Cytoreductive surgery in the elderly – is it feasible?

(accepted for publication: hepatogastroenterology)

Herwart Mueller*, Michal Hahn*, Jaromir Simsa**
* Dept. of Surgical Oncology, Hospital Hammelburg, Germany
Head: Dr. med. Herwart Mueller, FACS
*Dept. of Surgery, Praha University, Czech Republic

Key words: peritoneal carcinomatosis - cytoreduction – intraperitoneal chemotherapy - elderly patients – complications

Abstract

Background: Cytoreductive surgery and intraperitoneal hyperthermic chemoperfusion (HIPEC) is an aggressive treatment for patients with peritoneal malignancies. While promising, this therapeutic approach is still associated with significant morbidity and mortality. Surgical risk in elderly patients is even higher, since these people suffer from frequent co-morbidities, resulting in poorer performance status. Whether this type of major cancer surgery is feasible in elderly patients is an ongoing question.
Methods: Retrospective analysis of elderly patients, undergoing cytoreductive surgery during a period of three years in one centre. Criteria of patients´ eligibility were peritoneal carcinomatosis of different origin, age > 65 years, good general status, no extra-abdominal extension and no evidence of bowel obstruction. To reduce morbidity of surgical procedure special perioperative management program including intensified warming management, intra-operative fluid restriction, control of hyperglycaemia, increase of the tissue oxygenation, restriction of blood loss and adenosine receptor activation was employed.
Results: Between January 2004 and January 2007, 47 cytoreductive interventions have been carried out in 44 patients aged older than 65 years at the Department for Surgical Oncology KKH Hammelburg. Mean age of patients in this group was 71 years (min. 65 years, max 82 years). Mean duration of surgery was 5.3 hours (SD = 1.59; range 3.0 to 8.5 hours). Mean duration of the hospital stay was 19.3 days (SD = 9.55, range 11 to 58 days). The frequency of grade 3 and 4 complications was 17.0 %. There was no postoperative death registered within the 30 days after surgery (30-days mortality rate 0 %).
Conclusions: Incorporating new strategies to reduce morbidity makes aggressive cytoreduction procedure feasible in the majority of elderly patients. Age and advanced peritoneal malignancy should not preclude patients from the maximal surgical effort.

I. Introduction

Throughout the 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. This specific type of surgery claiming for complete removal of all visible tumour formations combined with heated intraperitoneal chemotherapy has been established as a standard of care for pseudomyxoma peritonei and appendiceal carcinoma (1-3). In peritoneal carcinomatosis of colon cancer this treatment has been documented to be superior to systemic chemotherapy alone in two randomised trials (4,5). For recurrent ovarian cancer secondary cytoreduction plus or minus HIPEC has been established as an effective tool to reach prolongation in disease free interval and survival. 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 (6-9). In peritoneal mesothelioma as well as peritoneal metastasised gastric cancer cytoreductive surgery plus HIPEC has been also associated with prolonged survival (10,11). On the other hand, these procedures are long lasting and technically demanding. Moreover, the combination of major surgical resection and cytotoxic chemotherapy is often resulting in significant morbidity. Majority of authors report high morbidity and mortality rates of 27%-56% and 0%-11% respectively (12-24).

The question of whether major cancer operations are worthwhile in elderly patients is becoming more important, as we are facing with a progressively aging population. Elderly patients are still frequently denied major operations out of concerns over increased morbidity. Generally, the surgical risk becomes higher with age, since elderly patients usually have several co-morbidities resulting in poor performance status (PS).

II. Material and methods

Patient eligibility

Between January 2004 and January 2007 forty-four patients older than 65 years with peritoneal carcinomatosis (PC) of different origin have been treated in The Department of Surgical Oncology, Hammelburg Hospital, Germany. Criteria of eligibility were PC of different origin, good general status, age > 65 years, 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.

