Traditional Cancer Therapies and Perioperative Implications

Introduction

Preoperative cancer therapies such as chemotherapy and radiation can have direct implications on perioperative management during cancer surgery. Chemotherapy is intended to prevent proliferation of malignant cells (cytostatic) and cause death of tumor cells (cytotoxic). It can be given at various stages during cancer treatment, including before surgery (neoadjuvant), after surgical resection (adjuvant), or as palliative therapy to improve quality of life. Chemotherapy is usually administered in cycles every 2–3 weeks, which allows patients to recover from its toxic effects. In this chapter, we focus on reviewing traditional chemotherapeutic agents, their toxicities on organ systems, and how to mitigate these effects perioperatively. Most commonly, patients experience toxicities related to cardiac, pulmonary, gastrointestinal, and hematologic systems. A full discussion of the perioperative implications of the numerous classes of chemotherapy is beyond the scope of this chapter. We have attempted to summarize the perioperative implications of chemotherapy in Table 4.1 . Radiation therapy has fewer systemic perioperative concerns, but patients do frequently present with late complications from therapy that may alter perioperative evaluation and management.

Cardiovascular

Cardiac toxicity from chemotherapy is common, with effects ranging from ECG abnormalities to congestive heart failure. These effects can continue for years after the cardiotoxic drug has been halted. In practice, cardiotoxicity can manifest as multiple different conditions, including (1) cardiac dysfunction, (2) cardiac ischemia, (3) cardiac arrhythmias, and (4) fibrosis and pericarditis ( Fig. 4.1 ). Risk of cardiotoxicity increases with the presence of preexisting cardiovascular risk factors (smoking, hypertension, diabetes, etc.), female sex, age >70 years, use of multiple chemotherapies, and prior radiation therapy to the mediastinum. ^,

Anthracyclines belong to the antimetabolite class of chemotherapeutics and include doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxanotrone, and valrubicin. Anthracycline-related cardiotoxicity ranges from 0.9% to 26% and depends on individual and cumulative doses. Four types of adverse cardiac toxicities related to anthracyclines are recognized. Acute cardiotoxicity occurs during and immediately after administration of the drug. Side effects include hypotension, vasodilation, and arrhythmias. Acute cardiotoxicity can occur up to 1–3 days after drug administration and can manifest as pericarditis and myocarditis. Early chronic cardiotoxicity occurs up to 1 year after completing treatment. Symptoms include dilated cardiomyopathy, congestive heart failure, and left ventricular dysfunction. Delayed chronic cardiotoxicity occurs more than 1 year after completing treatment, and symptoms include restrictive cardiomyopathy, dilated cardiomyopathy, and congestive heart failure. ^, Anthracycline-mediated toxicity is also related to the cumulative dose received by a patient. Limiting the total dose to 400–450 mg/m ² minimizes the risk of congestive heart failure to less than 5%. Cardiotoxicity can be detected by a rise in troponin level immediately after administration; however, this is not monitored in routine practice.

Taxanes belong to the class of microtubule assembly inhibitors and include paclitaxel, docetaxel, and cabazitaxel. These medications can be cardiotoxic in up to 2.3%–8% of patients. Cardiac side effects include bradycardia and autonomic dysfunction, most often manifesting as asymptomatic sinus bradycardia. When combined with anthracyclines, taxanes may induce cardiomyopathy by increasing the amount of anthracycline metabolites produced.

Fluorouracil (5-FU) is the third most common chemotherapeutic agent used for treatment of solid tumors. After anthracyclines, 5-FU is the second most common drug to cause cardiotoxicity manifesting as chest pain, atypical chest pain, and acute coronary syndrome, including myocardial infarction.

Monoclonal antibodies are an emerging class of treatment and include trastuzumab and bevacizumab. Trastuzumab has been associated with a 3%–64% risk of cardiac dysfunction. The risk is increased when administered concomitantly with other chemotherapeutics and with a length of treatment longer than 6 months. Cardiotoxicity is usually reversed when treatment is halted or can be managed with cardiac therapy. If cardiac dysfunction following therapy does not improve rapidly, treatment can include angiotensin converting enzyme (ACE) inhibitors and beta blockers. Bevacizumab inhibits vascular endothelial growth factor (VEGF) receptors and is commonly associated with hypertension. Due to VEGF inhibition, a decrease in nitric oxide increases peripheral vascular resistance leading to an increase in blood pressure. This can commonly be managed with ACE inhibitors and calcium channel blockers.

Tyrosine kinase inhibitors (sunitinib and sorafenib) were originally thought to be less toxic than other therapies due to their targeting of specific proteins. Their broad use has shown a variety of cardiac side effects, including hypertension, heart failure, QT prolongation, and myocardial ischemia. Hypertension has been reported in 15%–47% of patients on ­tyrosine kinase inhibitors and is much more likely in patients with renal cell carcinoma. Heart failure and left ventricular dysfunction occur more commonly with sorafenib (4%–8%), pazopanib (7%–11%), and sunitinib (2.7%–19%).

