Chemotherapy review

Jittipon Tantivit
B.Sc, Grad Dip (Pharmacotherapy), BCPS
Department of Clinical Pharmacy
Faculty of Pharmaceutical Sciences
Burapha University
Basic Principles of Cancer Therapy
• Cancer – unregulated cellular proliferation
• Treatment modalities
– Surgery
– Radiation
– Drug therapy
• Treatment of choice for disseminated cancers (leukemi
a, disseminated lymphomas, wide-spread metastases)

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Tissue Growth and Chemotherapy
• Chemotherapy drugs are more toxic to tissue
with high growth fraction
– Bone marrow
– Skin
– Hair follicles
– Sperm
– Gastrointestinal tract

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Obstacles to Successful Chemothe
rapy
• Toxicity to normal cells
• Absence of truly early detection
• Solid tumors respond poorly
• Heterogeneity of tumor cells
• Limited drug access to tumor cells
• Drug resistance

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Strategies for Achieving Maximum Be
nefits from Chemotherapy
• Dose intensity
• Intermittent vs continous infusion
• Combination
– Maximum cell kill within acceptable toxicity
– Suppression of drug resistance
– Broad coverage against multiple cell lines
• Explain with cell cycle kinetics

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Elsevier inc. item and derived items©2010 by saunders, an imprint of Elseveir Inc.
©2012 American society of health system pharmacist 8
 Optimizing dosing schedules

Elsevier inc. item and derived items©2010 by saunders, an imprint of Elseveir Inc. 9
Tumor growth kinetics

Chemotherapy of benefit

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 Body surface area
• Early research demonstrated that the metabolic rate
of various animals, and humans, was proportional to
their surface area
• Similarly, BSA was found to correlate with total bloo
d volume, cardiac output and renal function (each of
which influences drug distribution and elimination)
• These findings suggested that BSA might have value
in calculating drug doses, particularly in cancer che
motherapy

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Body Surface Area

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 Chemotherapy dosing
• 5% capping to full amount is acceptable
• Dose reduction due to toxicity is acceptable(a
pprox 20%)
• Cancer treatment usually have 3 goal
– Cure
– Extended survival
– Palliative
 Safety factor
• Please check before CMT recieving
• CBC
– Hb>10
– WBC(ANC>1500): ANC=WBC x %Neutrophil
– Platelet>100,000
• BUN/Cr
• LFT
• Echocardiography for cardiotoxic CMT ex Doxo
 Safety factor
• Dental examination
• Viral hepatitis screening
• Stool examination for parasite(esp steroid high
dose)
Classification of chemotherapeutic
agents
1. Alkylating agents
2. Antimetabolites
3. Plant alkaloids
4. Antitumor antibiotics
5. Miscellaneous

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Alkylating agents
ethylene immonium ion

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Cyclophosphamide

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 Cyclophosphamide
ADR
• Hemorrhagic cystitis
• N/V
• Alopecia
• Bone marrow suppression
• Secondary malignancy(bladder, lymphoma)

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 Hemorrhagic cystitis
• Haemorrhagic cystitis is a side effect unique to
cyclophosphamide and ifosfamide
• Acrolein generated from 4-hydroxycyclophosp
hamide is responsible for the urological toxicit
y
• Adequate hydration is used to prevent bladder
toxicity

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Mercaptoethanesulfonate sodium
• Mesna is used when large doses of cyclophosp
hamide are used or history of bladder toxicity
• In the blood stream mesna is very rapidly conv
erted to the inactive dimesna form
• In the kidney dimesna converts back to mesna
before accumulating in the bladder
• Mesna has short half life of 1.5 hours means t
hat administration is critical

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 Ifosfamide
• Ifosfamide is an analogue of cyclophosphamid
e with arguable clinical advantages
• Metabolism and end mechanism of action is si
milar
• There are however, distinct differences in toxic
ity
– Bladder toxicities is much greater with ifosfamide
– Risk of debilitating reversible neurotoxicity

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Platinum analogues

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 Platinum analogues
• Action similar to conventional alkylating agents
• Cisplatin and Carboplatin have two reactive site
s each and can effectively cross link DNA
• Extremely important part in the curative treatm
ent for solid malignancies
• Carboplatin modified ring structure reduced its
chemical reactivity but improved its side effect
profile compared to cisplatin

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 Clinical differences
Cisplatin Carboplatin
Myelosuppression / //
Nephrotoxicity // x
Ototoxic / x
Neuropathy / x
Emetogenicity //// //

