Newer Cancer Therapies and Perioperative Implications

Introduction

There have been rapid and substantial advances in cancer treatment with improved systemic therapies, including chemotherapy, hormone therapy, targeted therapy, and immunotherapy, as well as recent technologic advances in radiation therapy. This has led to new combinations and sequences of cancer treatment, including the use of neoadjuvant and adjuvant therapies in surgical patients. Therapeutic advances in cancer treatments have significantly improved outcomes for many malignancies and have led to an increase in the number of patients undergoing surgery. Many of these patients are experiencing extended survival and sometimes long-term remission; hence the adverse effects of their oncologic treatments may impact subsequent oncologic and noncancer surgery for an increasing number of cancer survivors. The preoperative evaluation of a cancer patient may be challenging because of the physiologic deconditioning that this disease and its treatments can impose. It is important to identify individual patient risk factors and consider age-related comorbid conditions and cancer symptoms. It is also important to recognize the potential sequelae of various types of cancer therapies and their clinical implications on a patient’s baseline functional status. A comprehensive history and physical examination can help guide targeted preoperative testing for the potential effects of specific cancer therapies and aid in medical optimization prior to surgery. Care may be further complicated by disruption of normal anatomy as a result of prior surgery and radiation, as well as vital organ dysfunction from systemic treatments leading to cardiopulmonary instability under general anesthesia. Postoperative management must meticulously account for the above maintaining great vigilance for complications related to surgery, thromboembolic events, wound healing, infection, and further deterioration of previously affected organ systems. This chapter provides an overview of the potential adverse effects of newer systemic chemotherapies, targeted therapies, and radiation therapy; describes recent advancements in cancer treatments; and reviews the impact of these newer cancer treatments and potential implications for the perioperative care of the cancer patient.

Surgical Considerations

Approximately 90% of patients with solid tumors will undergo a surgical resection for either cure or palliation. There have been major advances in surgical techniques, including minimally invasive approaches such as laparoscopic surgery, video-assisted thoracic surgery, ^, robotic surgery, and improved intraoperative image guidance techniques such as Brainlab navigation. Additionally, indications for image-guided interventions, including endovascular embolization and ablations, continue to expand. These improvements can potentially result in improved safety and lower incidence of perioperative complications, but also mean that an increasing number of patients with advanced disease and likely multiple rounds of prior systemic treatments or local therapies are becoming candidates for surgical and image-guided interventions. Almost all cancer patients in the United States receive more than one treatment modality. The increasing use of preoperative therapies, including radiation therapy, interventional therapies, chemotherapy, targeted therapies, and immunotherapies, influences how cancer patients are surgically managed and require attention to planning with other oncology colleagues regarding the timing of surgery. Developments in effective systemic therapies have resulted in many cancers becoming chronic diseases, which require special considerations to reduce treatment-related toxicities in order to optimize survivorship. With the rapid development of new cancer therapies, cancer surgeons and anesthesiologists must understand the importance of relevant cancer-specific, considerations in the perioperative period, and undergo continuing education and training throughout their career.

It is also important for oncologic surgeons to understand the principles of the cancer in managing complex patients, work closely with other oncology disciplines, and know which patients need to be referred to high-volume specialty centers for optimal management, especially if they are at high risk of toxicity or complications. The development of cancer centers that incorporate multidisciplinary teams of specialists which participate in comprehensive treatment planning for patients with specific oncologic conditions has improved outcome for many patients over recent years. As such, there is increasing demand for cancer care to be delivered by specialists in multidisciplinary cancer centers. It has been demonstrated that surgeons who perform technically demanding procedures at centers with higher volumes achieve better outcomes with complex disease. In addition, operative mortality has been shown to be significantly higher for patients treated at hospitals with lower annual caseloads for these procedures. This does not mean that all cancer patients require treatment at high-volume centers. If patients are diagnosed early, many initial treatments are relatively protocolized and can be adequately provided in the community setting. For relatively more complex cases, increased utilization of telemedicine has facilitated cancer patient care at local hospitals by providing input from surgical oncology specialists. These specialists assist by providing educational leadership within the general surgical community and have a central role in defining standards for treating surgical patients with cancer to achieve optimal care.

Chemotherapy and Targeted Therapy

The toxicity of cancer chemotherapy drugs and targeted agents and their relevance to perioperative management relates to the specific agents used. The most common toxicities encountered include cardiovascular, pulmonary, and hematologic toxicities, although gastrointestinal, hepatic, renal, endocrine, nutritional, and metabolic effects should also be considered. Awareness of the common side effects associated with these various chemotherapeutic and targeted agents can direct preoperative clinical testing and subsequent patient management to ensure a well-prepared surgical patient. As with any preoperative evaluation, the considerations for the patient with cancer who is undergoing surgery can be grouped by organ system. Systemic therapies have been associated with cardiovascular toxicities (including ischemia, cardiomyopathy, conduction system abnormalities, and hypertension), pulmonary toxicity, hematologic toxicities (including cytopenias and coagulopathies), gastrointestinal toxicities (colitis), hepatotoxicity, nephrotoxicity, and endocrinopathies, all of which can complicate perioperative care of the cancer patient. These complications are described in greater detail earlier in this book. A quick review of systemic agents and their associated toxicities in cancer patients undergoing surgery is provided in Tables 5.1 – 5.5 .

