CTCAE v.5

A.P. Chen, MD
Director, Developmental Therapeutics Clinic
Division of Cancer Treatment and Diagnosis
National Cancer Institute
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CTCAE v 5: Assessing Drug
Induced Hepatic Injury
Alice Chen, M.D.
NCI Core Committee
March 18, 2015
CTCAE History
• The Cancer Therapy Evaluation Program (CTEP) of NCI
developed the original Common Toxicity Criteria (CTC)
in 1983 to aid in the recognition and grading severity
of adverse effects of chemotherapy
• CTCAE v4 was released in May 2009
• All AEs were MedDRA terms
• Categories became SOC
• CTEP stopped supporting all prior versions of CTCAE as of
Sept 2010
• Ongoing lifecycle governance was established
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Process
• NCI Core Committee (CC) has monitored the comments since
publication of v4.0 in 2009
– Helpdesk email
– TRI-CTEP’s AE contractor
– Personal communications
• The CC has met as needed to monitor the comments and use
of CTCAE v4
• Reviewed the impact of the comment
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Frequency of use
Confusion of grade
Clinical significance
MedDRA terms
• Consulted experts
– Working Group members from v4
– NIH members
– Academic Experts
What has not changed in CTCAE v5
• SOCs and term placement within SOCs
• MedDRA Terms
• 5 grades with no change in the general
guidelines for grade definition
• No deletion of AE terms
• ULN or LLN will remain instead of actual
values
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Changes in CTCAE v5
New AE terms
Clarification of Definitions
Add, clarify or change grading
Editorial Changes
Navigational Notes
Index
Examples of new AEs
• Disease Progression
– Though not AE, this was added to allow tracking
• Bacteremia
• Reactivation of viral infection
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Hep B
Shingles
Epstein-Barr virus
Cytomegalovirus Infection reactivation
• Pregnancy Loss (replaces Fetal death)
• Budd-Chiari Syndrome
• Nephrotic Syndrome
Examples of changed or revised
definitions
• Spleen Disorder
– An disorder abnormality of the spleen
• Diarrhea
– A disorder characterized by an increase in
frequency and/or loose or watery bowel
movements
• Peripheral sensory/motor neuropathy
– A disorder characterized by damage or
dysfunction of the peripheral sensory/motor
nerves
Examples of added and changed grades
• Grade 4 myositis
• Grade 1 Capillary Leak Syndrome
• Death Neonatal
– Change grade 5 to grade 4 so patient could
continue on study
Examples of grade clarifications
• Allergic reaction added bronchospasm to
grade 3
• Proteinuria add 3+ proteinuria to grade 2 and
4+ proteinuria to grade 3
• Sleep Apnea clarify associated with
“pulmonary” hypertension
• Diarrhea added limiting instrumental ADL to
grade 2
• Seizure added “new onset seizures (partial or
generalized)” to grade 3
Examples of Navigational Notes
• Direct to a more definitive AE term
– Under Enterocolitis directed to consider Colitis if
site of abnormality known
• Direct to a different AE
• Direct to include another AE
– AST, ALT, Bilirubin: Consider also reporting
Hepatic failure if appropriate
• Death NOS, Sudden Death or Disease
Progression
– If death is due to a specific AE, report as grade 5
under that AE
CTCAE v4: Hepatic Toxicities
Hepatobiliary Disorder SOC
• Bile Duct Stenosis, Biliary Fistula, Cholecystitis
• Gallbladder (fistula, necrosis, obstruction,
pain, perforation)
• Hepatic (failure, hemorrhage, necrosis, pain)
• Portal (hypertension, vein thrombosis)
• Budd-Chiari syndroe
• Perforation bile duct
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CTCAE v4: Hepatic Toxicities
Infections and Infestations SOC
Biliary tract infection
Gallbladder infection
Hepatic infection
Hepatitis viral
Hepatitis B reactivation
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CTCAE v4: Hepatic Toxicities
Investigational SOC
Activated PTT, INR increased,
ALT, AST, Alk Phos, GGT increased
Blood bilirubin
Fibrinogen decreased
Haptoglobin decreased
Areas of Discussion
Alkaline proposal to map grade 3&4 to grade 2, change
phos
definition of grade 1 to > Baseline -2.5 xULN, grade 2
increased >2.5xULN
proposal to map grade 3&4 to grade 2, change
GGT
definition of grade 1 to > Baseline -2.5 xULN, grade 2
increased >2.5xULN
grade4 in
ALT, AST, The need for grade 4 (life-threatening) AST, ALT given
Bili
these should be reported as hepatic failure
• Other AEs we need to add
• Other CTCAE changes that would assist in better
assessment of drug induced liver injury in drug
development?
Resources
• Where to find CTCAE
http://evs.nci.nih.gov/ftp1/CTCAE/About.html
http://ctep.cancer.gov/protocolDevelopment/d
efault.htm
How to contact us?
[email protected]
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