Complications after cytoreductive surgery using intraoperative chemohyperthermic perfusion

The dissertation is devoted to the study of postoperative complications arising during combined treatment of peritoneal carcinomatosis using cytoreductive surgery and intraoperative chemohyperthermic perfusion of the abdominal cavity. The work combines experimental substantiation of the temperature and technical parameters of perfusion with clinical analysis of risk factors and measures for the prevention of complications in patients with advanced forms of gastric cancer, colorectal cancer, and genital tumours. Particular attention is paid to the "hard" temperature regimen of perfusion, its influence on the rate and character of complications, and to the possibilities of pharmacological correction of the disturbances identified. The practical significance of the research is connected with the introduction of the developed technique into practical healthcare institutions and with the use of the results in the educational process.

Systemic chemotherapy, which has proven itself in the treatment of patients with malignant tumours of a number of internal organs, is practically ineffective in peritoneal carcinomatosis. In order to achieve a high intra-abdominal concentration of the chemotherapeutic agent, loco-regional chemotherapy has an advantage over systemic chemotherapy; however, without cytoreductive surgery and hyperthermia, no substantial improvement in the clinical outcomes of treatment of patients with peritoneal carcinomatosis can be achieved (Zhavrid E.A. et al., 1997; Tarasov V.A. et al., 2002, 2005; Grinev M.V. et al., 2002; Belyaev A.M. et al., 2003, 2004; Kitayev A.V., 2005; B. Sadeghi et al., 2000). The rationale for combining cytoreductive surgery with intraperitoneal chemotherapy with hyperthermia lies in the high local concentration of the drug and the cytotoxic effect, which is enhanced through the increased cytotoxicity and penetrative capacity of chemotherapeutic agents in tissues under hyperthermia (Dahl O. et al., 1999). Hyperthermia combined with the use of tropic chemotherapeutic agents is an important factor in intensifying therapy. The increase in cytotoxicity of chemotherapeutic agents under hyperthermia is determined by several cofactors (Davydov M.I. et al., 2001): activation of membrane lipid peroxidation, impairment of DNA repair in tumour cells, and disturbance of microcirculation in tumour implants. The cytotoxic action of hyperthermia on tumour cells is more effective the less vascularised the tumour is and the smaller the residual tumour size; the enhanced penetration of the chemotherapeutic agent under hyperthermia rises through a decrease in interstitial pressure within the tumour tissue.

The combined treatment, consisting of cytoreductive surgery and intraoperative chemohyperthermic perfusion, that is, the simultaneous action of three therapeutic components, is a sufficiently effective but also substantially aggressive method. At the same time, despite the high rate of complications and mortality (Osinsky D.S. et al., 2003; Tarasov V.A. et al., 2005), such a combination is effective in the treatment of patients with peritoneal carcinomatosis. A.J. Witkamp and co-authors (2001), when treating patients with peritoneal carcinomatosis caused by colorectal cancer, achieved a reduction in mortality to 3%, with a complication rate of 38%; 2- and 3-year survival amounted to 45% and 23%, respectively. Through combined treatment that included intraperitoneal chemohyperthermic perfusion in patients with appendiceal tumours, 2-year survival was achieved in 85% of cases; 5-year survival was recorded in 50% of patients with tumours of the colon (Sugarbaker P.H., 2001). In ovarian cancer, mortality amounted to 4%, with complications occurring in 27% of patients (Deraco M. et al., 1999). The cited data on the effectiveness of combined treatment of patients with intra-abdominal cancer with peritoneal dissemination are not isolated. Nevertheless, this aggressive method of treatment requires optimisation in order to enhance its antitumour effect, reduce the rate of complications, and more clearly define the indications for its application.

The majority of publications are devoted to the hyperthermic regimen of intraperitoneal chemotherapy at a temperature of 42–43°С, and only some of them consider the mild regimen (no more than 42°С) and the hard regimens (above 43°С) of hyperthermic perfusion. However, the results of these methods, even under the generally accepted hyperthermia regimens, differ considerably among authors with respect to complication rates.

A need arose to conduct studies on the complications associated with the use of cytoreductive surgery and intraoperative chemohyperthermic perfusion in the "hard" temperature regimen, and to search for methods of preventing the complications that develop.

The aim of the present work is to improve the outcomes of combined treatment (cytoreductive surgery and intraoperative chemohyperthermic perfusion) in patients with advanced abdominal tumours and peritoneal carcinomatosis through the identification of preoperative and intraoperative risk factors, the prevention of possible postoperative complications, and their timely correction.

