PRINCIPLES OF CANCER CHEMOTHERAPY

12/17/2014 bbinyunus2002@gmail.com 1

• INTRODUCTION
– DEFINITIONS
– GOALS
– CELL CYCLE
– CLASSIFICATION
• PRINCIPLES
– PRE-CHEMOTHERAPY ASSESSMENT
– COUNSELLING
– OPTIMIZATION
– MODALITIES
– ADMINSTRATION
– MANAGEMENT OF SIDE EFFECT AND FOLLOW UP
• COMMONLY USED ANTICANCER REGIMEN
• CHEMORESISTANCE
• FUTURE TRENDS
• CONCLUSION

INTRODUCTION
• DEFINATIONS
– CANCER: A group of disease involving abnormal
cell growth with the potential to invade or spread
to other part of the body.
– CHEMOTHERAPY: the term chemotherapy is
describe as the use of chemicals or drugs to treat
cancer.
– CYTOTOXIC DRUG: lysis both normal and cancer
cells

INTRODUCTION
• GOALS OF CANCER CHEMOTHERAPY
– Curative: eradication
» induction: Given with the intent of inducing complete
remission(eliminate clinical evidence) when initiating a
curative regimen
» Consolidation: Repetition of the induction regimen in a
patient who has achieved a complete remission.
» Maintainance : Long-term, low-dose, single or combination
chemotherapy in a patient who has achieved a complete
remission. To prevent recurrence.
– Palliative:
» Provide comfort
» Improve/prolong quality of life

INTRODUCTION
• CELL CYCLE
Understanding the cell cycle is necessary in
cancer chemotherapy
It is a series of events that takes place in a
proliferating cell (normal and malignant )
leading to its division and duplication

5- phases

INTRODUCTION
• Phases of cell cycle
– G₀ Phase(resting phase)
• The cell has not started diving.
• They spend much of their lives in this phase.
• When the cell get a signal to reproduce, they move
into the G₁ Phase.
• Limitation to successful eradication of many tumours
by chemotherapy. They re-enter the cycle after therapy.

INTRODUCTION
• G₁ PHASE(Pre-synthetic phase)
– The cell starts to produce proteins and enzymes
necessary for DNA synthesis.
– During this phase, RNA synthesis occurs.
– This phase last about 18 to 30 hours.

INTRODUCTION
• S-PHASE(synthetic phase)
– DNA synthesis
– Cellular DNA is duplicated in preparation in
preparation for cellular division.
– Length of time S phase is approximately 18-30hrs.
– A weak link, and large number of anticancer agent
act.

INTRODUCTION
• G₂ Phase (pre-mitotic phase)
– the cell checks the DNA
– Gets ready to start splitting into 2 cells.
– Here both protein, RNA, and the precursors to the
mitotic spindle apparatus are produced.
– This phase is very short 1-2hrs.

INTRODUCTION
• MITOTIC PHASE
– In this phase, which last only 30-60min, the cell
actually split into 2 new cells.

INTRODUCTION
• Significance:
– Drugs works mainly on cells that are active(not in
the Go)
– Some drugs specifically attack cells in a particular
phase
– Determine drug combination
– How often drug is given base on timing.

INTRODUCTION
• CELL CYCLE TIME
• GROWTH FRACTION
• TUMOUR BURDEN

INTRODUCTION
• CELL CYCLE TIME/GENERATION;
– The amount of time required for cell to move from
one mitosis to another.(time to complete one
cycle)
– Shorter time results in higher kill when exposed to
specific agents.

INTRODUCTION
• Growth fraction
– The percentage of cells actively dividing at a given
point in time. High growth fraction results in higher
cell kill with exposure to specific agent.
• Tumour burden
– The size of the tumour as determine by the number
of cells present. The cancer with a small tumour
burden are usually more responsive to therapy.
Higher tumour burden the greater the greater the
probability of development of resistance.

