Version May 2024
INTRODUCTION — The National Cancer Institute (NCI) of the National Institutes of Health (NIH) has published standardized definitions for adverse events (AEs), known as the Common Terminology Criteria for Adverse Events (CTCAE, also called "common toxicity criteria" [CTC]), to describe the severity of organ toxicity for patients receiving cancer therapy. This topic presents selected tables describing some of the AEs graded in the most recent CTCAE (version 5.0), which was published in November 2017 and became effective in April 2018 [1]; it also provides references for other adverse event reporting systems.
Additional information about specific chemotherapy and radiation therapy-associated toxicity is presented in separate topic reviews, which are mentioned under the disease-specific headings included herein.
General effects of radiation therapy and molecularly targeted agents (eg, vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors) are also discussed in separate reviews. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis".)
CTCAE OVERVIEW — CTCAE stands for Common Terminology Criteria for Adverse Events; these criteria are also called "common toxicity criteria." In CTCAE, an adverse event (AE) is defined as any abnormal clinical finding temporally associated with the use of a therapy for cancer; causality is not required. These criteria are used for the management of chemotherapy administration and dosing, and in clinical trials to provide standardization and consistency in the definition of treatment-related toxicity.
Several updates of the CTCAE have been published. There is no set schedule for the publication of updates; typically a version is available for several years and new updates are released to improve clarity, to reflect advances in scientific underpinnings, or, for version 4.0, to harmonize with the medical dictionary for regulatory activities (MeDRA) system organ class (SOC). Version 4.0 was published in 2009 and was replaced by version 5.0 (v5.0) in 2018. A comprehensive listing of the v5.0 CTCAE is available from the National Cancer Institute (NCI) on the Cancer Therapy Evaluation Program (CTEP) website.
Changes from version 4.0 to 5.0 include some differences in the grade for certain AEs (eg, cytokine release syndrome, hyperglycemia) and/or in terminology (eg, the term "prehypertension" is no longer used). The major organ system categories are the same as in version 4.0, and many of the AE grades have not been changed.
In general, toxicity is graded as mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4), with specific parameters according to the organ system involved. Death (Grade 5) is used for some of the criteria to denote a fatality occurring during treatment. Approximately 10 percent of the AEs in the NCI CTCAE represent clinician-reported symptoms. Versions of the CTCAE that rely on patient-reported outcomes are discussed below. (See 'Other adverse event reporting systems' below.)
CTCAE CATEGORIES — The following represents a selection of some of the adverse events (AEs) graded in the most recent CTCAE (version 5.0 [v5.0]). A comprehensive listing of the v5.0 CTCAE is available from the National Cancer Institute (NCI) on the Cancer Therapy Evaluation Program (CTEP) website.
Cardiac — Cardiac AE criteria include the following:
●Heart failure (table 1)
●Right ventricular dysfunction (table 2)
●Left ventricular systolic dysfunction (table 3)
●Reduced ejection fraction (table 4)
●Sinus bradycardia (table 5)
●Prolongation of the corrected QT interval (QTc) on the electrocardiogram (table 6)
Cardiac toxicities of radiation and specific chemotherapeutic drugs are discussed in the following UpToDate topic reviews:
●(See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity".)
●(See "Risk and prevention of anthracycline cardiotoxicity".)
●(See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)
●(See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)
●(See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
Dermatologic — Cutaneous complications include the following:
●Alopecia (table 7)
●Acneiform rash (table 8)
●Bullous dermatitis (table 9)
●Hyperhidrosis (excessive sweating) (table 10)
●Maculopapular rash (table 11)
●Palmar-plantar erythrodysesthesia syndrome (table 12), which is also referred to as acral erythema or hand-foot syndrome. This table is also used for grading the severity of hand-foot skin reaction, which is seen with sorafenib, sunitinib, and other agents targeting the vascular endothelial growth factor (VEGF) receptor. This syndrome has a different clinical and histologic appearance from the classic form of palmar-plantar erythrodysesthesia that is associated with conventional cytotoxic chemotherapy agents.
●Pruritus (table 13)
●Radiation dermatitis (table 14)
●Skin hypopigmentation (table 15)
●Stevens-Johnson syndrome (table 16)
●Toxic epidermal necrolysis (table 17)
●Other skin and subcutaneous disorders (table 18)
Further discussions of chemotherapy-associated alopecia and cutaneous toxicity, as well as radiation-related dermatitis, are presented separately:
●(See "Alopecia related to systemic cancer therapy".)
●(See "Acute complications of cranial irradiation", section on 'Alopecia and radiation dermatitis'.)
●(See "Cutaneous adverse effects of conventional chemotherapy agents".)
●(See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)
●(See "Radiation dermatitis".)
