What is the recommended treatment plan for a patient with a history of left parietal and right frontal lobe lesions, on immunotherapy (IT), with a new 3 mm enhancing lesion and decreased size of existing lesions?

Treatment Recommendation for New Brain Lesion on Immunotherapy

Continue current immunotherapy without modification and obtain confirmatory MRI in 4-8 weeks, as this imaging pattern is consistent with immune-related unconfirmed progression (iUPD) requiring confirmation before declaring treatment failure. 1

Rationale Based on iRECIST Criteria

The current imaging findings demonstrate a mixed response pattern that is characteristic of immunotherapy treatment:

• Responding lesions: Left parietal lesion decreased from 8 mm to 5 mm; right frontal lesion less conspicuous with decreased surrounding FLAIR hyperintensity 1
• New lesion: 3 mm enhancing inferior left parietal focus with minimal surrounding edema 1

According to iRECIST guidelines, the appearance of new lesions during immunotherapy constitutes iUPD (immune-related unconfirmed progression), not confirmed progression (iCPD). 1 This is a critical distinction because:

• New lesions ≥5 mm or any increase in new lesion size at the next assessment (4-8 weeks later) would confirm iCPD 1
• If the new lesion remains stable or decreases, the patient maintains iUPD status and can continue treatment 1
• The simultaneous decrease in existing target lesions suggests ongoing therapeutic benefit despite the new small focus 1

Clinical Decision Algorithm

Step 1: Assess Clinical Stability 1

• Confirm no worsening of performance status
• Verify no clinically relevant increase in neurological symptoms
• Document absence of new focal deficits attributable to the new 3 mm lesion

Step 2: Continue Immunotherapy if Clinically Stable 1

• The patient should remain on current immunotherapy regimen without interruption
• Treatment beyond initial radiographic progression is appropriate when clinical stability is maintained 1
• Premature discontinuation risks stopping an effective therapy during the immune response evolution phase 1

Step 3: Obtain Confirmatory Imaging 1

• Schedule repeat brain MRI with contrast in 4-8 weeks (not sooner, not later) 1
• Use identical imaging protocol including DWI and FLAIR sequences 1
• Measure the new 3 mm lesion and all previously identified target lesions 1

Step 4: Interpret Follow-up Imaging 1

• If new lesion increases ≥5 mm OR additional new lesions appear: Confirms iCPD, consider treatment change 1
• If new lesion stable or decreased AND target lesions continue responding: Continue immunotherapy, status remains iUPD or converts to partial response 1
• If all lesions (including new lesion) decrease: Assign immune-related partial response (iPR), continue treatment 1

Critical Pitfalls to Avoid

Do not apply traditional RECIST 1.1 criteria, which would classify any new lesion as immediate progression requiring treatment discontinuation. 1 This approach fails to account for:

• Pseudoprogression (initial inflammatory response mimicking tumor growth) 1, 2
• Delayed immune responses that may take 8-12 weeks to manifest radiographically 1
• Mixed response patterns where some lesions respond while others transiently appear 1

Do not obtain confirmatory imaging before 4 weeks, as this interval is insufficient to distinguish pseudoprogression from true progression. 1

Do not wait beyond 8 weeks for confirmatory imaging, as prolonged delays may compromise the patient's ability to receive effective salvage therapy if true progression is occurring. 1

Do not discontinue immunotherapy based solely on the appearance of a single small (3 mm) new lesion when existing lesions are responding and the patient is clinically stable. 1

Differential Diagnosis Considerations

While continuing immunotherapy, remain vigilant for alternative diagnoses that may present as new enhancing lesions:

• Progressive multifocal leukoencephalopathy (PML): Unlikely given the small size, peripheral enhancement pattern, and minimal surrounding edema, but consider if additional lesions develop or clinical deterioration occurs 1
• Radiation necrosis: Not applicable if no prior radiation therapy
• Infectious/inflammatory processes: Less likely with isolated 3 mm focus and stable clinical status
• True tumor progression: Will be confirmed or excluded by 4-8 week follow-up imaging 1

Monitoring Beyond Confirmatory Scan

If the confirmatory scan shows continued response or stability:

• Continue immunotherapy with imaging every 8-12 weeks 1
• Maintain clinical assessments before each treatment cycle 1
• Document performance status and neurological examination at each visit 1

The simultaneous regression of existing lesions while a new small lesion appears is a recognized pattern during effective immunotherapy and should not trigger premature treatment discontinuation in a clinically stable patient. 1