3.

Advantages and disadvantages of methods to diagnose pseudoprogression after immunotherapy

Methods to identify pseudoprogression	Type of tumor	Advantages	Disadvantages
NSCLC, non-small cell lung cancer; IL-8, interleukin-8; US, ultrasonography.
Biopsies of enlarged lesions or new lesions	Enlarged visible lesions that can be biopsied	Can provide the histopathology for the physician to judge the evolution of tumor and guide the clinical practice	Invasive procedure and may be refused by the patient. The biopsy tissue does not represent the whole lesion sometimes
Radiographic follow-up	All kinds of tumors with measurable lesions	Convenient and noninvasive and can avoid a premature discontinued immunotherapy for pseudoprogression	Can accelerate progression if the patient experiences hyperprogression; can impede the use of effective treatments for those who are experiencing true progression
SPION T2-weighted contrast MRI + PET-CT	Suitable for all kinds of tumors (theoretically)	Can distinguish inflammatory cell infiltration from the enlarged tumor tissue	Theoretical method; no clinical studies have been performed to prove its effectiveness
US	Superficial or subcutaneous lesions	Convenient and economical, and can distinguish blood flow volume in the lesions	Reliability can differ depending on the operator
Circulating tumor DNA	Melanoma	Consistent with tumor burden and reflects the dynamic change of the tumor	No current criteria for the diagnosis of pseudoprogression; high costs limit clinical use
Serum IL-8 levels	Tumor cells of patients; positively correlate with tumor burden	Convenient and economical, the dynamic monitor of IL-8 can reflect the change in tumor burden	Theoretical methods; no published clinical studies prove the correlation between IL-8 and pseudoprogression