Strategies to reduce perioperative morbidity in cytoreductive surgery

von

Herwart Müller 1), Michael Hahn 1), Lutz Weller 1), Jaromir Simsa 2)

1) Dept. of Surgical Oncology, Hammelburg Hospital, Germany
2) Dept. of Surgery, Hospital Kolin, Czech Republic

ABSTRACT

Background: Peritoneal carcinoma has been regarded as a uniformly lethal clinical entity. Cytoreductive surgery and intraperitoneal hyperthermic chemoperfusion (HIPEC) is an aggressive treatment for patients with peritoneal malignancies. While promising, this therapeutic regimen has been associated with significant morbidity, long hospital stay and an increased risk for perioperative mortality. Purpose of this study was to evaluate the possibility to reduce morbidity by use of strategy aiming to reduce inflammatory response associated with cytoreductive surgery plus HIPEC.

Methods: 241 consecutive patients underwent cytoreductive surgery plus HIPEC during the period of 4 years (1/03 - 12/06). All patients were managed through multivisceral resection followed by HIPEC using an open technique. Peritonectomy was performed with the goal of total eradication of all visible tumour formations.

Results: 276 procedures were performed in 241 patients with 27 re-resections and 4 re-re-resections. Male/female ratio was 134/142. Mean age was 49 years (range 26-82). Optimal cytoreduction difined as CC-0 and CC-1 resection could be reached in 230 cases (83.3 %). Complication rate (Feldman scale grade 3/4) and 30-day mortality rate were as follows: 2003: 26.5%, 2% 2004: 20%, 0% 2005: 14%, 1% 2006: 10%, 0%.

Conclusions: The results of this study demonstrate the possibility to reduce the perioperative risk of cytoreductive surgery plus IPHC. The described strategy aiming the reduction of inflammatory response was able to reach a morbidity level which stands in line with other major oncologic operations.

Keywords: peritoneal carcinomatosis - intraperitoneal chemotherapy - hyperthermia cytoreduction - complications - inflammatory response

INTRODUCTION

Throughout last decade cytoreductive surgery combined with intraperitoneal hyperthermic chemoperfusion (HIPEC) has been established as a promising treatment regimen for selected patients with peritoneal metastases and peritoneal-based malignancies (1,2). This specific type of surgery claiming for complete removal of all visible tumor formations combined with heated intraperitoneal chemotherapy has been established as standard of care for pseudomyxoma peritonei and appendiceal carcinoma (3-7). In peritoneal carcinosis of colon cancer this treatment has been documented to be superior to systemic chemotherapy alone in a randomized trial performed by NCI Amsterdam in 2003 (8-11). For recurrent ovarian cancer secondary cytoreduction plus or minus intraperitoneal chemotherapy has been established as an effective tool to reach prolongation in disease free interval and survival (12-14). In a retrospective analysis published by Memorial Sloan-Kettering Cancer Center specific prognostic factors could be defined influencing outcome of re-resected patients leading to guidelines for further therapy (15). In peritoneal mesothelioma as well as peritoneal metastasized gastric cancer cytoreductive surgery plus HIPEC has been associated with promising results leading to prolonged survival (16-18).
Cytoreductive procedures are generally long lasting, technically challenging and it is not surprising that significant morbidity may result as major surgical resections are combined with cytotoxic chemotherapy. Major morbidity and mortality rates of 19-56% and 0-12% respectively have been reported (19-21). Cytoreduction consists of three different treatment modalities: aggressive surgery, chemotherapy and local hyperthermia. These modalities alter physiologic immune balance by initiating a systemic inflammatory response, leading to dysregulation between immune cells and endothelium, resulting in tissue damage and complications. Inflammation is considered a dual process since it combines two functionally different characteristics: one that repairs and another that produces damage. Inflammation is part of a physiological process for repairing damage. However, when this process is not controlled and inflammation spreads, it loses its repairing function and may even cause damage (22,23).
Throughout last decade different publications showed a clear correlation between surgery dependent expression of pro-inflammatory molecules, hypercoagulability, postoperative immune suppression and postoperative complications and infections (24,25). This pathophysiologic event is characterized by release of potent inflammatory mediators into the circulation. Among these pro- and anti-inflammatory cytokines such as IL-6, IL-8 or IL-10 play a dominant role as local and systemic regulators in the acute inflammatory response. Cytokines like IL-6 together with cell adhesions molecules such as endothelial leucocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1) regulate the complex interaction of immune cells, the endothelium and the extracellular matrix.. Increased levels of these molecules are also thought to be responsible for the development of severe inflammatory response syndrome (SIRS) and adult respiratory distress syndrome (ARDS), leading to side-effects and complications.
Throughout last years in the Department of Surgical Oncology, Hammelburg Hospital a comprehensive perioperative management program was used aiming the reduction in morbidity associated with cytoreductive interventions. This perioperative management program contains strategies to reduce inflammatory response associated with extensive cytoreductive surgery plus hyperthermic application of cytostatics. The program is based on intensive perioperative warming, intraoperative fluid restriction, intensified management of hyperglycaemia, adenosine receptor activation, increased tissue oxygenation and reduced blood loss. Each of these strategies have shown efficacy in prospective randomized trials. Here we present our experience supporting the contention that cytoreductive surgery and HIPEC can be performed with morbidity and mortality that is similar to other major surgical procedures.