Patient evaluation

A complete history, physical examination, complete blood cell count with differential, serum biochemistry including tumour-marker determination, urine-analysis, spirometry, computer tomography (CT) scan of the abdomen, ECG and ECG after work were obtained at baseline. Patients were monitored throughout the treatment by recording history, toxic events, complete blood cell counts and serum biochemistry. 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.
After laparotomy, the diagnosis of PC was confirmed by frozen section and scored the extent of PC according to Sugarbaker’s peritoneal index (52). This index takes into account the number of invaded areas (maximum 13) and the size of the tumour nodules (<5 mm, 5 mm to 5 cm, >5 cm).

Treatment plan

Treatment plan consisted of multi-visceral resection plus peritonectomy to reach a complete removal of all visible tumour structures as the first step. HIPEC was added at the end of each surgical procedure.

Surgical procedure

Under general anaesthesia and complete hemodynamic monitoring, careful abdominal exploration was taken through a median laparotomy from xyphoid to pubic area. Starting at the left upper quadrant a complete peritonectomy procedure was carried out according to Sugarbaker´s technique (21). Adapted to the location of the malignant granulations as guided by the surgeon, exploration and extemporaneous biopsies were 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 of the peritoneum and posterior wall, Glisson´s capsula and mesenteric peritoneum. Small remnant malignant granulations at mesentery of small or large bowel were destroyed using electro surgical fulguration. Using a tip-ball surgery the aim of peritonectomy procedure was to remove all visible malignant structures on one hand and 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 (53). 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. Robinson-catheter was placed in the centre of abdominal cavity for inflow. Four Jackson-Prett catheters (15 mm) were placed into the abdominal cavity with one catheter in each quadrant as collectors of the perfusate. Thermo 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. Intra-abdominal temperature was kept between 42°C and 43°C. Afterwards, cytostatic solution was completely evacuated.

Patients´ follow-up

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

Cytostatics

Cytostatics for HIPEC procedure have been used according to the type of primary tumour (see Table 1). The dosage was adjusted to age of patient with higher grad of dosage reduction in older patients (age>65 and <75 dosage reduction of 20 %, age>75 years dosage reduction of 30 %). All cytostatics have been applied as the bolus at the beginning of HIPEC when adequate temperature has been reached.

Table 1 - Cytostatics used for HIPEC procedure.

Perioperative management

Using a combination of different warming blankets, body temperature was kept at the level of 36.0 C°. The probe for monitoring body temperature was located in the urinary bladder and in the oesophagus. If the temperature dropped down below 34.0 C° surgery was terminated.

The blood glucose level was assessed every two hours during the surgery and every three hours after finishing the operation for the first 5 days. In case of increase of blood glucose levels above 120 mg/dl, continuous insulin therapy has been started. The aim of insulin treatment was to keep the glucose level below 120 mg/dl.

At the beginning of anaesthesia, continuous infusion of the adenosine started with a dosage of 30 mg per day. This infusion was continued for the first three postoperative days in a same dosage.

In case of increased or excessive bleeding, proteinase inhibitor therapy has been initiated using the kallikrein inhibitor Aprotinin. After a loading dose of 1 Million Kallikrein Inhibitor Units (KIU), 250.000 KIU has been applicated every hour until the end of surgery.

During a surgery, restrictive fluid management has been also used. The aim of intra-operative management was not to exceed pre-operative body weight at end of surgery by 1 kg. In case of transient hypovolemia, Hydroxyethylstarch (HES 0.6/130) has been used.

Postoperatively, high concentrated oxygen was applied for the first five postoperative days using an insufflations rate of 6 litres per minute.

Postoperative morbidity

The severity of complication was graded according to the Feldman’s classification [21]. Grade one complications, defined as 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.

