Chemotherapy, Immunosuppression, and Anesthesia

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Chemotherapy, Immunosuppression, and Anesthesia BEN CHORTKOFF AND DAVID STENEHJEM

CHAPTER OUTLINE Chemotherapy Drugs That Cause DNA/RNA Damage Drugs That Suppress Proliferation: Microtubule-Binding Agents Molecular Therapies, Growth Inhibitors, and Targeted Therapies Monoclonal Antibodies Antimetastasis Therapy Immunotherapy How Anesthetics Might Affect Cancer Opioids Volatile Anesthetics Propofol Local Anesthetics Other Factors

T

he concept of “immunosurveillance” describes a homeostatic balance whereby cells that undergo transformation into cancer cells are normally eliminated or kept in check by the immune system.1,2 In 1985 an autopsy study found that 36% of “normal” thyroid glands showed occult carcinomas, even though the incidence of clinically diagnosed thyroid cancer is onethousandth of that rate in the same population.3 In 1987 another group found in situ breast carcinoma in 20% of autopsy examinations of women 20 to 54 years of age who died of unrelated causes.4 The expected incidence of clinically diagnosed breast cancer is on the order of about 0.1%. These studies found cancer cells 102 to 103 more frequently than cancer is manifest clinically. Malignant transformation of cells within the body is relatively common but clinical cases of cancer rarely result. The transformed cells are typically kept in check by immunosurveillance. Once cancer is identified in a patient, treatment may include chemotherapy and radiation therapy aimed at killing the cancer cells, surgery to excise solid tumors, and immune therapy aimed at helping the immune system eliminate or at least modulate cancer cells. Surgical excision remains the best therapy for control of solid tumors (either with or without adjuvant therapies) and is what most often brings patients under the care of the anesthesiologist. Patients with nonsolid tumors (e.g., leukemias) may come to the

operating room for biopsy or diagnostic staging. Patients also present for unrelated surgery regardless of the type of cancer and regardless of the stage of cancer therapy. Given the prevalence of newly diagnosed cancers each year (approximately 1,700,000 among a total population in the United States of 320,000,000 [0.5%]), along with the ever-increasing rate of survival of patients with a history of cancer (14,500,000 [4.5% of the population]),5 it is clear that anesthetists will frequently encounter patients in all stages of cancer and cancer treatment (Table 38.1). They therefore have a responsibility to understand how cancer therapies might influence anesthetic management. In addition, researchers are exploring how anesthetic management might influence cancer. This chapter highlights end-organ effects of common chemotherapies and reviews current concepts about anesthetic effects on cancer. Both may prove important in determining the best possible anesthetic plan for the individual patient with cancer.

Chemotherapy Using systemic medications to poison a cancer cell often results in collateral damage. The majority of chemotherapies target the cancer cell’s most distinctive feature, its rapid division and proliferation. However, cell division is not unique to the cancer cell. Disrupting cell division also affects normal functioning cells in involved and uninvolved internal organs, causing both acute and chronic injury after prior and/or cumulative exposures. Understanding the mechanisms by which the different chemotherapeutics inflict injury on the target cancer cells helps predict and elucidate what injuries might occur in the rest of the body. For example, agents that interfere with DNA replication are effective against rapidly proliferating tumors but also harm areas where rapid cellular turnover is the norm (e.g., the intestinal mucosa and bone marrow). Agents that affect the activity of microtubules within the cell will affect microtubule function not only during cellular division, but also in the performance of other microtubule activities (e.g., the preparation and delivery of synaptic vesicles at the neuromuscular junction). Disrupting synaptic vesicles causes peripheral neuropathies. Finally, agents that kill rapidly dividing cells by generating oxygen free radicals also injure cells with high metabolic activity such as cardiac myocytes, leading to cardiomyopathies. Conventional cancer drugs have a very narrow therapeutic index. They are highly toxic to both the targeted cancer cells and nontargeted cells. The “maximum tolerated dose” has the highest probability of decreasing tumor burden and is usually the prescribed 753



CHAPTER 38  Chemotherapy, Immunosuppression, and Anesthesia 753.e1

Abstract

Keywords

In the United States, nearly 5% of the population has or has had cancer. Anesthetists frequently encounter patients in all stages of cancer and cancer treatment. This chapter highlights the short term and long term end-organ effects of common chemotherapeutics relevant to the anesthetist and reviews current concepts about how anesthetics may impact cancer and cancer survival.

cardiotoxicity pulmonary fibrosis oxygen free radicals malignancy metastasis monoclonal antibodies immunotherapy angiogenesis

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TABLE The 12 Most Frequent Cancers in the 38.1  United States

Primary Cancer

New Diagnosesa

Survivorsb

Breast

249,000

3,131,440

Lung

224,000

430,000

Prostate

181,000

2,975,970

Colorectal

134,000

1,245,800

Bladder

77,000

455,520

Melanoma

76,000

528,860

Non-Hodgkin lymphoma

73,000

569,800

Thyroid

64,000

470,020

Kidney

63,000

389,000

Leukemia

60,000

177,940

Endometrial

60,000

624,890

Pancreatic

53,000

All sites

1,685,210

14,483,830 (4.5% of people in the United States)

a

Estimated number of patients with a new diagnosis of each cancer in 2016. Estimated number of patients living with a diagnosis of the specific cancer as of January 2014 (American Cancer Society, 2016). Available at: https://www.cancer.org/content/dam/ cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2016/ cancer-facts-and-figures-2016.pdf.

b

dose. Anesthetists should therefore anticipate that their patients who have received chemotherapy have received near-toxic doses at which organ injury may occur. In relation to surgery, chemotherapy can be administered (1) before surgical excision, as neoadjuvant therapy, to facilitate surgery by reducing tumor burden, killing micrometastases, and potentially decreasing the survivability of tumor cells liberated during surgical manipulation; (2) after surgical excision, as adjuvant therapy, in an attempt to eradicate clinically undetectable residual tumor burden; or (3) unrelated to surgical timing, as palliative therapy, to ameliorate patient symptoms. Medications used to kill cancer cells can be divided into three broad categories. The first category directly damages DNA and/ or ribonucleic acid (RNA), and includes alkylating agents, antimetabolites, antineoplastic antibiotics, and topoisomerase inhibitors. The second category suppresses proliferation of dividing cells by interfering with microtubule function. The third category includes targeted therapies, also known as precision medicine therapies. Targeted therapies are molecules that hinder specific cellular enzymes unique to or overexpressed in malignant cells. Targeted therapies can also be molecules made to attach to specific cell membrane antigens to mark the cell and facilitate recognition of the cancer by the immune system.

Drugs That Cause DNA/RNA Damage Alkylating Agents The prototypical alkylating agent, mechlorethamine (an analog of the chemical warfare agent mustard gas) is a simple molecule

