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Introduction
Cancer is the second leading cause of death in the United States, exceeded only by heart disease. The lifetime risk of developing cancer is estimated to be one in three for both men and women. The lifetime risk of dying from cancer is one in five. About 90% of patients with cancer require surgery for reasons both related and unrelated to the cancer diagnosis. Furthermore, approximately two-thirds of people diagnosed with cancer survive for at least 5 years, meaning that a growing number of patients will come to surgery in the context of or after cancer treatment.
The anesthetic implications of cancer stem not only from the cancer itself but also from the therapies employed for its treatment. In addition, since the median age at diagnosis is 66 years, patients with cancer often have comorbid conditions that affect their perioperative course.
Mechanism
Cancer results from an accumulation of genetic mutations, which causes dysregulation of cellular proliferation. Genes are involved in carcinogenesis by virtue of inherited traits that predispose to cancer (e.g., altered metabolism of potentially carcinogenic compounds), mutation of a normal gene into an oncogene that promotes the conversion of normal cells into cancer cells, or inactivation of a tumor suppressor gene thus triggering malignant transformation. A critical gene related to cancer in humans is the tumor suppressor p53 . This gene is not only essential for cell viability but critical for monitoring damage to deoxyribonucleic acid (DNA). Inactivation of p53 is an early step in the development of many types of cancer. Stimulation of oncogene formation by carcinogens is a major contributor to cancer development. It has been estimated that nine modifiable factors cause 35% of cancer deaths worldwide: smoking, alcohol, diets low in fruits and vegetables, obesity, inactivity, unsafe sex, urban air pollution, use of solid fuels, and contaminated injections in healthcare settings. About 20% of cancer deaths worldwide are attributable to tobacco.
The fundamental event that causes cells to become malignant is an alteration in their DNA structure. These mutations occur in cells of target tissues, with these cells then becoming ancestors of the entire future tumor cell population. Evolution to more undifferentiated cells reflects high mutation rates and contributes to the development of tumors that are resistant to therapy.
Cancer cells must evade the host’s immune surveillance system, which is designed to seek out and destroy tumor cells. Most mutant cancer cells stimulate the host’s immune system to form antibodies. This protective role of the immune system is apparent in those with acquired immunodeficiency syndrome (AIDS) and recipients of organ transplants who are maintained on long-term immunosuppressive drugs. These individuals have an increased incidence of cancer.
Diagnosis
Most cancers produce solid tumors. Cancer often becomes clinically evident when tumor bulk compromises vital organ function. The initial diagnosis is often made by aspiration cytology or biopsy. Monoclonal antibodies that recognize antigens for specific cancers may aid in the diagnosis of cancer. A commonly used staging system for solid tumors is the TNM system based on tumor size (T), lymph node involvement (N), and distant metastases (M). This system groups patients into stages ranging from best (stage I) to poorest (stage IV) prognosis. Tumor invasiveness is related to the release of various tumor mediators that modify the surrounding microenvironment in such a way as to permit cancer cells to spread along the lines of least resistance. Lymphatics lack a basement membrane so local spread of cancer is influenced by the anatomy of the regional lymphatics. For example, regional lymph node involvement occurs late in squamous cell cancer of the vocal cords because these structures have few lymphatics, whereas regional lymph node involvement is an early manifestation of supraglottic cancer because this region is rich in lymphatics. Imaging techniques, including computed tomography (CT) and magnetic resonance imaging (MRI), are used for further delineation of tumor presence and spread.
Treatment
Most cancers are treated by a multimodal approach involving surgery, radiation therapy, and/or chemotherapies that vary by tumor type and stage. The development of more effective treatments has dramatically improved cancer survival. However, use of these more powerful therapies is associated with toxicities and side effects that have the potential to affect nearly every organ system. Some of these effects are transient; others produce permanent sequelae. All of them have important potential consequences in the perioperative care of cancer patients.
Traditional chemotherapy
Traditional chemotherapy involves the use of cytotoxic agents that target rapidly dividing cells and interfere with replication. They are divided into classes based on mechanism of action: alkylating agents, antimetabolites, antibiotics, microtubule assembly inhibitors, hormonal agents, and various miscellaneous or mixed-mechanism drugs. Alkylating agents form reactive molecules that cause DNA cross-linking problems such as abnormal base pairing and strand breaks that interfere primarily with DNA but also ribonucleic acid (RNA) and protein synthesis and replication. Antimetabolites are structural analogs of folic acid, purines, or pyrimidines that block enzymes necessary for nucleic acid and protein synthesis. Antitumor antibiotics form complexes with DNA or RNA that inhibit their subsequent synthesis. Microtubule assembly inhibitors include the vinca alkaloids and taxanes, both of which act on the mitotic process by interfering with microtubule assembly or disassembly.
