Chemotherapy Toxicity

This presentation details the basics of cancer, chemotherapy, and toxicity associated with chemotherapeutic drugs.

1. Chemotherapy
Toxicity
Ashley Chow, Rachel Conklin, Selina
Darmalingum, Nhi Diep, Mary Jeane Fenn,
Ariella Inzunza, Carly Kuzma, Michelle
Lavrichenko, Michael Lim, Carly Mackay, Fatima
Malik

2. Cancer - >15.5 Million Americans have
experienced cancer by 1/1/2016
●Group of disease characterized by
uncontrollable growth and spread of
abnormal cells
●If left untreated → death
●Childhood cancer causes are normally
unknown
●Established cancer causes
○External Factors (lifestyle, tobacco,
obesity, alcohol)
○Internal factors (nonmodifiable gene
defects, hormones, immune
conditions)
●Cancer growth can go undetectable
for 10+ years after exposure
Prevention
●Large amount of cancers could be
prevented
●190,500k of the 600,920 deaths in the
US caused by cancer were the result of
cigarette smoking
●HPV, HBV, HCV and HIV can be
prevented via
○Behavioral changes
○Vaccination
○Treatment of infection

3. Cancer - Cases and Deaths

4. Treatment Options
●Depends on the cancer, where it started and how much it has spread
●Sometimes said treatments aren’t for curing the cancer, more for control of symptoms
and slowing growth
●Goal: Best quality of life
●Can include
○Surgery (removal of tumor)
○Targeted therapy
○Hormonal therapy
○Radiation
○Chemotherapy

5. Chemotherapy
●Used to kill cancer cells
●ROA - IV, IM or PO
●Once it reaches the bloodstream, it spreads and “shrinks the cancer” → alleviation of
symptoms; prolonging life; prevention of further metastasis by targeting different stages
of the cell cycle
●Sometimes used alone or in combo in order to
○Shrink tumors prior to radiation or surgery
○After surgery or radiation to kill the remainder of the cancer cells
○If the cancer returns
●Side Effects
○Infections - caused by cancer itself in combination with treatment (immunosuppression)
○Neuropathy; Acute Renal Failure
○Hepatotoxicity
○Neurotoxicity
○Chemobrain
○Others - Heart, lung and heme

6. Immune System Purpose
●The immune system neutralizes foreign
substances that enter the body such as bacteria,
viruses and other organisms
●Must differentiate between self and nonself
antigens
●Consists of the innate and adaptive immune
systems which work together to clear the body of
xenobiotics.

7. Immune toxicity
Results of Toxicity -
●Immunosuppression
●Endocrine Dysfunction
●Inflammatory bowel disease
●Pruritus and skin rashes
●Interference with DNA replication and incomplete cell division
●Attack on self antigens leading to autoimmune diseases
●Hemorrhagic cystitis
●Depletion of B and T cells.

8. Chemotherapy Drugs That Affect the
Immune System - Check-Point Inhibitors
●Ipilimumab and Nivolumab are drugs used for
cytotoxic immunotherapy in malignant melanoma.
●Ipilimumab acts as an anti cytotoxic T lymphocyte
associated antigen 4 (CTLA-4) antibody.
●Ipilimumab is associated with severe toxicity such as
skin rashes and autoimmune diseases.
●Nivolumab is a second class PD-1 inhibitor with a
favorable toxicity profile
●Its toxicities include interstitial pneumonia, colitis,
and vitiligo.