Table 5.1

Chemotherapeutic and Targeted Agents Associated With Myocardial Ischemia

Drug	Incidence
Bevacizumab	0.6%–1.5%
Capecitabine	3%–9%
Docetaxel	1.7%
Epirubicin	0.9%–3.3%
Erlotinib	2.3%
5-Fluorouracil ^,	1%–68%
Gemcitabine ^,	Rare
Paclitaxel	<1%–5%
Sorafinib	2.7%–3%
Vinblastine	Rare
Vincristine	Rare
Vinorelbine	1.19%

Table 5.2

Chemotherapeutic and Targeted Agents Associated With Left Ventricular Dysfunction and Cardiomyopathy

Drug	Prevalence or Incidence
Bevacizumab ^,	1.7–3
Bortezomib	2–5
Clofarabine	27
Cyclophosphamide	7–28
Dasatinib	4
Docetaxel	2.3–8
Doxorubicin	3–26
Epirubicin	5%
Idarubicin	5–18
Imatinib mesylate	0.5–1.7
Ifosfamide	17
Lapatinib	1.5–2.2
Mitoxantrone	36%
Sunitinib ^,	2.7–11
Trastuzumab	2–28

Table 5.3

Chemotherapeutic and Targeted Agents Associated With Pulmonary Toxicity

Drug	Pulmonary Toxicity	Incidence
Bevacizumab	Hemoptysis	Up to 20%
Bleomycin	Pulmonary fibrosisBronchiolitis obliterans organizing pneumoniaPulmonary veno-occlusive disease	Up to 20%
Busulfan	Pulmonary fibrosisPulmonary alveolar lipoproteinosis	4%–10%
Carmustine	Interstitial lung disease/pneumonitisPulmonary fibrosis	Up to 35%
Cyclophosphamide	Interstitial lung disease/pneumonitisPulmonary fibrosis	<1%
Cytosine arabinoside	Noncardiogenic pulmonary edemaPleural effusion	12.5%
Dasatinib	Pleural effusion	7%–35%
Docetaxel	Noncardiogenic pulmonary edemaPleural effusion	Up to 23%
Gefitinib	Interstitial lung disease/pneumonitis	1%–2%
Gemcitabine	Interstitial lung disease/pneumonitisNoncardiogenic pulmonary edema	5%–8%
Imatinib mesylate	Pleural effusion	7%–35%
Methotrexate	Noncardiogenic pulmonary edemaPulmonary fibrosis	1%–7%
Mitomycin	Interstitial lung disease/pneumonitisPulmonary fibrosis	<10%
Nilotinib	Pleural effusion	7%–35%
Paclitaxel	Pleural effusion	1%
Rituxumab	Interstitial lung disease/pneumonitis	1%
Temsirolimus	Interstitial lung disease/pneumonitis	30%
Trastuzumab	Interstitial lung disease/pneumonitisPulmonary hypertension	Rare

Table 5.4

Chemotherapeutic and Targeted Agents Associated With Hepatotoxicity

Drugs	Hepatic Toxicity
Methotrexate, sunitinib, pazopanib, regorafenib, brentuximab	Acute hepatic necrosis
Asparaginase, carmustine, floxuridine, lapatinib, imatinib, idelalisib, other tyrosine kinase inhibitors, interferon	Acute hepatitis
Estrogens, chlorambucil, cyclophosphamide, temozolomide, lenalidomide, azathioprine, mercaptopurine, erlotinib, floxuridine	Cholestasis
Azathioprine, flutamide, trabectedin	Hepatocellular-cholestatic hepatitis
Cytarabine, floxuridine	Biliary stricture
Tamoxifen, methotrexate, corticosteroids, L-asparaginase, 5-fluorouracil, trabectedin	Nonalcoholic fatty liver
Imatinib	Reactivation of chronic hepatitis B
High doses of alkylating agents (busulfan, melphalan, cyclophosphamide, etc.), high doses of mitomycin C and carboplatin, chronic administration of thiopurines (azathioprine, mercaptopurine, and 6-thioguanine), dacarbazine, oxaliplatin	Veno-occlusive disease
Azathioprine, thioguanine, mercaptopurine, methotrexate	Nodular regenerative hyperplasia
Estrogen, androgens	Hepatic adenoma
Methotrexate	Fibrosis or cirrhosis
Sunitinib and pazopanib	Ischemia

