What is pseudo‑progression in a patient receiving immune‑checkpoint inhibitor therapy who shows radiologic tumor growth but remains clinically stable (no new symptoms, stable performance status, and no laboratory evidence of disease acceleration)?

Understanding Pseudoprogression in Immunotherapy

Pseudoprogression is an initial increase in tumor size or appearance of new lesions on imaging that mimics disease progression, but is followed by subsequent tumor stabilization or shrinkage—it represents an actual therapeutic response rather than treatment failure. 1

The Core Definition

Pseudoprogression occurs when imaging studies show progressive disease by standard RECIST 1.1 criteria (new target lesions, unequivocal progression of non-target lesions, or increase in sum of target lesion measurements), but continued follow-up imaging demonstrates stabilization or regression of these same lesions. 1 This phenomenon typically occurs in patients who remain symptomatically stable or even improving clinically despite radiographic worsening. 1

The mechanism involves infiltration of inflammatory cells and immune-mediated edema causing temporary lesion enlargement, followed by delayed tumor cell destruction. 1

Clinical Context and Frequency

The actual incidence of pseudoprogression is lower than many clinicians expect:

• Occurs in fewer than 10% of patients treated with checkpoint inhibitors overall 2
• In melanoma specifically, only 7% of patients treated with anti-PD-1 therapy experience atypical progression or pseudoprogression 2
• In non-small cell lung cancer, pooled data shows up to 8% of patients treated beyond RECIST-defined progression had subsequent partial responses 1
• One lung cancer series reported pseudoprogression in 12.2% of patients treated with nivolumab, most commonly within the first 12 weeks (fourth cycle) 3

Distinguishing Features from True Progression

Key clinical indicators that suggest pseudoprogression rather than true progression include: 1

• Stable or improved clinical condition
• No worsening of performance status from baseline 2
• Absence of new or worsening disease-related symptoms
• No requirement for intensified symptom management 2
• No severe laboratory abnormalities
• Lack of clinically significant additional progression on confirmatory imaging 1

The Confirmatory Imaging Approach

When pseudoprogression is suspected, obtain repeat imaging in 4-8 weeks after initial progression is detected. 2 This timeframe balances the need to identify pseudoprogression against the risk of allowing true progression to advance to the point where patients become unfit for salvage therapy. 2

True progression is confirmed when: 2

• Additional new lesions appear on follow-up imaging, OR
• New lesion target measurements increase ≥5 mm from initial progression

The modified iRECIST criteria were specifically designed to capture pseudoprogression by requiring confirmatory imaging (CT2) before declaring definitive progression. 1

Management Algorithm

For clinically stable patients with radiographic progression:

1. Assess clinical stability using the specific criteria above (performance status, symptoms, laboratory values) 2

2. If clinically stable: Continue immunotherapy and obtain confirmatory imaging in 4-8 weeks 2

3. If clinically unstable: Discontinue immunotherapy immediately—continuing treatment beyond progression is not recommended for unstable patients 2

4. Before continuing treatment: Engage in shared decision-making with the patient, discussing the uncertainty of pseudoprogression versus true progression, the risk of continuing ineffective therapy, and the low probability (<10%) that pseudoprogression is actually occurring 2

Critical Pitfalls to Avoid

Do not wait longer than 8 weeks for confirmatory imaging in most cases, as prolonged delays risk disease progression that renders patients unfit for subsequent effective therapies. 2 The European Society for Medical Oncology explicitly warns that "treatment past true progression could reduce subsequent effective therapies if the patient is no longer fit enough to tolerate any further treatment." 2

Do not assume pseudoprogression is common. Given its occurrence in fewer than 10% of patients, the default assumption should be true progression unless clinical stability strongly suggests otherwise. 2

Continuing immunotherapy beyond confirmed progression is NOT generally recommended according to European Society for Medical Oncology consensus guidelines (Level III evidence). 2 While FDA analysis showed subsequent responses in 19% of patients treated beyond progression, this must be weighed against the risk of delaying effective salvage therapy. 2

Emerging Diagnostic Tools

Ultrasonography may help differentiate pseudoprogression from true progression by detecting reduced tumor blood flow (approximately 20% reduction within 50 days) even when tumor size increases, preceding eventual tumor shrinkage by about 100 days. 4 This can be particularly useful for accessible lesions such as regional lymph nodes or subcutaneous metastases. 4

Novel biomarkers including circulating tumor DNA (ctDNA) and IL-8 levels are being investigated to identify pseudoprogression earlier, though these are not yet standard practice. 5, 6