Introduction
Chemotherapeutic, or antineoplastic, agents are the mainstay of treatment for many types of cancer. While they exert their therapeutic effect by killing malignant cells, they can also damage or kill noncancerous cells. Additionally, chemotherapeutic drugs generally have a narrow therapeutic index and are administered with high supervision to minimize off-target effects. Because they are often administered in infusion clinics or under supervision by a clinician, overdose of chemotherapeutics is rare.
With the expansion of chemotherapeutics to involve more cancers and an expanded scope, including in the treatment of autoimmune and other immunologic disorders, accidental exposure to these agents has been increasing.1 While it is not necessary to know every chemotherapeutic agent, emergency physicians should be broadly familiar with these medications in order to diagnose and treat patients appropriately. This article briefly reviews the different classes of chemotherapeutic drugs and discusses two life-threatening oncologic emergencies: tumor lysis syndrome and methotrexate toxicity.
Classes of Chemotherapy Drugs
There are traditionally five categories of antineoplastic agents that encompass most chemotherapeutics used today: alkylating agents, antibiotics, antimetabolites, antimitotics, and platinum-based compounds (Table 1). The general mechanism of action of most chemotherapeutic agents is to disrupt cellular growth and proliferation. Each class accomplishes this goal through different pathways. Alkylating agents bind to certain nucleic acids, causing structural defects, strand breaks, mispairings, and ultimately arresting cell development at different points in the cell cycle.1 Antibiotics are generally isolated from bacteria and inhibit RNA and/or DNA synthesis.2 Antimetabolites are a broad category of medications that interfere with specific cellular metabolites to block DNA synthesis.1,2 Antimitotics are derived from plant alkaloids and interrupt the assembly of microtubules, preventing cell division via interfering with RNA and DNA synthesis.1,2 Platinum-based compounds inhibit DNA synthesis by causing cross-linking and structural defects.3
Two newer categories of chemotherapeutics include protein kinase inhibitors (ex. gefitinib) and monoclonal antibodies (ex. trastuzumab), which target specific cellular proteins, such as growth factor receptors.1 These medications are engineered to target tumor cells specifically and are becoming more common with ongoing research and development into individualized cancer treatments. Less is known about toxicologic effects of these newer agents due to their relative infancy in use.
|
Class |
Examples |
|
|---|---|---|
|
Alkylating agents |
Busulfan, dacarbazine, ifosfamide |
|
|
Antibiotics |
Danorubicin, bleomycin, dactinomycin |
|
|
Antimetabolites |
Methotrexate, mercaptopurine, fluorouracil |
|
|
Antimitotics |
Paclitaxel, vinblastine, vincristine |
|
|
Platinum-based compounds |
Cisplatin, carboplatin, oxaliplatin |
|
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is an oncologic emergency that occurs when tumors or malignancies rapidly break down. TLS is most often seen with the initiation of chemotherapy. However, it can also occur spontaneously in high-grade cancers with high tumor burdens. Patients with hematologic malignancies, such as lymphoma and leukemia, are at higher risk than other types of cancer, as they generally have high proliferative rates and are highly sensitive to chemotherapy. However, TLS is also a well-reported phenomena in solid tumors.4
Marked electrolyte abnormalities are seen in TLS, including hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia, due to rapid cell death and lysis of cancerous cells.5 As a result, renal failure, cardiac arrhythmias, and cardiac arrest can occur. Because of these complications, it is important for emergency physicians to be aware of this condition and have a high clinical suspicion when taking care of both adult and pediatric patients with cancer.
In the ED, laboratory evaluation is crucial in diagnosing tumor lysis syndrome. Notably, it is important to obtain a complete blood count, metabolic panel, calcium, phosphorus, uric acid, lactate dehydrogenase, and urinalysis. Aggressive intravenous (IV) hydration is the mainstay of treatment. Rasburicase, which is a form of recombinant urate oxidase, may also be used to help break down uric acid and prevent complications caused by TLS. Hemodialysis and ICU admission for monitoring of electrolytes may be necessary in severe cases of TLS.
