Principles of Cancer Chemotherapy; My presentation as a Medical Officer, in the department of Surgery, Trauma and Surgical Centre, Ondo

1. PRINCIPLES OF
CANCER
CHEMOTHERAPY
EGBEKUN I.E. (MB;BS Ib)
TRAUMA AND SURGICAL CENTRE, ONDO, ONDO
NIGERIA. 01-04-2014

2. Introduction
Historical perspective
Chemotherapeutic agents
Cellular kinetics
Tumor kinetics
Administration of Chemotherapy
Definition of terms
Side effects/toxicity
Advancement in cancer chemotherapy

3. INTRODUCTION

4. Cancer is an abnormal growth of cells
caused by multiple changes in gene
expression, leading to dysregulated
balance of cell proliferation and cell death
and ultimately evolving into a population of
cells that can invade tissues and
metastasize to distant sites, causing
significant morbidity and, if untreated, death
of the host.

5. Chemotherapy: the use of any drug to treat
any disease, but in the context of cancer,
chemotherapy refers to the use of drugs for
cancer treatment.
Other modalities of cancer treatment
include surgery, radiation, immunotherapy
etc

6. History of Chemotherapy

7. History of Chemotherapy
Mustard gas was used as a chemical
warfare agent during World War I and was
studied further during World War II.
So, in the 1940s, several patients with
advanced lymphomas were given the drug
intravenously, rather than by inhalation the
irritating gas.

8. History of Chemotherapy
Their improvement, although temporary,
was remarkable. That experience led
researchers to look for other substances
that might have similar effects against
cancer.
As a result, over a hundred antineoplastic
drugs have been developed.

9. Tumorigenesis

10. Tumour characteristics
• Self sufficiency in
growth signals
• Insensitivity to ant-
growth signals
• Evading apoptosis
• Limitless replicative
potential
• Sustained
angiogenesis
• Tissue invasion
and metastasis

11. Tumour markers
Products of the metabolic activity of
tumours and are either tumour derived or
tumour-associated although not necessarily
tumour-specific.
May be secreted (into blood, urine or other
body tluids) or expressed (at the cell
surface) in quantities larger than those in
normal tissue.
E.g. PSA, CEA, alpha fetoprotein, CA 15-3,
HER2

12. Chemotherapeutic agents

13. Alkylating agents
Mechanism of action
Base alkylation resulting in DNA cross-
linking
Single strand breaks
Double strand breaks and strand
misreading

14. Alkylating agents
Classes
Nitrogen mustards: chlorambucil,
cyclophosphamide
The platinum drugs (cisplatin, carboplatin
Nitrosoureas: streptozocin, carmustine
Alkyl sulfonates: busulfan
Triazines: dacarbazine , temozolomide
Ethylenimines: thiotepa, altretamine

15. Anti-tumor Antibiotics
Anthracyclines
Other Anti-tumor atibiotics

16. Anti-tumor Antibiotics
Anthracyclines
Mechanism of action
Anthracyclines derived from the fungus Streptomyces
percetus var caesius.
interfere with enzymes involved in DNA replication.
Intercalate between strands of DNA double helix
formation of drug free radicals
inhibition of topoisomerase II
Examples:
daunorubicin ,doxorubicin, epirubicin, mitoxantrone

17. Other Anti-tumor Antibiotics
Bleomycin: preferentially intercalates DNA at
guanine-cytosine and guanine-thymine
sequences
inducing single-strand and double-strand
DNA breaks
Actinomycin-D: inhibits DNA-dependent
RNA synthesis by intercalating DNA at
guanine-cytosine base pairs

18. Antimetabolites
Purine analogues
Pyrimidine analogues
Antifolates
Substituted ureas
Adenosine deaminase inhibitors

19. Antimetabolites
Mechanisms of action
compete with normal metabolites for the catalytic
or regulatory site of a key enzyme
substitute for a metabolite that is normally
incorporated into DNA and RNA
nonlinear dose-response curve, such that after a
certain dose, no more cells are killed despite
increasing doses (fluorouracil [5-FU] is an
exception).