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 Carboplatin dosing
• Most chemotherapy agents are dosed base on
body surface area (BSA).
• Often results in over‐ and under‐dosing with ca
rboplatin, since it does not take renal function
variations into consideration
• Calvert formula: Dose=AUC x (GFR + 25)
– The value of 25 mL/min is the constant used to cor
rect for carboplatin non‐renal clearance and irrever
sible binding to tissues
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Thrombocytopenia is Carboplatin’s Dose
Limiting Toxicity(DLT)

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 Oxaliplatin
• 3rd generation platinum derivative
• Forms bulky DNA adducts and induces cellular
apoptosis
• Synergy with 5-FU; Down regulation of thymid
ylate synthase by Oxaliplatin
• Toxicity profile differs from those of carboplati
n and cisplatin

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 Oxaliplatin
• Renal dysfunction, alopecia and ototoxic effects a
re uncommon
• Neuropathy is more frequent-
– Transient dysesthesias, manifested as numbness or ti
ngling of the hands and feet and the oral or perioral r
egions, which are exacerbated by exposure to low te
mperature
– Cumulative dose-dependant sensory neuropathy in w
hich peripheral dysesthesias and parathesias persist b
etween cycles of therapy
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 Antimetabolites
• Structural analogues of naturally occurring substance
s
• Substitute themselves for purines or pyrimidines or t
hey can inhibit critical enzymes that are involved in n
ucleic acid synthesis
– They affect DNA, RNA, protein synthesis and cellul
ar replication
• 3 drug categories:
– Folate Antagonists
– Pyrimidine Antagonists
– Purine Antagonists

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Methotrexate

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 Toxicities
• Bone Marrow Suppression
• Emetogenic potential with high dose
• Mucositis and diarrhea
• Nephrotoxicity
• Hepatotoxicity
• Dermatologic Effects
• Pneumonitis

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 Drug interactions
Caution if give MTX high dose
• Sulfonamide
• Penicillin
• NSAIDs
• Vitamin C
• Omeprazole

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Leucovorin

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Pemetrexed

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Glucarpidase(carboxypeptidaseG2)

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 Toxicities
• Hematologic-Myelosuppression
• Musculoskeletal-Arthralgia
• Renal-Mild renal dysfunction(reversible)
• Cardiovascular- Lower extremity edema
• CNS-Fatigue
• Gastrointestinal-nausea, vomiting, mucositis, diarrhe
a
• Skin-Cutaneous rash
• Liver-Reversible elevations of LFTs
 Toxicities
• Premedication with oral dexamethasone 4 mg
bid for 3 days prior to pemetrexed has been us
ed to reduce the incidence and severity of ras
h
• Folic acid(350 mcg-5mg daily) and vitamin B12
(1000-1500 mcg every 9 weeks) have been sho
wn to reduce the incidence of toxicities

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 Cytarabine (Ara-C)
• Pyrimidine nucleoside antimetabolite
• Cytarabine acts similar to the nucleoside, cytid
ine
• Cytarabine acts in 2 ways to stop DNA replicati
on
– Inhibits DNA polymerase(stop DNA elongation)
– Incorporated into DNA(error in replication, transcri
ption, translation)

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 Cytarabine (Ara-C)
Ara-C
Cytidine deaminase Deoxycytidine kinase

Ara-U Ara-CMP
dCMP deaminase
dCMP kinase

Ara-UMP Ara-CDP

NDP kinase

Ara-CTP
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 Toxicities
• Myelosuppression (DLT)
• Hepatic-jaundice and elevations in serum bilir
ubin, transaminases and alkaline phosphatase
• Alopecia
• Diarrhea, mucositis
• Pulmonary edema
• Dermatologic
– Maculopapular rash, erythema, blistering and peel
ing of skin, especially on hands and feet

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 High dose Cytarabine (HIDAC)
• Cerebellar dysfunction (10-20% with HIDAC)
– Usually within 6-8 days after therapy
– Manifests as ataxia, slurred speech, unsteady hand
writing, unsteady gait, nystagmus, diplopia, tremo
r
– Occurs by accumulation of ara-U or ara-CTP directl
y causing nerve damage
• Nausea and vomiting – Highly emetic > 1g/m2
• Conjuctivitis/corneal toxicity

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 Gemcitabine
Gemcitabine

Deoxycytidine kinase

Gemcitabine Triphosphated
Incorporated into DNA strands Inhibits ribonucleotide reductase

Inhibit DNA polymerase activity

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 Toxicities
• Myelosuppression (DLT)
• Fever/flu-like symptoms/myalgias
• Rash-macular, erythematus, pruritic
• Diarrhea
• Transient elevations in transaminases
• Phlebitis
• Pneumonitis
• TTP/HUS