MATERIAL and METHODS

Patient eligibility

Between January 2003 and December 2006 276 operations have been performed in 241 patients with peritoneal carcinomatosis (PC) of different origin in Department for Surgical Oncology, Hammelburg Hospital, Germany. Criteria of eligibility were a PC of different origin, a good general status, no extra-abdominal extension and no evidence of bowel obstruction. Bulky clinical or radiological PC has been included only, if resection seems to be possible. Presence of one or two liver metastases, easily resectable, was not a contraindication. All patients had already received prior intravenous chemotherapy. A rapid progression of PC under systemic chemotherapy was a contraindication to surgery.

Patient Evaluation

A complete history, physical examination, complete blood cell count with differential, serum biochemistry including tumour marker determination, urinanalysis, spirometry, computer tomography (CT) scan of the abdomen, and ECG including ECG after work were obtained at baseline. Patients were monitored throughout treatment by recording history, toxic events and complete blood cell counts; serum chemistry. No Pet-scan imaging was carried out. All patients had histological confirmed tumour disease, adequate performance status with Karnofsky-index of 80 and better, normal haematological function (granulocyt count > 2000 /µl, platelet count > 100.000 /µl) adequate liver and renal function (bilirubin < 3.0 mg/dl, creatinin < 2.0 mg/dl), acceptable spirometric values and no other severe concomitant, active medical illness. All patients gave written informed consent. At laparotomy the diagnosis of PC was confirmed by frozen section and the extent of PC was scored according to Sugarbaker's peritoneal index (1). This index takes into account the number of invaded areas among a total of 13, and the maximum size of tumour nodules among three possible groups (<5 mm, 5 mm to 5 cm, >5 cm).

Treatment plan

Treatment plan consisted of multivisceral resection plus peritonectomy to reach a complete debulking of all visible tumor structures as the first step. At the end of each surgical procedure intraperitoneal chemohyperthermia (HIPEC) was added. Early postoperative infusions of cytostatic agents into peritoneal cavity (EPIC) have not been integrated into treatment plan.

Surgical procedure

Under general anesthesia and complete hemodynamic monitoring, careful abdominal exploration was taken through a median laparotomy from xyphoid to pubis. Starting at left upper quadrant a complete peritonectomy procedure was carried out according to Sugerbaker´s technique (1,2). Adapted to the location of the malignant granulations as guided by the surgeon, exploration and extemporaneous biopsies peritonectomy was performed in the following areas : right diaphragmatic cupula, left diaphragmatic cupula, greater omentum, lesser omentum, omental bursa, right paracolic gutter, left paracolic gutter, Douglas pouch, anterior wall peritoneum, posterior wall peritoneum, Glisson capsula and mesenteric peritoneum. Small remnant malignant granulations at mesentery of small or large bowel were destroyed using electrosurgical fulguration. Using tip-ball surgery aim of peritonectomy procedure was to remove all visible malignant structures on one hand and to prevent severe blood loss on the other hand.

