Perioperative Care of the Colorectal Cancer Patient

Introduction

Colorectal cancer is the third most commonly diagnosed cancer worldwide with an estimated 1.8 million new cases in 2018, but ranks second in terms of mortality (after lung cancer) with an estimated 881,000 associated deaths per annum. Approximately 50% of all colorectal cancer patients die from metastatic disease, with around 20% found to have metastases at time of presentation. A higher incidence of colorectal cancer is found in developed societies, with evidence that elements of lifestyle common in developed countries such as higher consumption of processed foods, red meat, and alcohol, as well as obesity increase the risk of colorectal cancer development. However, incidence and mortality rates have been declining in developed countries in recent years due to improvements in public health programs, screening, early diagnosis, and treatment. Worryingly, incidence rates are increasing in those under 50 years of age, particularly for rectal cancers, and cancers are more likely to be detected at an advanced stage in this cohort.

Presentation, Diagnosis, and Treatment

Asymptomatic colorectal cancer may be detected by screening, or patients may present with a constellation of symptoms, including passing blood per rectum, abdominal pain, altered bowel habit, and symptomatic anemia. Occasionally, advanced cancers may present as surgical emergencies with bowel obstruction, perforation, or massive bleeding. Diagnosis is typically performed via endoscopy and biopsy of the lesion, with determination of the extent of local and distant disease spread requiring radiologic investigation in the form of CT, MR, and/or PET imaging. Pathologic staging uses the TNM (tumor, nodal involvement, metastasis) system and provides the most important factor in determining patient prognosis. The depth of tumor invasion of the bowel wall determines the T stage, regional lymph node involvement determines the N stage, and presence or absence of metastases determines the M stage (see Fig. 25.1 ). Aside from the TNM stage, other factors affecting prognosis include poorly differentiated histology, perineural, or lymphovascular invasion; aneuploid DNA chromosomal patterns; and elevated serum carcinoembryonic antigen (CEA). In 20% of patients with metastatic disease at the time of presentation, the most commonly affected sites are the liver, lungs, and peritoneum. Eighty percent of newly diagnosed colorectal cancers are localized to the colon and/or local lymph nodes.

Surgical excision is the appropriate treatment modality for localized disease, with the aim of surgery of curative intent being the removal of the diseased segment of bowel attached to its vascular pedicle and the associated lymphatic drainage system (see Fig. 25.2 ). For rectal cancers, total mesorectal excision (TME), which entails complete en bloc resection of the rectum along with the mesorectum containing the rectal blood supply and lymphatics, results in reduced recurrence rates. Primary anastomosis to restore bowel continuity is generally appropriate in straightforward elective procedures, with formation of proximal defunctioning colostomy or ileostomy reserved for emergency or complex cases or for those with low rectal resection (<8 cm from anal canal). Lesions invading or attached to adjacent structures or organs frequently require more complex resection requiring multispecialty surgical involvement. Patients with metastatic disease at time of presentation are typically treated with chemotherapy; however, if metastases are limited to isolated lesions in the liver or lung, then metastasectomy can be considered and can significantly improve survival. Radiotherapy is infrequently used in the treatment of colon cancer, but it often plays an important role in the neoadjuvant or adjuvant treatment of rectal cancer where it has been shown to reduce local recurrence in stage III tumors. Neoadjuvant radiotherapy is often given concomitantly with low-dose chemotherapy and commonly causes bowel and bladder dysfunction, rectal bleeding, dermatitis, and increases the risk of leakage from surgical anastomoses. In some patients, a complete pathologic response may result from such therapy giving consideration to rectal preservation (i.e., avoidance of surgery) in association with “watchful waiting,” although precise selection criteria are yet to be determined.

Perioperative Considerations of Neoadjuvant Chemotherapy

In addition to the patient’s general physiologic status, preexisting comorbidities, and the pathologic effects of the malignant process, the perioperative physician must take into account the multisystem effects of neoadjuvant chemotherapy, if it has been employed. Patients should be assessed preoperatively for the presence of symptoms and signs suggestive of concerning systemic toxicity, particularly with respect to the cardiac, respiratory, hematologic, and immune systems. 5-Fluorouracil (5-FU) has provided the mainstay of chemotherapy for metastatic colorectal cancer for decades and is used in combination with other agents in a variety of treatment protocols. Perhaps the most familiar regime is FOLFOX (5-fluorouracil, oxaliplatin, leucovorin—otherwise known as folinic acid); FOLFIRI consists of 5-FU in combination with the cytotoxic alkaloid irinotecan, with FOLFIRINOX adding leucovorin and oxaliplatin; CAPOX replaces 5-FU with its prodrug capecitabine administered alongside oxaloplatin.