composed of an electrophilic backbone carrying an alkyl side chain (Fig. 38.1). As an agent of war, mustard gas was a potent vesicant or blistering agent causing initial injury to exposed surfaces, including skin, eyes, and when inhaled, the lungs. Absorption would then lead to a drastic reduction in cell production in bone marrow and lymphatic tissue. During DNA replication, the alkyl group becomes covalently bonded to a DNA nucleotide (usually guanine) and physically interferes with subsequent transcription and cell division. On a molecular level this may be considered analogous to placing a set of handcuffs on rapidly dividing DNA (Fig. 38.2). The alkylating agents are toxic in all phases of the cell cycle but are most lethal to rapidly proliferating tissues. Subcategories of alkylating agents (Table 38.2) include nitrogen mustards (e.g., cyclophosphamide), nitrosureas (e.g., carmustine), alkyl sulfonates (e.g., busulfan), and platinum drugs (e.g., cisplatin). The alkylating agents are used to treat Hodgkin lymphoma, lymphosarcoma, leukemias, and bronchogenic sarcomas. Normal rapidly dividing cells—for example, bone marrow, intestinal mucosa, and hair follicles—are also killed along with the targeted tumor. The platinum-based chemotherapeutic agents are listed with the alkylating agents although they do not “alkylate” DNA (they do not have an alkyl group). They do act in the same manner by permanently binding to (hand-cuffing) guanine residues in DNA. Their main use is with testicular and ovarian cancers, bladder cancer, head and neck cancer, and small cell lung cancer. Oxaliplatin is used in metastatic colorectal cancer. The platinum-based agents additionally cause peripheral neuropathies and acute and chronic nephrotoxicity. The alkylating agents have side effects mostly limited to bone marrow suppression and gastrointestinal tract effects, although late-onset pulmonary fibrosis is associated with long-term therapy (especially cyclophosphamide, busulfan, and the nitrosureas). Platinum-containing agents uniquely cause neuropathies and nephrotoxicity. Cyclophosphamide uniquely inhibits plasma pseudocholinesterase activity and can prolong the effect of succinylcholine.6–8 (Remifentanil, unlike succinylcholine, has an ester group that is metabolized by nonspecific blood and tissue esterases. Cyclophosphamide would not be expected to alter its metabolism.)9

Antimetabolites The antimetabolites are analogs of normal metabolites and inhibit cell growth and division (Table 38.3). Methotrexate is a folic acid analog, 5-fluorouracil is an analog of uracil (Fig. 38.3), and 6-mercaptopurine is a guanine analog. The analogs inhibit enzymes or cause them to synthesize aberrant molecules. They are frequently used in the treatment of colorectal, bladder, and pancreatic cancers as well as for leukemia. The antimetabolites affect all proliferating cells, causing side effects of immunosuppression, severe nausea and vomiting, ulcerative stomatitis and diarrhea, hemorrhagic enteritis, and potentially intestinal perforation, but there are few recognized long-term end-organ effects that alter anesthetic management. Antineoplastic Antibiotics The antineoplastic antibiotics are almost wholly produced by Streptomyces bacteria. The Streptomyces are a genus of soil bacteria from which scientists harvest antibiotics (e.g., streptomycin, neomycin, tetracycline, chloramphenicol), antifungals (e.g., nystatin, amphotericin B), antiparasitics (ivermectin), and antitumor compounds (e.g., actinomycin D, bleomycin, and the anthracyclines). The antitumor compounds can be classified based on the

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• Fig. 38.1

  Mechlorethamine (structure shown in top panel) is the first chemotherapeutic alkylating agent and is an analog of the WWI chemical warfare agent mustard gas. The picture (shown in the bottom panel) is a sobering illustration of the toxicity of these compounds, depicting British soldiers suffering the effects of mustard gas. It initially causes blistering to exposed surfaces (e.g., skin, eyes, lungs) and subsequently produces profound bone marrow and lymphatic cell suppression. (Photo: Military.com by Joseph V. Micallef.)

primary mechanism by which they damage DNA. One group causes DNA alkylation, and another damages DNA by inhibiting topoisomerase II and by generating oxygen free radicals (Fig. 38.4). The boundaries are not sharp and some crossover exists—for example the aminoquinones alkylate but also produce oxygen free radicals. The importance in the distinction lies in the cardiotoxicity of the agents that produce free radicals. The antitumor antibiotics that alkylate DNA show few long-term end-organ effects, whereas those that generate oxygen free radicals (e.g., the anthracyclines) are probably the most frequently cited and well-studied class of cardiotoxic anticancer agents.10 (Table 38.4) Antineoplastic antibiotics are often used to treat breast and bladder cancers as well as leukemias and lymphomas. Many cause acute cardiotoxicity (arrhythmias, hypotension, decreased contractility) within a week of initiation of therapy as well as chronic cardiotoxicity that can develop late. The mechanism of the late cardiotoxicity is cardiomyocyte apoptosis largely owing to oxidative stress induced by reactive oxygen species (free radicals) generated intracellularly. Oxygen free radicals are generated within mitochondria and by a second pathway involving intracellular iron complexes. The heart is rich in mitochondria and has relatively poor ability to rid itself of oxygen free radicals. Cardiotoxicity is further amplified by topoisomerase inhibition in the cardiomyocyte that alters calcium channel activity.10 Acute cardiomyocyte injury from anthracyclines (e.g., doxorubicin (Adriamycin and daunorubicin) is associated with elevated serum troponin levels.

Acute doxorubicin toxicity is reversible, whereas subacute or chronic injury is irreversible. Acute, subacute, and chronic toxicity are related to the cumulative dose administered. The incidence of cardiomyopathy is about 4% when the cumulative dose is 500 to 550 mg/m2, 18% at 550 to 600 mg/m2, and 36% at greater than 600 mg/m2.11 Toxicity peaks at about 1 to 3 months after treatment and presents as biventricular congestive heart failure. Chest or mediastinal radiation, a previous history of cardiac injury, hypertension, and coadministration of other cardiotoxic chemotherapeutics (e.g., trastuzumab) increase the incidence of chronic cardiomyopathy. Late-onset dilated or restrictive cardiomyopathy can present years or decades after anthracycline treatment and can be first revealed during exposure to the myocardial-depressant effects of anesthetics.12,13 In addition, the biventricular failure has been shown to be poorly responsive to inotropes in animal models.14 Analogs of the polycyclic aromatic antibiotics have been developed with the goal of decreasing the cardiotoxicity associated with anthracyclines (Table 38.5). Other important antineoplastic antibiotics include the enediynes, actinomycin D (dactinomycin), and bleomycin. The enediynes include antibiotics that are produced by species other than Streptomyces. They damage DNA by oxidation (binding the DNA backbone and removing hydrogens), cleaving the DNA strands. They are highly toxic and their poor selectivity for cancer cells limits their current use. This might be overcome

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TABLE 38.2  Alkylating Agents by Subclass

Triazines and Hydrazines

Ethyleneimines

Alkyl Sulfonates

Platinum Drugsa

Dacarbazine

Thiotepa (Thioplex)

Busulfan

Cisplatin

Carmustine (BCNU, BiCNU)

Temozolomide

Hexamethyl-melamine (HMM, altretamine, Hexalen)

Treosulfan

Carboplatin

Cyclophosphamide (Cytoxan)

Chlorozotocin

Procarbazine

Mannosulfan

Oxaliplatin

Melphalan (Alkeran)

Ethylnitrosourea (ENU)

Nedaplatin

Ifosfamide (Ifex)

Fotemustine

Satraplatin

Trofosfamide

Lomustine (CCNU)

Triplatin tetranitrate

Estramustine

Nimustine N-nitroso-N-methylurea (NMU) Ranimustine (MCNU) Semustine Streptozocin

Nitrogen Mustards

Nitrosureas

Mechlorethamine

Arabinopyranosyl-N-methyl-N-nitrosourea (Aranose)

Chlorambucil

a

Platinum-based agents do not literally alkylate but act like the other agents by binding to the guanine residue in DNA.

Your days of uncontrolled replication are over!

TABLE 38.3  Antimetabolites

Folate Analog

Pyrimidine Analogs

Purine Analogs

Methotrexate

5-Fluorouracil Floxuridine Capecitabine Gemcitabine Cytarabine (Ara-C)

6-Mercaptopurine Azathioprine 6-Thioguanine

Guanine CH3

Guanine

N

5-Fluorouracil

Uracil

O

O F

HN O “The Alkylator”

• Fig. 38.2

Alkylating agents can bind to a single nucleotide leading to DNA fragmentation or can crosslink two nucleotides halting replication by essentially “hand-cuffing” the DNA. The cartoon shows DNA “handcuffed” when an alkylating molecule crosslinks its guanine nucleotides. To simplify the cartoon, the hand-cuffs are shown crosslinking two opposing guanine nucleotides. In actual DNA molecules, guanine pairs with cytosine. The guanine nucleotides crosslinked by alkylating agents are in the same strand of DNA, not directly opposed.  

