Complications and Management of Radical Cytoreduction

Radical cytoreduction consists of complex surgical procedures that may include extended peritonectomy, diaphragmatic resections, lymphadenectomy, and multiple visceral resections. As a result, it may be difficult to determine which of these innumerable procedures contributes to a specific complication. Patients undergoing cytoreductive surgical procedures are predisposed to predictable major morbidity, and this may be accentuated by their general medical condition and comorbidities. Perioperative planning in accordance with updated evidence-based guidelines should be implemented for every patient scheduled for a cytoreductive surgical procedure. This chapter focuses on the details of a comprehensive preoperative patient assessment and prevention and efficient management of related complications.

Complication Classification Systems

Patients undergoing cytoreductive surgery may be predisposed to intraoperative injuries, which occur in approximately 10% of procedures. Current data show that 17% to 63% of patients will develop complications of various levels of severity in the first 30 days after operation.

Historically, the first system developed for grading postoperative complications was the Clavien-Dindo classification. The revised system ranks complications into five categories based on the therapy required to correct the complication and whether the complication is life-threatening or causes subsequent disability ( Table 14.1 ). Under this classification, grade I and II complications are those that require medical treatments. Grade III complications consist of those requiring surgical, endoscopic, or radiologic intervention. Grade IV complications are those that are life-threatening and require an intensive care unit admission or any complication requiring prolonged intubation or re-intubation. Death is considered a grade V complication. Chi and co-workers published a scoring system for grading secondary events associated with surgery. Grade 1 complications are those requiring oral medications and/or bedside interventions. Grade 2 complications are those requiring intravenous medications, transfusions, or parenteral nutrition. Grade 3 complications are defined as those requiring reoperation, a radiologic or endoscopic therapeutic procedure, or intubation. Residual disabilities are categorized as grade 4 complications, and deaths as grade 5. The major difference between the two scoring systems concerns the fourth grade (grade IV, life-threatening complications in the Clavien-Dindo classification, and grade 4, residual disabilities in the grading system developed by Chi and colleagues). Use of scoring systems such as the National Cancer Institute Common Terminology Criteria for Adverse Events is possible but probably less appropriate in the context of surgery because they were developed for grading adverse events associated with the use of a medical treatment or procedure.

Table 14.1

Clavien-Dindo Classification of Surgical Complications

From Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg . 2009;250(2):187–196.

Grades	Definition
Grade I	Any deviation from the normal postoperative course without the need for pharmacologic treatment or surgical, endoscopic, or radiologic interventions. Allowed therapeutic regimens are antiemetics, antipyretics, analgesics, diuretics, and electrolytes and physiotherapy. This grade also includes wound infections opened at the bedside.
Grade II	Requiring pharmacologic treatment with drugs other than those allowed for grade I complications. Blood transfusions and total parenteral nutrition are also included.
Grade III IIIa IIIb	Requiring surgical, endoscopic, or radiologic intervention. Intervention not under general anesthesia. Intervention under general anesthesia.
Grade IV IVa IVb	Life-threatening complication (including CNS complications) ^a requiring IC or ICU management. Single-organ dysfunction (including dialysis). Multiorgan dysfunction.
Grade V	Death of a patient.
Suffix d	If the patient has developed a complication at the time of discharge, the suffix d (for disability ) is added to the respective grade of complication. This label indicates the need for follow-up to fully evaluate the complication.

CNS, Central nervous system; IC, intermediate care; ICU, intensive care unit.

a Brain hemorrhage, ischemic stroke, subarachnoid bleeding, but excluding transient ischemic attacks (TIAs).

Minor events (grades I and II according to the Clavien-Dindo classification and grades 1 and 2 according to Chi and colleagues) are the most common types of complications and account for approximately two-thirds of all complications. In the currently reported data, the incidence of major morbidity (grades III and IV or 3 and 4) ranges between 2.5% and 27%, if all events occurring within the first 30 days after operation are considered. Medical complications, with the exclusion of infectious disease, occur in 10% to 18% of patients and include myocardial infarction, cerebrovascular accident, acute organ failure, and thromboembolism. Infections occur in 7% to 10% of patients. Although a rare complication, patients may die from immediate postoperative complications.

The length of hospital stay is prolonged beyond 8 to 10 days in approximately 25% of patients owing to postoperative-associated morbidity. Recently there has been increasing emphasis on the assessment of quality of life after a surgical procedure, and maintenance of quality of life should be a major priority when one is considering patients for cytoreductive procedures. Several tools are available for assessing quality of life after an operation The ovarian cancer–specific quality-of-life questionnaire (QLQ-OV28) developed by the European Organisation for Research and Treatment of Cancer (EORTC) as a supplement to the validated core QLQ-C30 is one of the more commonly used tools in assessing quality of life after cytoreductive surgery. It consists of an assessment of general health, appetite, sleep, pain, digestive and respiratory disorders, and body image.

