Pseudoprogression and hyperprogression in lung cancer: a comprehensive review of literature

Abstract

Purpose: Immune checkpoint inhibitors are associated with clinical benefit in lung cancer. However, response patterns to immunotherapy, including pseudoprogression and hyperprogression, are difficult to diagnose, and their mechanisms remain unclear. This review aimed to describe two response patterns observed in lung cancer, namely pseudoprogression and hyperprogression, including their epidemiology, diagnostic characteristics, and plausible mechanisms.

Methods: We performed a comprehensive literature search in the PubMed database, using keywords "pseudoprogression", "hyperprogression", and "lung cancer", among others. The literature was examined for pseudoprogression and hyperprogression characteristics and plausible mechanisms.

Results: Pseudoprogression manifests in multiple forms; however, the immune system-related response criteria and biopsy data are helpful to make accurate diagnosis. Serological biomarkers, such as neutrophil-to-lymphocyte ratio (NLR) and circulating tumor DNA (ctDNA), might help distinguish pseudoprogression from true progression. The incidence of hyperprogression ranges within 5-19.2%, depending on definition. The unique response pattern of rapid progression is observed not only with immunotherapy, but also with other treatment regimens. Molecular mutations and amplifications may result in hyperprogression; however, the exact mechanism remains unclear.

Conclusion: Atypical response patterns, such as pseudoprogression and hyperprogression, are increasingly common in clinical practice. Immune-related response criteria can help diagnose pseudoprogression. Molecular mechanisms of hyperprogression remain unclear. Biomarkers for pseudoprogression and hyperprogression are required.

Keywords: Hyperprogression; Immunotherapy; Lung cancer; Pseudoprogression.

Fig. 1

a The difference between pseudoprogression and hyperprogression. Pseudoprogression is characterized by an initial increase in tumor size always followed by subsequent shrinkage during immunotherapy, while hyperprogression is manifested as continuous and rapid growth of tumor lesion. b Potential mechanism of hyperprogression. The blockade of PD-1/PD-L1 axis might lead to: (a) the extensive expansion of Treg cells, excessive contrasuppression breaks the homeostatic host–cancer cell equilibrium resulting in Teff inactivation (Champiat et al. 2018); (b) compensatory upregulation of other immune checkpoints and modulators, such as TIM3 (Ellestad et al. 2014), CD80 (Champiat et al. 2018), CTLA-4 and LAG3 (Huang et al. 2017); (c) the aberrant inflammation induced by Th1 and Th17 (Dulos et al. 2012), and IL-10 complementary release (Lamichhane et al. 2017); (d) the secretion of immunosuppressive cytokines resulting from the aberrant polarization of M2 macrophages (Mantovani and Sica 2010), dendritic cells (DCs) (Lamichhane et al. 2017) and myeloid-derived suppressor cells (MDSCs) (Huang et al. 2006)