Potentials of Non-Invasive 18F-FDG PET/CT in Immunotherapy Prediction for Non-Small Cell Lung Cancer

Abstract

The immune checkpoint inhibitors (ICIs), by targeting cytotoxic-T-lymphocyte-associated protein 4, programmed cell death 1 (PD-1), or PD-ligand 1, have dramatically changed the natural history of several cancers, including non-small cell lung cancer (NSCLC). There are unusual response manifestations (such as pseudo-progression, hyper-progression, and immune-related adverse events) observed in patients with ICIs because of the unique mechanisms of these agents. These specific situations challenge response and prognostic assessment to ICIs challenging. This review demonstrates how ¹⁸F-FDG PET/CT can help identify these unusual response patterns in a non-invasive and effective way. Then, a series of semi-quantitative parameters derived from ¹⁸F-FDG PET/CT are introduced. These indexes have been recognized as the non-invasive biomarkers to predicting the efficacy of ICIs and survival of NSCLC patients according to the latest clinical studies. Moreover, the current situation regarding the functional criteria based on ¹⁸F-FDG PET/CT for immunotherapeutic response assessment is presented and analyzed. Although the criteria based on ¹⁸F-FDG PET/CT proposed some resolutions to overcome limitations of morphologic criteria in the assessment of tumor response to ICIs, further researches should be performed to validate and improve these assessing systems. Then, the last part in this review displays the present status and a perspective of novel specific PET probes targeting key molecules relevant to immunotherapy in prediction and response assessment.

Keywords: FDG; NSCLC; PET/CT; immune checkpoint inhibitors (ICI); immunotherapy; lung cancer; prognosis; response.

FIGURE 1

A 58-year-old male patient with metastatic intrahepatic cholangiocarcinoma was treated with the third line of ipilimumab. After four cycles of treatment, compared with ¹⁸F-FDG PET/CT maximum intensity projection (MIP) image (A) before treatment, the posttreatment ¹⁸F-FDG PET/CT (B-D), (I,J) demonstrates the following: 1) multiple soft tissue density nodules in the peritoneum, which were larger in volume and higher in FDG uptake than before ((A,B) hollow arrows); 2) multiple nodules without FDG uptake in both lungs, some of which are larger in volume than before and some of which have no change compared with before (cannot be shown in MIP images- (A,B)); 3) the lymph nodes with increased FDG uptake in mediastinal areas and bilateral hilar, which were smaller in volume and FDG-uptake lower than before ((A,B) hollow triangles); and 4) multiple foci of increased FDG uptake in bones: the FDG-uptake degree in vertebral body of lumbar 4 was significantly lower than before ((A) gray triangle); the right acetabular lesion was the new lesion ((B) gray triangle); the remaining ostial lesions were higher than those before ((A,B) black line arrows). According to PERCIMT criteron: SMD was confirmed for the number of the newly FDG-positive lesions is less than 4. Meanwhile, in the light of imPERCIST5, PMD was also evaluated for the sum of SUL_peak of the patient’s top five target lesions after treatment was more than 30% higher than that of the top five target lesions before treatment. As a result of clinical follow-up, the patient was confirmed PD and those lesion above were validated as metastases. PD was determined for the appearance of new lesion based on PECRIT. PMD was determined for new FDG-avid lesion at SCAN-2, which can be considered as UPMD in the line with iPERCIST. But the patient didn’t receive the next ¹⁸F-FDG PET/CT between days 21 and 28 after treatment or 4–8 weeks later, so it could not be evaluated according to PECRIT and iPERCIST. Follow-up results showed the PFS for ICI was 6 months. Additionally, this posttreatment PET/CT displayed: 1) newly patchy ground glass density foci in both lungs, with increased FDG uptake (C- PET axial image, D-CT axial image); 2) diffuse increased FDG uptake in ascending colon, transverse colon, descending colon, sigmoid colon and rectum (i-PET axial image) which is new compared with the previous one, and the corresponding colonic walls were not significantly thickened ((J)-CT axial image). The patchy ground glass shadows of both lungs gradually disappeared during chest CT follow-up ((E–H)-CT axial images). Combined with clinical information, the patchy ground glass shadows of both lungs were diagnosed as immunerelated pneumonia. Under the administration of MDT, the diffuse increase of glucose metabolism in the colon was considered as immune-related colitis.