Preoperative Risk Assessment for Complications

Candidates for cytoreductive surgery should be assessed before operation to evaluate risk factors based on age, general medical condition, and comorbidities. This will help the surgeon determine who is the ideal candidate for such a procedure.

Patient age is a key factor in predicting postoperative complications. In fact, patients aged 75 years or older have been shown to have a twofold higher risk of postoperative morbidity and prolonged hospitalization than younger patients. Similarly, the mortality risk is up to 10 times higher in this patient population. Chronologic age alone is not reliable when determining risk estimation, and several scoring systems should be used. The most commonly used scoring system is the physical status classification of the American Society of Anesthesiologists (ASA). This classification consists of a validated risk adjustment score for both general and cytoreductive surgery. Risks of morbidity and mortality are known to be two to four times greater for patients with an ASA score of III or IV. However, there are conflicting data regarding the value of this system in determining with accuracy the risk of intraoperative complications and the complexity of intraoperative and postoperative medical care. The current literature shows that more than 80% of candidates for cytoreductive surgery have an ASA score of II or III. The Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) Performance Status and Charlson Comorbidity Index are also accurate in predicting morbidity, mortality, and length of hospital stay, but their importance with regard to risk adjustment models is probably less pronounced.

Preoperative comprehensive assessment of associated comorbidities and visceral functions is crucial because it allows patients at high risk for complications to be properly selected, to receive preoperative optimization, and to undergo intensive nursing and close monitoring.

Patients with a history of cerebrovascular disease, cardiac ischemia, arrhythmia, or valvulopathy and those with chronic bronchitis and pulmonary obstructive disease, asthma, or emphysema are at high risk for postoperative decompensation and subsequent major complications. In patients with compromised respiratory function secondary to pleural effusion, one may consider pleural drainage, pleuroscopy, and talcum pleurodesis. Diabetes increases the risk of postoperative infection, particularly of the surgical site, in addition to the risks of postoperative exacerbation and worsening of already existing end-organ damage. Patients with renal or liver disease may also present challenges with regard to the risk of postoperative complications. Anemia is associated with increased risk of postoperative morbidity and mortality. This is related in part to the fact that in patients with preexisting anemia, the physiologic compensatory mechanisms are already activated. Therefore, capacities of adaptation to an acute perioperative anemia are reduced, particularly in the presence of associated cardiovascular or respiratory impairment. Additional risks are iatrogenic and inherent to intraoperative blood transfusion, which is typically recommended in cases of acute hemorrhage regardless of its severity and of the patient’s condition. Preoperative correction of anemia may decrease these risks.

Coagulopathies are also a factor to consider in patients with advanced ovarian cancer. The major mechanism involved is a humoral-mediated paraneoplastic syndrome, but other factors such as tumor burden, chemotherapy, surgery, and acute blood loss may trigger coagulation abnormalities. The risk of thromboembolism is significant in patients with ovarian cancers, and up to 20% will develop thromboembolic events. Patients with preexisting deep vein thrombosis or pulmonary embolism are at high risk of postoperative mortality. In those who require inferior vena cava filter placement because of contraindications of anticoagulation or recurrence of pulmonary embolism despite optimal anticoagulation, postponement of the operation should be considered.

Malnutrition is ubiquitous in patients with advanced ovarian cancer, principally because of the mechanical compressive effect of ascites and tumor masses on the digestive tract. In some cases, the bowel is obstructed by invasive carcinomatosis lesions or is affected by motility disorders. Other cancer-related factors such as anorexia and cachexia may also be implicated. Preoperative assessment of nutritional status based on estimation of weight loss and levels of serum albumin, prealbumin, and transferrin is necessary to identify severely malnourished patients (weight loss >10%, albumin level <30 g/L, prealbumin level <10 mg/dL). These patients are known to be at high risk for postoperative morbidity and mortality, particularly in relation to infectious complications. The published literature shows that approximately 17% of patients scheduled for cytoreductive surgery have albumin levels below 35 g/L. The impact of low levels of albumin and prealbumin on the risk of complications was assessed in ovarian cancer cytoreduction by Geisler and colleagues. Their results showed that patients with prealbumin levels lower than 10 mg/dL have a 10-fold higher risk of major morbidity than those with higher levels (60% vs. 6%, respectively). The risk of bowel anastomotic leak is seven times higher if the serum albumin level is below 30 g/L. Other studies have shown that serum albumin is unequivocally the strongest predictor of postoperative adverse outcomes.

