For surgical residents presentation

1. Principles of cancer chemotherapy
By
Dr Olofin

2. Outline
• Introduction
– Definitions
– Goals
• The cell cycle
• Classification of chemotherapeutic
agents
• Principles
– Pre-chemotherapy assessment
– Counselling
– Optimization
– Modalities
– Administration
– Management of side effect and follow up
• Commonly used anticancer regimen
• Chemoresistance
• Future trends
• Conclusion

3. Introduction
Definitions
– 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

4. 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.
» Maintenance : 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

5. The 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

6. Phases of cell cycle
1. G₀ Phase (resting phase)
• The cell has not started dividing.
• 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.
2. 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.

7. 3. 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.
4. 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.
5. Mitotic phase
– In this phase, which last only 30-60min, the cell actually split into 2 new cells.

8. • 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.
• Cell cycle time
• Growth fraction
• Tumour burden

9. • 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.
• 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.
– The higher tumour burden the greater the greater the probability of development of
resistance.

10. 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

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

12. 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 ( Streptozocin), platinum (Cisplatin, carboplatin)

13. Phase-dependent
• They kill cells only in specific parts of cell cycle.
– Mitotic phase: Vinca alkaloid ( vincristin, vinblastine) Taxanes (Pacletaxel,
Doxetaxel)
– S-Phase: Antimetabolites (hydroxyurea, methotraxate, Ara-C, 5-FU, 6-MP, 6-
TG), Antibiotics (Actinomycin D, Doxorubicine, epirubicin
– G1- Phase: Corticosteroid, Anti-tumour antibiotics
– G2-Phase: Anti-tumour antibiotics

14. 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

15. 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
TAXANES e.g paclitaxel, docetaxel Bind to tubulin. Stop disassembly of
mitotic spindle
neuropathy skin rash & myelosuppresion
MISCELLANEOUS
L-Asparaginase, Nitrosourea Cis-
platinium

16. MECHANISM OF ACTION OF
CYTOTOXICS

17. 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
MelanomaRenal 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

18. 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

19. Principles
1. Pre-chemotherapy assessment
2. Counselling
3. Optimization
4. Modalities
5. Administration
6. Management of side effect and follow up

20. 1. Pre-chemotherapy assessment
• Aim
– Establish diagnosis
– Fitness of patient
• Methods
– Clinical evaluation
– Laboratory investigations
• Clinical evaluation
– History
• Detail history
• Systemic involvement
• Co-morbidities
• Performance status

21. 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
– a measure for the required intensity of palliative care.
– measure of quality of life
– Utilizes two main scales: Karnofsky score and Eastern Cooperative Oncology
Group (ECOG) system

22. ECOG 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
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

23. • Physical examination
– The extent of primary and metastatic disease via the general and thorough
systemic examination
– Body surface area
•√ 𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔) ×ℎ𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚)/3600

24. • Laboratory test
– Diagnostic: histology
– Extent:
» imaging ;CXRay, CT, MRI,PET,SPET
» Uss
» LFT
– Baseline:
» FBC
• PCV- 30%
• WBC<3 ×10⁹/L
• PLT <75, 75-150, >150 ×10⁹/L
» U/E/Cr
» Stool microscopy- Strogiloides Stercoralis
– Others; depend on the type of cancer e.g tumour markers

25. 2. Counselling
• 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

26. • The aim of the therapy most clearly be stated to patient and relative
– Curative
– Palliative
• Modalities of treatment
• Informed consent obtained

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

28. 4. Optimization
– Anaemia
– Dehydration
– De-worming
– Malnutrition
– Control of infection
– Dialysis -Uremia

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

30. • 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; blood
transfusion
• Ablative dose: ablation of tumour and stem cells, in conjunction with stem cell
transplantation
• Adjusted dose: reduced dose in renal impairment.

31. • Routes of administration
– Oral
– Intravenous
• Bolus
• Infusion
– Arterial infusion
– Extracorporeal limb perfusion
– Intracavitory
– Intrathecal
– Subcutaneous
– Intramuscular
– Topical

32. • 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 administration)

33. • 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
– 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.

34. 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

35. Monitoring
– Premedication vital signs take, then regular monitoring
– 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

36. Safety
– Chemotherapeutic agent are hazardous
• 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 feaces

37. 5. 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.

38. • 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 before chemo, set
fresh not pre-existing line, monitor line, start with vesicant.)
• Stop immediately
• Antihistamine
• Hydrocortisone
• Analgesics
• Care of ulcer when developed

39. • Systemic
– Haemopoietic; Myelosuppresion
• Treat emergencies- aneamia, throbocytopenia, treat infection
– Gastrointestinal; nausea, vomiting, anorexia, constipation, diarrhea
• 5-HT antagonist- ondasetron
– Hypergycalcaemia;
• Bisphosphonate
• Corticosteroid

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

41. Follow-up
• Complication
– History
– Physical examination
– Laboratory investigation- repeat baseline and histology, tumour marker
– Treat complication as they arise
• Response
• Resistance

42. 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

43. Chemo-resistance
• 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

44. 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

45. 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

46. 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.

47. 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

48. •Thank you