III. Results

Between 1/2004 and 1/2007, 47 cytoreductive interventions have been carried out in 44 patients aged older than 65 years at the Department for Surgical Oncology, KKH Hammelburg. Mean age of patients in this group was 71 years (min. 65 years, max. 82 years). Tumour histology was as follows: pseudomyxoma 2x, adenocarcinoma of the peritoneum 1x, appendicle carcinoma 1x, cervical cancer 1x, colorectal carcinoma 6x, stomach cancer 1x, small bowel cancer 2x, mesothelioma 6x, sarcoma 7x, including five cases of Müllerian mixed tumour, ovarian cancers 17x, including one case of Fallopian cancer.

Extent of peritoneal carcinosis

Extent of peritoneal involvement has been determined by use of the Sugarbaker´s Peritoneal Carcinosis Index (PCI) (12,52). Mean PCI was 16 (SD = 8.3, range 4 to 33). Complete cytoreduction has been reached in 35 out of 47 operations with 25 CC-0 resections and 11 CC-1 resections (optimal cytoreduction rate 74.4 %). Sub-optimal cytoreduction was recorded in 7 patients (CC-2 resection) with one two-step operation. In the last 5 cases, only insufficient debulking was possible (CC-3 resection). Extensive peritoneal involvement of the peritoneal mesothelioma was recorded in 4 out of these 5 incomplete cytoreductions. These patients suffered from extensive mutilating ascites leading to poor general condition.

Quality of perioperative management program

Body temperature was measured continuously throughout operative procedure plus first five postoperative days. A drop of body temperature below 35.0 C° has been documented only in one case of long time lasting procedure. Temperature management was therefore effective in 46 of 47 cases (97.9 %). Blood glucose level has been determined every two hours during surgery and every three hours in the first five postoperative days. For this time period a glucose level < 120 mg/dl has been reached in 57 % of all cases, < 150 mg/dl in 76 %, < 180 mg/dl in 93 % and < 210 mg/dl in 100 % of all cases. The optimal blood glucose management defined as a glucose level below 120 mg/dl, was able to achieve only in 57 % of cases.
Oxygen saturation has been measured continuously during the surgery and within the first five postoperative days. High concentrations of supplemental oxygen (6 litres/min.) have been given throughout this time period. Optimal blood oxygen saturation, defined as a level of > 98 %, has been achieved in 93 % of all cases.

Surgical procedures

In these 47 operations 47 bowel anastomoses had been carried out. Transient diverting ileostomy has been used in all cases with the need for extensive adhesiolysis or bowel reconstruction. Closure of the ileostomy was performed two months later. Anastomotic leakage was recorded in one patient three weeks after surgery (anastomotic leakage rate 2.1 %). Number and extent of these 47 cytoreduction in 44 elderly patients shows Table 2.

Table 2 – The type of surgical intervention.

Perioperative morbidity and mortality

Recorded side effects and complications in these elderly patients were seldom and transient. The frequency of grade 3 and 4 complications was 17.0 %. Review of all complications shows Table 3. There was no postoperative death registered within the 30 days after surgery (30 days mortality rate 0 %). Mean duration of the surgery was 5.3 hours (SD = 1.59; range 3.0 to 8.5 hours) and mean hospital stay 19.3 days (SD = 9.55, range 11 to 58 days).

Table 3 – Morbidity of all cytoreductive operations (n=47).

Survival

Determination of the survival was feasible in the largest subgroup of 17 patients with recurrent ovarian / fallopian cancer. Mean age in this subgroup was 70.6 years (min. 66 years, max. 81 years). Median survival after two years has not been reached. Survival curve of these patients shows Figure 1.
Figure 1 – Survival curve of patients with recurrent ovarian/fallopian cancer (n=17).