Several studies have reported an upward trend in the risk of major postoperative morbidity in patients with large volume ascites. However, none has shown statistically significant results.

Obesity seems to not be correlated with additional major morbidity with the exception of the substantial risk of surgical site infection. Smoking is correlated with a high risk of postoperative complications. Noxious pulmonary effects of smoking are known to be reversible after 4 weeks of cessation, but there is no evidence of a subsequent decrease in postoperative morbidity risks. Chronic alcohol intake increases the risk of perioperative complications as a consequence of its deleterious effect on the functions of cardiac, hepatic, coagulation, and immune systems. Alcohol cessation at least 4 weeks before operation is associated with a decrease in postoperative morbidity, but there is no evidence of a beneficial effect on mortality risk.

The timing of the cytoreductive procedure also affects the rate of perioperative complications. Data from prospective studies indicate that interval debulking procedures are associated with lower rates of perioperative complications. Rates of morbidity and mortality are lower, with decreases in blood loss, length of hospital stay, and median time to start of postoperative chemotherapy in comparison with primary cytoreduction. Major complications occur in approximately 6% of cases after interval cytoreduction versus 22% after up-front procedures.

Surgical Complexity Scores

The rate of postoperative complications is directly related to the surgical extent and the number of visceral resections. Published studies have demonstrated that patients undergoing more than three extended procedures have a threefold to fourfold higher risk of adverse outcomes compared with those who do not undergo any extended procedure. One of the strategies to determine the extent of the procedure has been the development of surgical complexity scores that allow surgeons to gain an objective sense of the aggressiveness of the procedure. In a study by Aletti and colleagues, the authors proposed a surgical complexity score specifically for cytoreductive surgery in ovarian cancer; 1 to 3 points are assigned to every procedure performed during the operation, and points are then added, allowing categorization as low-, intermediate-, and high-complexity operations ( Table 14.2 ).

Table 14.2

Surgical Complexity Scoring System Proposed by Aletti and Colleagues ¹⁵

Procedure	Points
TAH-BSO	1
Pelvic peritoneum stripping	1
Abdominal peritoneum stripping	1
Omentectomy	1
Pelvic lymphadenectomy	1
Paraaortic lymphadenectomy	1
Small bowel resection/s	1
Large bowel resection	2
Rectosigmoidectomy	3
Diaphragm stripping or resection	2
Splenectomy	2
Liver resection	2
Complexity Score Groups	Total
1 (low)	≤3
2 (intermediate)	4–7
3 (high)	≥8

TAH-BSO, Total hysterectomy and bilateral salpingo-oophorectomy.

Surgical Procedures as Predictors of Perioperative Complications

Lymphadenectomy is reported to be performed in 33% to 40% of cytoreductions, which may be explained by the persistent controversy concerning its therapeutic value in patients without bulky lymph node disease, in addition to the substantial number of recurrences in patients who already received lymphadenectomy during up-front or interval surgery. In other studies, authors reported lymphadenectomy rates of up to 83.6%. Lymphadenectomy is associated with risks of intraoperative vessel injury (4%) and postoperative lymphocyst (13%).

Extensive upper abdominal procedures are frequently performed (27%–38%) during primary cytoreductive surgery. Diaphragm peritonectomy, possibly associated with full-thickness resection, is the most common; it is performed in 13% to 35% of cases. Hepatobiliary resections may be required in the rare cases with true parenchymal involvement. Approximately 1.5% to 10% of patients undergo hepatic complex procedures. A splenectomy is performed in up to 36% of patients. Splenectomy is associated with distal pancreatectomy in 0.5% to 4% of cases. Resections of tumor or lymph nodes from the porta hepatis or celiac area are reported in approximately 0.2% to 5% of cases, whereas gastric resection is required in less than 0.5% of cases. Data from the literature show that extensive upper abdominal procedures increase the mean operative time by 1.5 times, the mean blood loss by 2 times, and the rate of intraoperative transfusion by 6 times. However, none of these studies found a significant increase in the postoperative morbidity and mortality in relation to such procedures. In these patients, major complication rates are 6% to 22%, and approximately 60% of patients are hospitalized for 5 to 10 days.

Bowel resections are performed in 30% to 50% of primary debulking operations. Approximately one-third of them include multiple digestive tract resections including large bowel, small bowel, or both. Bowel resections increase operative time and blood loss and are associated with prolonged hospital stay and a substantial risk of major morbidity, particularly if there are multiple resections. Bowel resections including only the small intestine are performed in 5% to 20% of patients, and data from several studies show that such procedures do not increase the risk of postoperative morbidity or mortality after cytoreductive surgery. Large bowel resections are performed in 10% to 41% of patients and consist frequently of rectosigmoid resection (5%–14% of cases). Total or subtotal colectomy is performed in 3.2% of patients. Large bowel resections increase the risk of major complications by three times, but there is no evidence that there is an associated increase in the mortality risk.