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 Fluorouracil

After 24 hours First 24 hours

Requires an active form of folic acid
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 Toxicities
• Myelosuppression
 More common with bolus administration
• Stomatitis,Diarrhea
 More common with continuous infusion
• Skin
 Alopecia, nail discoloration, hyperpigmentation, radiosensitization, photose
nsitivity, serpentine vein discoloration, desquamatic rash of hands and feet
• Neurologic
 Somnolence, ataxia
• Ocular
 Conjunctivitis, lacrimation, blepharitis, and photophobia

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 Capecitabine
Capecitabine

carboxylesterase

5'-deoxy-5-fluorocytidine (5'-DFCR)

cytadine deaminase

5'-deoxy-5-fluorouridine (5'-DFUR)

thymidine phosphorylase

5-fluorouracil (5-FU)
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 Toxicities
• GI:Diarrhea , nausea/vomiting , mucositis
• Hand-foot syndrome
– Palmar-plantar erythema
– Median number of cycles to onset is 2
– Vitamin B6 200-300 mg/day demonstrated an advantage
• Hematologic:Neutropenia, anemia, thrombocytopenia(mild) l
ymphopenia(serious)
• Skin: Rash, dermatitis
• Fatigue, anorexia, paraesthesia, & headache
• Cardiac: chest pain, MI, dysrhythmias, cardiogenic shock

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PPE or HFS

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Plant alkaloids

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 Vinca alkaloids
• Inhibition of microtubule assembly through tu
bulin interaction and disruption
• Specific for M phase
• Correlations have been made between cytotox
icity and dissolution of mitotic spindles
• Low concentrations
stabilize microtubule length and leads to inhibition of m
itosis
• High concentrations
disruption of microtubules
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 Vinca alkaloids
• Other mechanisms
– Disrupts structural integrity cells rich in tubulin as well
as the cell membrane and functions
– Induces morphological changes in cells during G1 and S
phases
– Competes for transport of amino acids into cells
– Inhibits purine biosynthesis
– Inhibits RNA, DNA and protein synthesis by blocking gl
utamic acid utilization
– Inhibits angiogenesis
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 Adverse Effects
Vincristine Vinblastine
Hematologic Mild DLT
Neurologic DLT Less than VCR
GI Constipation Constipation and
stomatitis
Endocrine SIADH

Intrathecal is contraindicated

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 Taxanes
• Inhibit microtubular disassembly and cell cycle
phase specific for the M Phase
• Paclitaxel and docetaxel

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 Taxanes
Paclitaxel
• Hypersensitivity reactions: p
re-medication is mandatory
• Sensory peripheral neuropa
thy is dose limiting
• Paresthesia is common and
distribution follows a glove/
stocking distribution
• Arthralgia/myalgia
• Myelosuppression
Docetaxel
• Non-cardiac, non-renal oed
ema which appears to be th
e result of capillary damage
• Effects are cumulative with r
epeated cycles
• Prophylactic use of dexamet
hasone
• Myelosuppression
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 Anti-tumor Antibiotics
• Anthracyclines
• Bleomycin
• L-Asparaginase
• Etoposide

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 Anthracyclines
Mechanism:
– Inhibit topoisomerase II
– Bind covalently to double strand DNA
– Insert between base pairs of DNA (intercalation)
– Free radical formation
• Form hydroxy radical  cleave DNA
– Require iron or copper

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Topoisomerase II inhibitors prevent the rejoi
ning DNA

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 Generation of free radicals
• Anthracyclines participate in chemical redox re
actions and hence are capable of propagating
free radical formation
• Free radicals are highly destructive, and can ca
use considerable damage to DNA
• Mechanism of anthracycline induced cardio to
xicity

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 Anthracycline induced
cardiomyopathy
• Total lifetime cumulative dose is:
– Doxorubicin 400-450mg/m2
– Daunorubicin 450-550mg/m2
– Epirubicin 900-1000mg/m2
– Idarubicin 150mg/m2
• Based on bolus administration
• No pre-existing cardiovascular disease, hepatic i
mpairment, previous mediastinal radiotherapy o
r high dose cyclophosphamide
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 Other toxicities
• Nausea/vomiting
• Mucositis
• Extravasation
• Myelosuppression
• Hyperpigmentation
• Alopecia
• Onycholysis

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 Bleomycin
• Bleomycin is notable cytotoxic drug
• Hematological toxicity is unusual
• Cell cycle specific, having greatest effect on cells in
the S and G2 phase
• It acts by combining with Fe++ to form a reactive c
omplex, which associates strongly with DNA and is
able to generate O2 free radicals
• Type I hypersensitivity can occur (fevers and chills)

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 Toxicities
• It has a unique and serious lung toxicity
• Lung and skin tissues are relatively low in the en
zyme bleomycin hydrolase
• Lifetime cumulative dose of 300 IU
– Lung irradiation
– Concurrent use of high oxygen conc, and renal impair
ment increases the risk
• Skin Toxicity is marked by bullous reactions over
palms or hands
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 L-Asparaginase
• Catalyzes the conversion of L-asparagine to aspartic a
cid and ammonia
• Results in rapid and complete depletion of L-asparagi
ne
• Lack of intracellular asparagine results in decrease of
protein synthesis and apoptosis

