Abstract |
Lung cancer constitutes the primary cause of mortality associated with malignancy on a global scale, with Non-Small Cell Lung Cancer (NSCLC) being its most prevalent histological subtype. Despite extensive research efforts spanning over three decades, the prognosis of patients with metastatic NSCLC remains poor. The introduction of immunotherapy into clinical practice has revolutionized oncology worldwide. Immunotherapy, delivered in the form of monoclonal antibodies targeting proteins that act as immune checkpoint inhibitors, offers the potential for prolonged remission in a small but significant subset of patients afflicted by a broad spectrum of neoplasms, including NSCLC.
However, following the initial enthusiasm, a plethora of research inquiries emerged as a result of the necessity to enhance the clinical outcomes for our patients. A minority, approximately one-third, of patients receiving immunotherapy for NSCLC will derive clinical benefit from it. Additionally, the mechanisms of primary and acquired resistance to these monoclonal antibodies remain incompletely understood, and there exists a lack of predictive and prognostic biomarkers. Until now, only the levels of PD-L1 protein expression on the surface of cancer cells or immune cells within the tumor microenvironment have been statistically correlated with clinical outcomes in the prospective clinical trials which led to the regulatory approval of these drugs. Considering these aforementioned factors alongside the escalating cost of administering these medications, which places increasing economic strain on national healthcare systems, the identification of essential biomarkers becomes imperative. This is necessary not only for optimizing patient selection for immunotherapy in NSCLC, but also for decoding the mechanisms underlying primary and acquired resistance.
A multitude of clinical, laboratory, and radiological parameters have been linked to the clinical outcome of patients with NSCLC undergoing cytotoxic chemotherapy. Furthermore, pharmaceutical agents such as antibiotics and steroids have been associated with diminished immune response and are frequently administered to patients with neoplasms undergoing immunotherapy. Moreover, factors associated with the pathogenesis of the cancer cachexia syndrome, diagnosed in approximately half of NSCLC patients, have been linked to reduced immune response and susceptibility to infections. Finally, the composition of adipose tissue in the human body has been indicated as a prognostic indicator in cancer patients and a significant regulator of the immune system, primarily in preclinical models.
The objective of this doctoral dissertation was to conduct a prospective observational registry study on patients with NSCLC who received therapy at the Oncology Clinic of the University Hospital of Heraklion. The aim was to explore potential associations between clinical and laboratory factors, as well as the presence of cancer cachexia syndrome and adipose tissue composition, with the clinical outcome of these patients. During the two-year period from November 15, 2017, to November 15, 2019, prospective clinical, laboratory, and radiological data were collected for 83 patients with NSCLC who received immunotherapy at the University Hospital of Heraklion.
The first publication resulting from this study analyzed the clinical and laboratory data of the 66 patients in our cohort who received immunotherapy as a second-line treatment. Prolonged administration of antibiotics (cumulatively for more than 14 days) and the presence
of secondary osteopathic lesions emerged as independent negative predictive factors
for disease stabilization after immunotherapy administration. Furthermore, these factors
were also identified as independent prognostic factors for reduced survival. Interestingly,
administration of antibiotics did not impact patient outcomes; only prolonged administration
had a significant effect. The data were further analyzed using the JADBio artificial
intelligence platform, which identified prolonged antibiotic administration, body mass
index (BMI), and the presence of hepatic and bone metastases as significant factors associated
with an increased likelihood of disease progression, indicating a less favorable
response to immunotherapy. The resulting algorithm demonstrated an ability to predict
disease stabilization probability at approximately 80%. These findings highlighted the pivotal
role of the microbiome in orchestrating an effective immune response, as well as the
adverse impact of the presence of osteopathic secondary lesions on the clinical outcome of
metastatic NSCLC patients receiving immunotherapy.