20. Antimetabolites
Classes
Pyrimidine analogues
 Uracil: 5-fluorouracil (5-fluoro-2’-deoxyuridine)
 Cytosine: Cytosine arabinoside; 5-azacytidine
Purine analogues
 Adenine: 6-mercaptopurine
 Guanine: 6-thioguanine
Adenosine deaminase inhibitor: Cladribine, Fludarabine
Folate analogues: Methothrexate
Substituted ureas:Hydroxyurea

21. Mitotic inhibitors
Vinca Alkaloids
Taxanes
Epothilones: ixabepilone
Estramustine

22. Vinca Alkaloids
Derived from the periwinkle plant Vinca
rosea.
inhibit polymerization of tubulin resulting in
impaired mitotic spindle formation in the M
phase.
Examples: Vincristine, Vinblastine,
Vinorelbine

23. Taxanes
semisynthetic derivatives of extracted
precursors from the needles of yew plants.
promote microtubular assembly and
stability, resulting in mitotic arrest
Examples: Docetaxel, Paclitaxel

25. Topoisomerase inhibitors
Camptotecins: inhibit topoisomerase I
interrupting the elongation phase of DNA
replication.
Examples: Irinotecan, topotecan
Podophylotoxins: Inhibits topoisomerase
II activity by stabilizing the DNA-
topoisomerase II complex;
Examples: Etoposide, Teniposide

27. Corticosteroids
Mechanism of action: unclear –induce
apoptosis of lymphoblasts and effective in
lymphoid malignancies.
Examples: prednisone, dexamethasone

28. Miscellaneous chemotherapeutic
agents
L-asparaginase: converts asparagine to
aspartate and NH3. Normal cells can reverse this
process to form asparagine.
Lymphoblasts lack asparagine synthetase and
die without preformed asparagine in plasma.
Drug has activity in acute lymphocytic leukemia.
Bortezomib: proteosome inhibitor

29. Other types of anticancer drugs
Other drugs and biological treatments are
also used to treat cancer.
target different properties that set cancer
cells apart from normal cells.
less serious side effects because they are
targeted to work mainly on cancer cells, not
normal, healthy cells.

30. Hormone therapy
sex hormones, or hormone-like drugs, that change
the action or production of female or male
hormones.
They are used to slow the growth of breast,
prostate, and endometrial (uterine) cancers, which
normally grow in response to natural hormones in
the body.
Prevent the cancer cell from using the hormone it
needs to grow, or prevent the body from making
the hormones.

31. Hormonal therapy
Examples
The anti-estrogens: fulvestrant, tamoxifen,
and toremifene
Aromatase inhibitors: anastrozole,
exemestane, and letrozole
Progestins: megestrol acetate
Estrogens: Estradiol
Anti-androgens: bicalutamide, flutamide,
and nilutamide
Gonadotropin-releasing hormone (GnRH),
agonists or analogs: leuprolide and
goserelin

32. Other types of anticancer drugs
Targeted therapies: more selective than
traditional chemotherapy drugs.
Most attack cells with mutant versions of
certain genes, or cells that express too
many copies of a particular gene.
Examples of targeted therapies include
imatinib (Gleevec®), gefitinib (Iressa®),
sunitinib

33. Other types of anticancer drugs
Biologic response modifiers:
(Immunotherapy) is a type of treatment that
mobilizes the body's immune system to fight
cancer.
Examples
Monoclonal antibodies: rituximab,
alentuzumab
Nonspecific immunotherapies/adjuvants:
BCG, IL-2, Interferon-α

34. Immune modulating drugs: thalidomide
Cancer Vaccines: Provenge- for advanced
prostate ca

35. Other types of anticancer drugs
Differentiating agents:
These drugs act on the cancer cells to
make them mature into normal cells.
Examples include the retinoids, tretinoin
and bexarotene , as well as arsenic trioxide.

36. Cellular kinetics

37. Cellular kinetics
G1 phase: This phase
lasts about 18 to 30
hours.
S phase: lasts about
18 to 20 hours.
G2 phase: This phase
lasts from 2 to 10
hours
M phase (mitosis):
lasts only 30 to 60
minutes, the cell
actually splits into 2
new cells.

38. Cellular kinetics
Some drugs specifically attack cells in a
particular phase of the cell cycle (the M or
S phases, for example).
Understanding how these drugs work helps
oncologists predict which drugs are likely to
work well together.

39. Cell cycle phase specific
Primarily affect cells that are actively
replicating
Cell cycle phase-non-specific
More toxic
More effective for slow-growing tumors

40. S PHASE DEPENDENT M PHASE DEPENDENT
Cell cycle phase specific drugs
Antimetabolites
6-mercaptopurine
5-fluorouracil
Methothrexate
Hydroxyurea
Fludarabine
G1 PHASE DEPENDENT
L-Asparaginase
Vinca Alkaloids:
Vincristin
Podophylotoxins:
Etoposide
Taxanes: Docetaxel
G2 PHASE DEPENDENT
Bleomycin
Camptotecins:
Irinotecan