The growth of certain tumor types, notably breast and prostate, is responsive to hormonal agents. Hormones are not cytotoxic so they often stimulate tumor regression but do not cause cell death. Several other drugs have been shown to have anticancer properties. The epipodophyllotoxins act by inhibiting the topoisomerase II enzyme, which causes DNA strand breaks that lead to apoptotic cell death. The topoisomerase I inhibitors work by a similar mechanism but on a different enzyme.
Targeted chemotherapy
Targeted therapy involves a new set of chemotherapeutics directed against specific processes involved in tumor cell proliferation and migration. The first targeted therapy was that developed for estrogen receptors present with certain types of breast cancers. Binding of estrogen to estrogen receptors is an important step in the growth of these tumor cells, and estrogen receptor blockade turned out to be an effective way to mitigate tumor spread.
Other targeted therapies have been developed against a number of cell processes, including secretion of growth factors that facilitate gene expression, angiogenesis (creation of new blood vessels), cell migration, and tumor growth. These include endothelial growth factor (EGF), vascular endothelial growth factor (VEGF), and matrix metalloproteinases. These growth factors are involved in growth and differentiation of normal cells, but they are usually overexpressed or mutated on cancer cells. Binding of growth factors to receptors on the cell membrane induces a cascade of signal transduction events that often involve activation of the enzyme tyrosine kinase. Absence of these signals may lead to apoptosis. Drugs have now been developed that block these growth factors, their receptors, or their associated tyrosine kinases. Included among the targeted therapies are monoclonal antibodies that act on extracellular receptors such as EGF and VEGF, as well as small molecules that penetrate cell membranes and block intracellular signaling pathways. Cancer cells have the ability to mutate and develop resistance to targeted therapies so targeted therapies are often used in conjunction with other drugs.
Radiation
Radiation induces cell death by causing damage to DNA. The sensitivity of a cell to radiation injury is influenced by its phase in the cell cycle and its ability to repair DNA damage. X-rays and γ-rays are the forms of ionizing radiation most commonly used to treat cancer. Radiation timing and delivery is adjusted to maximize therapeutic benefit and minimize damage to surrounding tissue. Radiation can be administered through external beam technology or implanted into a target organ (e.g., radiation “seeds” for prostate cancer). Technologic advances such as three-dimensional imaging and conformal radiotherapy, which allow radiation energy to be conformed to tumor shape, have helped minimize damage to surrounding tissue. Radiation may also be delivered systemically through the use of radionuclides administered intravenously and targeted to a tumor site. For example, isotopes of iodide salts have an important role in the treatment of thyroid neoplasms. Organs have variable resistance to the effects of radiation. The testes, ovaries, and bone marrow are among the most sensitive, while bone is among the most resistant.
Side effects of cancer treatment
Bone marrow suppression, cardiovascular, and pulmonary toxicity, as well as central and peripheral nervous system damage, are among the most serious side effects of cancer treatment. However, dysfunction of nearly every organ system has been described. The following sections present a system-specific review of toxicities related to cancer treatment. Tables 27.1 and 27.2 summarize the side effects of selected chemotherapies and radiation treatment.
TABLE 27.1
Toxicities of Commonly Used Chemotherapies
| Agent | Effects |
|---|---|
| Adriamycin | Cardiac toxicity, myelosuppression |
| Arsenic | Leukocytosis, pleural effusion, QT interval prolongation |
| Asparaginase | Coagulopathy, hemorrhagic pancreatitis, hepatic dysfunction, thromboembolism |
| Bevacizumab | Bleeding, congestive heart failure, gastrointestinal perforation, hypertension, impaired wound healing, pulmonary hemorrhage, thromboembolism |
| Bleomycin | Pulmonary hypertension, pulmonary toxicity |
| Busulfan | Cardiac toxicity, myelosuppression, pulmonary toxicity |
| Carmustine | Myelosuppression, pulmonary toxicity |
| Chlorambucil | Myelosuppression, pulmonary toxicity, SIADH |
| Cisplatin | Dysrhythmias, magnesium wasting, mucositis, ototoxicity, SIADH, peripheral neuropathy, renal tubular necrosis, thromboembolism |
| Cyclophosphamide | Encephalopathy/delirium, hemorrhagic cystitis, myelosuppression, SIADH, pericardial effusion, pericarditis, pulmonary fibrosis |
| Erlotinib | Deep venous thrombosis, pulmonary toxicity |
| Etoposide | Cardiac toxicity, myelosuppression, pulmonary toxicity |
| Fluorouracil | Acute cerebellar ataxia, cardiac toxicity, gastritis, myelosuppression |
| Ifosfamide | Cardiac toxicity, hemorrhagic cystitis, renal insufficiency, SIADH |
| Methotrexate | Encephalopathy, hepatic dysfunction, mucositis, platelet dysfunction, pulmonary toxicity, renal failure, myelosuppression |
| Mitomycin | Myelosuppression, pulmonary toxicity |
| Mitoxantrone | Cardiac toxicity, myelosuppression |
| Paclitaxel | Ataxia, autonomic dysfunction, myelosuppression, peripheral neuropathy, arthralgias |
| Sorafenib | Cardiac ischemia, hypertension, impaired wound healing, thromboembolism |
| Sunitinib | Adrenal insufficiency, cardiac ischemia, hypertension, thromboembolism |
| Tamoxifen | Thromboembolism |
| Thalidomide | Bradycardia, neurotoxicity, thromboembolism |
| Tretinoin | Myelosuppression, retinoic acid syndrome |
| Vinblastine | Cardiac toxicity, hypertension, myelosuppression, pulmonary toxicity, SIADH |
| Vincristine | Autonomic dysfunction, cardiac toxicity, peripheral neuropathy, SIADH, pulmonary toxicity |
SIADH, Syndrome of inappropriate antidiuretic hormone secretion.
