Discussion

The current study found that the incidence of HPD after treatment with pembrolizumab as a second-line therapy was 9.6%. Higher NLRs and ∆PMMA before treatment with pembrolizumab were associated with a higher risk for the development of HPD. Our results suggest for the first time that in the population of patients who do not respond early to platinum-based chemotherapy, some patients who are at risk for the development of HPD on immunotherapy exist.
ICIs may promote tumor growth kinetics in certain patients and lead to the development of HPD with an incidence in the range from 4% to 29% in different studies [17, 22] There is no uniform definition for HPD, even though some authors still doubt its existence because it is an ad hoc observation [23]. The majority of researchers rely on the rate of target lesion growth for defining HPD [17, 24, 25]. Since this underestimates the rate of development of metastasis, we included in our study involvement of new lesions as a part of the definition for HPD. In conjunction with others, our results suggest that a dramatic increase in tumor growth induced by ICIs is restricted to a relatively small subpopulation of patients, approximately 10% [17, 22]. We could not find any association between HPD and age, sex, PS, PD-L1 status, or number of metastatic sites.
Although how and why HPD occurs are still unclear, our results shed some light on this problem. Our results show that the NLR is an important risk factor for the development of HPD. It is well known that high baseline NLR and PLR values and their derivations are linked significantly with worse OS and PFS in patients with NSCLC treated with ICIs [6, 15]. Although there is no clear explanation for this phenomenon, neutrophils and platelets may promote tumor progression as well as metastases by exercising a direct effect on tumor cells or by indirectly affecting other components of the tumor microenvironment [26, 27]. This effect is achieved through the secretion and release of various chemokines and cytokines, including transforming growth factor-beta, vascular endothelial growth factor, IL-6, IL-8, matrix metalloproteinases and the formation of neutrophil extracellular traps [27]. Neutrophils are considered the most important inflammatory cell population in the tumors of NSCLC patients and promote metastasis, thus potentially compromising the antitumor immune response [28]. Recent studies reported that blood neutrophils, identified by the NLR, were directly linked with the number of intratumoral neutrophil populations, which may have the potential to compromise the antitumor immune response [29]. Lower counts of lymphocytes usually reflect an impairment of cell-mediated immunity. It has been shown that increased infiltration of lymphocytes in the tumor region is associated with better responsiveness to treatment and prognosis in patients with solid tumors [30]. To further complicate the results, it has been shown that activation of tumor lymphocytes could trigger local inflammation and matrix and metabolism modifications that could lead to tumor escape [31]. Moreover, in murine models, it has been shown that HPD is associated with vast infiltration in the tumor microenvironment of primary myeloid cells (mostly precursors of neutrophils and macrophages), which express high levels of activation and inhibitory receptors [32].
Consistent with others, our research finds a positive relationship between sarcopenia and the NLR [33, 34]. Cancer-associated cachexia is a well-known negative prognostic marker with an incidence of up to 40% in the cancer population [35]. Although there are differences in the definitions used for cachexia and sarcopenia, they are often indistinguishable in clinical practice, and cachexia and its key feature inflammation could lead to sarcopenia [36]. It was shown that sarcopenia measured via ∆PMMA with a CT scan at the L3 position is much more reliable than body mass index, and it is widely used, with a variety of cutoff values [16, 37, 38]. A recent report showed that patients receiving immunotherapy may be particularly susceptible to cancer-associated cachexia [39]. This may explain at least in part why in some patients with pre-existing sarcopenia, immunotherapy may induce rapid tumor growth; upregulation of stress hormone production together with preexisting systemic immunosuppression and the presence of high inflammatory markers such as NLR accelerate tumor growth and thus ultimately lead to HPD.
Several limitations were identified in our study. First, our study is retrospective and has a relatively small sample size; therefore, there is potential for bias. Moreover, the predictive value of the NLR and sarcopenia was not compared to that of some genetic predictive markers, such as EGFR , MDM2 and DNMT3A . Similarly, tumor mutational burden was not available. Second, in our study, only 112 patients (67%) were available for evaluation of the ∆PMMA. Finally, due to the vague and unclear definitions of HPD in the literature, our definition for this phenomenon might be criticized.
Despite these limitations, our results suggest for the first time that patients with a high NLR and sarcopenia before immunotherapy are at higher risk for hyperprogression and short overall survival. This may be helpful to clinicians in their choice of treatment, especially for patients who progressed rapidly on platinum-based chemotherapy and with high NLRs and sarcopenia; perhaps a combination of chemotherapy and immunotherapy or new molecules in clinical trials could be used for these patients. Drugs that are capable of transforming neutrophils into a functional state with antitumor activity are needed to improve patient outcomes.
Informed consent: For this type of study, formal consent is not required.
Funding: None declared.
Conflicts of Interest: The authors declare that they have no conflicts of interest.