Combined Treatment of Advanced Forms of Colon Cancer

The dissertation is devoted to the problem of treating advanced forms of colon cancer, including locally advanced tumors, metastatic liver disease, and peritoneal carcinomatosis. The author examines the epidemiology of colorectal cancer in Russia and abroad, noting a steadily high level of morbidity and mortality, as well as the insufficient effectiveness of existing screening and surgical treatment methods. The aim of the study is to improve the treatment results of this category of patients through the development and substantiation of combined and cytoreductive surgical interventions supplemented with various chemotherapy regimens (intraperitoneal, systemic, intraoperative, and adjuvant).

The work is based on the analysis of extensive clinical material, including the characteristics of clinical observations, diagnostic and chemotherapy methods, as well as the evaluation of immediate and long-term results of combined treatment. The study substantiates a diagnostic algorithm, tactical and technical aspects of combined operations, indications for synchronous and metachronous interventions in liver metastases, as well as methods of cytoreductive operations in combination with peritonectomy and intraperitoneal chemotherapy in peritoneal carcinomatosis.

Relevance of the problem. Over the past decade, the number of patients with advanced forms of colon cancer has not only remained steadily high, but there has also been a tendency toward worsening indicators. The incidence of colorectal cancer is steadily increasing both in Russia and in all economically developed countries. About 700,000 new cases of colon cancer are registered annually worldwide. In more than 500,000 patients, colorectal cancer is the cause of death (Quasar Collaborative Group, 2002). The average annual increase in the incidence of colon cancer worldwide over the past fifteen years has been approximately 3% per year. The highest rates are observed in France, where colorectal cancer has taken first place. In the USA, Canada, and Western European countries, malignant neoplasms of this localization have risen to second place among all oncological diseases (Chissov V.I., Starinsky V.V., 2004). The incidence among the population of Russia over the past 4 years has increased by 13% in men and 14% in women. Up to 50 thousand cases of colon cancer are registered annually. Currently, colorectal cancer ranks 3rd among men and 4th among women in the structure of oncological morbidity in Russia (Davydov M.I., Aksel E.M., 2004).

The characteristics of the clinical course of colon cancer and the absence of effective, highly sensitive screening methods for detecting precancerous conditions and early forms of the disease do not allow a significant improvement in the early diagnosis of colorectal cancer and a reduction in the frequency of advanced forms of malignant neoplasms of the colon. Therefore, at present, one of the main directions for improving the treatment results of patients in this category is the development and introduction into clinical practice of combined methods capable of exerting the most effective impact on advanced forms of cancer of this localization.

According to many domestic and foreign authors, from 20% to 45% of colon cancer patients are admitted to surgical hospitals with distant metastases, and in 6% - 18.5% locally advanced cancer is detected. In another 27% - 44% of patients, metastases in regional lymph nodes are found. Therefore, the problem of treating colon cancer patients with disseminated forms, as well as with locally advanced tumor growth, is relevant for surgeons, oncologists, and coloproctologists.

The surgical method still remains the main one in the treatment of colon cancer patients. Improvement of surgical techniques, the emergence of new technologies facilitating the performance of complex surgical operations, and anesthetic support have made it possible to reduce the number of complications and postoperative mortality. However, the long-term results of surgical treatment over the past 15 years have not changed significantly, and the 5-year survival rate ranges from 30% to 70%. The main causes of death are dissemination of the process and tumor recurrence, and almost half of all seemingly timely and clinically radically operated patients die within 5 years after surgery. Advanced forms of colon cancer (the presence of distant metastases, peritoneal carcinomatosis, or a locally advanced tumor invading adjacent organs, large vascular trunks, and bone structures) are the main reason for refusing active surgical tactics. Often, patients in this group undergo symptomatic palliative operations, which are associated with a large number of postoperative complications and high rates of postoperative mortality. The quality of life of these patients deteriorates significantly due to the growing effect on their body of the unremoved primary colon tumor and the progression of metastatic growth. The average life expectancy of these patients does not exceed 3-7 months.