INTRODUCTION
• REGULATION/ CHECK POINTS
• To repair DNA damage ,
• Regulation is lost in cancer cells.
– INHIBITORS:
• Cyclin dependent kinase inhibitors lead generation of
P53, Rb which inhibits at G₁/S(restriction point), G₂/M
and M phase.
– PROMOTERS:
• Cyclin dependent kinase + proteins → E2F, cyclin D1, A
and B drives the cycle at S and G2 phase

CLASSIFICATION
• Base on
– The phases of cell cycle (Bruce and colleagues
1966)
• Non-phase dependent
• Phase dependent
– Mechanism of action/biochemical activity
• Cytotoxics
• Immunotherapeutic agents
• Targeted therapy
• Steroids and Non-steroidal Hormones

NON-PHASE DEPENDENT
• Toxic to both cycling cells and those in Go
phase.
• They kill cells by direct DNA damage
• Kills exponentially with increasing dose.
– Alkylating agents; e.g nitrogen mustard,
cyclophosphamide, Procarbazine, Dacarbazine
– Nitrosoureas
– Cisplatin

PHASE-DEPENDENT
• They kill cells only in specific parts of cell cycle.
– MITOTIC PHASE
• Vinca alkaloid
– vincristin,
– vinblastin
• Taxanes
– Pacletaxel
– Doxetaxel
– S-PHASE
• Antimetabolites e.g hydroxyurea, methotraxate, Ara-C, 5-FU, 6-MP, 6-TG
• Antibiotics; Actinomycin D, Doxorubicine, epirubicin
– G1- PHASE
• Corticorsteroid
• Antitumour antibiotics
– G2-PHASE
• Antitumour antibiotics

Base on mechanism of
action/biochemical activity
CYTOTOXIC AGENTS
– Alkylating agent
– Antimetabolite
– Vinca alkaloids
– Antimitotic antibiotic
– Taxanes
– Miscellaneous compounds
• Antiproliferative enzymes; L-asperaginase
• Cisplatine
• Nitrosourea

CHEMOTHERAPUETIC AGENT MECHANISM OF ACTION SIDE EFFECT
ALKYLATING AGENT
Cyclophosphamide,
chlorambucil, thiothepa,
melphalan etc
Interferes with cross linkage
of DNA
Myelosupression
Hemorrhagic cystitis
Skin rash
Flu-like syndrome
ANTIMETABOLITES
• Folic acid antagonist e.g
methotraxate
• Purine antagonist e.g 6-
mercaptopurine,
• Pyrimidine antagonist e.g
5-fluorouracil
Interfere with nucleic acid
synthesis because they are
analogues of normal
metabolites
Mucositis, Nephropathy,
Hepato-toxicity & Hand &
foot syndrome
VINCA ALKALOID- vincristin,
vimblastin
Cause mitotic arrest via
spindle fiber inhibition
Neuropathy, constipation,
Mucositis & myelosuppresion
ANTITUMOUR ANTIBIOTIC
e.g adramycin, daunorubicin,
actinomycin D, bleomycin
Bind to DNA to block RNA
production
cardio toxicity, pulmonary
toxicity & myelosuppresion

CHEMOTHERAPEUTIC AGENT MECHANISM OF ACTION SIDE EFFECT
TAXANES e.g paclitaxel,
docetaxel
Bind to tubulin. Stop
disassembly of mitotic
spindle
neuropathy skin rash &
myelosuppresion
MISCELLANEOUS
L-Asparaginase
Nitrosourea
Cis-platinium

MECHANISM OF ACTION OF
CYTOTOXICS

IMMUNO-THERAPUETIC
AGENTS
MECHANISM OF ACTION CLINICAL USE
Levamisole
(antihelmenthic)
immunomodulator Adjuvant in colonic
cancer in combination
with 5-FU
Interleukin-2(IL-2) Enhances NK-cells and
tumour specific T-cells
Melanoma
Renal cell ca
Neuroblastoma
NHL
Interferon Enhance NK-cells
Re-expression of HLA
gene
Kaposi’s sarcoma
Multiple myeloma
Leukemia
BCG Stimulate immune
response
CIS of the bladder,