Table 5.5

Chemotherapeutic and Targeted Agents Associated with Nephrotoxicity

Drugs	Renal Toxicity
Cisplatin, azacitidine	Salt wasting
Cisplatin, carboplatin, cetuximab, panitumumab	Magnesium wasting
Ifosfamide	Proximal tubular dysfunction
Sorafenib, sunitinib	Acute interstitial nephritis
IL-2, denileukin diftitox	Hemodynamic acute kidney injury (capillary leak syndrome)
Bevacizumab, tyrosine kinase inhibitors, gemcitabine, cisplatin, mitomycin C, interferon	Thrombotic microangiopathy
Interferon, pamidronate	Focal segmental glomerulosclerosis, minimal change disease
Platinums, zoledronate, ifosfamide, mithramycin, pentostatin, imatinib, diaziquone, pemetrexed	Acute tubular necrosis
Methotrexate	Crystal nephropathy
Cisplatin, ifosfamide, azacitidine, diaziquone, imatinib, pemetrexed	Fanconi sydrome
Cisplatin, ifosfamide, pemetrexed	Nephrogenic diabetes insipidus
Cyclophosamide ^a, vincristine	Syndrome of inappropriate antidiuresis

a Cyclophosamide is also associated with hemorrhagic cystitis.

Newer Systemic Treatments: Immunotherapy

Systemic treatment of cancer has changed dramatically over the past two decades. Antineoplastic chemotherapy classically targets cell proliferation by delivering drugs intravenously in a cyclic schedule resulting in systemic toxicities. A newer era of anticancer therapy emerged with targeted agents such as monoclonal antibodies that target more specific tumor cell antigens such as the CD20 protein in lymphoma, vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) in colon cancer. In addition to targeted antibodies, numerous oral tyrosine kinase inhibitors with different targets and indications have been developed for various hematological and solid tumors based on the principle of killing tumor cells by interrupting intracellular signals essential for cell proliferation and survival. Side effects associated with targeted agents are generally more specific to the treatment target than cytotoxic chemotherapies.

Over the last decade, immunotherapy has emerged as one of the most promising new cancer therapies and has become a component of standard treatment regimens for almost all solid tumors. Chimeric antigen receptor (CAR) T cells and checkpoint inhibitors activate immune effectors decreasing their tolerance and allowing them to attack cancer cells. While cytotoxic cancer drugs cause adverse events by compromising defense mechanisms, the new classes of immune therapeutics often induce enhanced inflammatory responses and autoimmunity. As such, the potential adverse effects of immunotherapy have introduced new challenges for perioperative management of these cancer patients. In addition, immunotherapy is most commonly used in combination therapy with chemotherapies, targeted therapies, or other immunotherapy agents. Hence the toxicities associated with immunotherapy often compound the side effects of systemic cancer therapies.

Immune checkpoint inhibitors (ICI) represent a promising emerging therapeutic modality by which the ability of tumor cells to evade immune cell activation via expression of inhibitory receptors at the cell surface is blocked. Monoclonal antibodies have been developed to target receptors and ligands involved in inhibitory signaling, including CTLA-4, PD-1, and PD-1L. Toxicities related to ICI can affect a variety of organ systems of great relevance in the perioperative period. Most commonly, gastrointestinal toxicities are seen, including nausea, vomiting, hepatitis, and enterocolitis. Hypophysitis is common, leading to various endocrinopathies, including primary adrenal and thyroid hormone insufficiency. This can cause cardiovascular compromise presenting as refractory vasoplegia, and signs and symptoms of hypothyroidism that can be severe and in rare cases, proceed to myxedema coma. Pituitary enlargement is noted on brain MRI, and confirmatory testing is performed based on laboratory results. Treatment involves discontinuation of the agent for mild cases, thyroid hormone supplementation, and corticosteroids along with supportive measures when indicated. Long-term hormone supplementation is needed in some cases. Pulmonary toxicity presenting as pneumonitis can occur especially when treating lung carcinoma and can lead to respiratory insufficiency requiring increasing levels of respiratory support. Cardiovascular toxicities are rare, occurring in <1% of patients treated with ICI and include perimyocarditis, dysrhythmias, and heart failure. Though rare, cardiovascular complications carry a grave prognosis; treatment involves discontinuation of the offending agent, administration of pulse dose corticosteroids, and supportive care in a cardiac care unit if indicated. ^, ^,

