Stage IV NSCLC: Pathophysiology, Symptoms, and Prognosis

Q1... (Answer)
Stage – IV NSCLC (non-small cell lung cancer) is regarded as an advanced stage of
pulmonary cancer associated with metastatic invasion (Myers & Wallen 2019). NSCLC is
categorized into large cell carcinoma, squamous cell carcinoma, and adenocarcinoma that
variably impact the normal physiological function of the pulmonary lobes, thereby causing
chest pain and shortness of breath in the affected patient (Cappiello 2012, p. 6). The stage –
IV NSCLC rapidly metastasizes to various body organs including the vertebral column,
esophagus, trachea, great vessels, mediastinum, bronchi, pericardium, diaphragm, pleura, and
liver. The stage – IV NSCLC cancer cells invade the contralateral lung after affecting
mediastinal and peribronchial lymph nodes. Adenocarcinoma invades the peripheral
pulmonary location and causes the development of inflammation, wounds, and scars across
the lung surface. The squamous cell lung carcinoma invades the proximal bronchus and
pulmonary cavity. The exfoliation tendency of NSCLC with hypercalcemia is responsible for
its metastasis to other significant body organs. The pathophysiological mechanisms of
NSCLC utilize PD-L1 (Programmed death-ligand 1) protein in the context of minimizing the
normal physiological response of T cells against the cancer cells (Zappa & Mousa 2016).
This eventually elevates the scope of lung cancer metastasis to other vital organs. The large-
cell lung carcinoma leads to the development of focal necrosis and atypical cells. The
undifferentiated cancer cells predominantly cause pulmonary fibrosis that directly impacts
vital capacity, tidal volume, and total lung capacity of the affected patient. These pathological
outcomes drastically impact the breathing capacity of the affected patient. Nigel in the
presented case experiences similar pathophysiological changes across the pulmonary surface
that lead to the development of chest pain and shortness of breath. Shortness of breath in
Nigel’s case proves to be a prognostic determinant of his NSCLC. Dyspnea in NSCLC is
predicted through a substantial deterioration in the patient’s pulmonary function. The
reduction in residual volume, forced vital capacity, forced expiratory ratio, forced expiratory
flow, and carbon monoxide diffusion capacity of the NSCLC patient’s lungs markedly
deteriorates his breathing potential (Ban et al. 2016). Dyspnea/shortness of breath in this
manner indicates the most advanced form of pulmonary cancer. Stage – IV NSCLC manifests
with the development of numerous metastatic nodules across pancreas body, right
supraclavicular lymph nodes, and left lower/upper pulmonary lobes (Lee et al. 2013). The
locoregional dissemination of NSCLC cells the cardiac structure and superior vena cava leads
to the development of chest pain and shortness of breath in the affected patient (Holgersson

2017). Accordingly, Nigel’s shortness of breath/breathing difficulty in the presented scenario
reveals the advanced form of his pulmonary cancer (i.e. Stage – IV NSCLC).
Q2... (Answer)
Cisplatin IV administration to the stage IV NSCLC patient substantially elevates his platinum
concentration inside the pancreas, testicle, muscle, kidney prostate, and liver (Johnstone,
Suntharalingam & Lippard 2016). Hepatic metastasis in the presented context substantially
elevates the patient’s platinum concentration across the liver cells. This abnormal elevation of
platinum concentration inside the liver cells impacts the hepatic first-pass metabolism of
cisplatin in a manner to increase the maximum platinum RBC concentration within 1.5-2.5
hours of its administration. Similarly, the hepatic metastasis reduces the terminal half-life of
cisplatin to 36-47 days following a biphasic trend. The deteriorated hepatic first-pass
metabolism and hepatic enzymes’ elevation (under the impact of secondary liver cancer) in
the presented scenario will delay the metabolic processing of cisplatin and its urinary
excretion (Astolfi et al. 2013). This will eventually elevate systemic toxicity and related
clinical complications for Nigel in the presented scenario. The hepatic impairment under the
impact of secondary liver metastasis in the presented scenario will lead to a 27% reduction in
docetaxel’s total body clearance (FDA_Docetaxel 2013). This outcome could eventually
increase the systemic exposure of docetaxel to 38%. The defects in hepatic functionality that
lead to a two-fold elevation of AST, ALT, and alkaline phosphatase in levels in NSCLC
patient significantly delay the first-pass metabolism of docetaxel, thereby leading to its
systemic toxicity. Furthermore, a substantial decrease in the first pass liver metabolism in the
patient’s Stage – IV NSCLC/secondary liver metastasis under the impact of hepatic cell mass
reduction leads to a multi-fold elevation in morphine’s total systemic bioavailability
(Soleimanpour et al. 2016). This defect induces 70% elevation in the systemic bioavailability
of morphine in the NSCLC patient. The elevated serum concentration of morphine in this
scenario substantially delays its elimination half-life, thereby increasing the risk of adverse
events. The hepatic impairment under the impact of liver metastasis deteriorates/delays the
half-life or clearance of ondansetron, which is otherwise recorded as 5.7 hours (CCF 2012).
Hepatic insufficiency in secondary liver carcinoma elevates absolute bioavailability of
ondansetron to a considerable extent. Furthermore, severe hepatic impairment reduces the
hepatic first-pass metabolism that eventually impacts the bonding percentage of ondansetron
with plasma proteins (GlaxoSmithKline_Australia 2012). The reduced ondansetron clearance
under the impact of hepatic insufficiency warrants the reduction of its dosage to 0.15mg/kg in

