and rotational modes; open fields and with shielding of vital organs. In this case, radiation exposure was used in various combinations and sequences with surgical intervention and chemotherapy in patients with both localized and widespread tumor processes.

Radiation therapy for ovarian cancer has traditionally been used as an adjunctive treatment for patients with tumors that have not responded to chemotherapy and for patients with relapses after primary treatment, including chemotherapy and surgery. Radiation therapy may also be useful for palliative treatment of incurable patients with symptomatic pelvic tumors or distant metastases.

Prof. A. A. Mikhanovsky, PhD O. V. Slobodanyuk. Modern aspects of diagnostics and treatment of ovarian cancer.