N H

H

H

HN O

N H

H

• Fig. 38.3  Antimetabolites are molecular analogs similar enough to be incorporated into enzymatic pathways but different enough to disrupt the outcome. 5-fluorouracil is an analog of uracil and differs from it by a single fluorine atom. It inhibits thymidylate synthetase, thereby interfering with DNA synthesis; it also is incorporated into ribonucleic acid (RNA), which damages RNA’s ability to synthetize proteins.

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•• • • •• O O = O2 = Oxygen •• • • •• + e–

TABLE 38.4  Antineoplastic Antibiotics

•• • • •• • O O = O2– = Superoxide anion •• • • •• + e– •• • •• O• • O • = O2–2 = Peroxide •• • • ••

757

Add hydrogen

Reduced by catalase and glutathione peroxidase

Alkylate DNA

Alkylate and Produce Oxygen Radicals

Inhibit Topoisomerase Type II and Produce Oxygen Radicalsa

Adozelesin

Mitomycin C

Anthracyclinesb

Actinomycin D (Dactinomycin)

Bizelesin

Streptonigrin

Anthracenedionesc

Fostriecin

Brostallicin

Anthrapyrazoles

Bleomycin

Carzelsin

Enediynesd

CC-1065

Miscellaneous

Reduced by superoxide dismutase •• •• H ••O •• O •• H •• •• Hydrogen peroxide

• •• O •H •• • Hydroxyl radical

•• H •• O •• H •• Water

• Fig. 38.4

  Oxygen free radicals. A free radical is “an especially reactive atom or group of atoms that has one or more unpaired electrons.” Oxygen free radicals, also known as reactive oxygen species (ROS), occur when oxygen is used in a cell but is incompletely reduced to water. Oxygen free radicals, like peroxide, have an unpaired electron in their outer orbit that can destructively interact with lipid membranes, causing lipid peroxidation, or can similarly harm proteins and DNA. Cellular defenses against ROS include the enzymes superoxide dismutase, which catalyzes the reduction of the superoxide radical to oxygen and hydrogen peroxide; catalase, which catalyzes the reduction of hydrogen peroxide; and glutathione peroxidase, which catalyzes the reduction of hydrogen peroxide and the hydroxyl radical to water. Cardiomyoctes are rich in mitochondria (key cellular sites for the production of hydrogen peroxide) and are relatively lacking in catalase.50 This makes them particularly susceptible to injury by oxygen free radicals. (“Free Radical” Merriam-Webster.com Merriam-Webster, n.d. Web. 28 July 2018.)

in the future by conjugating these compounds to tumor-targeting entities such as monoclonal antibodies (MAbs). Actinomycin D disrupts DNA transcription by binding to DNA at transcription initiation sites and preventing elongation by RNA polymerase. It can cause liver toxicity, specifically hepatic veno-occlusive disease and clotting disorders, that might not manifest for days after treatment ends. Bleomycin interacts with iron to produce oxygen free radicals. It is inactivated by the enzyme aminohydrolase (bleomycin hydrolase) that is found throughout the body except in the skin and lungs. Because of the scarcity of aminohydrolase in the skin, approximately 20% of patients receiving bleomycin therapy develop painless flagellate hyperpigmentation in their skin.15 In the lungs, where aminohydrolase activity is particularly low, alveolar epithelial cells accumulate bleomycin. Bleomycin injures the pulmonary endothelium, causing increased capillary permeability and edema, and the edema leads to even greater accumulation of bleomycin. Necrosis of the type I alveolar epithelium stimulates increased migration of macrophages, which recruit additional inflammatory cells that release oxygen radicals and stimulate fibroblast activity.16 Exposure to high oxygen concentrations as part of operative anesthesia has been associated with potentiation of bleomycin pneumotoxicity and acute respiratory distress syndrome. A report of the deaths of five patients with acute respiratory distress syndrome–like symptoms after surgical procedures involving exposure to approximately 40% inspired oxygen concentrations 6 to 12 months after bleomycin treatment led to this association.17 This led to a recommendation to limit supplemental oxygen to

Other Antineoplastic Antibiotics

Duocarmycins Mithramycin A Tallimustine a The underscored text represents subcategories of the antineoplastic antibiotics as listed in Table 38.5. b Acute cardiotoxicity includes arrhythmias, hypotension, and depression of contractility. Chronic toxicity results in cardiomyocyte apoptosis and can manifest a year or longer after exposure as congestive heart failure refractory to inotrope therapy. c Developed to have less cardiotoxicity d Produced by species other than Streptomyces. They are toxic but poorly selective for cancer cells, so current efforts are underway to conjugate these compounds with tumor-targeting molecules such as monoclonal antibodies.

<30%, or as necessary to maintain oxygen saturation as measured by pulse oximetry (SpO2) at 90% or above. Subsequent studies have identified other risk factors, including excessive intraoperative intravenous (IV) fluids and transfusions,18 preexisting renal failure, preexisting pulmonary disease, and tobacco use.18,19 Proximity to bleomycin infusion might be more important than high inspired oxygen concentrations, but minimizing inspired oxygen (<30% if possible) remains an important anesthetic guideline for reducing postoperative pulmonary complications.20 When anesthetizing patients who have been exposed to antineoplastic antibiotics, four points should be considered: 1. Subclinical asymptomatic cardiomyopathies can exist despite normal resting cardiac function.13 These can be unmasked by anesthesia. 2. If congestive heart failure manifests, it is often refractory to inotrope therapy.14 3. Actinomycin D can cause hepatotoxicity and coagulation abnormalities. 4. Bleomycin pulmonary fibrosis can be potentiated by exposure to elevated inspired oxygen, by excessive IV fluids, and by blood transfusions.18

Topoisomerase Inhibitors Topoisomerase enzymes are important for the proper activity of RNA and DNA polymerase. Polymerases separate DNA strands to transcribe base codes (whether to produce messenger RNA [mRNA] and proteins or to duplicate DNA in preparation for cellular division). As the polymerase separates segments of DNA, the remaining portion of the strands becomes more densely coiled (Fig. 38.5). Topoisomerase enzymes cleave the hypercoiled segments

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TABLE 38.5  Antineoplastic Antibiotics That Inhibit Topoisomerase Type II and Produce Oxygen Radicals

Anthracyclines

Anthracenediones

Anthrapyrazoles

Enediynes

Doxorubicin (Adriamycin, Doxil, Myocet)

Mitoxantrone

Losoxantrone

Calicheamicin

Daunorubicin

Ametantrone

Teloxantrone

Esperamicin

Idarubicin

Pixantrone

Piroxantrone

Dynemicin

Amrubicin

Kedarcidin

Epirubicin

Maduropeptin

Valrubicin

Neocarzinostatin

Pirarubicin

Lidamycin

Berubicin Carubicin Esorubicin Detorubicin Duborimycin Zorubicin Aclarubicin

of DNA, relax the DNA strands, and then reattach the cleaved ends, thereby allowing the transcription to progress. There are two classes of topoisomerase enzymes separated by whether they cleave one strand of the DNA (topoisomerase type I) or both strands (topoisomerase type II) as they relieve the hypercoiled state of the native DNA. Inhibitors of topoisomerase are specific to type I or type II. The two most common topoisomerase type I inhibitors are the camptothecin derivatives topotecan and irinotecan. Topotecan is used in the treatment of ovarian cancer, small cell lung cancer, cervical and renal cell cancers, as well as leukemias and lymphomas. Irinotecan is used for colorectal cancers. The major adverse effects include immunosuppression and, especially with irinotecan, diarrhea. Diarrhea from irinotecan can be severe, and anesthetists might anticipate hypovolemia, metabolic acidosis, and hypokalemia after recent treatments. Among the most common topoisomerase II inhibitors are the epipodophyllotoxins (extracted from the mandrake plant, the most common example being etoposide), and the group of antineoplastic antibiotics mentioned earlier (e.g., Adriamycin). The major risk of the type II topoisomerase inhibitors is related to the fact that they also produce oxygen free radicals, as previously described for the anthracycline antibiotics, leading to cardiotoxicity (Table 38.6).

