What is the Dili (Diagnostic Imaging Laboratory Intervention) protocol?

DILI Protocol: Management of Drug-Induced Liver Injury in Oncology Clinical Trials

The DILI (Drug-Induced Liver Injury) protocol is a structured approach to detect, assess, and manage suspected drug-induced liver injury during oncology clinical trials, with specific thresholds for action based on baseline liver function. 1

Baseline Categories and Action Thresholds

The DILI protocol stratifies patients into categories based on baseline liver function:

Baseline ALT Categories:

• Normal/near normal ALT baseline (<1.5× ULN) 1
• ALT of 1.5 to <3× ULN at baseline 1
• ALT ≥3× ULN and ≤5× ULN (patients with liver metastases or primary hepatocellular/biliary tract cancer) 1

Baseline Total Bilirubin Categories:

• Normal (<ULN) 1
• Abnormal (1-2× ULN) 1
• Patients with TBIL >2× ULN are generally excluded from clinical trials 1

Management Algorithm

For Patients with Normal/Near Normal Baseline ALT (<1.5× ULN):

• Monitor closely when ALT rises above 3× ULN 1
• Withhold study drug when ALT rises above 5× ULN 1
• Initiate evaluation for alternative causes when ALT rises above 5× ULN 1
• Consider interrupting/stopping study drug with more modest ALT elevations if accompanied by TBIL ≥2× ULN 1

For Patients with Baseline ALT 1.5-3× ULN:

• Monitor closely when ALT rises above 4× ULN 1
• Withhold study drug when ALT rises above 6× ULN 1
• Initiate evaluation for alternative causes when ALT rises above 6× ULN 1
• Consider interrupting/stopping with more modest ALT elevations if accompanied by TBIL ≥2× ULN or ≥3× ULN for those with abnormal baseline levels 1

For Patients with Baseline ALT 3-5× ULN:

• Monitor closely when ALT rises above 6× ULN 1
• Withhold study drug when ALT rises above 8× ULN 1
• Initiate evaluation for alternative causes when ALT rises above 8× ULN 1
• Consider interrupting/stopping with more modest ALT elevations if accompanied by TBIL changes 1

Evaluation of Suspected DILI

When DILI is suspected, the protocol recommends:

• Comprehensive evaluation for alternative causes of liver injury 1
• Assessment of cholestatic pattern: patients with normal ALP rising to ≥2× ULN, or abnormal ALP at study entry with doubling of baseline value should be evaluated 1
• Investigation with contrast-enhanced CT or MRI imaging to rule out progressive liver or bone metastases 1
• Expert opinion assessment rather than scoring algorithms (such as RUCAM) alone for causality assessment 1

Rechallenge Considerations

For patients who may benefit from rechallenge after suspected DILI:

• Rechallenge should be limited to patients with documented benefit from treatment and limited/no viable alternative options 1
• Delay rechallenge until sufficient resolution of liver test elevations to predefined levels 1
• Rechallenge is generally not recommended for cases with Hy's Law criteria or signs of hepatic decompensation 1
• Avoid rechallenge in patients with allergic/hypersensitivity features (rash, fever, lymphadenopathy, facial edema, arthralgias, eosinophilia, atypical lymphocytosis) 1
• Consider defining positive rechallenge as ALT ≥3× ULN and ≥2× baseline value 1

Special Considerations

• For patients with cirrhosis, modest ALT elevations may be significant; action should be guided by signals of hepatic decompensation (elevations in bilirubin, INR changes, symptoms) 1
• When elevated liver tests at baseline reduce with treatment response, use the nadir ALT value as the "new" baseline for subsequent management 1
• Immune checkpoint inhibitors have specific management protocols with early steroid treatment often leading to resolution 1

Common Pitfalls and Caveats

• Transient ALT elevations may represent adaptive responses rather than progressive liver injury, especially with certain oncology compounds 1
• Cholestatic patterns of liver injury in oncology patients are frequently due to disease progression rather than DILI 1
• Standard DILI assessment tools may not be accurate in oncology settings due to confounding factors like long drug half-lives and multiple concomitant medications 1
• Steroid treatment for non-immune checkpoint inhibitor DILI has limited evidence but may mask response to rechallenge 1

The DILI protocol provides a structured framework specifically designed for oncology clinical trials, acknowledging the unique challenges of monitoring hepatotoxicity in cancer patients with potentially abnormal baseline liver function.