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CHAPTER 95: Toxicities of Chemotherapy 891

CHAPTER Toxicities of Chemotherapy still of clinical importance, are those involving the liver, kidneys, and
systemic reactions (infusion and anaphylactoid). While the focus will
95 Kaye E. Hale be on acute toxicities, certain subacute and chronic toxicities will also be
discussed. As the long-term survival of cancer patients improves, these
less acute complications may confound the presentation and diagnosis
of elderly patients admitted to the ICU for seemingly unrelated acute
illnesses. Importantly, the diagnosis of drug-related toxicity is most
often a diagnosis of exclusion, relying on dose and temporal exposure
KEY POINTS
to an agent known to cause organ toxicity, and management is largely
• Most antineoplastic agents have toxic side effects. supportive. Adding to the challenge of diagnosing drug toxicity is the
• New antineoplastic agents are frequently being developed and not continued development of new agents and combinations of therapies.
all side effects are known. Other acute complications of cancer treatment including tumor lysis
• Diagnosis or organ dysfunction due to drug toxicity is largely a syndrome will be discussed under oncologic emergencies.
diagnosis of exclusion.
• Maintaining a level of clinical suspicion is key to detection of drug REVIEW OF ANTICANCER THERAPIES
toxicity.
• Therapy for drug-induced toxicity is largely supportive. Cancer therapies are classified by mechanism of action and the phase of
• Myelosuppression is a common toxic side effect from high-dose the cell cycle during which the drug targets its action. Cell cycle–specific
agents refer to drugs whose activity requires the target cell to be within a
combination chemotherapy regimens used in leukemia and bone
marrow transplant patients. certain phase of cell division or proliferation. To review, the five phases of
the cell cycle are Gap 0 (G0), Gap 1 (G1), synthesis (S), Gap 2 (G2), and
• Pulmonary toxicity may manifest as ARDS especially in patients mitosis (M). Cells in G0 are dormant cells with potential to be stimulated to
undergoing treatment for hematologic malignancies (eg, cytara- proceed further in the cell cycle. G1 is a phase of RNA and protein synthesis
bine or gemcitabine) and pulmonary fibrosis (eg, bleomycin). in preparation for DNA synthesis and replication which occurs during S
• Cardiotoxic side effects of anthracyclines such as doxorubicin can phase. Following DNA synthesis during G2 phase, the cell readies itself
lead to refractory heart failure if not identified and managed early, by RNA and protein synthesis in preparation of mitosis, or cell division.
while treatment with 5-FU may precipitate symptoms of acute MI due Chemotherapy agents that are cell cycle– specific include antimetabolites,
to vasospasm in patients with underlying risk factors for heart disease. vinca alkaloids, taxanes, and epipodophyllotoxins. All other classes of
• Mucositis of the oropharynx and GI tract is painful and can lead to agents are cell cycle nonspecific (though some overlap) and include alkylat-
dehydration and malnutrition. Severe cases of oral mucositis may ing agents, nitrosoureas, antibiotics, hormones, and hormone antagonists.
require intubation for airway protection. Biologic response modifiers are also cell cycle nonspecific and include inter-
• Intractable nausea, vomiting, and diarrhea can lead to dehydra- ferons, recombinant interleukin-2, and tumor necrosis factor. Over the last
tion, hypovolemia, and electrolyte disturbances. decade, the development of targeted anticancer therapies has improved our
• Nephrotoxicity is a dose-limiting side effect of cisplatin and causes ability to selectively damage malignant cells based on their unique charac-
renal salt wasting syndrome. teristics. Examples of targeted therapies include tyrosine kinase inhibitors,
• During treatment with methotrexate, special attention must be mTOR kinase inhibitor, gene expression modulators, retinoic acid recep-
tor modifiers, proteasome inhibitors, epidermal and vascular endothelial
paid to urinary pH to avoid precipitation in the renal tubules
resulting in ATN and renal obstruction. growth factor inhibitors, histone deacetylase inhibitors, and monoclonal
antibodies. Several agents may overlap these rather indistinct classifications,
• Both peripheral and central nervous system toxicities, includ- while others defy classification, such as thalidomide and hydroxyurea.
ing posterior reversible encephalopathy syndrome (PRES), are Alkylating agents (including nitrogen mustards among others) alter
reported after high-dose chemotherapy. and destroy DNA structure, leading to cell death. Nitrosoureas are
• The spectrum of severity of hypersensitivity reactions ranges from alkylating agents that are lipid soluble, thus capable of crossing the
flushing and rash to anaphylactic shock. Common causes of these blood-brain barrier. The platinum compounds have broad antineoplas-
reactions include paclitaxel, platinum compounds, and monoclonal tic activity that also functions by binding and disrupting DNA structure,
antibodies. therefore they are classified under alkylating agents.
• Venous thromboembolic disease is a well-known complication of The antimetabolites are synthetic precursors of DNA synthesis that
tamoxifen. compete with naturally occurring purines, pyrimidines, and folates to
• Thrombotic thrombocytopenic purpura (TTP) or thrombotic interrupt the cell cycle and cause cell death. Because of their specificity
microangiopathy has been associated with mitomycin, cisplatin, for the S phase of the cell cycle, they are particularly effective against
and gemcitabine. rapidly proliferating tumors.
Many anticancer therapies are naturally derived products such as
enzymes or antibiotics. Several antibiotics, both natural and synthetic,
INTRODUCTION have antitumor properties. The anthracycline antibiotics as well as their
semisynthetic and synthetic derivatives act by intercalating DNA base
As treatment for cancer continues to evolve with the development of pairs, thereby inhibiting DNA synthesis. The antibiotics bleomycin and
new therapies and improved survival, we can expect an ever-growing dactinomycin generate reactive oxygen species resulting in DNA strand
number of cancer patients to be admitted to intensive care units (ICUs). breaks while mitomycin cross-links DNA like the previously described
Whether they require ICU care due to acute complications of treatment alkylating agents. L-asparaginase is a naturally occurring enzyme that
or underlying illnesses, it is important for the intensivist to be aware cleaves the amino acid L-asparagine on which tumor cells are dependent.
of the myriad of anticancer therapies and their toxicities. The follow- Vinca alkaloids are plant extracts that bind microtubules and prohibit
ing chapter will review the classification of commonly used anticancer mitosis, leading to cell death. Taxanes also cause cell death by forming
therapies and the various organ system toxicities they can cause. Organ abnormal mitotic spindle fibers. Camptothecins inhibit topoisomerase I
systems commonly affected by antineoplastics include the bone marrow, which prevents normal DNA transcription and replication from occur-
pulmonary, cardiovascular, neurologic (both central and peripheral), ring. Epipodophyllotoxins interfere with topoisomerase II activity, thereby
dermatologic, and gastrointestinal. Less common reactions, though prohibiting proper condensation and packaging of DNA after cell division.

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