Drugs That Suppress Proliferation: Microtubule-Binding Agents Microtubules are part of the cytoskeleton of cells. They are filamentous proteins that form long polymers, composed of α- and β-tubulin heterodimers. They provide basic organization of the cytoplasm, including the positioning of organelles, the moving of vesicles and granules, and packaging work within the mitochondria

(Fig. 38.6). Their activity is critical in actively dividing cells as they create the mitotic spindle that helps segregate chromosomes during cellular division. Disruption of microtubule function prevents cellular proliferation. The microtubule-binding agents do not distinguish between tubulin activity in mitosis and tubulin activity that transports synaptic vesicles (packages of neurotransmitter prepared for release in neurons) or tubulin activity within the Golgi apparatus involved in packaging proteins into vesicles. Thus the disruption of microtubule dynamics can diminish neurotransmitter preparation and delivery in nonproliferating cells; this often manifests as neurotoxicity. Microtubule activity is also important in cell migration. Inhibition of tubule activity suppresses cell migration by vascular endothelial cells. This produces a favorable antiangiogenic side effect, starving potential metastases of needed blood supply. Medications that affect the microtubules are classified into two major groups based on whether they disrupt function by stabilizing or destabilizing the microtubule apparatus within cells (Table 38.7). The taxanes (e.g., paclitaxel [Taxol]), originally isolated from the bark of the Pacific yew tree, stabilize microtubules and act principally by binding to guanosine diphosphate–bound tubulin. This impedes dynamic polymerization and depolymerization and halts the conveyer-like activity that the cell depends on for cytoplasmic transport and cell division. In addition, paclitaxel induces apoptosis by binding to the apoptosis inhibitor protein Bcl-2 (B-cell lymphoma 2). Docetaxel is a second-generation partially synthetic taxane that not only stabilizes tubulin, but also inhibits vascular endothelial growth factor (VEGF). It also displays immunomodulatory and proinflammatory activity. The tubulin stabilizers cause dividing cells to stall in the most radiosensitive phase (G2/M) of the cell cycle, and therefore may be used as adjuncts for radiation therapy.21

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During transcription or replication, polymerases separate DNA strands causing adjacent segments to become supercoiled. as strands pull apart

I I X X

X X

Topoisomerase cleaves DNA, unwinds one twist, and reattaches the cleaved ends. Without topoisomerase the coiling becomes too tight for polymerase to act.

I I

So much tension! Let me help you unwind.

OTOP RASE E M ISO

“the Inhibitor” We are shutting this place down!

PO E TO RAS E M ISO

• Fig. 38.5

  During transcription or replication, polymerases separate DNA strands causing adjacent segments to become tightly supercoiled. The drawing depicts the action of topoisomerase, which cleaves tightly coiled DNA, then reattaches the ends with one twist removed. The cartoon shows topoisomerase working hard to relax a tight DNA. When a topoisomerase inhibitor like adriamycin enters the scene, the DNA supercoiling cannot be relaxed thereby blocking transcription and replication.

The vinca alkaloids, originally extracted from leaves of the Madagascar periwinkle plant, destabilize microtubules and cause depolymerization. Vinca is the Latin name for the periwinkle genus. Alkaloids are secondary metabolites (organic compounds, often with a defense role, not directly involved in the normal growth, development or reproduction of plants, bacteria, and fungi) and are so named because of the alkalinity of the extracted compounds. Similar to the taxanes, exposure to the vinca alkaloids leads to significant neuronal dysfunction and subsequent peripheral neuropathies, loss of deep tendon reflexes, cranial nerve paralysis (especially cranial nerve VI, the abducens nerve). They cause wasting and paresis of extensor muscles, depression, convulsions, and hallucinatory psychoses. Generalized sensory and motor dysfunction can persist indefinitely after termination of therapy. For patients who have received microtubule inhibitors, anesthetists should be aware of potential motor and sensory neuropathies, and the role they may play in the use and monitoring of depolarizing and nondepolarizing muscle relaxants. Wasting and paresis of

extensor muscles may increase fall risk. In addition, partial palsy of the cranial nerves may lead to double vision, disconjugate gaze, hoarseness, facial palsies, or other symptoms that might be misinterpreted as cerebral ischemia. Previously unnoticed neuropathies may be unmasked in the postoperative period owing to residual anesthetic or neuromuscular blockade effects.

Molecular Therapies, Growth Inhibitors, and Targeted Therapies The classical approach to fighting cancer has focused on poisoning rapidly dividing cells, an effective but nonspecific attack against dysfunctional cellular proliferation, one of the hallmarks of malignancy. Chemotherapeutics that damage rapidly dividing DNA, interfere with RNA synthesis, or interrupt cell division by hindering microtubule function are limited by (1) the collateral damage they cause to normal cells and (2) cancer cell mutations that defeat the effectiveness of the poison. Other hallmarks of malignant cells

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TABLE 38.6  Topoisomerase Inhibitors

TABLE 38.7  Microtubule Binding Agents

Type I

Type II

Tubulin Stabilizers

Camptothecan (causes severe cystitis)

Podophyllotoxins 1. Etoposide 2. Teniposide

Topotecan (FDA approved for ovarian cancer)

Amsacrine

Gimatecan

Antineoplastic antibiotics: Anthracyclines 1. Daunomycin (Daunorubicin) 2. Doxorubicin (Adriamycin) 3. Epirubicin 4. Detorubicin 5. Carubicin 6. Idarubicin 7. RTA 744 Anthracenediones (mitoxantrone) Anthrapyrazoles 1. Teloxantrone 2. Piroxantrone Dactinomycin Fostriecin Streptonigrin

1. Taxanes a. Taxol b. Docetaxel c. Larotaxel d. Ortataxel e. TPI 287 2. Epothilones 3. Rhazinilam 4. Eleutherobin 5. Peloruside A 6. Laulimalide

Irinotecan (nausea/vomiting, severe diarrhea)

Quinoxalines 1. Chloroquinoxaline 2. XK469

Second-generation camptothecan derivatives 1. Lurtotecan 2. Exatecan 3. Rubitecan

Asulacrine isethionate

Third-generation camptothecan derivatives 1. Diflomotecan

Razoxane

Stealth-CKD602

Elliptinium

Karenitecin

Amonafide

Indolocarbazoles 1. Rebeccamycin 2. NB-506 3. Edotecarin 4. AT2433 5. Lamellarins

Batracylin

Indenoisoquinoline

include robust survival (self-sufficiency in growth signals and insensitivity to anti-growth signals), ability to invade and metastasize, initiate and sustain angiogenesis, and evade normal apoptosis pathways.22 Targeted therapies focus on molecular level functioning (or malfunctioning) of intracellular regulatory processes that activate or inactivate proteins involved in controlling these hallmarks of malignancy. Given the rapid expansion of medications in this category, including monoclonal antibodies (mAb), kinase inhibitors,

