Safety Endpoints in Cancer Clinical Trials
Toxicity criteria in oncology/hematology clinical trials
To standardize the reporting of adverse reactions in clinical trials, the National Cancer Institute (NCI) has developed Common Terminology Criteria for Adverse Events (NCI CTCAE). The NCI CTCAE was most recently updated in June 2010 (version 4.03). Clinical trials that began earlier than this date may use earlier versions of the NCI CTCAE when reporting adverse reactions. According to the NCI CTCAE, adverse reactions are reported by grade (level of severity) on a scale of 1 to 5. Generally, the descriptions follow the guidelines below.
NCI CTCAE definitions of severity for adverse reactions1
Degree of severity
|1||Mild, with mild or no symptoms; no interventions required|
|2||Moderate; minimal intervention indicated; some limitation of activities|
|3||Severe but not life threatening; hospitalization required; limitation of patient's ability to care for him/herself|
|4||Life threatening; urgent intervention required|
|5||Death related to adverse event|
Common adverse reactions by grade
The following table shows NCI CTCAE grades for some adverse reactions commonly observed in clinical trials in oncology/hematology. This list is not all-inclusive; please consult the NCI CTCAE for a full list of adverse reaction criteria.
|Anemia||Hgb <LLN to 10.0 g/dL||Hgb <10.0 g/dL to 8.0 g/dL||Hgb <8.0 g/dL; transfusion indicated||Life-threatening consequences; urgent intervention indicated||Death|
|Neutropenia||Neutrophils <LLN to 1500/mm3||Neutrophils <1500/mm3 to 1000/mm3||Neutrophils <1000/mm3 to 500/mm3||Neutrophils <500/mm3||N/A|
|Thrombocytopenia||Platelets <LLN to 75,000/mm3||<75,000/mm3 to 50,000/mm3||<50,000/mm3 to 25,000/mm3||<25,000/mm3||N/A|
|Hepatic failure||N/A||N/A||Asterixis; mild encephalopathy; limitation of self care||Moderate to severe encephalopathy; coma; life-threatening consequences||Death|
|Creatinine increase||>1 to 1.5 × baseline; >ULN to 1.5 × ULN||>1.5 to 3.0 × baseline; >1.5 to 3.0 × ULN||>3.0 × baseline; >3.0 to 6.0 × ULN||>6.0 × ULN||N/A|
|Fatigue||Relieved by rest||Not relieved by rest; limitation of instrumental ADL||Not relieved by rest; limitation of self-care ADL||N/A||N/A|
|Febrile neutropenia||N/A||N/A||ANC <1000/mm3 with single temperature reading >38.3°C (101.0°F) or sustained temperature ≥38.0°C (100.4°F) for >1 hour||Life-threatening consequences; urgent intervention indicated||Death|
|Fever||38.0°C to 39.0°C (100.4°F to 102.2°F)||>39.0°C to 40.0°C (102.3°F to 104.0°F)||>40.0°C (>104.0°F), lasting ≤24 hours||>40.0°C (>104.0°F), lasting >24 hours||Death|
|Infections and infestations||Asymptomatic or mild symptoms; observations only; intervention not indicated||Moderate symptoms; minimal intervention indicated; limitation of instrumental ADL||Severe or medically significant but not immediately life threatening; hospitalization indicated; limitation of self-care ADL||Life-threatening consequences; urgent intervention indicated||Death|
|Infusion reactions||Mild, transient reaction; interruption/intervention not indicated||Interruption indicated, but responds promptly to symptomatic treatment; prophylactic medications indicated for ≤24 hours||Prolonged (not rapidly responsive to treatment and/or infusion interruption); recurrence of symptoms following initial improvement; hospitalization indicated||Life-threatening consequences; urgent intervention indicated||Death|
ADL=activities of daily living; ANC=absolute neutrophil count; LLN=lower limit of normal; ULN=upper limit of normal.
- US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Updated June 14, 2010. Accessed August 24, 2017.