In the second scientific publication, the impact of cachexia syndrome presence on the
clinical outcome of 83 patients with metastatic NSCLC receiving immunotherapy was
investigated. Patient classification concerning the underlying cachexia syndrome
was based on criteria previously established by the international consensus for this
syndrome’s study in 2011. These criteria included weight loss exceeding 5% during the last
six months before immunotherapy initiation, or any degree of weight loss > 2% and BMI
< 20 kg/m2, or skeletal muscle mass index at the level of the third lumbar vertebra (LSMI)
< 55 cm2/m2 for males and < 39 cm2/m2 for females. LSMI was calculated using computed
tomography images of the abdomen at immunotherapy initiation and every 3 months
thereafter, employing the Slice-O-Matic Tomovision method. Half of the cohort patients
under study were diagnosed with cachexia syndrome. Cachectic patients exhibited statistically
significantly lower response rates to immunotherapy compared to non-cachectic
patients. Furthermore, the presence of cancer cachexia syndrome independently predicted
an increased likelihood of disease progression as the optimal treatment response. Lastly,
cachexia syndrome presence independently predicted reduced survival in patients with
NSCLC receiving immunotherapy. This study, the first prospective investigation into the
effect of cachexia syndrome on the clinical outcome of immunotherapy-treated patients,
revealed that the presence of cancer cachexia syndrome constitutes an independent negative
predictive and prognostic factor in patients with NSCLC undergoing immune checkpoint
inhibitor therapy. Further research at translational and molecular levels concerning the
metabolic dysregulation associated with cachexia syndrome presents a promising avenue
for deciphering the mechanisms underlying both primary and secondary resistance to
immunotherapy.
In the third publication, prospective data from 52 patients in our cohort with sufficient
or appropriate radiological data were analyzed. The objective of this study was to explore
the impact of differential adipose tissue compartment composition and skeletal muscle
tissue density on the therapeutic effectiveness of immunotherapy. Tissue composition was
calculated by measuring the density of different types of adipose tissue (visceral, subcutaneous,
and intramuscular fat) and muscle at the level of the third lumbar vertebra using
computed tomography scans at immunotherapy initiation, applying the Slice-O-Matic
Tomovision technique. Densities were converted into indices [Intramuscular Fat Index (IMFI), Visceral Fat Index (VFI), Subcutaneous Fat Index (SFI), Lumbar Skeletal Muscle
Index (LSMI)] by dividing these values by the patients’ height squared. Patients were classified
dichotomously based on their initial values of IMFI, VFI, and SFI, according to the
median value for their gender. Muscle tissue classification was also dichotomous. The classification
thresholds for LSMI were 55 cm2/m2 for males and 39 cm2/m2 for females, which
were previously established by the international consensus for defining cachexia syndrome
and serving as numerical thresholds for sarcopenia. Patients responding to immunotherapy
had significantly higher SFI distributions compared to non-responders. The presence of
sarcopenia and low subcutaneous fat density index were both significantly correlated with
reduced survival in our cohort patients. An interesting finding was that in the univariate
analysis exploring the correlation of IMFI, VFI, SFI, and LSMI as continuous variables with
patient survival, the only variable that showed a statistically significant positive correlation
was the subcutaneous fat density index. This study, the first prospective investigation into
the effect of adipose tissue distribution on immunotherapy-treated NSCLC patients, highlighted
the potential impact and significant role of subcutaneous adipose tissue density on
immune response against malignancies at a clinical level.
In conclusion, the scientific publications resulting from this doctoral thesis emphasized
the significance of concomitant medications, particularly antibiotic treatment, as well as
secondary bone lesions in the efficacy of immunotherapy in NSCLC patients. Moreover,
the two publications investigating the influence of cachexia syndrome and adipose tissue
distribution represent a “proof of concept” at a clinical level for the predictive and prognostic
importance of metabolic dysregulation as a phenomenon occurring due to neoplastic
processes in patients receiving immune response-modulating therapy. The study examining
cachexia syndrome underscored the central role of advanced cachexia syndrome as a
negative prognostic and predictive biomarker in the current era of immunotherapy. The
results of the third study, revealing the predictive and significant role of subcutaneous fat
density, represent clinical evidence of an additional and underexplored role. Further research
at translational and molecular levels regarding the specific characteristics of the tumor
microenvironment in cachectic patients as well as those with adipose tissue metabolic deregulation
could serve as a pivotal link in the chain for discovering new biomarkers and
therapies aiming to optimize immunotherapy as a cornerstone in cancer management.
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