Tubulin Destabilizers 1. Alkaloids a. Indoles i. Vinca alkaloids 1. Vinblastine 2. Vincristine 3. Vindesine 4. Vinorelbine 5. Vinflunine ii. Colchicine alkaloids 1. Colchicine 2. Demecolcine 3. Trimethylcolchicinic acid b. Quinolones and isoquinolones c. Pyrrolidines d. Pyridines and piperidines e. Pyrrolizidines and quinolizidines f. Purines g. Terpenoids 2. Benzoylphenylureas

and other enzymatic pathway blockers, these drugs are considered broadly by mechanism of action. Although these molecules are considered “targeted therapies” and are more specific in their action on proteins identified with cancer cells, it is important to be aware that the proteins that are targeted may also have roles in normal cells. For instance, kinase inhibitors and mAbs can damage cardiac myocytes. They can cause prolongation of the QT interval resulting in arrhythmias, and cause myocyte apoptosis resulting in cardiomyopathies and congestive heart failure. The targeting of epidermal growth factor receptor (EGFR, a transmembrane tyrosine kinase) serves as an example of how mAbs and tyrosine kinase inhibitors (TKIs) can be used to disrupt malignant activity. Other growth factor receptors have also been identified as protein targets where inhibition can similarly suppress malignant activity. These growth factor receptors are vascular endothelial growth factor (VEGF, which controls blood vessel development); platelet-derived endothelial growth factor (PDGF, which controls blood vessel development and cell growth); insulinlike growth factor (IGF, which activates signaling pathways that ultimately result in cell proliferation and resistance to apoptosis); and fibroblast growth factor (FGF, which controls cell growth). In humans, the epidermal growth factor receptor (EGFR) is known as the human epidermal receptor (HER) and is homologous to a viral oncogene first identified in the late 1970s called erythroblastic

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Tubulin dimer α-Tubulin

β-Tubulin

Microtubule Cross-section

A

B Mitochondrion Perikaryon Lysosome Microtubule

Multivesicular body

Nucleus

Rough endoplasmic reticulum

Axon end

Transport vesicle Golgi

C • Fig. 38.6

  Microtubules are part of the cytoskeleton of cells and are involved in organizing and separating chromosomes during cell division, moving vesicles and granules within the cell, and promoting cellular migration. Panel A is a simplified diagram of the microtubule built by the polymerization of alpha and beta tubulin dimers; Panel B is a flourescence microscopy image (Michael Davidson, Florida State University, 2015) showing the role of the mirotubules (stained green) in a dividing cell. Panel C illustrates another critical function of microtubules, the delivery of neurotransmitter packed vesicles to the axonal synapse. Microtubule binding agents like the vinca alkaloids indiscriminately disrupt all of the microtubule activities and result in toxicities such as peripheral neuropathies, loss of deep tendon reflexes, cranial nerve (VI) paralysis, and neuromuscular wasting.

leukemia viral oncogene (ErbB). There are four closely related members in this receptor family and they are named by convention EGFR/ErbB-1 (or just EGFR), HER2/ErbB-2 (or just HER2), HER3/ErbB-3, and HER4/ErbB-4. These receptors sit in the cell wall with an extracellular binding area that responds to ligands such as epidermal growth factor, transforming growth factor-α, and neuroregulin (Fig. 38.7). Following the protein inward, there is a hydrophobic transmembrane section, and then, within the cell, an intracellular portion that catalyzes the phosphorylation of tyrosine

residues in proteins (i.e., tyrosine kinase). Adding phosphate to a tyrosine residue in a protein acts to turn on (or turn off) that protein’s activity that then affects a multitude of basic cellular activities, including growth, survival, proliferation, adhesion, migration, differentiation, and apoptosis.23 Preclinical studies showed that artificially activating EGFR promotes multiple tumorigenic processes, including stimulating proliferation, angiogenesis, and metastasis, as well as protecting cells from apoptosis.24 These receptors are normally present in all eukaryotic cells, but many types of solid tumors exhibit

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EGF

EGFR

Monoclonal antibodies act here

Cell membrane

Phosphorylation

Intracellular signaling proteins

Intracellular signaling cascade

Tyrosine kinase inhibitors act here Intracellular signaling proteins

Cell proliferation, angiogenesis, inhibition of apoptosis

Nucleus

• Fig. 38.7  Epidermal growth factor receptor (EGFR) is one of a family of closely related receptor tyrosine kinsases. EGFR is a transmembrane protein that has an extracellular binding area, a hydrophobic transmembrane section, and an intracellular portion where its tyrosine kinase activity turns on or shuts down various cellular activities through phosphorylation mediated intracellular signaling. Epidermal growth factor (EGF) is the natural ligand that activates the receptor. Chemotherapeutic agents can target the ligand or any portion of the receptor. Monoclonal antibodies are typically aimed at the extracellular portion while the tyrosine kinase inhibitors interfere with the intracellular kinase signaling domain. elevated levels of EGFR, elevated activity of EGFR, and/or elevated presence of EGFR ligands. Cancers that overexpress EGFR are often aggressive and are associated with poor patient outcomes. Anticancer strategies focused on EGFR may target the extracellular portion or the intracellular portion of the kinase. Extracellular inhibitors bind either to the ligands of the receptors or to the receptor itself. Binding the receptor itself not only creates a blockade, but also initiates endocytosis of the receptor, bringing the receptor and antibody into the cell, and eliminating the receptor’s presence and activity. In addition, receptor endocytosis creates an opportunity to design a “poison pill” or “magic bullet.” Toxic substances (e.g., chemotherapy or radioactive particles) can be attached to an antibody designed to bind to an extracellular receptor. The toxic substance is taken into the cell (along with the receptor) by endocytosis, killing the targeted cell. Tyrosine kinase inhibitors (by convention given names ending in “-nib”) target the intracellular portion of the kinase and block EGFR from adding phosphoryl groups from adenosine triphosphate ATP to proteins (specifically to tyrosine residues) (Table 38.8). The TKIs produce significantly less severe adverse effects compared with conventional chemotherapy drugs. Side effects include fatigue, diarrhea, rashes, anorexia, and anemia. Interstitial lung disease is a rare complication with gefitinib and erlotinib, but when it occurs about one-third of the cases are fatal.25 Lapatinib may rarely cause

cardiotoxicity or liver damage manifesting as late as several months after treatment. Some kinase inhibitors (e.g., pazopanib, vandetanib, and nilotinib) cause QT prolongation and elevate risk for torsades de pointes. Patients receiving these kinase inhibitors will likely be monitored with serial electrocardiograms by their oncology teams. Perioperative medications known to prolong QT intervals should be used judiciously. Other small molecule enzyme pathway inhibitors and examples of each include proteasome inhibitors (bortezomib), mechanistic target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus), phosphoinositide 3-kinase inhibitors (idelalisib), histone deacetylase inhibitors (vorinostat, belinostat, panobinostat), and hedgehog pathway blockers (vismodegib).

Monoclonal Antibodies MABs are laboratory-produced antibodies that bind to specific cellular antigens, such as a protein present on the surface of cancer cells but absent from (or expressed at lower levels by) normal cells. MABs are made by injecting a mouse with a specific human antigen of interest, harvesting from the mouse’s spleen the B cells producing the antibody to the antigen, and then fusing those cells with immortal myeloma cells in vitro. The resulting hybridoma (fused B-cell and myeloma cell) undergoes repeated mitosis and is cultured

CHAPTER 38  Chemotherapy, Immunosuppression, and Anesthesia



into a community of identical cells (clones), all producing the single desired antibody. The resulting mouse antibodies are made less immunogenic (less foreign) by grafting the important portions onto human antibody segments. The antibody is classified differently depending on how much of the mouse antibody has been substituted with human antibody (Fig. 38.8). If the constant region (Fc) is human and the antigen-binding region (Fab) is mouse, the antibody is classified as “chimeric.” If in addition, part of the variable region is human, the antibody is classified as “humanized.” By convention, the names given to the resulting antibodies identify the antibodies as monoclonal, describe their status as “mouse,” “chimeric,” “humanized,” or “fully human,” and identify their target tumor site. The naming convention works from the back of the name to the front. Monoclonal antibody names all end with “-mab”. Preceding “mab” is either “o” for mouse, “xi” for chimeric, “zu” for humanized, or “u” for human. The letters immediate preceding o, xi, zu, or u identify the target of the antibody. For example, “-ci-” is used for an antibody targeting the circulation, “-li-” for lymphocyte (immune system), “-ne-” for nervous system, “-mul-” for musculoskeletal, and a “-tu-” for multiple tumor types. The