Methotrexate Toxicity
Methotrexate is a structural analog of folate and is categorized as an antimetabolite. It works by inhibiting dihydrofolate reductase and thymidylate synthetase, which ultimately prevents DNA and RNA synthesis. It is used as a chemotherapeutic agent and in the treatment of various other medical conditions, including rheumatoid arthritis and ectopic pregnancies.6
While overdoses of most chemotherapeutics are uncommon, methotrexate overdose is well-reported and likely related to a higher frequency of methotrexate use beyond the treatment of malignancies. Methotrexate was the most common chemotherapeutic agent to be reported for overdose to the California Poison Control System from 2009-2019, which makes it particularly relevant to emergency physicians.7
Toxicity from methotrexate is secondary to effects directly from the drug itself, in addition to its metabolites 7-hydroxy methotrexate and 2,4-diamino-N(10)-methylpteroic acid. The most common side effects from methotrexate toxicity include nausea, vomiting, and elevations in alanine aminotransferase and aspartate aminotransferase, which can occur as early as a few hours after ingestion. More severe side effects include stomatitis, kidney failure, hepatitis, neurologic dysfunction, and myelosuppression, which may be delayed several days beyond methotrexate ingestion.6 Patients with renal impairment are at a higher risk of experiencing methotrexate toxicity due to drug excretion in the urine, and as little as a single dose of methotrexate can cause severe toxicity in any patient on renal replacement therapy.8
Treatment of methotrexate toxicity primarily includes the antidote leucovorin, also known as folinic acid, to facilitate essential biochemical processes that require folate. Supportive care is also a cornerstone of the treatment of methotrexate toxicity. Urinary alkalinization with sodium bicarbonate and IV hydration may need to be used to mitigate renal effects, which can propagate toxicity via impaired excretion. Hemodialysis can be used to remove methotrexate.6 Glucarpidase is a recombinant bacterial enzyme that can rapidly lower methotrexate levels, although this is not readily available and is generally used as a rescue therapy. Often initiating supportive care early on is necessary, as methotrexate levels may be either unavailable or undetectable when a patient is symptomatic. Granulocyte-macrophage colony-stimulating factor (GM-CSF) may also be considered in an inpatient setting in patients with refractory pancytopenia. Patients experiencing systemic effects from methotrexate toxicity should be admitted to the hospital, as many require intensive care unit admission.6
Conclusion
Chemotherapeutic emergencies such as tumor lysis syndrome and methotrexate toxicity are rare but can be life-threatening. It is important for emergency physicians to be familiar with chemotherapeutic agents and have high clinical suspicion for these pathologies in patients on active chemotherapy.
References
- Wang, R. Chapter 50, Chemotherapeutics. In: Goldfrank’s Toxicologic Emergencies, Vol. 11. Mcgraw-Hill Education; 2019:756-66.
- Amjad MT, Chidharla A, Kasi A. Cancer Chemotherapy. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.
- Zhang C, Xu C, Gao X, Yao Q. Platinum-based drugs for cancer therapy and anti-tumor strategies. Theranostics. 2022 Feb 7;12(5):2115-2132.
- Papapanou M, Athanasopoulos AE, Georgiadi E, Maragkos SA, Liontos M, Ziogas DC, Damaskos D, Schizas D. Spontaneous tumor lysis syndrome in patients with solid tumors: a scoping review of the literature. Med Oncol. 2023 Jul 11;40(8):233.
- Adeyinka A, Kaur A, Bashir K. Tumor Lysis Syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.
- Wang, R. Chapter 51, Methotrexate, 5-Fluorouracil, and Capecitabine. In: Goldfrank’s Toxicologic Emergencies, Vol. 11. Mcgraw-Hill Education;2019:767-74.
- Ontiveros S, Hogue B, Kreshak A, Coyne C, Cantrell L, Minns A. Oral Chemotherapeutic Ingestions Reported to a Poison Control Center Treated in a Health Care Facility. Am J Ther. 2023 Mar-Apr 01;30(2):e103-e107.
- Yang XL, Chen YJ. Fatal Toxicity Induced by a Single Low Dose of Methotrexate in a Hemodialysis Patient With End-Stage Kidney Disease. Am J Ther. 2024 Dec 24. Epub ahead of print