TABLE 27.2
Common Side Effects of Radiation Therapy
| System | Acute | Chronic |
|---|---|---|
| Skin | Erythema, rash, hair loss | Fibrosis, sclerosis, telangiectasias |
| Gastrointestinal | Malnutrition, mucositis, nausea, vomiting | Adhesions, fistulae, strictures |
| Cardiac | Conduction defects, pericardial effusion, pericardial fibrosis, pericarditis | |
| Respiratory | Airway fibrosis, pneumonitis, pulmonary fibrosis, tracheal stenosis | |
| Renal | Glomerulonephritis | Glomerulosclerosis |
| Hepatic | Sinusoidal obstruction syndrome | |
| Endocrine | Hypothyroidism, panhypopituitarism | |
| Hematologic | Bone marrow suppression | Coagulation necrosis |
Cardiovascular system
Anthracyclines such as doxorubicin (adriamycin) and idarubicin are the chemotherapeutic drugs most often associated with cardiotoxicity. These drugs are commonly used to treat cancers such as leukemias and lymphomas. Anthracyclines impair myocyte function via the formation of free radicals, which interfere with mitochondrial activation and cause lipid peroxidation. Cardiotoxicity may be acute or chronic. Acute toxicity begins early on in treatment with the development of dysrhythmias, QT prolongation, and cardiomyopathy and then reverses with discontinuation of therapy. Chronic toxicity (left ventricular dysfunction and cardiomyopathy) can occur in an early-onset form usually within 1 year of treatment or a late-onset form that can occur several years or decades after completion of therapy. Risks factors for cardiotoxicity include a large cumulative dose of drug (for doxorubicin, >500 mg/m 2 ), a history of high-dose bolus administration, a history of concomitant radiation, or use of other cardiotoxic agents. The cardiotoxicity of doxorubicin may be decreased by the use of free radical scavengers such as dexrazoxane or liposomal preparations.
Mitoxantrone, which is structurally similar to the anthracyclines, has also been associated with cardiomyopathy, as have other drugs, including cyclophosphamide, clofarabine, interferon, and certain of the tyrosine kinase inhibitors. Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2). It and other HER2 antibodies have also been implicated as causing left ventricular heart failure in a small subset of patients.
Baseline echocardiography is recommended for all patients prior to initiation of chemotherapy with a known risk of cardiotoxicity. Periodic echocardiography is advised in patients, although the optimal surveillance strategy has yet to be established.
Pericarditis, angina, coronary artery vasospasm, ischemic electrocardiogram (ECG) changes, and conduction defects are other cardiac complications related to cancer chemotherapy. Fluorouracil and capecitabine cause the highest incidence of chemotherapy-related ischemia. Estimates vary widely from 1% to 68% for fluorouracil and 3% to 9% for capecitabine. Other drugs that may cause myocardial ischemia are the vinca alkaloids, interferon, and etoposide.
Arrhythmias may also result from chemotherapies. Paclitaxel and thalidomide can cause severe bradycardia requiring pacemaker implantation. Arsenic, lapatinib, and nilotinib frequently cause QT prolongation. Platinum-based drugs such as cisplatin have precipitated conduction abnormalities related to electrolyte imbalance.
