Is it appropriate to perform an interim PET‑CT scan in patients receiving Nivolumab (240 mg IV) plus AVD (doxorubicin 25 mg/m², vinblastine 6 mg/m², dacarbazine 375 mg/m²) chemotherapy?

Interim PET-CT in Nivolumab-AVD: Current Evidence and Recommendations

Yes, interim PET-CT can be performed in patients receiving Nivolumab-AVD (N-AVD), though its role in treatment modification remains investigational and differs from established ABVD protocols.

Evidence from Nivolumab-AVD Studies

The landmark NIVAHL trial and subsequent studies provide specific data on interim PET-CT use with N-AVD:

• In the NIVAHL trial for early-stage unfavorable Hodgkin lymphoma, interim PET-CT after 2 cycles of N-AVD showed remarkably high response rates: 100% objective response with 87% complete metabolic response (CMR) 1.

• After 4 doses of nivolumab monotherapy (in the sequential arm), 96% achieved objective response with 51% CMR 1.

• The final analysis with 41 months median follow-up demonstrated 100% overall survival and 98-100% progression-free survival, suggesting that interim PET findings did not necessitate treatment changes in this population 2.

Key Differences from Traditional ABVD Protocols

Traditional ABVD Approach

The ESMO guidelines establish clear interim PET-CT protocols for ABVD:

• For advanced-stage disease, interim PET after 2 cycles of ABVD (Deauville score ≥4) identifies patients who benefit from switching to intensified protocols like BEACOPPescalated 3.

• In intermediate-stage disease, positive interim PET (Deauville ≥3) after 2 cycles of ABVD warrants treatment escalation to BEACOPPescalated 3.

Nivolumab-AVD Context

The role of interim PET-CT for treatment modification in N-AVD is fundamentally different and not yet established:

• No treatment escalation protocols exist for positive interim PET-CT during N-AVD therapy, as the regimen already represents an intensified, immunotherapy-based approach 1, 2.

• The S1826 trial in adolescents with advanced-stage disease showed 93% 3-year PFS with N-AVD, with minimal need for protocol-specified radiotherapy (only 1 patient), suggesting excellent disease control regardless of interim findings 4.

Practical Recommendations for Interim PET-CT Use

When to Perform Interim PET-CT

Perform interim PET-CT after 2 cycles (4 doses) of N-AVD if:

• Baseline disease assessment requires confirmation of response for clinical decision-making 1.
• The patient is enrolled in a clinical trial with mandated interim imaging 2.
• There is clinical concern about disease progression or inadequate response 1.

Interpretation Considerations

Use Deauville 5-point scale for interpretation, but recognize important caveats:

• Nivolumab can cause spurious PET findings due to immune activation and inflammatory changes, potentially leading to false-positive results 5.

• In the concurrent pembrolizumab-AVD study, some patients with persistent PET uptake at end-of-treatment but negative circulating tumor DNA (ctDNA) did not relapse, highlighting the complexity of PET interpretation with checkpoint inhibitors 5.

• Deauville scores ≤3 indicate CMR, but even patients with higher scores may achieve excellent outcomes with continued N-AVD 1, 2.

Treatment Modification Based on Interim PET-CT

Do NOT routinely modify N-AVD therapy based on interim PET-CT results:

• The NIVAHL trial did not incorporate treatment changes based on interim PET, yet achieved outstanding outcomes 1, 2.

• Unlike ABVD, where positive interim PET prompts escalation to BEACOPPescalated, N-AVD already incorporates checkpoint inhibition and represents an intensified regimen 3.

• Patients who discontinued pembrolizumab early due to toxicity in the concurrent pembrolizumab-AVD study did not experience progression, suggesting that complete therapy may not be necessary in all cases 5.

End-of-Treatment PET-CT

End-of-treatment PET-CT remains essential for final response assessment:

• Post-treatment PET-CT using Deauville criteria has superior specificity (95.7%) compared to conventional CT (76.4%) and predicts overall survival 6.

• Final staging should include PET-CT after completion of all therapy to guide surveillance strategies 3.

Important Caveats and Pitfalls

Immune-Related Considerations

Be aware of immune-related phenomena that can confound PET-CT interpretation:

• Thyroid dysfunction occurred in 15% of NIVAHL patients (predominantly female), which can affect metabolic imaging 2.

• Immune-related adverse events including transaminitis occurred in some patients, potentially affecting hepatic uptake patterns 5.

• Diffusely increased splenic uptake may occur with immune activation and should not automatically be interpreted as disease involvement 7.

Timing Considerations

Optimal timing for interim PET-CT with N-AVD:

• After 2 cycles (4 doses of nivolumab) appears most informative based on NIVAHL data 1.

• Avoid performing PET-CT during active immune-related adverse events or within 10 days of G-CSF administration 7.

Clinical Context

Consider the clinical scenario when ordering interim PET-CT:

• For early-stage unfavorable disease, the NIVAHL protocol achieved 100% overall survival without treatment modifications based on interim PET 2.

• For advanced-stage disease, the S1826 trial demonstrated 93% 3-year PFS with N-AVD, suggesting that routine interim imaging may not alter management 4.

Surveillance Strategy

If interim PET-CT is performed and shows CMR (Deauville ≤3):

• Continue planned N-AVD therapy without modification 1, 2.

If interim PET-CT shows incomplete response (Deauville ≥4):

• Continue planned N-AVD therapy, as escalation options are not established and outcomes remain excellent 1, 2.
• Consider correlation with ctDNA if available, as this may provide additional prognostic information 5.
• Ensure completion of planned therapy unless clear progression is documented 2.