CAR T cells are another emerging form of immunotherapy demonstrating remarkable success at treating some hematologic malignancies, including B-ALL and non-Hodgkin’s lymphoma. CAR T cells are patient’s own T lymphocytes that are transfected ex vivo to express special chimeric receptors containing sufficient built-in costimulation to fully activate an immune response upon recognition of tumor-associated antigens. Unfortunately, cost and their toxicity profile hinder widespread use. This therapy is currently only possible at tertiary care centers that are capable of managing associated side effects that could be life-threatening. The main side effects are cytokine release syndrome (CRS) and neurotoxicity. CRS results from an exaggerated inflammatory response that leads to shock and multiorgan dysfunction. It presents typically within days of CAR T-cell administration and ranges in severity from mild tachycardia, tachypnea, and electrolyte abnormalities to refractory vasoplegic shock, respiratory compromise, coagulopathy, multiorgan failure, and death. Mild cases can be closely monitored; however, more severe cases may require additional interventions, including fluid resuscitation; respiratory support, including mechanical ventilation; and vasopressors and ionotropic agents for hemodynamic support.

Neurotoxicity is a separate entity that usually presents days after CRS and is characterized by an expressive aphasia with focal neurologic deficits. It can range in severity from mild word-finding difficulties to refractory status epilepticus, cerebral edema, and brain herniation leading to death. The exact etiologies of CRS and neurotoxicity are not well understood. The only FDA-approved agent to treat these toxicities is the IL-6 binder tocilizumab. Corticosteroids are also helpful in the management of severe cases in addition to supportive therapies.

Table 5.6 describes the toxicities associated with immunotherapy and potential impact on the perioperative course of the cancer patient.

Table 5.6

Toxicities Associated With Immunotherapy and Potential Impact on Perioperative Course of the Cancer Patient

Drug	Class	Toxicity	Potential Impact on Perioperative Course
Ipilimumab	ICI (anti-CTLA-4)	Hypophysitis, adrenal insufficiency, hypothyroidism, gastroenteritis, pulmonary toxicity, dysrhythmias, cardiomyopathy	Patients may develop refractory hypotension due to primary adrenal insufficiency requiring stress dose hydrocortisone, may require thyroid hormone supplementation, aspiration risk due to protracted nausea and vomiting, at risk for hypoxemia including post-operative respiratory insufficiency/failure due to pulmonary toxicity, dysrhythmias in the perioperative period.
Nivolumab	ICI (anti-PD-1)
Pembrolizumab	ICI (anti-PD-1)
Atezolizumab	ICI (anti-PD-1L)
Tisagenlecleucel	CAR T cell (anti-CD19)	Cytokine release syndrome (CRS), neurotoxicity	Acute postinfusion side effects occur days to weeks following administration. Patients are usually pancytopenic as a result of conditioning chemotherapy. CRS presents as a hyperinflammatory state resulting in vasoplegia, pulmonary edema, cardiac dysrhythmias, and coagulopathy. Neurotoxicity may present with altered level of consciousness, increased ICP, epileptiform activity, and risk of cerebral herniation.
Axicabtagene ciloleucel	CAR T cell (anti-CD19)	Cytokine release syndrome (CRS), neurotoxicity

Anti-CD19 , B-lymphocyte antigen CD19, also known as CD19 molecule (Cluster of Differentiation 19); anti-PD-1 , programmed cell death protein 1; anti-PD-1L , programmed cell death-1 ligand 1; CAR T , chimeric antigen receptor T cells; CTLA , cytotoxic T-lymphocyte-associated antigen; ICI , immune checkpoint inhibitors; ICP , intracranial pressure.

Table 5.7 reviews potential toxicities resulting from newer cancer therapies and corresponding perioperative care measures that enhance outcome for the cancer patient.

Table 5.7

Potential Toxicities Resulting From Newer Cancer Therapies and Corresponding Perioperative Care Measures to Enhance Outcomes

Immune checkpoint inhibitors

Should include:

•

Complete history and physical examination inclusive of absence of cardiac, pulmonary, gastrointestinal side effects.
•

Imaging as needed including CXR or CT, PFTs, EKG.
•

Thyroid function tests, cortisol levels.
•

Aspiration precautions, thyroid hormone supplementation, and stress dose corticosteroids should be considered if needed based on findings.

CAR T cells

•

Must be aware of these patients.
•

Corticosteroids should be avoided as they could affect yield by suppressing T-cell populations.
•

Patients who have recently received CAR T cells should be evaluated for potential toxicity including any evidence of cytokine release syndrome and neurotoxicity.
•

An EKG should be obtained to rule out dysrhythmias and conduction or repolarization abnormalities. Tocilizumab should be considered for the treatment of any patient exhibiting signs of severe CRS. Patients should also be assessed for any evidence of neurotoxicity and any signs or symptoms of increased ICP and routine precautions should be undertaken accordingly. Patients experiencing severe neurotoxicity can be treated with pulse dose corticosteroids and antiepileptic agents when clinically indicated based on presentation.