Hypertension has emerged as a relatively common side effect of treatment with newer targeted chemotherapies such as bevacizumab, trastuzumab, sorafenib, and sunitinib, occurring in as many as 35% to 45% of patients. The pathophysiology of the cardiac damage related to the use of these drugs is probably directly related to inhibition of EGF and VEGF. Although important to tumor cell proliferation, these growth factors also play a role in normal myocyte growth, repair, and adaptation to pressure loads. On the other hand, hypotension is relatively common with administration of monoclonal antibodies due to a massive release of cytokines.
Patients with cancer are considered to be in a hypercoagulable state independent of treatment; however, certain chemotherapeutics further increase this risk. These include bevacizumab, estramustine, thalidomide, and tamoxifen.
Patients who receive radiation to the mediastinum are at risk for developing myocardial fibrosis, pericarditis, valvular fibrosis, conduction abnormalities, and accelerated development of coronary artery disease. Incidence is related to cumulative radiation exposure as well as concomitant administration of cardiotoxic chemotherapies.
Respiratory system
Pulmonary toxicity is a well-recognized complication of bleomycin therapy. Other agents associated with pulmonary damage include busulfan, cyclophosphamide, methotrexate, lomustine, carmustine, mitomycin, busulfan, and the vinca alkaloids. The mechanism of injury differs for each drug. In the case of bleomycin, free radical formation seems to be a factor. EGF receptor blockade is the postulated mechanism reported with erlotinib and gefitinib, both of which are EGF receptor blockers. Type II pneumocytes possess EGF receptors that play a role in alveolar repair.
Pneumonitis or bronchiolitis obliterans with organizing pneumonia (BOOP) occurs in up to 10% of patients treated with bleomycin, depending on dose. Pulmonary fibrosis can develop decades after treatment. Risk factors include preexisting lung disease, smoking, and radiation exposure. Baseline and serial pulmonary function testing and chest x-rays are often performed. It has widely been taught that intraoperative exposure to high concentrations of oxygen may exacerbate preexisting bleomycin-induced lung injury and contribute to postoperative ventilatory failure. While newer evidence suggests this may not be the case, current recommendations are still to minimize the inspired oxygen concentration to that required to maintain oxygen saturation between 90% and 92%. Pretreatment with corticosteroids has been suggested as a means to minimize perioperative pulmonary complications.
Many other chemotherapies have been associated with pulmonary toxicity. These include mitomycin C, epirubicin, busulfan, methotrexate, fludarabine, carmustine, and all-trans retinoic acid.
Interstitial pneumonitis and pulmonary fibrosis are complications of radiation to the thorax or total body irradiation. Symptoms typically begin within the first 2 to 3 months of treatment and generally regress within 12 months of treatment completion. However, subclinical abnormalities on pulmonary function testing reportedly occur in up to 50% of patients exposed to radiation for treatment of childhood cancers. Radiation recall pneumonitis is a recognized clinical syndrome in which patients with prior radiation exposure manifest symptomatic pneumonitis after exposure to a second pulmonary toxin.
Renal system
Many of the chemotherapeutic agents can be nephrotoxic; among the most commonly cited are the platinum-based chemotherapeutics such as cisplatin, high-dose methotrexate, and ifosfamide. Renal insufficiency and hypomagnesemia are the typical presenting signs of cisplatin-related nephrotoxicity. Ifosfamide usually causes proximal tubule dysfunction marked by proteinuria and glucosuria. Leucovorin, a folic acid precursor, can be helpful in treating methotrexate-related renal failure. Renal insufficiency usually resolves with cessation of treatment and supportive therapy. Prehydration and avoidance of other nephrotoxins limit the risk of renal toxicity. Pretreatment with the organic thiophosphate amifostine is sometimes used for the prevention of cisplatin-induced nephrotoxicity.
Cyclophosphamide is often associated with the syndrome of inappropriate antidiuretic hormone (SIADH) via a direct effect on renal tubules, but this condition is usually benign. The most serious side effect of cyclophosphamide is hemorrhagic cystitis, which can cause hematuria severe enough to produce obstructive uropathy.
Induction chemotherapy or high-dose radiation can induce tumor cell lysis that causes the release of large amounts of uric acid, phosphate, and potassium. Hyperuricemia can cause uric acid crystals to precipitate in renal tubules, leading to acute renal failure. Calcium phosphate deposition may exacerbate the condition. Radiation exposure can cause glomerulonephritis or glomerulosclerosis with permanent injury marked by chronic renal insufficiency and systemic hypertension.
Hepatic system
Antimetabolites such as methotrexate, as well as asparaginase, arabinoside, plicamycin, and streptozocin, have been associated with acute liver dysfunction. However, chronic liver disease is uncommon. Radiation-induced liver injury is also typically dose dependent and reversible.