Intraperitoneal chemohyperthermia procedure (HIPEC)

At the end of each surgical procedure a HIPEC perfusion was carried out, using the open `Coliseum´ technique. This technique has been used to allow temperature homogeneity and complete diffusion of the peritoneal instillation in the whole peritoneal cavity (2). The skin edges were tented up on the self-retaining retractor to build up an open cavity and to allow safe administration of cytostatic solution. For establishment of perfusion four Jackson-Prett catheters (15 mm) were placed into the abdominal cavity with one catheter in each quadrant. These catheters were used as the collectors of the perfusate. For inflow, a Robinson-catheter was placed in the center of abdominal cavity. Thermic probes were also inserted into the abdominal cavity behind the liver and in the Douglas pouch. Perfusion time was 60 minutes at a mean flow rate of 1500 ml/min. Intraabdominal temperature was 42-43°C. Perfusion duration was 60 min from the time when optimal temperature (42°C) was reached. Afterwards, cytostatic solution was evacuated completely.

Patients´ follow-up

All the patients included in this study were postoperatively transferred to an intensive care unit for a minimum of 24 hours and later to the surgical department. Clinical, biologic, and radiologic follow-up of the patients was repeated on a monthly basis after discharge from the hospital.

Cytostatics

Cytostatics for HIPEC procedure have been used dependent to histology of primary tumour. The dosage was adjusted to age and general condition of patient. All cytostatics have been applicated as the bolus application at start of HIPEC when adequate temperature have been reached.

Table 2: Cytostatics used for hyperthermic peritoneal perfusion (HIPEC)

Postoperative morbidity

Complications were graded according to the classification of Feldman et al. (26) Grade 1 complications, defined as a minor (i.e. complications which resolve if left untreated or which require simple bedside procedure without drugs except analgesics, antipyretics, antidiarrheals or oral antibiotics), were not included.

RESULTS

Between 1/2003 and 12/2006 276 cytoreductive interventions have been carried out in 241 patients at the Department for Surgical Oncology KKH Hammelburg. Mean age of the patients was 49 years (min. 25, max 82 years). Tumour histology was as follows: appendiceal cancer 14x, colorectal 56x, gastric cancer 20x, mesothelioma 10x, ovarian cancer 99x, carcinoma of the Fallopian tube 3x, adenocarcinoma of the peritoneum 2x, pseudomyxoma peritonei 5x, sarcoma of the different origin 21x, others like carcinoma of the small bowel or urachus 11x.
Extent of the peritoneal involvement has been determined by use of the Sugarbaker´s Peritoneal carcinosis index (PCI); mean PCI was 17 (SD = 8.3, range 4 to 33). Complete cytoreduction has been reached in 230 out of 276 operations with 155 CC-0 and 75 CC-1 resections (optimal cytoreduction rate 83.3 %). Mean number of peritonectomy procedures was 3.2 ranging from 1 to 6. Mean number of bowel anastomosis was 1.6 ranging from 0 to 6.

Morbidity

Complications which occurred after cytoreductive surgery and HIPEC are listed in Table 3.

In the entire group of 276 operations 34 complications grad 3/4 did occur, leading to an over-all morbidity rate of 12.3 %. Throughout the years a slight, but significant reduction in morbidity could be documented starting in 2003 with 26.5 %, 20.0 % in 2004, 14 % in 2005 and ending with 10.0 % in 2006. Anastomotic leak was a rare event with 3 in 276 operations (1.1 %). In 7 cases a spontaneous small or large bowel perforations were documented leading to a perforation rate of 2.5 %. The bowel perforations were most frequently located on small bowel surfaces extensively traumatized by the surgical resection of tumour implants. However, spontaneous small perforation has to be documented in a non-traumatized bowel surface area as well. Thrombembolic events were infrequent and occurred in 2 cases (0.72 %).
Three out of 276 patients died as a result of severe septicaemia in one case, mycosis dependent neutropenic septicaemia in the second case and anastomotic leakage combined with severe peritonitis in last case. 30- days mortality rate was 1.1 %.