Oxaliplatin is a third-generation platinum agent and is infrequently associated with nephrotoxicity, with reported cases of acute tubular necrosis, renal tubular acidosis, hemolytic anemia, and acute kidney injury. Hypertension may also develop as a result. Serial renal function tests may demonstrate a deteriorating trend during or after oxaliplatin treatment. Perioperative physicians managing patients presenting with oxaliplatin-related kidney injury should of course avoid causing further perioperative deterioration in renal function by paying particular care to preventing hypotension and hypovolemia, and avoiding concomitant use of nephrotoxins (e.g., nonsteroidal antiinflammatory drugs [NSAIDs]) where possible.

5-FU is a pyrimidine analogue and is associated with commonly occurring adverse effects on the heart and bone marrow. Myelosuppression typically occurs within 7 days of commencing treatment, reaching a nadir at 14 days and recovering at 20 days. Extreme vigilance is required for the potential development of infection during this period, with a low threshold for commencing antimicrobial treatment. Full recovery from 5-FU-related anemia and thrombocytopenia might not have occurred prior to the patient presenting for surgery. 5-FU causes the second-highest incidence of cardiotoxicity of all chemotherapeutic agents (anthracyclines having the highest incidence). ECG changes, angina, and myocardial infarction may complicate 5-FU treatment, with induced coronary vasospasm suspected of being the underlying cause. 5-FU-induced cardiotoxicity usually resolves spontaneously following cessation of treatment, although in the acute phase the patient may require symptomatic treatment with calcium channel blockade or nitrates. However, the perioperative physician should have a high index of suspicion and further investigate patient-reported cardiac symptoms as appropriate (with cardiology referral for ECG, exercise stress testing, cardiac perfusion imaging, coronary angiography, etc., as appropriate). Although patients are likely to have completed 5-FU therapy prior to surgery, in the event of patients on current 5-FU therapy presenting for emergency surgery, it should be noted that several drugs interact with 5-FU and may precipitate cardiac toxicity; these include (but are not limited to) metronidazole, cimetidine, phenytoin, fosphenytoin, and hydrochlorothiazide.

Capecitabine is an orally administered prodrug of 5-FU and is selectively converted to 5-FU mostly within cancer cells. It has a more favorable side effect profile than intravenous 5-FU in terms of a lower incidence of myelotoxicity. However, it causes cardiotoxicity with a frequency as high as 5-FU, and perhaps even higher when coadministered with oxaliplatin. Management as before is cessation of capecitabine treatment with symptomatic treatment as required.

Irinotecan is a camptothecin derivative, commonly used as a second-line agent in patients with 5-FU-resistant disease. It commonly causes neutropenia and has significant gastrointestinal side effects with vomiting, diarrhea, and abdominal pain occurring frequently. More rarely it can cause pulmonary, hepatic, or skin toxicity.

Anemia and Perioperative Blood Transfusion

The majority of colorectal cancer patients are iron deficient at time of presentation, with many of these being overtly anemic. Indeed symptomatic anemia is a common presenting complaint with patients reporting fatigue, lethargy, or dyspnea. Iron deficiency has been found to be present in 60% of colorectal cancer patients at presentation with 40% meeting the diagnostic criteria for iron-deficiency anemia (hemoglobin below 12 g/dL in females and 13 g/dL in males as per the WHO definition); iron-deficiency is particularly common in right-sided colonic tumors, with an incidence of up to 80%. ^, Although gastrointestinal bleeding is the most obvious cause of anemia, malnutrition, anemia of chronic disease, and neoadjuvant chemotherapy-induced bone marrow suppression may also contribute to the anemic state.