Urinary tract resections are performed in 0.1% to 3% of cytoreductions and consist frequently of partial cystectomy and/or ureterectomy.

Selection of Patients for Surgery

In accordance with 2016 guidelines from the European Society of Gynaecological Oncology (ESGO), a comprehensive preoperative assessment by an expert multidisciplinary team is recommended in order to select patients with unresectable disease and those who can be debulked up-front to no residual tumor but with reasonable morbidity, taking into account their performance status and comorbidities. When patients have been appropriately evaluated and considered ideal candidates for surgery, then all details of the procedure and the intended approach should be discussed at length. If a patient is not deemed an ideal candidate for surgery, then all the appropriate measures should be taken to address the issue of concern and proceed with neoadjuvant chemotherapy to treat the primary disease.

Preoperative Care Planning and Prevention of Complications

According to the Enhanced Recovery After Surgery (ERAS) Society guidelines, correction of severe anemia (hemoglobin levels <7 g/dL) is recommended before operation. Iron deficiency and other underlying disorders should be corrected to improve a patient’s response to the intraoperative hemorrhage and avoid or at least minimize the need for perioperative transfusions. Glycemic control should also be optimized and includes preoperative oral carbohydrate loading to improve preoperative well-being and reduce postoperative insulin resistance.

Thromboembolic Prophylaxis

In accordance with ERAS guidelines, patients with preexisting deep vein thrombosis or pulmonary embolism who are on anticoagulation must be transitioned to heparin-based anticoagulation. Operation should be delayed for at least 1 month after the diagnosis of a thromboembolic event. For other patients, venous thromboembolism prophylaxis including the obligatory use of a pharmacologic agent is recommended despite an associated increase in the risk of bleeding. Low-molecular-weight heparin with the highest prophylactic dose (enoxaparin, 40 mg; dalteparin, 5000 IU) or, alternatively, low-dose unfractionated heparin (5000 IU) should be administered 12 to 2 hours before operation (12–10 hours if a neuraxial anesthesia/analgesia is planned and 4–2 hours otherwise). In addition, use of gradient compression elastic stockings or intermittent pneumatic compression devices is recommended and should be continued during the operation.

Nutritional Support

Support with oral and/or parenteral nutrition should be recommended for severely malnourished patients (weight loss >10%, albumin level <30 g/L, prealbumin level <10 mg/dL). Monitoring of nutritional status may be performed on the basis of clinical and laboratory test results. Patients should undergo surgery with prealbumin levels higher than 10 mg/dL.

Smoking and Alcohol Cessation

In accordance with ERAS guidelines, physical activity is encouraged, along with cessation of smoking and alcohol intake at least 4 weeks before surgery.

Preoperative Antibiotics

Preoperative administration of antibiotics is recommended because it is correlated with a decrease in the risk of surgical site infection. Use of third-generation cephalosporins or clindamycin is accepted. Additional doses may be required in obese patients and in prolonged procedures, in particular when duration exceeds two half-lives of the antibiotic used.

Postoperative Care Planning

Intensive Care Unit Hospitalization

Ten percent to 30% of patients require immediate postoperative intensive care hospitalization. During this period, repetitive clinical assessment is the cornerstone of monitoring. Routine use of laboratory tests should be rationalized with targeting of disorders related to expected or suspected complications. These studies are crucial primarily to exclude extremely serious complications such as disseminated intravascular coagulation, acute respiratory distress syndrome, or systemic inflammatory response syndrome (SIRS), particularly in the context of intraoperative significant hemorrhage, severe visceral failures, and intensive resuscitation.

Glycemic Control

Postoperative hyperglycemia is associated with parenteral infusion and nutrition. Optimization of glycemic control is crucial because it is correlated with a decrease in infectious morbidity and mortality risks.

Fluid Management

Fluid management requires a comprehensive evaluation of losses and fluid shift. The third space phenomenon is common and is characterized by accumulation of fluids in the peritoneal and pleural cavity. Albumin administration may be useful if profound hypoalbuminemia (<2 g/dL) is present. Use of diuretics may be required in patients with delayed transcellular fluid clearance and/or inadequate diuresis. According to ERAS guidelines, optimal management should take into account cardiac and renal functions in order to avoid fluid overload and maintain normovolemia and diuresis. Major blood pressure fluctuations should also be avoided to prevent vital organ ischemia or hemorrhage.

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