Immunotherapies that employ immune checkpoint modulators (ICMs) have emerged as an effective treatment for a variety of solid cancers, as well as a paradigm shift in the treatment of cancers. Despite this breakthrough, the median survival time of glioblastoma patients has remained at about 2 years. Therefore, the safety and anti-cancer efficacy of combination therapies that include ICMs are being actively investigated. Because of the distinct mechanisms of ICMs, which restore the immune system’s anti-tumor capacity, unconventional immune-related phenomena are increasingly being reported in terms of tumor response and progression, as well as adverse events. Indeed, immunotherapy response assessments for neuro-oncology (iRANO) play a central role in guiding cancer patient management and define a “wait and see strategy” for patients treated with ICMs in monotherapy with progressive disease on MRI. This article deciphers emerging research trends to ameliorate four challenges unaddressed by the iRANO criteria: (1) patient selection, (2) identification of immune-related phenomena other than pseudoprogression (i.e., hyperprogression, the abscopal effect, immune-related adverse events), (3) response assessment in combination therapies including ICM, and (4) alternatives to MRI. To this end, our article provides a structured approach for standardized selection and reporting of imaging modalities to enable the use of precision medicine by deciphering the characteristics of the tumor and its immune environment. Emerging preclinical or clinical innovations are also discussed as future directions such as immune-specific targeting and implementation of artificial intelligence algorithms.

PurposeThis study aims to predict hematological toxicity induced by 223Ra therapy. We investigated the value of metabolically active bone tumor volume (MBTV) and total bone lesion activity (TLA) calculated on pretreatment fluorine-18-fluorocholine (18F-FCH) PET/CT in castrate-resistant prostate cancer (CRPC) patients with bone metastases treated with 223Ra radionuclide therapy.Patients and methods18F-FCH PET/CT imaging was performed in 15 patients with CRPC before treatment with 223Ra. Bone metastatic disease was quantified on the basis of the maximum standardized uptake value (SUV), total lesion activity (TLA=MBTV×SUVmean), or MBTV/height (MBTV/H) and TLA/H. 18F-FCH PET/CT bone tumor burden and activity were analyzed to identify which parameters could predict hematological toxicity [on hemoglobin (Hb), platelets (PLTs), and lymphocytes] while on 223Ra therapy. Pearson’s correlation was used to identify the correlations between age, prostate-specific antigen, and 18F-FCH PET parameters.ResultsMBTV ranged from 75 to 1259 cm3 (median: 392 cm3). TLA ranged from 342 to 7198 cm3 (median: 1853 cm3). Patients benefited from two to six cycles of 223Ra (n=56 cycles in total). At the end of 223Ra therapy, five of the 15 (33%) patients presented grade 2/3 toxicity on Hb and lymphocytes, whereas three of the 15 (20%) patients presented grade 2/3 PLT toxicity.Age was correlated negatively with both MBTV (r=−0.612, P=0.015) and TLA (r=−0.596, P=0.018). TLA, TLA/H, and MBTV/H predicted hematological toxicity on Hb, whereas TLA/H and MBTV/H predicted toxicity on PLTs at the end of 223Ra cycles. Receiver operating characteristic curve analysis allowed to define the cutoffs for MBTV (915 cm3) and TLA (4198 cm3) predictive for PLT toxicity, with an accuracy of 0.92 and 0.99.ConclusionTumor bone burden calculation is feasible with 18F-FCH PET/CT with freely available open-source software. In this pilot study, baseline 18F-FCH PET/CT markers (TLA, MBTV) have shown abilities to predict Hb and PLT toxicity after 223Ra therapy and could be explored for patient selection and treatment optimization.

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