Dissatisfaction with the results of treatment of patients with advanced forms of colon cancer has led to the search and development of new approaches to solving this problem. Thus, combined multivisceral surgical interventions for locally advanced colon cancer have been increasingly introduced into clinical practice, and the percentage of resectability is increasing every year. This fact, however, has not led to a decrease in the number of disease relapses in the long term. Therefore, in order to achieve maximum ablastics and devitalization of tumor cells, additional methods of therapeutic influence have been proposed, such as various types of radiation therapy (pre-, intra-, and postoperative), as well as intraperitoneal chemotherapy. In recent years, experience has been accumulating worldwide in cytoreductive operations aimed at the maximum possible reduction of the malignant neoplasm mass - removal of both the primary colon tumor and distant metastases. The goal of these operations is to achieve optimal cytoreduction and create a favorable background for subsequent antitumor drug therapy.

An aggressive surgical approach is most widely implemented for liver metastases, which are one of the main causes of death in colon cancer patients (Patyutko Yu.I., 1998; Nordlinger B., 1996; Wang P., 2005).

Currently, numerous studies are being conducted aimed at determining the indications for cytoreductive interventions on the liver and identifying prognostic factors (volume of liver resection, number of metastases, etc.), and the effectiveness of additional treatments (regional, systemic chemotherapy) is being evaluated in colon cancer patients with liver metastases. In recent years, a thermal ablation technique has been introduced, the use of which gives preliminary encouraging results. Nevertheless, a unified approach to the treatment of this category of patients has not been formed.

Cytoreductive interventions have been performed in recent years for peritoneal carcinomatosis. This form of the disease represents the most complex problem in the treatment of colon cancer patients. The majority of oncologists consider carcinomatosis as a terminal stage, for which there are no effective methods of treatment and which is limited to symptomatic intervention, or, in some cases, palliative resection of the colon. In cytoreductive interventions, removal of the primary tumor is supplemented by peritonectomy. The surgical stage is combined with intraperitoneal chemotherapy, the use of which leads to damage to tumor complexes and reduces their ability to implant. Analysis of the obtained results showed that the performance of cytoreductive operations increases the life expectancy of patients and improves its quality, but most importantly, the probability (albeit in a small number of observations) of radical treatment is preserved.

Metastases of colon cancer to the ovaries, para-aortic lymph nodes, and lungs occur less frequently than metastatic liver damage (in 1.5 - 7% of observations).

In recent years, various chemotherapy techniques have been intensively developed worldwide for patients with advanced forms of colon cancer. However, statistical data indicate that the use of antitumor drug therapy in this category of patients does not always improve the results of surgical treatment.

Thus, the growing number of patients with advanced forms of colon cancer and, most importantly, the unsatisfactory treatment results force oncologists and coloproctologists to seek new ways of combined treatment. This problem is becoming increasingly relevant, and the present study was conducted to address it.

Aim of the study. To improve the results of treatment of patients with advanced forms of colon cancer.

To achieve this aim, the following tasks were formulated:

1. To determine the place and frequency of advanced forms of the disease in the overall structure of colon cancer patients.

2. To assess the influence of the sex and age of patients, tumor localization in the colon, and histological structure on the occurrence of advanced forms of colon cancer.

3. To substantiate the algorithm of necessary diagnostic measures in patients with advanced colon cancer.

4. To develop tactical and technical aspects of performing combined interventions using intraperitoneal chemotherapy in patients with locally advanced colon cancer. To study the features of the postoperative course and determine the nature of postoperative complications.

5. To evaluate the effectiveness of combined operations for locally advanced colon cancer in combination with various methods of adjuvant chemotherapy.

6. To assess the possibilities of performing synchronous combined cytoreductive operations in colon cancer patients with liver metastases.