DISCUSSION

Despite advances in surgical technique and improvements in perioperative care, incidence of postoperative complications leading to morbidity and mortality has not been decreased. Postoperative morbidity depends on type and complexity of surgical procedure as well as on the patients´ associated factors like general condition, age and others. Cytoreductive surgery plus hyperthermic peritoneal perfusion is one of the most complex procedures in visceral surgery including multivisceral resection, local resections of peritoneal surfaces and intraperitoneal chemotherapy. Such procedures are generally long time lasting, technically challenging and combined with significant morbidity (19-21).
The initial traumatic insult caused by surgery establishes an inflammatory state, and within this inflammatory process a fine balance exists between the beneficial effects of inflammation (adaptive response) and the potential for the process itself to cause and aggravate tissue injury, leading to apoptosis or necrosis. We therefore hypothesize that an overwhelming inflammatory response to surgical injury is associated with complications and morbidity. If this implication is correct, a strategy aiming to reduce inflammatory response should be able to reduce the rate of surgery related complications. During last years we have established a comprehensive perioperative program combining treatment strategies able to reduce the extent of inflammation induced by surgical trauma like:

• intensive pre- and intra-operative warming,
• intraoperative fluid restriction,
• intensified hyperglycaemia management,
• increase in tissue oxygenation
• blood loss reduction
• adenosine receptor activation

All these strategies, except the last one, have shown efficacy in prospective randomized trials.

Intensified warming management

Avoiding hypothermia is a potentially important factor in preventing wound infection, possibly because it blunts the normal inflammatory response (27,28). Warming during abdominal surgery, in any case, is necessary for older patients with diminished muscle mass because body heat is largely derived from muscles. In a prospective randomized trial the positive effect of perioperative maintenance of normotherapy has been documented in three hundred patients undergoing abdominal, thoracic or vascular surgical procedures who either had documented coronary artery disease or were at high risk for coronary disease (29). In this study perioperative morbid cardiac events occurred less frequently in the normothermic group than in the hypothermic group. Risk reduction was 55 % when normothermia was maintained.
Melling et al. demonstrated the positive effect of perioperative warming management in another randomized trial of 421 patients with clean surgery (breast, hernia repair, varicosis) (30). Surgical site infections also occurred less frequently (14 % vs. 5 %) in the group of patients, who have been warmed pre- and intraoperatively.

Intra-operative fluid restriction

It has been demonstrated in clinical studies that an intravenous fluid overload during and after surgery will be associated with a decrease in muscular oxygen tension and a delay in recovery of gastrointestinal function (31). Furthermore, postoperative weight gain and intraoperative fluid overload have been associated with poor survival and complications (32-34). In a prospective multicenter trial of 172 patients undergoing elective colorectal surgery Brandstrup et al. showed a significant reduction in postoperative complications rate by use of intraoperative fluid restriction (35). Liberal fluid regimen was associated with an increase in complications of 51 %, whereas an infusion protocol aiming an unchanged body weight reduced complication rate to 33 %.

Intensified hyperglycemia management

Uncontrolled hyperglycemia may be associated with complications such as fluid and electrolyte disturbances and increased infection risk. Studies have demonstrated impairment of host defenses, including decreased polymorphonuclear leukocyte mobilization, chemotaxis, and phagocytic activity related to hyperglycaemia (36). Hyperglycaemia (blood glucose levels higher than 220 mg/dl) had been tolerated in critically ill patients not only because high blood glucose concentrations were believed to be a normal physiologic reaction in stressed patients and excess glucose is necessary to support the energy needs of glucose-dependent organs, but also because the true significance of short-term hyperglycemia was not known. Recent clinical data show that the use of intensive insulin therapy maintaining blood glucose concentrations between 80 and 110 mg/dl decreases morbidity and mortality in critically ill surgical patients Intensive insulin therapy minimizes dearrangements in normal host defense mechanisms and modulates release of inflammatory mediators.. In a study of over 500 patients, insulin therapy designed to maintain glucose levels between 80-110 mg/dl significantly reduced hospital mortality, with the greatest benefit in critically ill patients with a proven focus of infection (37).

Increase in tissue oxygenation

The availability of oxygen (O2) to cells in the wound area and the presence of adequate blood flow are important factors to the healing process. Oxygen plays a critical role in the formation of collagen, the growth of new capillaries and the control of infection. Perfusion and delivery of O² to tissue are closely related. Fibroblast synthesis of collagen is dependent on oxygen for the enzymatic hydroxylation of proline and lysine on the formation of collagen chains. A local tissue oxygen tension of 25 mmHg is needed to support this reaction at half its maximal rate (38). Although an adequate blood flow does not guarantee a sufficient supply of O², without it the provision of O² to healing tissues will be impaired. In a randomized trial of 500 patients undergoing colorectal surgery Greif and co-workers demonstrated the positive effect of postoperative supplemental Oxygen application in respect to surgical site infection (39). Absolute risk reduction for infection in this study was 6 %.