TARGET THERAPY MECHANISM OF ACTION CILNICAL USES
SMALL MOLECULES
Gefitinib
Erlotinib
Inhibits EGFR tyrosine
kinase thereby inhibiting
growth of cancer cells
Non-small cell cancer of
the lungs
MONOCLONAL
ANTIBODIES
Trastuzumab(Herceptin)
Rituximab(mabthera)
Bevacizumab
cetuximab
Selectively kill tumour cells
expressing certain
receptors
Trastuzumab is use Her-2
positive breast cancer

HORMONE CLINCAL USES
ANTI-ANDROGENS
Flutamide
oestrogen
Use with gosereline in the treatment of
metastatic prostate cancer
ANTI-ESTROGEN
Tamoxifen
Pure anti-oestrogen (fasodex)
Breast cancer
SELECTIVE AROMATASE
INHIBITORS
Anastrozole
2nd line in ER/PR +ve breast ca
AMINOGLUTETHIMIDE Breast and adrenal ca
PROGETINS
Medroxyprogesterone acetate
Breast and endometrial
LHRH analogue
Goserelin
Prostate and breast ca
CORTICOSTEROIDS
Dexamethasone
prenisolone
Breast ca as acombination, treatment of
hypercalcemia, raise ICP from brain
metastesis

PRINCIPLES
– PRE-CHEMOTHERAPY ASSESSMENT
– COUNSELLING
– OPTIMIZATION
– MODALITIES
– ADMINSTRATION
– MANAGEMENT OF SIDE EFFECT AND FOLLOW UP

PRE-CHEMOTHERAPY ASSESSMENT
• AIM
– Establish diagnosis
– Fitness of patient
• METHODS
– Clinical evaluation
– Laboratory test

• CLINICAL EVALUATION
– History
• Detail history
• Systemic involvement
• Co-morbidities
• Performance status

Performance status
• An attempt to quantify the general well
being and daily activity of a cancer patient.
– whether they can receive chemotherapy
– whether dose adjustment is necessary, and
– as a measure for the required intensity of
palliative care.
– measure of quality of life
– Utilises two main scales ; Karnofsky score and
Eastern Cooperative Oncology Group (ECOG)
system

Performance scaleECOG KARNOFSKY
0: fully active, able to carry on all predisease performance
without restriction.
100% - Normal; no complaints; no evidence of disease.
90% - Able to carry on normal activity; minor signs or
symptoms of disease
1 – Symptomatic but completely ambulatory (Restricted in
physically strenuous activity but ambulatory and able to carry
out work of a light or sedentary nature. For example, light
housework, office work)
80 %- Normal activity with effort; some signs or
symptoms of disease.
70% - Cares for self; unable to carry on normal activity or
to do active work
2 – Symptomatic, <50% in bed during the day Ambulatory and
capable of all self care but unable to carry out any work
activities. Up and about more than 50% of waking hours)
60% - Requires occasional assistance, but is able to care
for most of his personal needs.
50 %- Requires considerable assistance and frequent
medical care.
3 – Symptomatic, >50% in bed, but not bedbound (Capable of
only limited self-care, confined to bed or chair 50% or more of
waking hours)
40% - Disabled; requires special care and assistance.
30% - Severely disabled; hospital admission is indicated
although death not imminent.
4 – Bedbound (Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair)
20% - Very sick; hospital admission necessary; active
supportive treatment necessary.
10% - Moribund; fatal processes progressing rapidly.
5 – Death 0 - Dead
31

• Physical examination
– The extent of primary and metastatic disease via
the general and thorough systemic examination
– Body surface area
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3600

PRE-CHEMOASSESSMENT
• Laboratory test
– Diagnostic: histology
– Extent:
» imaging ;CXRay, CT, MRI,PET,SPET
» Uss
» LFT
– Baseline:
» FBC
• PCV- 30%
• WBC<2.5, 2.5-3.9 >4.0 ×10⁹/L
• PLT <75, 75-150, >150 ×10⁹/L
» U&Ecr
» Stool microscopy- Strogiloides Stercoralis
– Others; depend on the type of cancer e.g tumour markers