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 Hypersensitivity
• Manifests as urticaria, nausea, vomiting, and c
hills
• Less often by a serum sickness-like reaction or
anaphylaxis with hypotension, laryngospasm a
nd cardiac arrest, which is fatal < 1%
• Risk factors for hypersensitivity
• Single agent therapy
• Doses > 6000 IU/m2/d
• Repeated courses of treatment
• IV administration

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 Hypersensitivity
Two clinical methods to predict hypersensitivity
• Testing serum for L-asparaginase antibodies
– Antibody formation is noted in patients with hyper
sensitivity reactions
– Immunogenecity is less with intramuscular route
– PEG formulation is least immunogenic
• Skin testing
– Prior to the initial dose of E. coli L-asparaginase
– Test dose = 2 Units intradermally
– Observe for wheal and flare reaction for 1 hour

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 Impaired Protein Synthesis
• Decreased production of insulin
• Decreased production of albumin
• Decreased production of vitamin K-dependent
clotting factors and endogenous anticoagulant
s such as proteins C and S and antithrombin III

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 Other Toxicities
• Mild nausea/vomiting
• Tumor Lysis Syndrome (TLS)
• Minor bone marrow suppression effects
• Elevated AST, ALT, serum alkaline phosphatase, gamm
a globulin, hyperammonemia, and hyperbilirubinemi
a or jaundice
• Pancreatitis
– Caused by necrosis and inflammation of pancreati
c cells
– Dose-related
– Necessitates change of formulation or discontinua
tion of L-asparaginase therapy
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 Epipodophyllotoxins (Etoposide)
• Cell cycle specific agents that cause cell death by
inhibiting topoisomerase II
• IV solution should be diluted to a concentration
<0.4mg/ml
• Oral absorption is 50% when compared to IV
• Low CNS penetration
• Hepatic metabolism by CYP 3A4 and glucuronide
• Urine excretion 44-60%

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 Toxicities
• IV infusion should be over 30-60 minutes to av
oid hypotension
• Causes classical myelosuppression
• Hypersensitivity reactions (i.e. BP changes) ca
n occur in some patients
• Secondary leukemia

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Characteristics of secondary leukemia
Epipodophyllotoxin Alkylating agent
Typical interval 2–3 years 5–7 years
following
therapy
FAB M4/M5 M1/M2
classification
Karyotype 11q3 (MLL gene (–5)/del(5q), (–
abnormalities rearrangement) 7)/del(7q)
Preceding rare frequent
myelodysplasia

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Topoisomerase 1 inhibitor

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Irinotecan

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 Toxicities
• Alopecia
• Diarrhea
• Vomiting
• Weakness
• Neutropenia
• Fever
• Stomach pain and cramping
• Dyspnea
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 Hydroxyurea
• Blocks ribonucleotide reductase
• Impairs conversion of ribonucleotides to deox
yribonucleotides
• Inhibit thymidine incorporation into DNA
• S-phase specific

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 Toxicities
• GI: nausea, vomiting, diarrhea, stomatitis, con
stipation
• Skin: pigmentation, ulceration, rash
• Myelosuppression
• Close monitoring required
• Cessation may be necessary
• Usually reversible

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Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 89
Programmed T cell death 1 (PD-1)

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 Urothelial
cancer
Lung cancer
Breast cancer

Melanoma
Renal cancer
 Lung cancer
Renal cancer
Liver cancer
Colorectal cancer
Melanoma
Head and neck cancer
Bladder cancer
Hodgkin lymphoma

Melanoma
Lung cancer
Head and neck cancer
Hodgkin lymphoma
Urothelial cancer
Cervical cancer
Esophageal cancer
Renal cancer
Gastric cancer
Hepatic cancer
Immune checkpoint inhibitor ADR

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 Toxicity grading
• Common terminology criteria
• For stop or dosage modification
• Grade 0(normal) to 5(dead)
 TNM staging
• Usually has 4 stage
• Different by cancer type
• T=Tumor size
• N=Node involvement
• M=Metastasis
 Treatment response
• RECIST criteria(or modified RECIST for checkpo
int inhibitor therapy Beware
pseudoprogression
if treat with ICI
Survival classification
 Reference for life long learning
• www.nccn.org
• www.cancer.org
• http://www.asia4safehandling.org
• http://www.bccancer.bc.ca/
• https://www.cancernetwork.com/
• http://www.hoparx.org/

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THANK YOU VERY MUCH

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