The most severe form of liver dysfunction in cancer patients is sinusoidal obstruction syndrome. This usually occurs in patients receiving total body irradiation in preparation for hematopoietic stem cell transplantation (HSCT); however, several chemotherapies have also been associated with this syndrome, including busulfan, cyclophosphamide, vincristine, and dactinomycin. Mortality ranges from 19% to 50%.
Airway and oral cavity
Mucositis is a painful inflammation and ulceration of the mucous membranes of the digestive tract. Oral lesions begin as mucosal whitening followed by the development of erythema and tissue friability. Oral mucositis is a relatively common side effect of high-dose chemotherapy and radiation to the head and neck. Chemotherapies associated with mucositis include the anthracyclines, taxanes, and platinum-based compounds, as well as antimetabolites such as methotrexate and fluorouracil. Mucositis associated with chemotherapies often begins during the first week of treatment and typically resolves after treatment is terminated. Mucositis associated with radiation therapy usually has a more delayed onset. Patients with mucositis are at risk of infection from spread of oral bacteria. Narcotics are frequently required to achieve adequate analgesia. In its most severe form, pseudomembrane formation, edema, and bleeding may cause airway compromise or risk of aspiration.
Radiation to the head and neck can result in permanent tissue fibrosis, which may limit mouth opening and neck and tongue mobility. Airway fibrosis and tracheal stenosis may result in difficult ventilation and intubation that is not evident on physical exam.
Gastrointestinal system
Almost all chemotherapy and radiation produce gastrointestinal side effects. Nausea, vomiting, diarrhea, and enteritis are common. Diarrhea is frequent with fluorouracil, melphalan, anthracyclines, and the topoisomerase inhibitors. In the short term, these symptoms can produce dehydration, electrolyte abnormalities, and malnutrition, but they are usually transient. Radiation, however, may produce permanent sequelae such as adhesions and stenotic lesions anywhere along the gastrointestinal tract. Hemorrhagic pancreatitis is a unique complication associated with asparaginase.
Endocrine system
Hyperglycemia is a common side effect of glucocorticoid therapy, as is suppression of the hypothalamic-pituitary-adrenal axis, which may become evident during stress or surgery. Adrenal suppression is reversible but may it take up to a year for adrenal function to return to normal. SIADH can be seen with cyclophosphamide, ifosfamide, cisplatin, and melphalan, although symptomatic hyponatremia is uncommon.
Total body irradiation in the context of HSCT or radiation for head and neck cancers can cause panhypopituitarism and/or hypothyroidism, which typically becomes symptomatic during the first few years following treatment. Patients with a history of radiation exposure to the neck are also at increased risk of thyroid cancer.
Hematologic system
Myelosuppression is the most frequent side effect associated with chemotherapy. In most cases, this effect is transient, and blood cell counts return to normal within a week following therapy.
Bleeding is relatively common in patients on chemotherapy and may be the result of thrombocytopenia and/or platelet dysfunction. Depletion of vitamin K–dependent coagulation factors contributes to this problem. Bleeding has also been associated with the angiogenesis inhibitor bevacizumab as well as several of the tyrosine kinase inhibitors, particularly when used in conjunction with other drugs. For this reason it has been recommended that bevacizumab therapy be withheld prior to major surgery.
Tumors release procoagulants such as tissue factor that create a hypercoagulable state. Some chemotherapies can exacerbate this condition. Thalidomide and the related drug lenalidomide pose an especially high risk of venous thromboembolism, particularly when used in combination with glucocorticoids and doxorubicin. Other drugs associated with an increased risk of thromboembolism include cisplatin and tamoxifen.
Radiation-induced coagulation disorders occur as a delayed effect and involve coagulation necrosis of vascular endothelium. Postradiation bleeding in the rectum, vagina, bladder, lung, and brain have been reported.
Nervous system
Chemotherapy can cause a number of neurotoxic side effects, including peripheral neuropathy and encephalopathy. Virtually all patients treated with vincristine develop paresthesias in their hands and feet. Autonomic neuropathy may accompany the paresthesias. These changes are usually reversible. Cisplatin causes dose-dependent large-fiber neuropathy by damaging dorsal root ganglia. Loss of proprioception may be sufficiently severe to interfere with ambulation. Performance of regional anesthesia in patients being treated with cisplatin chemotherapy must be counterbalanced by the realization that subclinical neurotoxicity is present in a large percentage of these patients, and cisplatin neurotoxicity may extend several months beyond discontinuation of treatment. Paclitaxel causes dose-dependent ataxia that may be accompanied by paresthesias in the hands and feet and proximal skeletal muscle weakness. Corticosteroids (prednisone or its equivalent at >40 mg/day) may cause a myopathy characterized by weakness of the neck flexors and proximal weakness of the extremities. The first sign of corticosteroid-induced neuromuscular toxicity is difficulty rising from the sitting position. Respiratory muscles may also be affected. Corticosteroid-induced myopathy usually resolves when the drug is discontinued.