COUSELLING
• Adequate counseling
– Disease explained in simple terms that can be
understood
– Extent
– Plan of treatment
– Side effect expected
– Fair idea of prognosis
• Opportunity given to ask adequate questions and
get accurate answers
• A professional counsellor/ psychologist should be
involved

COUNSELLING
• The aim of the therapy most clearly be stated
to patient and relative
– Curative
– Palliative
• Modalities of treatment
• INFORMED CONSENT obtained

MODALITIES
• Modality is selected base on the type and
stage of the cancer.
• Neoadjuvant
• Adjuvant
• Multimodality
– Surgery
– Chemo-radiation

OPTIMIZATION
– Anaemia
– Dehydration
– De-worming
– Malnutrition
– Control of infection
– Dialysis -Uremia

ADMINISTRATION
• Choice of agents
– Type of cancer
– The stage
– Age
– Clinical state of patient
– Co-morbidities
– Treatment in the past
– Drug interactions

ADMINSTRATION
• The ORDER is written and signed
– Name, diagnosis, drug combination, number of cycles and
duration
• DOSE
– Calculate base on body surface area
– Dose prescription
• Standard dose ; anticipate mild side effect, minimal supportive care
• High dose; above standard, anticipated side effect, requires
supportive care; G-CSF, blood transfution
• Ablative dose; ablation of tumour and stem cells, in conjunction with
stem cell transplantation
• Adjusted dose; reduced dose in renal impairment.

ADMINISTRATION
• ROUTES OF ADMINSTRATION
– Oral
– Intravenous
• Bolus
• Infusion
– Arterial infusion
– Extracorporeal limb perfusion
– Intracavitory
– Intrathecal
– Subcutaneous
– intramuscular
– Topical

ADMINISTRATION
• Pre-chemotherapy medications
– IV fluids (allopurinol, alkylanizaton of urine) –
prevent risk of tumour lysis syndrome.
– Antiemetic: Ondansetron 0.15mg/kg given 30min
before commencement.
– Antidotes; leucovorin antidote for antifolate-
metothraxate. (Co-administered, after
admistration)

ADMINISTRATION
• MODES/METHODS
– Single agent continuous therapy
• Little value in modern cancer management
• - Low response rates.
• - Complete remissions were infrequent.
• - Kill small fractions of tumour cell
• - Potentiates the development of drug resistance

TREATMENT
NUMBEROFCELLS
KEY:
Normal cells
Tumour cells
Time
Effect of a Single Course of Cytotoxic Therapy on Tumour & Normal Tissues.

CYCLICAL CHEMOTHERAPY
• Drugs is given in cyclical fashion
• To prevent drug resistance
• This gives normal cells time to recover from
the drug’s side effects.

TREATMENT
NUMBEROFCELLS
KEY:
Normal cells
Tumour cells
Rx Rx
Rx
321
Time
Effect of Multiple Courses of Cytotoxic Therapy on Normal Tumour Cell population

COMBINATION CHEMOTHERAPY
Superior to single drug chemotherapy
Considerations:
• Drug should be active as a single agent
• Avoid drugs with similar toxicity
• To reduce toxicity
• Use drugs with different mech. of actions
• Use maximum therapeutic doses

ADMINISTRATION
• MONITORING
– Premedication vital signs take, then regular monitaring
– Mainly cardiovascular- cardiotoxicity
• Tarchcardia
• Arrhythmias
• S3 gallop
• Chest pain, tightness – acute coronary sydrome
• Esp anthracyclins, trastuzumab, cyclophophamide, pacletaxel
– Nausea, vomiting
– Breathing pattern
– Antidotes and emergency drugs

ADMINISTRATION
• SAFETY
– Chemotherapeutic agent are harzardous
• Mutagenic
• Teratogenic
• Carcinogenic
• Skin irritation
– Gloved, goggle and gowns when administering. In
a good ventilation to prevent inhalation of
droplets when preparing.
– Care in handling patient urine and faeces

Management of side effects
• Side effects results from; lyses of normal cells,
depends on the type of drug, dose, route and
individual response.
• Rapidly dividing cells are more affected; blood
cells, hair follicle, digestive tract and
reproductive tracts.