In order to administer chemotherapeutics safely, cardiac evaluation is advised in all patients before initiation of these drugs for whom a suspicion of potential cardiotoxicity exists. Left ventricular function can be monitored by cardiac MRI or echocardiography. Biomarkers such as troponins and nt-pro BNP can be used for detection of early cardiotoxicity if a clinical suspicion exists and may predict postoperative complications. ^, Interval monitoring of ECG is recommended for patients at risk for arrhythmias and QT prolongation. While most of the cardiotoxic effects of chemotherapy are reversible, anthracyclines can be associated with irreversible damage. Fortunately, perioperative management of chemotherapy-induced cardiomyopathy is consistent with ACC/AHA/HFSA guidelines for the management of heart failure.

In terms of perioperative considerations, side effects from radiation therapy that affect the cardiovascular system are of concern. Radiation therapy to the chest may result in several different forms of cardiovascular disease that develop over several months to years. Radiation triggers endothelial proliferation, which accelerates atherosclerosis, and microvascular ischemia and fibrin deposition, which cause fibrosis of the pericardium, myocardium, conduction system, and cardiac valves. The perioperative clinician should pay particular attention to signs of pericarditis, new murmurs, and ECG changes. Radiation therapy to the head and neck area can result in radiation-induced carotid stenosis. Combining radiation with chemotherapeutic agents that also have cardiovascular side effects poses an additional risk for developing cardiovascular disease.

Patients with cardiovascular disease are frequently on antiplatelet, antithrombotic, or anticoagulant medications for primary or secondary prevention of adverse cardiac or vascular events. Patients with recent cardiac stents may be on dual antiplatelet therapy, while others with recent venous thromboembolic events may be on full-dose anticoagulation. As such, a detailed history and medical management plan for these agents in line with current evidence and local guidelines should be addressed in the perioperative evaluation consultation. Consideration of the risks and benefits of stopping and/or continuing antithrombotics/anticoagulants should be noted at the time of perioperative evaluation.

Pulmonary

Pulmonary complications from chemotherapy most commonly involve infection. Side effects may occur from direct cytotoxicity to the lungs, oxidative damage, or disruption of collagen synthesis. Pulmonary toxicity can result from bleomycin, cyclophosphamide, nitrosoureas, mitomycin, busulfan, and methotrexate. Diagnosis of pulmonary toxicity can be difficult due to a large differential diagnosis of respiratory symptoms. Once pulmonary embolism, metastatic disease, and infection are ruled out, pulmonary toxicity needs to be considered. Methotrexate and cyclophosphamide are most commonly associated with pneumonitis.

Bleomycin-related pulmonary toxicity is usually dose dependent and can occur in 6%–10% of patients, occasionally being fatal. Patients exposed to a total of 270 mg have a 0%–2% chance of developing pulmonary toxicity, while patients receiving 360 mg have an incidence of 6%–18%. ^, Doses greater than 400 mg are avoided due to the increased rate of pulmonary complications. While pulmonary toxicity is most likely to occur in the first 6 months of treatment, the potential of exacerbating the condition with high oxygen concentrations remains throughout a patient's lifetime. Initial symptoms can include dry cough and shortness of breath and can progress to pneumothorax and pneumomediastinum in extreme cases. Radiographic findings include linear interstitial shadowing. Perioperatively, these patients should be maintained on minimal oxygen concentrations with use of positive end-expiratory pressure (PEEP) to optimize oxygenation. Postoperative care should include a comprehensive pain regimen, chest physiotherapy, and early mobilization. Although controversial, high inspired oxygen concentrations should be avoided in patients treated with bleomycin. While some studies have found high inspired oxygen concentration to be associated with acute respiratory distress syndrome (ARDS) and respiratory distress, others have found no association between Fio ₂ and development of ARDS. Instead, fluid balance, blood loss, and transfusion have been found to be associated with an increased likelihood of postoperative pulmonary morbidity. Conservative fluid management is recommended in this population.

While bleomycin is the most well-known agent that causes interstitial lung disease, other agents, such as the monoclonal antibodies (bevacizumab, trastuzumab), antimetabolites (capecitabine, 5-FU), and alkylating agents, are known to cause pneumonitis and fibrosis. ¹⁹ Patients who present with a history of dyspnea or shortness of breath should be evaluated for pulmonary compromise, and if needed, undergo further targeted testing for risk stratification. In most cases, asymptomatic patients need no further evaluation beyond a physical exam. Pleural effusions as a result of targeted therapy do occur with some frequency, and as such, preoperative thoracentesis may be needed to allow for adequate lung expansion, especially in the symptomatic patient. Docetaxel and tyrosine kinase inhibitors are known to have pleural effusions as side effects. ^,