Cancer chemotherapeutic drugs can cause encephalopathy, delirium, and/or cerebellar ataxia. Examples include high-dose cyclophosphamide, methotrexate, and ifosfamide. Prolonged administration of methotrexate, especially in conjunction with radiation therapy, can lead to progressive irreversible dementia.
Tumor lysis syndrome
Tumor lysis syndrome is caused by sudden destruction of tumor cells by chemotherapy or radiation, leading to the release of large amounts of uric acid, potassium, and phosphate. This syndrome occurs most often after induction treatment of hematologic neoplasms, such as acute lymphoblastic leukemia. Acute renal failure can occur because of uric acid crystal formation and/or calcium phosphate deposition in the kidney. Hyperkalemia and cardiac dysrhythmias are more likely in the presence of renal dysfunction. Hyperphosphatemia can lead to secondary hypocalcemia, which increases the risk of cardiac dysrhythmias from hypokalemia and can cause neuromuscular symptoms such as tetany.
Cancer immunology
Diagnosis
The use of monoclonal antibodies to detect proteins encoded by oncogenes or other types of tumor-associated antigens (TAs) is a common method for identifying cancer. TAs (α fetoprotein, prostate-specific antigen, carcinoembryonic antigen) are present on cancer cells and normal cells, but concentrations are higher in tumor cells. Monoclonal antibodies to various TAs can be labeled with radioisotopes and injected to monitor the spread of cancer. Because TAs are present on normal tissues, measurement of these antigens may be less useful for the diagnosis of cancer than for monitoring patients with known malignancies.
Immunomodulators
Tumor cells are antigenically different from normal cells, and evidence now confirms that the body is able to mount an immune response against TAs in a process similar to that which causes allograft rejection. However, because TAs also exist on normal cells, they are only weakly antigenic. Adjuvants are compounds that potentiate the immune response. Examples include the bacillus Calmette-Guérin (BCG) bacteria and naturally occurring interferons such as interleukin-2 (IL2), interferon-α (INF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF). These agents are used to augment the host’s intrinsic anticancer capabilities.
Cancer vaccines
Appreciation of the role of TAs in eliciting an immune response is now driving the development of cancer vaccines. Two types of cancer vaccines exist: preventive and therapeutic. The preventive vaccines target infectious agents know to contribute to cancer formation. Two preventive vaccines are currently marketed, one against human papillomavirus (HPV) types 6, 11, 16, and 18 and another against hepatitis B virus (HBV). HPV types 16 and 18 are responsible for approximately 70% of cervical cancers and are a causal factor in some cancers of the vagina, vulva, anus, penis, and oropharynx. Chronic HBV infection is a major risk factor for the development of hepatocellular carcinoma. HBV vaccination is now recommended in childhood as part of a strategy to reduce not only the risk of HBV infection but also the incidence of hepatocellular cancer.
The premise behind therapeutic cancer vaccines is that injection of tumor antigen can be used to stimulate an immune system response against tumor cells. In 2010, the US Food and Drug Administration approved the first therapeutic cancer vaccine, sipuleucel-T (Provenge), for the treatment of some cases of metastatic prostate cancer. This is an autologous vaccine produced by isolating antigen-presenting cells from the patient’s own immune system, then culturing this protein with a protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage-colony-stimulating factor (GM-CSF). Treatment elicits an immune response that has shown efficacy in reducing tumor progression. Vaccines are in development for a number of other cancers. Some of these are made from weakened or killed cancer cells that contain TAs, others from immune cells that have been modified to express TAs. Others are being made synthetically. A novel type of cancer vaccine uses naked DNA or RNA that codes for TAs. Injection of the vaccine either directly or via a virus carrier induces massive TA production, which in turn promotes a robust immune response that is intended to halt tumor progression.
Paraneoplastic syndromes
Paraneoplastic syndromes are pathophysiologic disturbances that accompany an estimated 8% of patients with cancer. Sometimes symptoms of a paraneoplastic syndrome manifest before the cancer diagnosis and may actually be the precipitant to cancer detection. Certain of these conditions (superior vena cava obstruction, increased intracranial pressure) may manifest as life-threatening medical emergencies.