TABLE 38.8  Tyrosine Kinase Inhibitors

Generic Name

Proprietary Name

Tyrosine Kinase Targets

Afatinib

Gilotrif

EGFR, HER2

Axitinib

Inlyta

VEGFR, C-KIT, PDGFR, BCR-ABL

Bosutinib

Bosulif

BCR-ABL, SRC

Cabozantinib

Cabometyx

VEGFR2, C-MET

Crizotinib

Xalkori

C-MET, ROS1

Dasatinib

Sprycel

BCR-ABL, SRC

Erlotinib

Tarceva

EGFR

Gefitinib

Iressa

EGFR

Imatinib

Glivec

BCR-ABL, C-KIT, PDGFR

Lapatinib

Tyverb

EGFR, HER2/NEU

Nilotinib

Tasigna

BCR-ABL, KIT, PDGFR, DDR, and others

Pazopanib

Votrient

FGFR, PDGFR, VEGFR, C-KIT and others

Regorafenib

Stivarga

VEGFR2-TIE2, and others

Sorafenib

Nexavar

VEGFR, PDGFR, C-RAF

Sunitinib

Sutent

PDGFR, VEGFR, C-KIT, and others

BCR-ABL, Fusion gene also known as the Philadelphia chromosome; C-KIT, also known as CD117 and stem cell growth factor receptor; C-MET, mesenchymal epithelial transition factor. also known as hepatocyte growth factor receptor, C-RAF, proto-oncogene, serine/threonine kinase; DDR, DNA damage responsive; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; HGFR, hepatocyte growth factor receptor; PDGFR, platelet-derived growth factor receptor; ROS1, c-ros oncogene 1; SRC, a nonreceptor tyrosine kinase first identified as causing sarcomas in chickens; TIE2, tyrosine kinase with immunoglobulin-like and EGF-like domains (also called TEK: tyrosine kinase, endothelial); VEGFR, vascular endothelial growth factor receptor.

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manufacturer selects the first few letters to individualize the final name. So, cetuximab (ce-tu-xi-mab) (reading from the back of the name) is a monoclonal antibody, chimeric, attacking multiple tumor types. Bevacizumab (beva-ci-zu-mab) is a monoclonal antibody, humanized, attacking circulation (antiangiogenic) (Table 38.9). The World Health Organization passed a revised nomenclature scheme dropping the source component of the name for monoclonal antibodies named after 2017. The intent is to simplify the names and allow more distinctive, less same-sounding, names. (World Health Organization International Nonpropriietary Names Programme, INN Working Doc.17.416, May 2017.) MAbs have been made to target (bind to) ligands (the molecular messenger) that stimulate tyrosine kinase receptors—for example, bevacizumab (Avastin) binds to vascular endothelial growth factor A (VEGF-A). Other MAbs target the extracellular receptor portions of transmembrane kinases—for example, trastuzumab (Herceptin) and pertuzumab (Perjeta) bind to the extracellular receptor portion of HER2, which is overexpressed in 25% to 30% of breast cancers. In another example, cetuximab (Erbitux) and panitumumab (Vectibix) bind to the receptor portion of EGFR. Binding the receptor decreases the aberrant activity of these kinases and leads to endocytotic removal of the protein from the cellular surface. Other MAbs are designed to target protein antigens uniquely expressed, or overexpressed, on the surface of malignant cells. For example, rituximab (Rituxan) binds to the protein antigen CD20 primarily found on the surface of B cells. Once bound, it

VH CH1

Heavy chain

VL CL

Light chain

CH2 CH3 Mouse -omab

Humanized -zumab

Chimeric -ximab

Human -umab

Mouse sequences

Human sequences

Glycosylation

Complementarity determining regions

Nature Reviews Cancer

• Fig. 38.8  Drawing of simplified mouse monoclonal antibodies with the substitutions that would change antibodies to chimeric, humanized, or human. CH, constant domain of heavy chain of immunoglobulin M; CL, constant domain of light chain of immunoglobulin M; VH, variable domain of heavy chain; VL, variable domain of light chain.

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TABLE Derivations of Names of Monoclonal 38.10  Antibodies

TABLE 38.9  Monoclonal Antibodies

Generic Name

Brand Name

Site of Action

Prefix

Bevacizumab

Avastin

VEGF-A

Choice

Cetuximab

Erbitux

EGFR-1

Panitumumab

Vectibix

EGFR-1

Trastuzumab

Herceptin

HER-2

Pertuzumab

Perjeta

HER-2

Nimotuzumab

EGFR-1 BIOMAb EGFR, Theracim, Theralo, Taixinsheng

Rituximab

Rituxan

CD20 on B cells

Ofatumumab

Arzerra

CD20

Others

Oregovomab

OvaRex

Target

Source a

=

rat

axo

=

e i o u xi

= = =

mul

cardiovascular fungal growth factor interleukins immunomodulating musculoskeletal

rat/mouse hybrid hamster primate mouse human chimeric

n(e) s(o) tox(a) t(u) v(i)

neural bone toxin tumors virus

zu

anibi b(a) c(i) f(u) gr(o) k(i) l(i)

angiogenesis inhibitor = bacterial = = = =

xizu

Suffix -mab

chimeric/ humanized hybrid humanized

CD22, CD33 (myelomonocytes), CD2 (T lymphocytes), CD52 IGF-1R GD2

Example: Avastin is bevacizumab (beva-ci-zu-mab), an angiogenesis inhibitor

CA125

beva

CA125, Cancer antigen 125; CD, cluster of differentiation; EGFR, epidermal growth factor receptor; GD2, ganglioside G2; HER-2, human epidermal growth factor receptor 2; IGF-1R, insulin-like growth factor 1 receptor; VEGF, vascular endotheliat growth factor.

induces antibody-mediated and complement-mediated cytotoxicity and marks the cells for attack by the T lymphocytes (Table 38.10). The infusion of MAbs can be expected to result in immediate flulike symptoms (that can be attenuated by pretreatment with steroids and antihistamines) and occasional anaphylaxis. MAbs can also cause long-term effects in the lungs (pulmonary fibrosis), in the liver as immune-mediated hepatitis (inhibitors of cytotoxic T-lymphocyte antigen 4 [CTLA4] and programmed cell death protein 1/programmed death ligand 1 [PD-1/PD-L1]), in the kidney as proteinuria from VEGF agents such as bevacizumab, and rarely, the heart by HER-2–directed therapies such as trastuzumab, pertuzumab, and ado-trastuzumab emtansine. The mechanisms of organ injury are poorly understood.

Antimetastasis Therapy Additional new strategies for minimizing cancer spread include targeting cellular mechanisms upon which the cell depends for successful metastasis. Targets include receptor proteins and messaging ligands that direct the cell to migrate, adhere, break down the surrounding matrix in its new home, and grow new blood vessels to feed and nurture the new tumor location. Specific inhibitors at each of these steps represent new opportunities to foil cancer spread. Currently under investigation are peptide inhibitors and MAbs that targets integrin, a transmembrane receptor that plays a major role in the migration and adhesion of cells; matrix metalloproteinase, which encourages angiogenesis; or chemokine receptors, which are responsible for cellular migration. Inhibiting these cellular mechanisms suppresses cell-cell interactions, cell-matrix interactions, migration, and angiogenesis.

ci

(cardiovascular)

zu

(humanized) mab

General Pollicies for Monoclonal Antibodies. World Health Organization. INN Working Document 09.251 Distr.: Public English Only 24/06/2009 website: www.who.int/medicines/services/ inn/generalpoliciesformonoclonalantibodies2009.pdf.

