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.