7. To evaluate the effectiveness of combined operations and adjuvant and therapeutic chemotherapy in patients with liver metastases.

8. To determine the indications for cytoreductive operations in combination with intraperitoneal chemotherapy in colon cancer patients with peritoneal carcinomatosis.

9. To evaluate the results of combined and surgical treatment for peritoneal carcinomatosis.

Scientific novelty.

• A diagnostic algorithm has been developed for patients with various forms of advanced colon cancer. It makes it possible to determine the degree of tumor spread and optimize treatment tactics.

• It has been proved that the occurrence of distant metastases, carcinomatosis, and local spread of colon cancer has no statistically proven dependence on tumor localization in the colon, histological structure of the neoplasm, sex, and age of patients.

• On a large clinical material, the expediency of combined and cytoreductive operations in advanced forms of colon cancer has been proven. Their performance leads to improved survival rates and quality of life.

• The necessity of intraperitoneal and systemic chemotherapy as part of combined treatment for locally advanced colon cancer has been substantiated. This allows a statistically significant increase in the 5-year survival rate of patients.

• An original method of adjuvant chemotherapy has been developed, including intraoperative intraperitoneal and early (from the 5th day after surgery) systemic chemotherapy. The use of this method made it possible to reduce the number of specific complications characteristic of the prolonged method of intraperitoneal chemotherapy.

• Indications for performing synchronous and metachronous combined interventions in colon cancer with liver metastases have been developed. Surgical tactics for performing synchronous interventions have been determined.

• The possibility of increasing life expectancy and improving the quality of life in patients with peritoneal carcinomatosis has been proven by performing resection of the colon with the tumor in combination with peritonectomy and intraperitoneal chemotherapy.

• Based on the analysis of long-term results, the high oncological effectiveness of cytoreductive and combined surgical interventions in combination with various methods of chemotherapy has been shown.

Practical significance of the study.

• The introduction of combined and cytoreductive surgical interventions in advanced colon cancer with the use of various methods of drug treatment will actually contribute to improving the results in this severe category of patients.

• The use of combined methods makes it possible to improve the quality of life of patients, prolong the relapse-free period and survival rates.

• The use of the developed treatment methods and the substantiation of the possibility of performing surgical interventions with restoration of the natural patency of the intestine will allow a significant part of patients to return to an active social and, in some cases, working life.

Main provisions submitted for defense:

• Combined interventions in patients with locally advanced colon cancer must be supplemented with intraperitoneal and subsequent systemic chemotherapy.

• Synchronous combined operations in colon cancer with liver metastases are indicated when segmental or bisegmental liver resections are possible. If extensive liver resections are necessary in the volume of right-sided hemihepatectomy or its subtotal resection, it is advisable to perform the intervention on the liver as a second stage.

• In patients with peritoneal carcinomatosis, the developed methods of cytoreductive operations, consisting of resection of the colon with the tumor, omentectomy, peritonectomy, in combination with intraoperative and early postoperative intraperitoneal chemotherapy, allow a significant improvement in the long-term treatment results.

The main provisions of the work were reported at: the V All-Russian Congress of Oncologists, Kazan, 2000; the V All-Russian Conference "Actual Problems of Coloproctology", Rostov-on-Don, 2001; the I Congress of Coloproctologists of Russia, Samara, 2003; the Problem Commission "Coloproctology" of the Interdepartmental Council on Surgery of the RAMS, 3.10.2003, Samara; the III Congress of Oncologists and Radiologists of the CIS, Minsk, 2004; the Scientific Conference with International Participation "Actual Problems of Coloproctology", Moscow, 2005; the VI All-Russian Congress of Oncologists, Rostov-on-Don, 2005.

Structure of the dissertation. The dissertation is written on 293 pages of typewritten text, consists of an introduction, 5 chapters, a conclusion, conclusions, practical recommendations, and a list of references (96 domestic and 264 foreign sources), contains 90 tables, and is illustrated with 46 figures.