Strategies to reduce blood loss

Bleeding during a surgical procedure is a common problem associated with both morbidity and death of surgical patients. Transfusion therapy is associated with the additional risks of allergic reaction and the transmission of infectious diseases such as hepatitis and the acquired immunodeficiency syndrome. The interest in antifibrinolytic drugs dramatically increased when Royston et al. demonstrated for the first time the effect of large-dose aprotinin in reducing intraoperative blood loss and transfusions in cardiac surgery (40). Aprotinin is a naturally occurring single-chain 58-amino acid polypeptide with a molecular weight of 6.512 Dalton. It has a broad inhibitory specificity for serine proteases, but its most important effect is to inhibit plasmin, trypsin and kallikrein of different origins (41,42). It forms a stoichiometric complex, completely inhibits the active site of each enzyme and leads to an inhibition of inflammatory response process.
Since then, many studies have been performed in this type of setting. Aprotinin is now widely used in cardiac surgery, and there have been trials in vascular and liver transplantation surgery, studying different doses and modes of administration. Generally, Aprotinin was able to decrease intra- and postoperative bleeding and blood transfusion in these settings (43-45).

Adenosine receptor activation

Many recent studies indicate that adenosine acting on A2-receptors can powerfully inhibit inflammation and reperfusion injury (46). Adenosine is a regulatory nucleoside that is generated in response to cellular stress and damage and is therefore increased during episodes of tissue hypoxia and inflammation. Adenosine receptors are present on most cells and organs. Adenosine, acting at specific A2 -receptors, inhibits some, but not all, neutrophil functions leading to an antiflammatory effect with high efficacy (47,48). The cellular responses seem to be mediated predominately by cyclic AMP and result in inhibition of oxidative burst in neutrophils, reduced TNF release by monocytes, reduced platelet activation and inhibition of lymphocyte activation (49-53). These responses prevent the release of pro-inflammatory cytokines and oxygen radicals, prevent endothelial cell activation, and greatly reduce microvascular occlusion, which can exacerbate tissue injury induced by surgical trauma (54). Adenosine inhibits phagocytosis, generation of toxic oxygen metabolites, and adhesion to endothelial cells, but does not inhibit degranulation or chemotaxis. The concentrations of adenosine that inhibit inflammatory cell function are similar to those observed in vivo and suggest a role for adenosine in the modulation of inflammation in vivo (55).
Peritoneal carcinomatosis has traditionally been regarded as a uniformly lethal pattern of cancer dissemination. HIPEC after satisfactory cytoreduction may improve the treatment results of such a disease. Patients with low grade mucinous tumors are undoubtedly the patients who benefit most from this treatment approach. However, some positive results have been recently reported for high grade malignancies such as colon or gastric adenocarcinomas. This combined modality treatment is associated with significant morbidity and a substantial risk of death. Major morbidity and mortality rates of 19%-56% and 0%-12%, respectively, have been reported (19-21).
The perioperative management program, we present here, was able to reduce the risk for severe complications (Feldman grad 3 / 4) from 26.5 % to at least 10.0 %. Treatment related mortality within 30 days after surgery was 1.1 %. Interestingly enough frequence of complications reported to be specific to this treatment form was low with a rate for anastomotic leak of 1.1 % and spontaneous bowel perforations of 2.5 %. Non-specific complications like thrombotic events were infrequent as well (0.72 %). This low rate of complications related to any kind of surgery as well as to this specific form of aggressive surgery seems to be dependent to the perioperative management program aiming to reduce inflammatory response related to surgical trauma. Further prospective studies are needed to confirm this conclusion. Nevertheless using this integrative perioperative management protocol it is possible to reduce the risk for severe complications related to cytoreductive surgery combined with hyperthermic peritoneal perfusion of cytostatics to a rate which stands in line with other major operations in oncologic surgery.

CONCLUSION

Cytoreductive surgery is now a standard procedure for management of selected patients with advanced peritoneal malignancy. Basis for further development of this specific multimodality treatment is the reduction of treatment related morbidity and mortality. Results of this study demonstrate the possibility to reduce the perioperative risk of cytoreductive surgery plus HIPEC. The described strategy aiming the reduction of inflammatory response was able to reach a morbidity level, which stands in line with other major oncologic operations.

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