Evidence points to an independent correlation between the severity of preoperative anemia and perioperative morbidity and mortality. ^, Allogeneic blood transfusion (ABT) is well known to carry its own risks and has a proven impact on clinical outcomes (including increasing the risk of postoperative infection, surgical intervention, and death). ABT has also been suspected of having a detrimental effect on colorectal cancer recurrence—a 2006 Cochrane meta-analysis of trials that examined the influence of ABT on oncologic outcomes following colorectal cancer surgery reported an overall odds ratio (OR) for cancer recurrence of 1.42 (95% CI, 1.20–1.67), although the authors stated that study heterogeneity and poor quality data on surgical techniques prevented the definitive establishment of a causal relationship. Given the risks associated with ABT, it should not be considered a “quick fix” to correct anemia on the day of surgery, and all efforts should be made to restore hemoglobin levels by safer means prior to surgery.

The concept of a perioperative blood management (PBM) program has evolved in recent years with the aim of preoperative correction of iron-deficiency anemia in order to significantly reduce clinical risk for colorectal cancer patients. Given the urgency of proceeding with surgical resection of a primary tumor the time in which iron-deficiency anemia can be treated preoperatively by a PBM program is limited. A recent trial randomized colorectal cancer patients to receive either oral or intravenous iron for at least 2 weeks preoperatively. Mean hemoglobin rise was significantly higher in the intravenous group (1.55 g/dL) compared to the oral group (0.50 g/dL, P < 0.001), although there was no significant difference in transfusion requirements between the two groups.

Intravenous iron provides a favorable risk-benefit profile in terms of speed of replenishment of iron stores and recovery of hemoglobin concentration with very low risks of significant allergic reaction to the infusate. Given the risks associated with ABT, it appears prudent (as well as cost effective) to minimize patient exposure to transfusion by considering intravenous iron deficiency treatment even if the allowed time period before surgery is short.

Preoperative Exercise and Prehabilitation

Preoperative exercise programs are being developed and evaluated for patients planned for elective colorectal operations. Such programs can be hospital- or community-based with the former often using cardiopulmonary exercise testing (CPEX) as an assessment tool. In general, compliance and completion rates are high with objective improvements in exercise capability occurring with six sessions over a 2-week period. Improved postoperative outcomes are expected but not yet conclusively proven, and more expansive programs now include nutrition and psychology preparation for patients facing this major intervention.

Enhanced Recovery After Surgery (ERAS) Protocols

Enhanced Recovery After Surgery (ERAS) protocols are combinations of evidence-based, multidisciplinary perioperative interventions that are applied to patient care with the aim of improving patient outcomes, hastening recovery, and reducing costs in the early postoperative period. ERAS as a concept in colorectal surgery was promoted by the surgeon Henrik Kehlet in Denmark in the 1990s, who hypothesized that a key factor underlying the development of serious postoperative complications (e.g., cardiac, pulmonary, infective) was the deleterious effects of the physiologic stress response to surgery. By inhibiting this metabolic stress response via a multifaceted approach, Kehlet suggested that the incidence of postoperative complications could be reduced, thereby improving patient morbidity and mortality, reducing length of stay, and reducing health care–related costs. Such an approach requires highly organized, protocolized care with coordinated delivery of the various elements between surgery, anesthesia, nursing, physiotherapy, and other disciplines involved in perioperative patient care.

The ERAS Society was founded in 2010 to guide the education and research of ERAS principles. The guidelines initially published in 2012 were for enhanced recovery for colonic resection patients, followed shortly after by guidelines for rectal resection. The ERAS Society published the fourth edition of the guidelines for colorectal surgery in 2018. The guidelines list 24 ERAS elements with each being given a recommendation grade from weak to strong depending on the nature and quality of the evidence base underlying each element (see Table 25.1 ). Compliance with ERAS protocols has been shown to significantly reduce the incidence of postoperative nonsurgical complications and shorten primary hospital admission in pooled data from randomized control trials (RCTs) and also international multicenter registry data. ^,

Not all ERAS programs incorporate all 24 recommendations, and some may incorporate other elements not included in the ERAS Society guidelines. It remains unclear which elements exert the greatest impact on clinical outcomes and whether a reduced set of ERAS protocol elements may provide substantially the same effect. However, compliance of 70% or greater with the elements of the ERAS protocol appears to be important in maximizing outcome improvements, regardless of whether open or laparoscopic approaches are examined. Overall, as a consensus-based formula derived from frequently updated clinical evidence, the ERAS guidelines provide an invaluable framework for optimizing the perioperative care of the colorectal cancer patient.