9. Immune System Toxicity -
Cyclophosphamide
●An alkylating agent part of the oxazaphosphorine
group
●Mechanism of Action:
-Introduces alkyl radicals into the DNA strand
-Causes DNA cross-linkage
-Interferes with DNA replication
-DNA is unable to complete the process of cell
division
●Toxicity:
-Kills cancer cells along with some replicating
healthy cells
-Decreases number of B and T cells in peripheral
blood and lymphatic tissue
-Decreases number of macrophages at sites of
inflammation
-Results in undesired immunosuppression

10. Main Kidney Functions

●Regulation of…
○Body fluids
○Blood concentration
○pH
○Osmolarity
○Hormone secretion
○Urine concentration and excretion
of waste and toxins

●Causes:
○Chronic medication use
○Infection
○Dehydration
○Urinary Tract Infection
○Decreased blood flow
○Autoimmune kidney disease


●Consequences:
○Loss of renal function
○Buildup of waste in the blood
○High blood pressure
○Anemia
○Nerve damage
○Weak bones
○Poor nutritional health
○Damage to other organs/ body
parts






Disease

11. Kidney - Pemetrexed (ALIMTA) Toxicity
●Used for the maintenance of advanced
pulmonary adenocarcinoma
●The therapy has been linked to
pemetrexed-induced tubular injury
●One study following the treatment of a
69-year-old man initiated on Pemetrexed
resulted in acute tubular necrosis with
interstitial inflammatory infiltrate of
mononuclear cells and interstitial fibrosis
occupying 40% of renal cortex
●The mechanism responsible for the renal
damage is still unknown.

12. Kidney - Cisplatin
●Chemotherapy drug used for tumors in
the head, neck, lungs, and testicular
germ-cell cancers
●Approximately ⅓ of patients develop
nephrotoxicity upon receiving a dose of
Cisplatin
●Dose-dependent toxicity
●20% of patients on high doses result
with acute kidney injury
●Nephrotoxicity by Cisplatin is
characterized by
○proximal tubule damage
○decreased glomerular filtration rate
○inflammation
○vascular injury

13. Kidney - Mitomycin C
●Used for pancreatic, breast, and GI cancer
●Known to cause thrombotic
microangiopathy, which is thrombosis in
the capillaries and arterioles (commonly
associated with acute kidney injury and
anemia)
●Destroys blood vessels and endothelial
cells in the kidney
●Decreases prostacyclin synthesis, which
results in microthrombi in the kidneys
●Dose-dependent toxicity

14. Neurotoxicity
●Central Nervous System = Brain + Spinal Cord
●Brain controls movements, speech, emotions, consciousness, and internal body function (Heart rate, breathing, and
body temperature)
●Blood brain barrier prevents most substances in the blood from going into the brain and helps maintain a constant
environment for proper nerve function. HOWEVER sometimes toxins can seep through the tight endothelial cells and
cause toxicity
●Toxicity depends on
○Dose of treatment delivered
○Route of administration
○Drug interactions
○Underlying diseases.
●Headache: most common especially with treatments that readily cross the blood brain barrier
●Seizures: occur with many intravenous chemotherapeutic drugs and high risk anti-epileptic medication are used for
seizure prophylaxis
-Astrocyte tasks: support the cells that
comprise the blood brain barrier as
well as maintaining the extracellular
ion balance, supplying nutrients to
nerve tissue and aiding in post
traumatic repair and scarring
processes

15. Neurotoxicity Cont.
Medication: CISplatin
★CISplatin:
○Two fold toxicity - kidney and brain
○Known to cause a chemobrain: cognitive defect due
to prolonged chemotherapy
■Ability to cross BBB and accumulate in
cerebrospinal fluid.
■Li study findings: exhibition of anxiety-like
behavior and impaired reference memory in
test objects (mice)

16. Liver
●The major function of the liver is metabolism of xenobiotics
●The liver also plays a role in protein synthesis
●Hepatotoxicity caused by chemotherapy can present in
multiple ways:
○Hepatatis
○Cholestasis
○Steatosis
○Sinusoidal obstruction
●Liver function tests are performed to detect hepatotoxicity:
○Alanine aminotransferase and aspartate
aminotransferase levels (AST/ALT enzymes)
○Alkaline phosphatase levels
○Serum albumin level
○Clotting factors and elevated prothrombin time

