[¹⁸F]FAPI PET/CT outperforms [¹⁸F]FDG in distinguishing nodal immune flare from lymph node metastases during immunotherapy for lung cancer.

Abstract

Nodal immune flare (NIF) is an immune-related adverse event affecting lymph nodes after lung cancer immunotherapy. Differentiating NIF from lymph node metastasis using [¹⁸F] fluorodeoxyglucose ([¹⁸F]FDG) is challenging. This study aimed to evaluate whether [¹⁸F] fibroblast activation protein inhibitor ([¹⁸F]FAPI), a novel tracer targeting fibroblast activation protein (FAP), can distinguish NIF from lymph node metastasis after immunotherapy. We retrospectively enrolled 589 lung cancer patients who received immunotherapy and subsequently underwent restaging by [¹⁸F]FDG PET/CT. Maximum standard uptake value (SUV_max) and false-positive rates were compared in 21 patients who underwent both [¹⁸F]FDG and [¹⁸F]FAPI. Immunohistochemistry for FAP, CD4 + and CD8 + T cells was performed. NIF occurred in 37 of 589 patients (6.3%) with a median onset time of 5.0 months. A total of 279 regional lymph nodes showed increased [¹⁸F]FDG uptake (median SUV_max 6.5). [¹⁸F]FDG demonstrated high false-positive rates for NIF (100% per patient, 93.3% per region). However, [¹⁸F]FAPI SUV_max in NIF was significantly lower than [¹⁸F]FDG (1.5 vs. 6.5; P < 0.001), reducing the false-positive rate to 33.3% per patient and 14.1% per region. After immunotherapy, both NIF and lymph node metastases showed prominent infiltration of CD4 + and CD8 + T cells, along with increased [¹⁸F]FDG uptake (all P > 0.05), indicating that a T-cell dominated inflammatory microenvironment underlies the elevated [¹⁸F]FDG uptake. In contrast, FAP expression and [¹⁸F]FAPI uptake were significantly lower in NIF than in lymph node metastases (P < 0.05), suggesting the absence of marked FAP in NIF. After immunotherapy in lung cancer, [¹⁸F]FAPI PET/CT outperforms [¹⁸F]FDG PET/CT in distinguishing NIF from lymph node metastases, reflecting a T-cell driven inflammatory microenvironment with low FAP expression in NIF. the Chinese Clinical Trial Registry: ChiCTR2100044944 (Registered: 1 April 2021, retrospectively registered, https://www.chictr.org.cn/showprojEN.html?proj=123995 ).