Immunotherapy MAbs targeted to cell surface antigens can act to help the host immune system. Specifically, T cells and natural killer (NK) cells recognize and attack the targeted malignant cell. Reawakening this part of the immune system is beneficial to survival in immunogenic cancers (e.g., melanoma, lung, renal, and head and neck cancers). Targeted therapies as well as nonspecific antiinflammatories can act to suppress other aspects of the immunoresponse, quieting the part of the immune system that facilitates cellular adhesion and angiogenesis, thereby decreasing metastatic risk. These and other methods of manipulating the host immune response to cancer are termed immunotherapy. Suppressing one part of the immune system, the interleukins and other cytokines (i.e., the messaging portion of the inflammatory process), may help decrease tumor metastasis, whereas stimulating a different part of the immune system, the cellular portion of the immune system (i.e., T cells and NK cells) facilitates killing malignant cells. Adding surgery to the mix further increases the complexity. Surgical manipulation of the tumor during excision can release tumor cells into the circulation. Growth hormone, epinephrine, serotonin, cytokines, and other neurohumeral substances secreted in response to stress are all important in healing, but they may also promote the survival of metastatic tumor cells. Meanwhile, stress and anesthetics have been shown to suppress the cellular component of immunity, potentially impeding the body’s ability to handle and eliminate liberated cancer cells. Manipulating the immune system to improve patients’ chances for a disease-free outcome is a complex and often conflicting challenge, but could also be an opportunity for anesthesiologists to influence outcome.



CHAPTER 38  Chemotherapy, Immunosuppression, and Anesthesia

How Anesthetics Might Affect Cancer In 1959 Bernard and Edwin Fisher injected carcinosarcoma cells intraperitoneally into rats and then examined the rats 5 months later. They found no evidence of tumor growth unless they subjected the rats to laparotomy 3 months after the injection. All of the rats that underwent laparotomy developed tumors within weeks of the surgery.26 Several consequences of surgery may promote metastasis including: shedding of cancer cells during surgical manipulation, a decrease in antiangiogenesis factors, an increase in growth factors, and immunosuppression.27 In humans, additional interventions associated with surgery might also affect cancer spread at the time of surgical excision. For example, perioperative blood transfusions cause a degree of immunosuppression that might increase the risk of cancer recurrence. In contrast, the intraoperative administration of corticosteroids, also expected to suppress the immune system, was associated with improved survival in a retrospective study of Whipple procedures for pancreatic cancer.28 Anesthetics, stress, opiates, pain, hypothermia, hyperglycemia, and other factors within the control of the anesthesiologist are immune modulators and may have a role in increasing or decreasing the recurrence rate of cancer immediately after surgical excision. Tumor excision surgery might not be the only time the homeostatic balance between tumor growth and the immune system’s ability to suppress tumor growth is at risk for disruption. Subclinical concentrations of tumor cells may be present long after a cancer has been excised. Circulating tumor cells were detected in one-third of breast cancer patients after mastectomy without evidence of disease for up to 22 years.29 Thus control over residual circulating tumor cells or subclinical micrometastases (minimum residual disease in patients after surgical excision) could, in theory, be influenced by subsequent and unrelated surgeries and anesthetics. Multiple authors suggest that anesthesia may contribute to the recurrence of cancer,30,31 that technique and drug choice can interact with the cellular immune system and affect long-term outcome,32 and that the type of anesthesia could indirectly promote malignant cell development.33 Patients who present for surgical excision of their cancer often have potentially curable solid tumors Yet, metastatic recurrence after perceived complete resection is the major cause of death. The identification of anesthetic techniques that decrease the risk of metastatic and/or recurrent disease after surgery might positively affect disease-free survival. Evidence is accumulating that suggests certain anesthetic techniques might be beneficial to patients undergoing cancer excision operations. In the future, it may be possible to enumerate specific directives on how the perioperative period and the medications used may influence the reemergence or the suppression of residual cancer cells.

Opioids Pain has been shown to suppress immune function and to promote metastasis in rats, and analgesic treatment with morphine prevented this effect.34 However, morphine has also been shown to (1) suppress immune function (NK T-cell activity, phagocytosis, cytokine activity); (2) stimulate angiogenesis; (3) increase prostaglandins, (4) activate mu receptors on breast and lung cancer cells as well as on NK cells, and (5) activate non-mu norepinephrine transporter (NET)-1 receptors found on breast and gastric cancer cells. Morphine stimulates endothelial proliferation, cell cycle progression, and angiogenesis in vitro and in vivo, leading to enhanced tumor neovascularization in breast cancer. The morphine antagonist

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naltrexone has been shown in tissue culture to suppress ovarian cancer cell proliferation equivalently to Taxol or cisplatin with shortterm exposure, but to stimulate growth after long-term exposure (possibly as a result of upregulation of mu receptors over time).35 Clinical studies support the possibility that opioids (endogenous or administered) might influence the progression of cancer. More than 2000 women with breast cancer were categorized by the genetic makeup of their mu receptors—specifically, by the presence or absence of a polymorphism in the mu-receptor gene known as A118G. The mutation results in a less responsive receptor; that is, individuals with the A118G mutation experience less analgesia from opioids. Women with the less responsive mu receptor (A118G) were significantly less likely to die from their breast cancer within 10 years of their diagnoses.36 Studies comparing survival in cancer patients who received standard versus narcotic-sparing anesthetic regimens (e.g., regional blockade for analgesia) have yielded provocative yet inconsistent results. In a retrospective study, 50 patients who received paravertebral blocks had one-quarter the recurrence rate of breast cancer compared with 79 patients whose pain was treated with morphine patient-controlled analgesia.37 In another study 102 patients undergoing open radical prostatectomy received combined epidural-general anesthetics and were compared with 123 patients whose analgesic requirements were treated with opiates. The patients receiving opiates had twice the recurrence rate using prostate-specific antigen serum concentrations as a surrogate for recurrence.38 Reviewing medical records for postoperative opioid use in 99 patients who had undergone video-assisted thoracic surgical lobectomy for non–small cell lung cancer, investigators found a strong association between the dose of opioid and the rate of recurrence.39 Other retrospective studies have not found a difference,40 and studies yielding an association between improved outcomes and decreased opioid have not been replicated.

Volatile Anesthetics Volatile anesthetics have long been known to moderately suppress the immune system. Studies from as early as the 1970s investigated whether this suppression increased the risk of postoperative wound infection, and no correlation was identified. Whether or not this low-level immune suppression hinders the host’s ability to kill malignant cells liberated during surgical manipulation has become a question of contemporary interest. There have been mixed results in rat models. In one study melanoma tumor cells were injected into the tail veins of mice receiving either oxygen alone, or 1.3 MAC of halothane or isoflurane. Twenty-one days later the lungs were examined for metastatic nodules. The mice receiving isoflurane had over twice and the halothane group had three times the number of nodules as controls.41 In a similar study design using a different tumor cell line, rats exposed to halothane showed a nonsignificant increase in the number of lung metastases compared to controls.42 In a third study, the halothane group did not differ from controls, but when a sham surgical procedure was added the number of metastases more than doubled in the lungs of the rats.43

Propofol Propofol seems to have less or no immunosuppression effects. In a study on rats receiving 1 hour of propofol, halothane, ketamine, or thiopental anesthesia, only propofol did not suppress NK T-cell activity, and this correlated with a lower count of retained tumor cells in the lungs of rats receiving propofol compared with the other anesthetics.42 Mice inoculated with thymoma tumor cells