17. Liver Toxicity- Methotrexate
●Methotrexate is a commonly used chemotherapy agent that has
many other uses, including treatment of rheumatoid arthritis
●MOA:
○dihydrofolate reductase inhibitor that is metabolized in the
liver via hydroxylation to form 7-hydroxy-methotrexate
●Suspected Mechanism of Toxicity:
○local folate deficiency
○Hepatotoxicity
○Cirrhosis
○Liver toxicity is more severe with prolonged methotrexate
use
●A recent study found a 17% decreased incidence of elevated
liver enzyme levels when methotrexate treatment was
supplemented with folic acid

Methotrexate

18. Liver Toxicity - 1-Asparaginase
●Escherichia coli derived chemotherapeutic that is used in the treatment of acute
lymphoblastic leukemia.
●MoA: 1-Asparaginase deaminates the amino acid asparagine. At therapeutic doses used
for acute lymphoblastic leukemia, 1-Asparaginase completely depletes asparagine from
the serum of patients.
●Without any asparagine, the liver is unable to synthesize proteins.
●Toxicity of 1-Asparaginase presents as:
○Decreased serum albumin
○Decreased coagulation factors
○Decreased lipoproteins
○Elevated alkaline phosphatases and AST/ALT
●According to a study, 40-87% of patients treated with 1-asparaginase have hepatic
steatosis upon autopsy
○This toxicity lasts up to 9 months after the last dose of 1-asparaginase.

19. Liver Toxicity: Oxaliplatin
●Platinum coordination complex agent
●Reacts with nucleophilic sites on DNA and proteins
●Adjuvant chemotherapeutic agent to treat colon and rectal
cancers
●Toxicity: causes sinusoidal obstruction syndrome
○by producing reactive oxygen species (ROS) and depleting
reserves of glutathione in sinusoidal endothelial cells. This
results in cellular injury
●Pathologic changes: sinusoidal dilation, hemorrhage around the
sinusoids, hepatocyte atrophy, and nodular regenerative
hyperplasia
○reported in 40% of patients treated with oxaliplatin who
underwent liver resection
○associated with increased risk of bleeding and
postoperative liver failure

20. Heart Toxicity - Anthracyclines
●Anticancer compounds that were originally derived from
Streptomyces
●Have anti-tumor activity
●Includes daunorubicin, doxorubicin and epirubicin, to name a few
●Used to treat a variety of cancers
●Anthracyclines are known to cause toxicity of the heart
●Leads to cardiac dysfunction manifested in left ventricular
enlargement, systolic dysfunction and mitral insufficiency
●Toxicity Mechanism:
○Redox recycling and the generation of reactive oxygen species
are responsible for cardiotoxicity
●Doxorubicin and 2nd generation, Epirubicin, are both known for
causing toxicity to the heart

21. Lung Toxicity - Bleomycin
●Bleomycin = Chemotherapy drug used to treat Hodgkin’s and
non-Hodgkin’s lymphoma
●MOA
○Inhibiting cancer cell synthesis by breaking its strands
○inhibits the synthesis of RNA and protein
●Manifested in pulmonary inflammation and lung fibrosis
●Toxicity Mechanism: binds DNA and chelates Iron, forming
intermediate capable of producing ROS
●Proinflammatory cytokines IL-18 and IL-1β have a role in the
mechanism of bleomycin-induced lung injury
●Bleomycin toxicity is worse and lung exacerbation is more
intense when given concomitantly with high doses of Oxygen (as
done in anesthesia and acute illness).

22. Haematological Toxicity - Gemcitabine
●Gemcitabine = Antimetabolite that stops the growth of cancer cells
●Can treat breast, ovarian, non-small cell lung, and pancreatic cancer
●Associated with an increase in thrombocytopenia, neutropenia, and
leukopenia
●A study of 31 patients substantiates this toxicity: “34.0% and 30.8%
incidence of anaemia and grade 3 neutropenia” and “3.8% and 7.7%
incidence of grade 3 and grade 4 thrombocytopenia” after being given the
combination: Gemcitabine-Carboplatin
○optimal effective dose could not be given in many of these patients due to the
haematological toxicity thus compromising treatment
●Lab monitoring while on Gemcitabine is crucial due to this known
associated heme toxicity
●As lean body mass decreases, correlation with higher toxicity

23. Questions?