Stage IV NSCLC: Pathophysiology, Symptoms, and Prognosis

This article provides an in-depth understanding of the pathophysiology, symptoms, and prognosis of stage IV NSCLC (non-small cell lung cancer). It explores the impact of metastasis on various body organs and discusses the prognostic determinants of the disease. The article also highlights the role of dyspnea as an indicator of advanced pulmonary cancer.

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

concentration. The displacement of cisplatin complex’s chloride ligands by water leads to the
configuration of highly lethal platinum complexes. Eventually, the binding of cisplatin
molecule with the DNA of lung cancer cells potentially ceases the synthesis of their RNA,
protein, and DNA. The cytotoxic nature of cisplatin induces the formation of cross-links (i.e.
interstrand and intrastrand) across the length of lung cancer cells’ DNA molecules (Zhu,
Song & Lippard 2013). Several mutations in the cancer cells under the impact of cisplatin
induces their apoptosis and extinction. Cisplatin also exhibits antimicrobial, radiosensitizing,
immunosuppressive, and bifunctional alkylating properties (Liu et al. 2018). Contrarily,
nivolumab in an anticancer agent that interacts with various T cell receptors (including PD-
L2 [programmed death ligand-2], PD-L1[programmed death ligand-1], and PD-1
[programmed cell death protein]) in the context of promoting cytokine production and T cell
proliferation (FDA_Nivolumab_Injection 2018). This drug does not modify the lung cancer
cells at the genetic level but elevates the potential of the immune system in the context of
enhancing its anti-tumor response. Nivolumab challenges PD-1 ligands’ upregulation while
modifying the tumor signaling pathways in a manner to promote the immune surveillance of
cancer cells by the active T cells. G4 (IgG4) human immunoglobulin monoclonal antibody or
nivolumab challenges the interaction of PD-1 receptors with PD-L2 and PD-L1 receptors that
induces the PD-1 pathway-related anticancer immune outcomes in the lung cancer patient
(FDA_Nivolumab_Injection 2018). The substantial cessation of PD-1 functionality reduces
the pace of cancer cells’ growth in stage – IV NSCLC patient. Docetaxel on the other hand
neither targets the immune system of the patient nor directly disfigures the chromosomal
function of the cancer cell lines (DrugBank 2019). This drug, however, utilizes its anti-
mitotic potential and reversibly integrates with cancer cells’ microtubules in the context of
challenging their growth pattern. Docetaxel potentially elevates the structural stability of
microtubules in a manner to disrupt the cancer cell capacity of utilizing their cytoskeleton for
tumor progression (DrugBank 2019). The beta subunit of microtubule’s tubulin proves to be
the preliminary target of docetaxel in the cancer patient (DrugBank 2019). The docetaxel-
microtubule complex proves to be a dynamically stable structure that does not allow the
disintegration of microtubules in the lung cancer patient (DrugBank 2019). The dynamic
instability of the microtubule is a prerequisite for their transportation function across the
cancer cell lines. Their stabilization directly impacts the mitotic division/differentiation of
cancer cells in the affected patient (DrugBank 2019).

Q5… (Answer)
Cisplatin administration to lung cancer patient leads to the development of nausea and
vomiting through 5HT-3 receptor mediation (Ranganath, Einhorn & Albany 2015). Cisplatin
administration induces anticipatory, delayed or acute, refractory, and breakthrough
vomiting/nausea in the cancer patient. The late acute nausea/vomiting develop after 12-24
hours of cisplatin administration. However, acute nausea/vomiting reportedly occurs after 12
hours of cisplatin injection to the lung cancer patient. Poor emetic control and dizziness lead
to the development of anticipatory nausea/vomiting prior during cisplatin chemotherapy
(Kamen et al. 2014). Nausea and vomiting episodes in relation to chemotherapy
administration usually occur under the impact of conditioned responses that initiate through
various environmental, olfactory, gustatory, and visual factors. Cisplatin predominantly
deactivates the functionality of intestinal mucosa’s mucus barrier under its lethal effect that
eventually leads to the development of mucositis. Cisplatin also impacts the PGM34-positive
goblet cell numbers as well as the villus height across the GI (gastrointestinal) tract
(Yamamoto et al. 2013). The eventual reduction in the physiological defense mechanism of
the intestinal mucosa leads to the development of GI complications, including nausea and
vomiting. Docetaxel predominantly leads to the initiation of neutropenic enterocolitis, colitis,
enterocolitis, dehydration, and resultant gastrointestinal perforation in the cancer patient (Ho
& Mackey 2014). Cisplatin administration leads to the development of esophageal ulceration,
colonic ulceration, and stomatitis that eventually lead to the development of nausea,
vomiting, anorexia, diarrhea, and other gastrointestinal complications (Boussios et al. 2012).
The administration of nivolumab to the cancer patient predominantly causes the development
of gastrointestinal adverse events including colitis, gastrointestinal reflux disease, and
diarrhea (Boike & Dejulio 2017). The development of intestinal infection under the impact of
nivolumab is based on lymphocytic infiltration across intestinal epithelium and lamina
propria. This eventually leads to the spontaneous bowel perforation under the sustained
impact of transmural inflammation (Boike & Dejulio 2017). These gastrointestinal
complications eventually lead to the clinical symptoms of nausea and vomiting in the treated
lung cancer patient.

Q6… (Answer)
Rapid IV administration of morphine to the presented lung cancer patient might cause the
development of chest wall rigidity and respiratory depression (FDA_Morphine_IV 2011).
This could occur under the impact of morphine’s central nervous system (CNS) depression
capacity that substantially elevates the risk of coma, sedation, hypotension, and respiratory
depression (FDA_Morphine_IV 2011). Eventually, the patient could exhibit respiratory
manifestations including hypercapnia, hypoxia, and breathing difficulty (Boom et al. 2012).
The initiation of morphine-induced respiratory depression in the presented case could be the
outcome of μ-opioid receptor activation across various CNS location including pons
(respiratory rhythm generating location) and pre-Bötzinger complex (Boom et al. 2012). The
extent of respiratory depression will be based on the morphine transfer rate and related
offset/onset profiles across the receptor location. The morphine-induced respiratory
depression in the presented case scenario will require the intramuscular administration of
naloxone (i.e. opioid receptor antagonist) in accordance with its limited elimination half-life
of thirty minutes (Boom et al. 2012). Morphine’s receptor kinetics in the presented case will
prove to be the rate-limiting factor in the context of reversing its respiratory depression
outcome. The slow and continuous administration of naloxone will minimize the intensity of
morphine-induced respiratory depression complications in the treated patient (Boom et al.
2012). However, naloxone administration in the presented scenario will not only reverse the
respiratory depression effect of morphine but also minimize its analgesic effect. Therefore,
the clinician could consider the coadministration of microglia cell stabilizers with naloxone
injection in the context of maintaining the analgesic efficacy of morphine while minimizing
its respiratory depression effect (Boom et al. 2012).

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