Common terminology criteria for adverse events

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 in patients receiving cancer therapy.

This topic presents selected tables describing some of the AEs graded using the NCI 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. CTCAE version 6.0 is expected in the fall of 2024.

Additional information about specific toxicities for systemic cancer therapies (chemotherapy, immunotherapy, and molecularly targeted agents) and radiation therapy is included under the appropriate disease-specific headings below.

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.

The CTCAE is periodically updated by the NCI, but 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 to harmonize medical terminology. CTCAE version 5.0 (v5.0) was published in November 2017 and became effective in April 2018. A comprehensive listing of CTCAE v5.0 is available from the National Cancer Institute (NCI) on the Cancer Therapy Evaluation Program (CTEP) website.

Changes to CTCAE 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 CTCAE version 5.0 (v5.0). A comprehensive listing of CTCAE v5.0 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 specific cancer therapies are discussed separately:

●(See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity".)

●(See "Risk and prevention of anthracycline cardiotoxicity".)

●(See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".)

●(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)

Cancer therapy-associated alopecia and cutaneous toxicity, as well as radiation-related dermatitis, are discussed 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 adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

●(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 due to cancer therapy are also discussed separately:

●(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 "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation".)

●(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)

●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 (table 36).

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:

●(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

Cytopenias — Hematologic AE criteria include decreases in neutrophil, platelet, hemoglobin, and lymphocyte (including CD4 cell) counts (table 41). In CTCAE v5.0, these are all separately graded under 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:

●(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".)

●(See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

●(See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

●(See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

Febrile 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 — Thromboembolic events are also graded:

●Arterial thromboembolism (table 42)

●Venous thromboembolism (table 43)

●Superior vena cava syndrome (table 44)

Prevention and treatment of thromboembolic disease in patients with cancer is discussed separately:

●(See "Risk and prevention of venous thromboembolism in adults with cancer".)

●(See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)

●(See "Thromboembolism in children with cancer".)

●(See "Multiple myeloma: Prevention of venous thromboembolism".)

Thrombotic microangiopathies — Thrombotic microangiopathies (TMAs) that are graded include:

●Thrombotic thrombocytopenic purpura (TTP) (table 45)

●Hemolytic uremic syndrome (HUS) (table 46)

The differences among TTP, HUS, and other TMAs are discussed separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Drug-induced thrombotic microangiopathy (DITMA)".)

Hepatobiliary — Hepatobiliary adverse events s include 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 systemic cancer therapy is discussed separately:

●(See "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy", section on 'Hepatotoxicity'.)

●(See "Hepatotoxicity of chemotherapy and other cytotoxic agents".)

●(See "Hepatotoxicity of molecularly targeted agents for cancer therapy".)

Kidney and urinary tract — Kidney and urinary tract adverse events include:

●Acute kidney injury, which is graded clinically (ie, whether hospitalization or dialysis is indicated). Increased creatinine is graded separately and classified under "Investigations" (table 48).

●Proteinuria (table 49)

●Cystitis (table 50)

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 nephrotoxicity and cystitis related to cancer therapy are discussed separately:

●(See "Nephrotoxicity of chemotherapy and other cytotoxic agents".)

●(See "Nephrotoxicity of molecularly targeted agents and immunotherapy".)

●(See "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients".)

Lung — Pulmonary AE criteria include:

●Dyspnea (table 51)

●Pneumonitis (table 52)

Pulmonary toxicity of systemic cancer therapy and radiation-related lung injury are discussed separately:

●(See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment".)

●(See "Pulmonary toxicity of molecularly targeted agents for cancer therapy".)

●(See "Pulmonary toxicity associated with chemotherapy and other cytotoxic agents".)

●(See "Toxicities associated with immune checkpoint inhibitors", section on 'Pneumonitis'.)

●(See "Radiation-induced lung injury".)

Metabolism and fluid balance — Electrolyte abnormalities related to cancer and 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).

Further details on electrolyte abnormalities frequently associated with cancer therapy, including tumor lysis syndrome, are discussed separately.

●(See "Etiology and evaluation of hypernatremia in adults".)

●(See "Diagnostic evaluation of adults with hyponatremia".)

●(See "Causes and evaluation of hyperkalemia in adults".)

●(See "Evaluation of the adult patient with hypokalemia".)

●(See "Diagnostic approach to hypercalcemia".)

●(See "Diagnostic approach to hypocalcemia".)

●(See "Hypermagnesemia: Causes, symptoms, and treatment".)

●(See "Hypomagnesemia: Evaluation and treatment".)

●(See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Musculoskeletal and connective tissue — 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 (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 discussed separately:

●(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 — 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 provides recommendations for submitting PROs data in cancer clinical trials [13].

Radiation therapy toxicity — For some toxicities related to radiation therapy, alternative grading criteria are available from the Radiation Therapy Oncology Group (RTOG) [14]. 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 – The National Cancer Institute (NCI) of the National Institutes of Health (NIH) has published standardized definitions for adverse events, known as the Common Terminology Criteria for Adverse Events (CTCAE), to describe the severity of organ toxicity in patients receiving cancer therapy. (See 'CTCAE overview' above.)

Version 5.0 (v5.0) of the CTCAE was released in 2017. Version 6.0 is expected in the fall of 2024. A comprehensive listing of all CTCAE criteria is available from the NCI on the Cancer Therapy Evaluation Program (CTEP) website.

●CTCAE categories with selected tables – The CTCAE categories are classified by organ system. Selected CTCAE tables are provided within the following sections:

•Cardiac – (See 'Cardiac' above.)

•Dermatologic – (See 'Dermatologic' above.)

•Gastrointestinal – (See 'Gastrointestinal' above.)

•General and systemic – (See 'General and systemic' above.)

•Hematologic – (See 'Hematologic' above.)

•Hepatobiliary – (See 'Hepatobiliary' above.)

•Kidney and urinary tract – (See 'Kidney and urinary tract' above.)

•Lung – (See 'Lung' above.)

•Metabolism and fluid balance – (See 'Metabolism and fluid balance' above.)

•Musculoskeletal and connective tissue – (See 'Musculoskeletal and connective tissue' above.)

•Neurologic and psychiatric – (See 'Neurologic and psychiatric' above.)

•Ocular – (See 'Ocular' above.)

●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.)