Management of side-effects
• LOCAL
– Flare reaction/thrombophebitis
• Irritation along the tracts. Triggering inflammation along the tract and
surrounding skin.
– Vesiculation
• From extravasation into surrounding subcutaneous tissue leading to vesicles
which subsequently ulcerates.
• Chemical burns
– Treatment ; (easily prevented- good vein, ensure no leakage b4
chemo, set fresh not pre-existing line, monitor line, start with vesicant.)
• Stop immediately
• Antihistamine
• Hydrocortisone
• Analgesics
• Care of ulcer when developed

Management of side effect
• SYSTEMIC
– Haemopoietic; Myelosuppresion
• Treat emergencies- aneamia, throbocytopenia, treat
infection
• Treatment with CSF
– Gastrointestinal; nausea, vomiting, anorexia,
constipation, diarrhea
• 5-HT antagonist- ondasetron
– Hypergycalcaemia;
• Bisphosphonate
• Corticostiroid

• Urinary- hemorrhagic cystitis- mesna
• Neurologic –peripheral neuropathy
• Cardiovascular ; Cardiomyopathy
• Respiratory ; pulmonary fibrosis
• Reproductive; infertility, menorrhagia.

FOLLOW-UP
• Complication
– History
– Physical examination
– Laboratory investigation- repeat baseline and
histology, tumour marker
– Treat complication as they arise
• Response
• Resistance

RESPONSE
WHO
Objective response – Change in longest diameter
of the target lesion
Complete; Disappearance of all known disease,
confirmed at ≥ 4 weeks.
Partial; ≥ 50% decrease from baseline, confirmed at
≥ 4weeks
Progressive ; ≥ 25% increase in one or more lesions
or appearance of new lesions
Stable; no change

CHEMORESISTANCE
• Reduction in the effectiveness or failure of
response could be primary or secondary
• Depend on grade of tumour, type of drug and
dose use.
• Mechanisms
– Overexpression of Adenosine triphosphate binding
cassette
– Inactivation of apoptosis
– Inactivation of nuclear factor- kB transcription factor
– Cancer stem cell

COMMONLY USED ANTICANCER
REGIMEN
• Breast cancer
– CMF
– CAF/VAC-P
– TAXANE BASED eg
» paclitaxel and xeloda
» Paclitaxel, cyclophosphamide and doxorubicine
• Gastric
– ECF
• Wilm’s
– Methotrexate or dactinomycin, douxorubicin and
vincristin

FUTURE TRENDS
• Tumour vaccine- stimulate the body to
produce CD4 cells which suppresses tumour
cells e.g sipuleucel-T, prostate G-vax still
under investigations
• Gene therapy

CONCLUSION
• Cancer chemotherapy is an important
component in cancer management singly or in
multi-modal therapy. They are toxic to normal
tissues hence require knowledge of drugs,
early recognition, and management of side
effect
• Adequate counseling is required for
compliance to treatment.

REFERENCES
• E.A Badoe et al, “Principles and Practice of surgery including pathology in
the tropics” 4th edition, Assembly of God Literature Center ltd, 2009
• M.A.R Al-Fallouji; “Postgraduate Surgery the candidate guide”. 2nd Edition.
Rced Educational and Professional Pub. Ltd 1998
• Sriram Bhat S “SRB manual of surgery” 4th edition Jaypee Brothers Medical
Publishers (P) Ltd
• Guidelines for the Safe Prescribing, Dispensing and Administration of
Cancer Chemotherapy “Clinical Oncological society of Australia” Nov. 2008
• Joseph O. Jacobson et al,” American Society of Clinical Oncology/Oncology
Nursing Society Chemotherapy Administration Safety Standards” journal
of clinical oncology. volume 27 number 32 november 10 2009.
• www.slideshare .net
• www.wikepedia .org

PRINCIPLES OF CANCER CHEMOTHERAPY

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