To achieve this aim, the following tasks were set:

1. To determine the main postoperative complications that arise after cytoreductive surgery with intraoperative chemohyperthermic perfusion.

2. To identify the main risk factors for the development of complications in cytoreductive operations performed for peritoneal carcinomatosis.

3. To identify the main risk factors for the development of complications in intraoperative chemohyperthermic perfusion.

4. To develop measures for the prevention and treatment of postoperative complications in patients with peritoneal carcinomatosis.

5. To evaluate the effectiveness of prevention and treatment of complications following surgical treatment with intraoperative chemohyperthermic perfusion.

SCIENTIFIC NOVELTY

The indications and contraindications for cytoreductive surgery have been defined for patients with advanced forms of gastric cancer, colorectal cancer, and genital cancer with peritoneal carcinomatosis.

The expediency of repeat operations with intraoperative chemohyperthermic perfusion in stage III (P3) peritoneal carcinomatosis according to Gilly F.N. (1994) has been substantiated.

It has been proved that, provided the developed temperature and time regimen of intraoperative chemohyperthermic perfusion is observed, it does not cause an increase in haematological complications.

It has been proved that, when cytoreductive surgery is tolerated, the use of intraoperative chemohyperthermic perfusion does not worsen the immediate result of the operation.

The postoperative complications directly related to intraoperative chemohyperthermic perfusion can be eliminated by an individualised programme of drug therapy.

SCIENTIFIC AND PRACTICAL SIGNIFICANCE OF THE WORK

The results of the study indicate the expediency of wider application of cytoreductive surgery with intraoperative chemohyperthermic perfusion in practical healthcare institutions, provided the recommended criteria of operative tolerance are observed.

It has been proved that intraoperative chemohyperthermic perfusion in the "hard" regimen (temperature 44°С, exposure 90 minutes) is an effective method of prevention and treatment of peritoneal carcinomatosis in the case of successful cytoreductive surgery within the volume R0–R1.

It has been established that the technique of intraoperative chemohyperthermic perfusion can be mastered in most practical healthcare institutions of the corresponding profile that have qualified personnel.

STATEMENTS PRESENTED FOR DEFENCE:

1. The method of intraoperative chemohyperthermic perfusion after cytoreductive operations is an effective treatment for ascites caused by peritoneal carcinomatosis.

2. Intraoperative chemohyperthermic perfusion in the "hard" regimen does not exert a decisive influence on the development and character of complications after cytoreductive operations (in experiment and clinic).

4. Complications directly related to intraoperative chemohyperthermic perfusion can be eliminated by adequate infusion and plasma-substituting therapy, prolonged drainage of the abdominal cavity, and analgesia.

5. Performance of hyperthermic intraperitoneal perfusion in the experiment does not impair the healing of entero-enteroanastomoses.

PERSONAL CONTRIBUTION OF THE AUTHOR TO THE RESEARCH. The personal contribution of the author consists in conducting anatomical and experimental studies, participating in the examination, surgical treatment, and postoperative care of the majority of patients who underwent cytoreductive operations with intraoperative chemohyperthermic perfusion, and in developing the technique and performing intraoperative chemohyperthermic perfusion in the "hard" regimen.

APPROBATION OF THE WORK

The main statements of the dissertation were reported at a meeting of the Department of Thoracic Surgery of GOU DPO SPb MAPO on 11 March 2006, at the Problem Commission "Surgery and Related Specialties" of GOU DPO SPb MAPO on 17 March 2006, and at a meeting of the Pirogov Surgical Society on 26 April 2006.

IMPLEMENTATION OF THE WORK

The results obtained have been introduced into the practical activity of the Department of Thoracoabdominal Surgery of City Hospital No. 26 of Saint Petersburg and are used in the educational process during lectures and practical classes with trainees at the Department of Thoracic Surgery of GOU DPO SPb MAPO.

STRUCTURE AND VOLUME OF THE DISSERTATION

The dissertation is set out on 149 pages of typescript, includes 25 tables and 34 illustrations, and consists of an introduction, a literature review, a description of clinical observations and examination methods, original research including anatomical and experimental studies, a conclusion, conclusions, and a bibliography comprising 47 domestic and 135 foreign authors. Three works on the topic of the dissertation have been published in domestic and foreign publications.