Fever and cachexia
Fever may accompany any type of cancer but is particularly likely with metastases to the liver. Increased body temperature may accompany rapidly proliferating tumors, such as leukemias and lymphomas. Fever may reflect tumor necrosis, inflammation, the release of toxic products by cancer cells, or the production of endogenous pyrogens.
Cancer cachexia is a frequent occurrence in cancer patients. In some cases, cancer appears to increase resting energy expenditure (REE). Cancer cells compete with normal tissues for nutrients and may eventually cause nutritive death of normal cells. Tumor factors such as proteolysis-inducing factor and host responses such as tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ), and IL6 also contribute to muscle atrophy and lipolysis. Hyperalimentation is indicated for nutritional support when malnutrition is severe, especially if surgery is planned.
Neurologic abnormalities
Paraneoplastic neurologic syndromes are the result of antibody-mediated damage to the nervous system. Antibodies produced by the host in response to TAs cross-react with elements of the nervous system, leading to neurologic dysfunction. The vast majority of paraneoplastic neurologic syndromes (80%) manifest before the diagnosis of cancer. They can affect both the central and peripheral nervous systems. They are relatively rare—occurring in about 1% of cancer patients—but occur disproportionately in those patients with small cell lung cancer, lymphoma, and myeloma. Examples include limbic encephalitis, paraneoplastic cerebellar degeneration, Lambert-Eaton myasthenia syndrome, and myasthenia gravis. Lambert-Eaton syndrome is caused by antibodies to voltage-gated calcium channel receptors and is commonly associated with small cell lung cancer. Myasthenia gravis is caused by antibodies to the acetylcholine receptor and is often present in patients with thymoma. Potentiation of neuromuscular blocking agents may be observed in these myasthenic disorders.
These paraneoplastic neurologic syndromes often present a diagnostic challenge because symptoms are nonspecific, and the underlying cancer diagnosis is usually unknown. The presence of antibodies in the serum to tumor-associated material (called onconeural antibodies) occurs in some but not all patients. Immunosuppression is the mainstay of treatment of these syndromes. Corticosteroids and immunoglobulin therapies are frequently employed. Plasmapheresis may also be required to reduce the antibody burden. Once diagnosed, screening for an underlying malignancy is indicated.
Endocrine abnormalities
Paraneoplastic endocrine syndromes arise from hormone or peptide production within tumor cells ( Table 27.3 ). Most occur after the diagnosis of cancer has been established. Treatment of the underlying tumor is the preferred management.
TABLE 27.3
Ectopic Hormone Production
| Hormone | Associated Cancer | Manifestations |
|---|---|---|
| Adrenocorticotropic hormone | Carcinoid, lung (small cell), thymoma, thyroid (medullary) | Cushing syndrome |
| Antidiuretic hormone | Duodenum, lung (small cell), lymphoma, pancreas, prostate | Water intoxication |
| Erythropoietin | Hemangioblastoma, hepatic, renal cell, uterine myofibroma | Polycythemia |
| Human chorionic gonadotropin | Adrenal, breast, lung (large cell), ovary, testis | Gynecomastia, galactorrhea, precocious puberty |
| Insulin-like substances | Retroperitoneal tumors | Hypoglycemia |
| Parathyroid hormone | Lung (small cell), lung (squamous cell), ovary, pancreas, renal | Hyperparathyroidism, hypercalcemia, hypertension, renal dysfunction, left ventricular dysfunction |
| Thyrotropin | Choriocarcinoma, testicular (embryonal) | Hyperthyroidism, thrombocytopenia |
| Thyrocalcitonin | Thyroid (medullary) | Hypocalcemia, hypotension, muscle weakness |
Syndrome of inappropriate antidiuretic hormone
SIADH secretion affects approximately 1% to 2% of cancer patients, with most cases related to small cell lung cancer. Headache and nausea are early symptoms that may progress to confusion, ataxia, lethargy, and seizures. Symptoms depend on the degree and rapidity with which hyponatremia develops. SIADH resolves with treatment of the underlying tumor. Vasopressin receptor antagonists and demeclocycline are the pharmacologic therapies available if symptoms are severe.
Hypercalcemia
Cancer is the most common cause of hypercalcemia in hospitalized patients and is considered a poor prognostic indicator. There are several different mechanisms for the hypercalcemia seen in cancer patients. The most common is secretion of a parathyroid hormone (PTH)–related protein by tumor cells that binds to PTH receptors in the bone and kidney. This type occurs commonly with squamous cell cancers of the kidneys, lungs, pancreas, or ovaries. Hypercalcemia can also be caused by local osteolytic activity from bone metastases, especially from breast cancer, multiple myeloma, and some lymphomas. Occasionally, tumors secrete vitamin D.