Gastrointestinal — Gastrointestinal AE criteria include the following:
●Oral mucositis (table 19)
●Nausea and vomiting (table 20); these are graded separately in CTCAE v5.0
●Dysphagia (table 21)
●Esophageal stenosis (table 22)
●Esophagitis (table 23)
●Gastroparesis (table 24)
●Constipation (table 25)
●Diarrhea (table 26)
●Enterocolitis (table 27)
Oral toxicity, treatment-related nausea and vomiting, gastroparesis, and enterotoxicity are also discussed in separate UpToDate topic reviews:
●(See "Oral toxicity associated with systemic anticancer therapy".)
●(See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting".)
●(See "Prevention of chemotherapy-induced nausea and vomiting in adults".)
●(See "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment".)
●(See "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)
●(See "Management of acute chemotherapy-related diarrhea".)
●(See "Overview of gastrointestinal toxicity of radiation therapy".)
●(See "Immune checkpoint inhibitor colitis".)
General and systemic
Capillary leak syndrome — Capillary leak syndrome can cause leakage of intravascular fluid into any extravascular space. It can lead to generalized edema, pulmonary edema, and multiorgan failure (table 28).
Fatigue — Fatigue is graded according to its impact on activities of daily living (table 29).
Performance status (PS) is not graded in the CTCAE. PS can be classified using the Karnofsky or the Eastern Cooperative Oncology Group (ECOG) scale (table 30).
Hypertension and hypotension
●Hypotension (table 31)
●Hypertension (table 32)
Immune system, infusion reactions, and extravasation — Immune reactions include cytokine release syndrome (CRS) (table 33), serum sickness (table 34), and allergic and anaphylactic reactions (table 35). If an allergic reaction is related to a drug infusion, the grading schema for infusion-related reactions should be used.
Complications of drug infusions include the following:
●Infusion-related reactions (table 36)
●Injection site reactions (table 37)
●Infusion site extravasation (table 38)
These are generally graded according to the degree of intervention needed.
Management of these complications are discussed separately in UpToDate:
●(See "Infusion reactions to systemic chemotherapy".)
●(See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)
●(See "Extravasation injury from cytotoxic and other noncytotoxic vesicants in adults".)
●(See "Overview of therapeutic monoclonal antibodies".)
●(See "Cytokine release syndrome (CRS)".)
Pain — Pain is graded by severity and effect on activities of daily living. Separate criteria are used to grade pain in different locations in the body; these should be consulted for specific grading of pain [1]. The table (table 39) summarizes some of the common features of pain grading. (See "Assessment of cancer pain".)
Weight loss — Weight loss is graded according to the percent decrease from the individual's baseline and the need for tube feedings or parenteral nutrition (table 40).
Hematologic — Hematologic AE criteria include decreases in neutrophil, platelet, hemoglobin, and lymphocyte (including CD4 cell) counts (table 41). In v5.0, most of these were moved to the "Investigations" category, which includes many types of laboratory values, imaging, and changes in measured parameters such as urine output or weight.
Hematologic consequences of cancer therapy are also discussed separately in UpToDate:
●(See "Causes of anemia in patients with cancer".)
●(See "Platelet transfusion: Indications, ordering, and associated risks".)
●(See "Overview of neutropenic fever syndromes".)
●(See "Diagnostic approach to the adult cancer patient with neutropenic fever".)
●(See "Risk assessment of adults with chemotherapy-induced neutropenia".)
The grading scheme for febrile neutropenia remains in the section on blood and lymphatic system disorders. Febrile neutropenia only has definitions for grades 3 through 5 toxicity (table 41). All patients with fever in the setting of chemotherapy-induced neutropenia require immediate medical attention regardless of the toxicity grade, as discussed in detail separately. (See "Overview of neutropenic fever syndromes" and "Fever in children with chemotherapy-induced neutropenia" and "Diagnostic approach to the adult cancer patient with neutropenic fever".)
Thromboembolic events are also graded:
●Arterial thromboembolism (table 42)
●Venous thromboembolism (table 43)
●Superior vena cava syndrome (table 44)
Thrombotic microangiopathies (TMAs) are separated into thrombotic thrombocytopenic purpura (TTP) (table 45) and hemolytic uremic syndrome (HUS) (table 46). Separate discussions in UpToDate discuss differences among these and other TMAs. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Drug-induced thrombotic microangiopathy (DITMA)".)
Prevention and treatment of thromboembolic disease in patients with cancer is discussed in separate topic reviews:
●(See "Risk and prevention of venous thromboembolism in adults with cancer".)
●(See "Thromboembolism in children with cancer".)
●(See "Multiple myeloma: Prevention of venous thromboembolism".)
Hepatobiliary — Hepatobiliary toxicity includes hepatic failure, portal hypertension, and laboratory evidence of liver dysfunction (table 47). In CTCAE v5.0, the laboratory findings of liver toxicity are graded separately under investigations. Portal hypertension and hepatic failure are classified under hepatobiliary disorders.