IV. Discussion

Cytoreductive surgery with intraperitoneal hyperthermic chemoperfusion is the treatment of choice for patients with peritoneal based malignancies or for selected cancers with peritoneal dissemination. This therapeutic approach is associated with significant morbidity and mortality. Cytoreduction consists of three different treatment modalities: aggressive surgery, chemotherapy and local hyperthermia. All of these strategies alter physiologic immune balance by initiating a systemic inflammatory response. This pathophysiologic event is characterized by release of many inflammatory mediators into the circulation. Among these pro- and anti-inflammatory cytokines, IL-6, IL-8 and IL-10 play a dominant role as local and systemic regulators of acute inflammatory response. Increased levels of these molecules are responsible for development of the Systemic Inflammatory Response Syndrome (SIRS) and the Adult respiratory distress syndrome (ARDS), which consequently lead to side effects and complications. IL-6 together with cell adhesion 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 extra-cellular matrix. Surgical trauma, cytostatics and hyperthermia are able to over-activate immune system, leading to imbalance of the regulation between immune cells and endothelium, resulting in tissue damage and consequent complications.
Advanced peritoneal malignancy in elderly patient is a medical challenge. The number of these patients is increasing with a progressively aging population. Surgical risk in this group of patients is high, since elderly people suffer from frequent co-morbidities, resulting in the poorer performance status (PS). Cardiovascular and pulmonary diseases are the most common. Detailed preoperative workup, including exercise echocardiography, is thus essential in this group. Moreover, exercise echocardiography is also feasible in very elderly patients, with a high prevalence of cardiac abnormalities.

When facing a progressively aging population, the question of whether major cytoreductive operations with aggressive intraperitoneal chemotherapy are worthwhile and feasible in elderly is very actual. The maximum effort to reduce perioperative morbidity and mortality is essential problem of these procedures in general and especially in the subgroup of elderly patients. A safe procedure with acceptable morbidity and mortality is the way, how to get profit for these patients, resulting in prolonged survival.

To reduce morbidity associated with cytoreductive interventions, comprehensive perioperative management program has been established throughout recent years in the Department of Surgical Oncology Hospital Hammelburg. The aim of this comprehensive perioperative management program is the reduction of inflammatory response induced by long lasting surgery combined with application of cytostatics. Throughout the last decade different publications showed a clear correlation between surgery dependent expression of pro-inflammatory molecules, postoperative immune suppression and postoperative complications and infections (25,26). Different strategies aimed to reduce surgery related complications have been used like intensive pre- and intra-operative warming, intra-operative fluid restriction, intensified hyperglycaemia management, increase of tissue oxygenation and strategies to reduce blood loss. Several prospective randomised trials showed efficacy of these methods (29,30,35,39,40).

Avoiding hypothermia is an important factor in preventing wound infection, possibly because it blunts the normal inflammatory response (27,28). The body heat is largely derived from muscles. Intensified warming management during abdominal surgery is therefore very important in elderly patients, presenting with diminished muscle mass. In a prospective randomized trial the positive effect of perioperative maintenance of normothermia 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, varices) (30). Surgical site infections occurred less frequently (14 % vs. 5 %) in the group of patients who have been warmed pre- and intraoperatively.

Intravenous fluid overload during and after surgery has been shown to decrease muscular oxygen tension and delaying the recovery of gastrointestinal function (31,32). Furthermore, postoperative weight gain and intraoperative fluid overload has been associated with poorer survival and higher rate of complications (33,34). Brandstrup and co-workers showed in a prospective multicenter trial of 172 patients undergoing elective colorectal surgery significant reduction in postoperative complications rate by use of intraoperative fluid restriction (35). Liberal fluid regimen was associated with an increase of complications of 51 %, whereas an infusion protocol aiming at unchanged body weight reduced complications´ rate to 33 %.

Uncontrolled hyperglycaemia may also be associated with complications such as fluid and electrolyte disturbances and increased risk of infection. Several studies demonstrated impairment of host defences, including decreased polymorphonuclear leukocyte mobilization, chemotaxis, and low phagocytic activity related to hyperglycaemia. Hyperglycaemia (blood glucose concentrations > 220 mg/dl) had been tolerated in stressed and critically ill patients. High blood glucose concentrations were believed to be a normal physiologic reaction to supply energy to glucose-dependent organs. Recent clinical data show, that the use of intensified insulin therapy to maintain tight blood glucose concentrations between 80 and 110 mg/dl decreases morbidity and mortality in critically ill surgical patients. In the study of Van den Berghe et al. with more than 500 patients, insulin therapy was designed to maintain glucose levels between 80-110 mg/dl. Patients with normal glycaemia showed reduced hospital mortality, with the greatest benefit in critically ill people with proven infection (36). Intensified insulin therapy management minimizes derangements of normal host defence mechanisms and modulates release of inflammatory mediators (37).

