How to manage suspected pseudoprogression in patients undergoing immunotherapy with checkpoint inhibitors like nivolumab (Opdivo) or pembrolizumab (Keytruda)?

Management of Suspected Pseudoprogression in Immunotherapy

Continue checkpoint inhibitor therapy in clinically stable patients with suspected pseudoprogression and obtain confirmatory imaging 4-8 weeks later to distinguish true progression from pseudoprogression. 1

Clinical Stability Assessment: The Critical Gatekeeper

Before continuing treatment beyond initial radiographic progression, you must establish clinical stability using these specific criteria 1:

• No worsening of performance status from baseline 1
• No clinically relevant increases in disease-related symptoms (pain, dyspnea) requiring increased palliative intervention 1
• No requirement for intensified symptom management including increased analgesia, radiotherapy, or other palliative care 1

If the patient is NOT clinically stable, discontinue immunotherapy immediately - these patients should not continue treatment beyond progression. 1

Confirmatory Imaging Protocol

For clinically stable patients with initial radiographic progression (iUPD):

• Repeat imaging in 4-8 weeks after initial progression is detected 1
• The 4-8 week window ensures patients remain fit for salvage therapies if true progression is confirmed 1
• Longer intervals may be considered only in tumor types where pseudoprogression is well-described (e.g., melanoma with CTLA4 inhibitors), especially when no effective salvage therapies exist 1

Interpreting Confirmatory Scans

Confirmed progression (iCPD) is established when 1:

• Additional new lesions appear on follow-up imaging, OR
• New lesion target measurements increase ≥5 mm from iUPD, OR
• Any increase occurs in new lesion non-target disease, OR
• RECIST 1.1-defined progression occurs in another lesion category 1

The Reality of Pseudoprogression Frequency

Pseudoprogression occurs in fewer than 10% of patients treated with checkpoint inhibitors 1. In melanoma specifically, atypical progression or pseudoprogression using RECIST criteria has been observed in only 7% of patients treated with anti-PD-1 therapy 1. This low frequency means the vast majority of patients showing radiographic progression have true disease progression, not pseudoprogression 1.

Treatment Beyond Confirmed Progression

Continuing immunotherapy beyond confirmed progression is NOT generally recommended 1. The ESMO consensus guidelines explicitly state this with Level III evidence 1.

However, the evidence shows nuance:

• FDA analysis of 2,624 patients treated with pembrolizumab or nivolumab showed subsequent responses in 19% (95/500) of patients treated beyond progression versus 16% (10/64) who were not 1
• Patients treated beyond progression had better prognostic factors (better ECOG performance status, lower LDH) 1
• Overall survival was similar between patients treated beyond progression and those who stopped in the CheckMate 066 trial 1

Shared Decision-Making Requirements

You must discuss imaging findings and the recommendation to continue treatment with the patient before proceeding 1. This conversation should cover:

• The uncertainty of whether this represents pseudoprogression versus true progression
• The risk of continuing ineffective therapy and delaying potentially effective salvage treatment 1
• The low probability (~7-10%) that this represents pseudoprogression 1

Clinical Monitoring During Continued Treatment

Beyond imaging, assess these parameters to detect true progression 2:

• ECOG performance status score - any decline suggests true progression 2
• Cancer pain numerical rating scale - worsening pain indicates progression 2
• Tumor markers - rising levels suggest true progression 2
• Neutrophil-to-lymphocyte ratio - increasing ratios may indicate progression 2

Common Pitfalls to Avoid

Do not continue treatment in clinically unstable patients - this is the most critical error, as it delays effective salvage therapy and may render patients too unfit for subsequent treatment 1. The guideline explicitly states that treatment past true progression "could reduce subsequent effective therapies if the patient is no longer fit enough to tolerate any further treatment" 1.

Do not wait longer than 8 weeks for confirmatory imaging in most cases - this timeframe balances the need to identify pseudoprogression against the risk of disease progression making patients unfit for salvage therapy 1.

Do not assume imaging alone tells the complete story - clinical assessment remains paramount, as pseudoprogression can occur with clinical improvement despite radiographic worsening 2, 3.

Special Considerations for Rechallenge

If a patient completes the maximum protocol-defined cycles and later progresses, rechallenge with the same checkpoint inhibitor shows clinical benefit in 70% of patients 4. This benefit is primarily restricted to patients who progress ≥1 year after stopping treatment and who were previously responsive to checkpoint inhibitors 4.