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

Grade

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.

Adverse reaction

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Cytopenias
Anemia Hb <LLN to 10.0 g/dL Hb <10.0 g/dL to 8.0 g/dL Hb <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
Hepatic failure N/A N/A Asterixis; mild encephalopathy; limitation of self care Moderate to severe encephalopathy; coma; life-threatening consequences Death
Renal
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
Other
Fatigue Relieved by rest  Not relieved by rest, limiting ADL  Not relieved by rest; limitation of self care  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  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.

References

  1. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Updated June 14, 2010. Accessed June 3, 2015.