The presence of adequate blood flow and availability of oxygen (O2) to cells in the wound area are other important factors for successful healing process. The oxygen plays a critical role in the formation of collagen, the growth of new capillaries, and the control of infection. Fibroblast synthesis of collagen is dependent on oxygen for the enzymatic hydroxylation of proline and lysine, when forming collagen chains. A local tissue oxygen tension of 25 mm Hg is needed to support this reaction at half of its maximal rate (38). Although an adequate blood flow does not guarantee a sufficient supply of O2, the lack of it will impair the healing process. Greif and co-workers demonstrated in a randomised trial of 500 patients undergoing colorectal surgery the positive effect of postoperative oxygen application to reduce surgical site infection (39). In this study, absolute risk reduction for surgical site infection was 6 %. Similar results presented Belda and co-workers in another prospective randomised trial (40).

Bleeding during a surgical procedure is a common problem associated with increase of the morbidity and mortality rates. The need of transfusion therapy brings additional risks, like allergic and toxic reactions and transmission of infectious diseases, especially hepatitis and acquired immunodeficiency syndrome. The interest in antifibrinolytic drugs dramatically increased when Royston et al. demonstrated the effect of large-dose aprotinin in reducing intraoperative blood loss and need of transfusions in cardiac surgery (41). Since then, many studies have been performed in this type of setting. Aprotinin is nowadays widely used in cardiac surgery. There are also several ongoing trials in vascular and liver transplantation surgery, concerning different doses and types of administration. In general, aprotinin showed efficacy for decreasing of intra- and postoperative bleeding and blood transfusions in these settings (41-45). 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 kallikreins of different origins (46). It forms a stochiometric complex, completely inhibits the active site of each enzyme and leads to an inhibition of inflammatory response process.

Adenosine receptors are presented in the majority of cells and organs. Adenosine, acting at the specific A2 receptors, inhibits some, but not all, neutrophil functions leading to an anti-inflammatory effect with high efficacy (47). Adenosine inhibits phagocytosis, generation of toxic oxygen metabolites and adhesion to endothelial cells. Degranulation and chemotaxis are not influenced. 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. A novel physiological role of endogenous adenosine became apparent following the demonstration, that activated neutrophils or endothelial cells release and respond to adenosine (48). Several groups of investigators have demonstrated that adenosine binds to A2A-ARs expressed on activated neutrophils to reduce the release of reactive oxygen species, such as superoxide anion or hydrogen peroxide and reduce adherence of neutrophils to endothelial cells (49). These studies provided evidence that inhibition of leukocyte adherence to endothelial cells may contribute to protective effect of adenosine on ischemia-reperfusion injury (50).

The above-mentioned strategies help to reduce morbidity of major cancer surgery and toxic chemotherapy. The combination of these techniques makes aggressive cytoreductive surgery with hyperthermic peritoneal chemotherapy feasible also in the group of elderly patients.

V. Conclusion

The number of elderly patients is increasing with a progressively aging population. Whether major cancer surgery is feasible in this group of patients is recently discussed. Frequent co-morbidities, advanced peritoneal malignancy and a very aggressive treatment lead to high morbidity and mortality rates. The only way how to get a profit for these patients is a safe procedure with acceptable morbidity. This can be reached by incorporating some of new strategies like intensified warming management, intraoperative fluid restriction, control of hyperglycaemia, increase of the tissue oxygenation, restriction of blood loss and adenosine receptor activation. Integration of these techniques into perioperative management program makes aggressive cytoreductive surgery feasible also in the elderly patients.

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