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were given subanesthetic concentrations of intraperitoneal propofol daily for 3 weeks and their cytotoxic T cells were harvested and tested for activity level. T-cell activity was enhanced compared with saline solution controls, and the tumor growth was suppressed during the study period.44 One study compared the effects of preoperative and postoperative blood serum on the growth of breast cancer cells in culture. Half of the women had been randomly assigned to receive a propofol infusion with paravertebral blocks for their breast cancer surgery; the other half received sevoflurane and morphine. The highest concentration of serum tested against the cultured breast cancer cells showed the postoperative serum suppressed cancer cell proliferation only for the patients who had received propofol. This finding was only at the highest concentration tested and did not extend to inhibiting migration or other cellular activity. Other differences between patients that might have contributed to an effect included lower pain scores, less opioid use, the addition of local anesthetic, and the absence of volatile anesthetic exposure in the propofol group.45

Local Anesthetics In vitro and animal data demonstrate direct tumoricidal activity and decreased metastatic risk with local anesthetics, and some retrospective human studies support the hypothesis that perioperative local anesthetic administration—whether subcutaneous, intravenous, or epidural— decreases the risk of tumor recurrence. Local anesthetics block voltage-gated sodium channels (VGSCs) in excitable cells. Tumor cells have been found to express an array of ion channels (including VGSCs) with subunit variants unique to the tumor. In vitro studies have shown the tumor variants of VGSCs are often more sensitive to lidocaine than those found on differentiated normal cells. Inhibiting the activity of VGSCs may decrease cellular metastatic behaviors like adhesion and migration, as well as impair proliferation.46 Independent of the VGSCs, local anesthetics appear to inhibit kinesin motor machinery and microtubule activity, inhibit inflammatory Src signaling, directly induce apoptosis in some tumor cells, and potentially inhibit potassium and calcium

channels in tumor cells.47 Rats injected intraperitoneally with breast adenocarcinoma cells showed significantly fewer metastases after surgical intervention when they received spinal bupivacaine before the surgery.43 Some retrospective studies in humans have supported improved survival when, for melanoma excision, local anesthetic was infiltrated into the skin48; for mastectomy local anesthetic was used to provide paravertebral blocks37; and for prostate surgery local anesthetic was administered epidurally.38 Attempts to reproduce these findings in humans have been inconclusive. If local anesthetics provide a survival benefit, it could be from direct effects on the cancer cells or indirect effects related to decreasing the stress response associated with otherwise painful stimuli, by decreasing perioperative opioid use, or by modulating inflammatory cytokines and shifting interleukin balances away from tumorigenic and toward tumoricidal.49

Other Factors Other factors within the control or manipulation of the anesthesiologist that influence stress response, perfusion, inflammatory response, and the immune system include β agonists, cyclooxygenase-2 (COX-2) inhibitors, ketamine, benzodiazepines, hypotension, hypovolemia, hypoxia, hypothermia, and allogenic blood transfusions. All of these factors in addition to ones previously mentioned are likely contributors to the complex milieu that either promotes tumor growth and survival, or inhibits tumor survival and proliferation. One day in the future the anesthesiologist may follow a protocol avoiding certain anesthetics and attending to the emotional and physical stress response with anxiolytics, steroids, COX-2 inhibitors, statins, β blockers, and peripheral or regional nerve blockade. The anesthesiologist might administer interleukins and other cytokines to stimulate NK cell activity, administer continuous systemic infusions of local anesthetic, and administer targeted angiostatins. Maintaining patient normothermia, avoiding hypotension, and avoiding hypoxia and hyperoxia may be shown to have as significant import on long-term tumor recurrence as on acute patient outcomes.

Key Points • Terminology reflecting chemotherapy timing in relation to surgical excision is as follows: a. Neoadjuvant: before surgical excision b. Adjuvant: after surgical excision c. Palliative: unrelated to timing of surgery • Alkylating agents suppress bone marrow and cause nausea, vomiting, and diarrhea. Additionally, the platinums cause neuropathies and cyclophosphamide may inhibit plasma pseudocholinesterase activity. • The anthracycline class of antineoplastic antibiotics is probably the most frequently cited and well-studied class of cardiotoxic anticancer agents. Oxygen free radicals are generated in the mitochondria. Cardiomyocytes are rich in mitochondria and are relatively susceptible to the toxic effects of reactive oxygen species. Cardiotoxicity is further amplified when topoisomerases are used with anthracyclines. • Cardiomyopathy from anthracyclines can present years or decades after exposure and may be poorly responsive to inotropes. • Bleomycin is inactivated by an enzyme that is scarce in alveolar epithelial cells. Thus bleomycin accumulates in alveolar cells

and via oxygen free radical generation causes injury, increased capillary permeability and edema, necrosis of type I alveolar cells, and pulmonary fibrosis. Exposure to high oxygen concentrations may potentiate this toxicity. Current recommendations are to limit supplemental oxygen to 30% or as necessary to maintain SpO2 of at least 90%. Judicious use of intravenous fluids, avoidance of blood transfusions, lung-protective ventilator management, and shorter surgical duration may also lower the risk of pulmonary fibrosis. • The microtubule inhibitors may cause motor and sensory neuropathies. • TKIs are small molecules that block the intracellular phosphorylation of proteins, the on/off switch for specific protein activity. TKIs cause significantly fewer side effects than conventional chemotherapy drugs. However, a subset can produce QT prolongation (e.g., pazopanib, vandetanib, and nilotinib). Patients are typically monitored with serial electrocardiograms by their oncology teams. Perioperative medications known to prolong QT intervals should be used judiciously.



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• Monoclonal antibodies are laboratory-produced antibodies that bind to specific cellular antigens, such as a protein present on the surface of cancer cells but absent from (or expressed at lower levels by) normal cells, extracellular receptors overexpressed in cancer cells, and/or the ligands that stimulate those receptors.

• Anesthetics, stress, opiates, pain, hypothermia, hyperglycemia, and other factors within the control of the anesthesiologist are immune modulators and may have a role in increasing or decreasing the recurrence rate of cancer after surgical excision. Future investigations are likely to define best anesthetic plans for specific cancers.

Key References

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Aakre BM, Efem RI, Wilson GA, et al. Postoperative acute respiratory distress syndrome in patients with previous exposure to bleomycin. Mayo Clin Proc. 2014;89:181–189. A retrospective cohort study of 316 Mayo Clinic patients exposed to bleomycin therapy and subsequent major surgery between the years 2000 and 2012. (Ref. 19). Gottschalk A, Sharma S, Ford J, et al. Review article: the role of the perioperative period in recurrence after cancer surgery. Anesth Analg. 2010;110:1636–1643. An overview of the ways perioperative anesthetic management could possibly influence cancer recurrence and metastasis. (Ref. 31). Huettemann E, Junker T, Chatzinikolaou KP, et al. The influence of anthracycline therapy on cardiac function during anesthesia. Anesth Analg. 2004;98:941–947. Echocardiography measurements during induction and maintenance of anesthesia indicate that previous treatment with anthracyclines may enhance the myocardial depressive effect of anesthetics even in patients with normal resting cardiac function. (Ref. 12). Koseoglu V, Chiang J, Chan KW. Acquired pseudocholinesterase deficiency after high-dose cyclophosphamide. Bone Marrow Transplant. 1999;24:1367–1368. A case report from MD Anderson Cancer Center of a child whose measured plasma pseudocholinesterase was severely depressed and whose recovery from succinylcholine was delayed for a surgery performed 9 hours after an infusion of cyclophosphamide. (Ref. 8). Lefrak EA, Pitha J, Rosenheim S, et al. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973;32:302–314. The cardiotoxic effects of Adriamycin were studied in 399 patients, concluding in a maximum dose recommendation of less than 550 mg/m2. (Ref. 11).

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