The term drug-induced liver injury (DILI), which is used to assign Grade 3 hepatic failure, is defined by Hy's law (ie, the drug causes hepatocellular injury, often transaminase elevations are much greater than three times the upper limit of normal, and no other reason can be found to explain the increased transaminases and total bilirubin) [2].
Hepatotoxicity from immune checkpoint inhibitors and hepatoxicity from chemotherapy or molecularly targeted agents in patients with underlying liver disease are discussed separately. (See "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy", section on 'Hepatotoxicity' and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents".)
Kidney and urinary tract — Acute kidney injury is graded clinically (ie, whether hospitalization or dialysis is indicated); increased creatinine is graded separately and classified under "Investigations" (table 48).
Proteinuria (table 49) and cystitis (table 50) are also graded.
Chronic kidney disease is also graded; however, experts prefer to classify chronic kidney disease according to published guidelines from expert groups such as the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) [3]. (See "Definition and staging of chronic kidney disease in adults", section on 'Definition and staging of chronic kidney disease'.)
Further discussions of chemotherapy-induced nephrotoxicity and cystitis related to cancer therapy are presented separately. (See "Nephrotoxicity of chemotherapy and other cytotoxic agents" and "Nephrotoxicity of molecularly targeted agents and immunotherapy" and "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients".)
Lung — Pulmonary AE criteria include:
●Dyspnea (table 51)
●Pneumonitis (table 52)
Pulmonary toxicity of chemotherapeutic, molecularly targeted agents, and radiation-related lung injury are discussed in separate topic reviews:
●(See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)
●(See "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents".)
●(See "Radiation-induced lung injury".)
Metabolism and fluid balance — Electrolyte abnormalities related to cancer therapy include hyper- and hyponatremia, hyper- and hypokalemia, hyper- and hypocalcemia, hyper- and hypomagnesemia, hyperuricemia, and hypophosphatemia (table 53). These are all graded separately under "Investigations."
Hyperglycemia and hypoglycemia are also graded (table 54), as is dehydration (table 55).
Musculoskeletal and connective tissue disorders — Osteonecrosis of the jaw is graded (table 56).
Neurologic and psychiatric — Neurologic disorders include paresthesias and motor and sensory neurotoxicity (table 57).
Specific cranial neuropathies are graded (eg, oculomotor nerve (table 58)). Hearing impairment is graded separately (table 59) and not considered to be an impairment of the vestibulocochlear nerve.
Agitation, confusion, and delirium are graded as psychiatric disorders (table 60).
Neurologic complications of chemotherapy and radiation therapy are also discussed separately in UpToDate:
●(See "Overview of neurologic complications of platinum-based chemotherapy".)
●(See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy".)
●(See "Acute complications of cranial irradiation".)
●(See "Complications of spinal cord irradiation".)
●(See "Brachial plexus syndromes", section on 'Neoplastic and radiation-induced brachial plexopathy'.)
●(See "Lumbosacral plexus syndromes", section on 'Radiation plexopathy'.)
●(See "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)
●(See "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)
Ocular — Ocular complications include inflammatory conditions such as uveitis (table 61) as well as disorders that affect vision and those that cause other ocular symptoms. (See "Ocular side effects of systemically administered chemotherapy".)
OTHER ADVERSE EVENT REPORTING SYSTEMS — Patient-Reported Outcomes (PRO) take into account the patient's perspective on adverse events (AEs), which may be under-detected using the existing CTCAE system [4]. A PRO version of the National Cancer Institute (NCI) CTCAE (PRO-CTCAE) has been developed and validated but is not yet in widespread use [4-6]. A systematic review of reports that compared CTCAE and PRO ratings using various PRO measures of AEs found fair to moderate agreement between the two systems, with large variations in many of the studies [7]. Translations of this document are available in other languages including German, Spanish, Danish, Japanese, and Korean [8-12].
The US FDA has issued some preliminary guidelines, which, when finalized, will provide recommendations on which PROs are appropriate to measure in cancer clinical trials.
For some toxicities related to radiation therapy, alternative grading criteria are available from the Radiation Therapy Oncology Group (RTOG) [13]. However, the NCI CTCAE criteria are also relevant to grading the severity of radiation therapy-related toxicity. (See "Radiation proctitis: Clinical manifestations, diagnosis, and management", section on 'Management'.)
SUMMARY
●Overview – This topic review presents tables of some of the toxicities graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 (v5.0), which was released in November 2017 and is effective as of April 1, 2018. (See 'CTCAE overview' above.)
●Selected CTCAE tables – Selected tables for CTCAE categories are provided in the sections above (see 'CTCAE categories' above). A comprehensive listing of the criteria is available from the NCI on the Cancer Therapy Evaluation Program (CTEP) website.
●Other adverse event reporting systems – References and links for other adverse event reporting systems such as the patient-reported outcomes (PRO-CTCAE) and criteria from the Radiation Therapy Oncology Group (RTOG) are listed above. (See 'Other adverse event reporting systems' above.)
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