The rapid onset of hypercalcemia that occurs in patients with cancer may present as lethargy or coma. Polyuria accompanies hypercalcemia and may lead to dehydration. Treatment includes hydration with normal saline. Intravenous bisphosphonates or calcitonin may also be indicated.
Cushing syndrome
Cushing syndrome is most commonly associated with neuroendocrine tumors of the lung such as small cell lung cancer and carcinoid. It is caused by tumor secretion of either adrenocorticotropic hormone (ACTH) or corticotropin-releasing factor (CRF). Clinical symptoms include hypertension, weight gain, central obesity, and edema. The diagnosis can be confirmed by measuring serum ACTH or CRF concentrations and with a dexamethasone suppression test, which involves administration of dexamethasone followed by measurement of urinary cortisol. Normally administration of dexamethasone causes a marked reduction in urinary cortisol concentration. In patients with paraneoplastic Cushing syndrome there is no reduction in urinary cortisol following dexamethasone administration. Treatment includes agents that block steroid production such as ketoconazole and mitotane. Antihypertensives and diuretics may also be needed for symptom management.
Hypoglycemia
Intermittent hypoglycemic episodes can occur with insulin-producing islet-cell tumors in the pancreas or with nonislet cell tumors outside of the pancreas that secrete insulin-like growth factor 2 (IGF-2). Patients with islet cell tumors demonstrate a high serum insulin level. In contrast, those with nonislet cell tumors that secrete insulin-like materials demonstrate a low serum insulin and an elevated IGF-2.
Several other active hormones can be secreted by tumor cells, the results of which produce predictable clinical signs and symptoms.
Renal abnormalities
Paraneoplastic glomerulopathies occur in a variety of different forms, including membranous glomerulonephritis, nephrotic syndrome, and amyloidosis. Many involve renal deposition of immunoglobulins or immune complexes containing tumor-associated antigens with host antibodies. Amyloidosis is marked by deposition of a unique protein called amyloid and is most often associated with renal cell carcinoma. Glomerulopathies are relatively common with lymphoma and leukemia.
Dermatologic and rheumatologic abnormalities
Paraneoplastic dermatologic and rheumatologic conditions can occur without overt evidence of malignancy, but their appearance should initiate surveillance for an underlying cancer. Acanthosis nigricans is a thickening and hyperpigmentation of the skin. It usually occurs in the axilla or neck and is most commonly related to insulin resistance or other noncancer-related conditions. When found on the palms it is almost always cancer associated—most often an adenocarcinoma. Dermatomyositis is an inflammatory condition that causes proximal muscle weakness as well as characteristic skin changes, including a rash on the eyelids and hands. It can be seen with ovarian, breast, lung, prostate, and colorectal cancers. Hypertrophic osteoarthropathy (commonly known as clubbing) involves subperiosteal bone deposition that causes a characteristic remodeling of the phalangeal shafts. It is classically associated with intrathoracic tumors or metastases to the lungs.
Hematologic abnormalities
Paraneoplastic hematologic syndromes are rarely symptomatic but usually are present with advanced cancer. Paraneoplastic eosinophilia is related to production of specific interleukins that promote eosinophilic differentiation and is most often seen with leukemia and lymphoma. Eosinophilia can sometimes cause wheezing or occasionally end-organ damage due to eosinophilic infiltration. Granulocytosis usually occurs with solid tumors, particularly large cell lung cancer. Pure red cell aplasia is commonly associated with thymoma but also occurs with leukemia and lymphoma. Underlying malignancy is the diagnosis in about a third of patients with thrombocytosis (platelet count >400,000/mL). This appears to be the result of tumor-released cytokines such as IL6.
Local effects of cancer and metastases
Superior vena cava syndrome/superior mediastinal syndrome
Obstruction of the superior vena cava is caused by spread of cancer into the mediastinum or directly into the caval wall, most often by lung cancer. Engorgement of veins above the level of the heart occurs, particularly the jugular veins and veins in the arms. Edema of the face and upper extremities is usually prominent. Increased intracranial pressure manifests as nausea, seizures, and decreased levels of consciousness and is most likely due to the increase in cerebral venous pressure. Compression of the great vessels may cause syncope.
Superior mediastinal syndrome is the combination of superior vena cava syndrome plus tracheal compression. Hoarseness, dyspnea, and airway obstruction may be present because of tracheal compression. Treatment consists of prompt radiation or chemotherapy for symptomatic relief. Bronchoscopy and/or mediastinoscopy to obtain a tissue diagnosis can be very hazardous, especially in the presence of coexisting airway obstruction and increased pressure in the mediastinal veins.
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