the presented scenario. Dexamethasone is prevalently used in the context of minimizing
cancer-related pain in NSCLC and secondary liver metastasis. Secondary hepatic metastasis
in Nigel’s case substantially elevates the half-life of dexamethasone while reducing its
mineralocorticoid outcomes. The defected first-pass hepatic metabolism in the presented case
will not only elevate the bioavailability of dexamethasone but also increase the risk of toxic
reactions that may lead to the development of hypoadrenalism, psychotomimetic effects,
immunocompromise, and myopathy (Kumar & Panda 2014). Accordingly, a reduced dosage
of dexamethasone is recommended in the context of inducing its anti-estrogenic effect in
non-small cell lung cancer cases (Wang et al. 2016).
Q3... (Answer)
Cisplatin therapy in the presented case is recommended for Nigel based on his adverse stage
– IV NSCLC prognosis (Socinski et al. 2013). Cisplatin exhibits a half-life of 20-30 minutes
after its intravenous administration. The 7-hourly and 2-hourly infusions of cisplatin are
followed by its monoexponential decay. The distribution volumes and total-body clearances
of cisplatin are reportedly recorded as 11-12L/m2 and 15-16L/h/m2 respectively
(FDA_Cisplatin 2015). The nucleophiles in the human body effectively displace cisplatin’s
chlorine atoms. Furthermore, the predominant molecular species of cisplatin at 0.1M
concentration interact with proteins, amino acids, and sulfhydryl groups, thereby leading to
its biological instability. The ratio of total free platinum to cisplatin across the blood plasma
substantially varies between 0.5-1.1 in accordance with the administered dosage
(FDA_Cisplatin 2015). The absence of reversible and instantaneous plasma protein binding
of cisplatin differentiates this drug from other similar medicines. Contrarily, cisplatin’s
platinum interacts with plasma proteins including gamma globulin, transferrin, and albumin.
The protein binding of 90% plasma platinum occurs after two hours of cisplatin
administration. The peak platinum concentration after cisplatin administration is recorded in
various body organs (FDA_Cisplatin 2015). The active secretion of platinum-containing
molecules inside renal cells is based on the rapid ultrafiltrable platinum’s renal clearance that
defeats the overall rate of glomerular filtration. The dose-dependent, variable, and non-linear
clearance of free platinum reciprocate with individual variability and urine flow rate under
the impact of tubular reabsorption and active secretion (FDA_Cisplatin 2015). Cisplatin in
the presented scenario will arrest NSCLC’s G2/M cell cycle in the context of minimizing the
differentiation of cancer cells (Sarin et al. 2017). Docetaxel in Nigel’s case will potentially
impact his microtubular network of the lung cancer cells in the context of deteriorating their

interphase cellular and mitotic functions. The binding of docetaxel with free tubulin will be
based on the configuration of microtubules bundles with the core objective of challenging the
mitotic processes of the lung cancer cells. Docetaxel a mean body clearance and half-lives of
21 L/h/m2 and 11.1 hours respectively (FDA_Docetaxel_Injection 2012). Approximately
97% of docetaxel binds with the plasma protein in the lung cancer patient. Dexamethasone
has no impact on docetaxel protein binding pattern (FDA_Morphine_IV 2011). CYP3A4
isoenzyme effectively metabolizes docetaxel under the impact of cytochrome P450 3A4.
Most of the docetaxel is excreted through feces under the impact of tertbutyl ester group’s
oxidative metabolism (FDA_Docetaxel_Injection 2012). Morphine IV in the presented
scenario will selectively interact with the mu receptor in the context of producing the desired
analgesia. The analgesic effects of morphine will be based on its interaction with endogenous
compounds and CNS opiate receptors (FDA_Morphine_IV 2011). Morphine will also
interact with respiratory centers in the brain stem in the context of inducing respiratory
depression. Morphine in the presented context will exhibit 54% and 36% muscle tissue
binding and protein binding respectively. 2-12% excretion of morphine will occur through
the patient’s kidneys. However, the terminal half-life of morphine will be based on 1.5-4.5
hours (FDA_Morphine_IV 2011). Furthermore, hepatic glucuronidation will facilitate the
overall clearance of morphine from the patient’s body. Ondansetron in the presented context
will block serotonin secretion and deteriorate the functionality of 5-HT3 receptors to
minimize/prevent the frequency of nausea and vomiting (AGDOH_TGA 2014). Hepatic
cytochrome P-450 enzymes effectively metabolize ondansetron in the patient’s body.
Ondansetron in the presented scenario will exhibit plasma clearance, mean elimination half-
life, and peak plasma concentration of 0.262L/h/kg, 5.5 hours, and 170ng/mL respectively.
Dexamethasone in the presented case will initiate its pharmacodynamic action within a short
duration based on its half-life of 120-140 minutes (Pub_Chem 2019). The anti-inflammatory
and metabolic impact of dexamethasone will substantially modify the patient’s immune
system response to his lung cancer cells in the presented context. This will effectively prevent
the occurrence of fluid/hypersensitivity reactions and related clinical complications (Chouhan
& Herrington 2011).
Q4... (Answer)
Cisplatin in the presented scenario will interact with sulfhydryl and water groups in the
context of displacing its chloride atoms (Nath et al. 2017). The integration of the unionized
form of cisplatin across the lung cell lines is based on the elevated plasma chloride