41. Cell cycle phase non-specific
drugs
 Nitrogen mustards:
cyclophosphamide
 Nitrosoureas:streptozocin
 Alkyl sulfonates: busulfan
 Triazines:dacarbazine
 Ethylenimines: thiotepa
 Platinum drugs :cisplatin
 Daunorubicin
 Doxorubicin
 Mitoxantrone
 ALKYLATING AGENTS
 ANTHRACYCLINES
(ANTITUMOR ANTIBIOTICS)

42.  Agents that are cell-cycle-phase–
nonspecific have a linear dose-response
curve; i.e the greater the dose of drug, the
greater is the fraction of cell kill.
However, cell-cycle-phase–specific drugs
have a plateau with respect to cell killing
ability, and cell kill will not increase with
further increases in drug dosage.

43. Goals of chemotherapy
Curative intent.
Control of tumor growth when cure is not
possible;
Palliation- to relieve symptoms (such as
pain)

44. Tumor Kinetics

45. Tumor Kinetics
The rate of growth of a tumor is a reflection
of the proportion of actively dividing cells
(the growth fraction), the length of the cell
cycle (doubling time), and the rate of cell
loss.
Tumors characteristically exhibit a sigmoid-
shaped Gompertzian growth curve, in
which tumor doubling time varies with
tumor size.

46. Tumors grow most
rapidly at small
tumor volumes. As
tumors become
larger, growth slows
based on a complex
process dependent
on cell loss and
tumor blood and
oxygen supply

47. Principle of exponential cell-kill
(log-kill hypothesis)
It states that a given dose of
chemotherapy, kills the same fraction of
tumor cells, regardless of the size of the
tumor at the time of the treatment.(first-
order kinetics)
Example: 2 log cell kill 106
—104
104
—102
4 log cell kill 106
— 102
104
— 100

49. Methods of Cancer Chemotherapy
use

50. Methods of Cancer Chemotherapy
use
Single agent
Continuous
Intermittent
Combination
Continuous
Intermittent
Sequential
Chemoradiation

51. Continuous single agent chemotherapy
Low response rates.
Complete remissions were infrequent.
Kill small fractions of tumour cell
Potentiates the development of drug resistance
Intermittent single agent chemotherapy,
eg, mitoxantrone, epirubicin, irinotecan
Often 2nd
line regimen
Metastatic disease
Palliative treatment

52. Combination chemotherapy
Combination chemotherapy accomplishes
three important objectives not possible with
single-agent therapy:
(1) It provides maximum cell kill within the
range of toxicity tolerated by the host for
each drug;
(2) it offers a broader range of coverage of
resistant cell lines in a heterogeneous
tumor population; and
(3) it prevents or slows the development of
new drug-resistant cell lines.

53. Principles of combination
chemotherapy
Drugs known to be active as single
agents. Preferentially, drugs that induce
complete remissions should be included.
Drugs with different mechanisms of
action; in order to allow for additive or
synergistic effects on the tumor.
Drugs with differing dose-limiting
toxicities; to allow each drug to be given at
full or nearly full therapeutic doses.

54. Principles of combination
chemotherapy
Drugs should be used in their optimal dose
and schedule.
Drugs should be given at consistent
intervals.
Drugs with different patterns of resistance
should be combined to minimize cross-
resistance.

55. Drug synergy, antagonism, and
additive effects
Drug effects are additive when their use in combination
gives results equivalent to their sequential independent
use.
Lesser effects suggest antagonism.
Greater effects suggest synergism.
 Drug A 60 % response rate
 Drug B 30 % response rate
 Drug A + B
60 % respond to A
12 % respond to B [30 % of 40
non-responders to A]
72 % = additive response rate

56. Administation of Cancer
Chemotherapy

57. Routes of administration
Systemic chemotherapy:
Oral (PO)
Intravenous (IV)
Regional chemotherapy
Intra-arterial
Intracavitary chemotherapy
Intravesical
Intrapleural
Intraperitoneal
Intrathecal
Intralesional/intratumoral
Topical

59. Choice of chemotherapy
Research
Stage of the cancer/Goal of therapy
The Health of the Patient
Previous cancer regimen used

60. Dosing considerations
Narrow therapeutic index, hence the need
for precision in dosing
Calculated based on BSA and body weight
Dosing for children and adults differ
Other considerations
 elderly
 poor nutritional status
 Obese patients
 Have already taken or are currently taking other medicines
 Have already had or are currently receiving radiation
therapy
 Have low blood cell counts
 Have liver or kidney diseases

61. Schedules(Cycles)
Each course of chemotherapy is generally
given at regular intervals called cycles.
A chemotherapy cycle may involve a dose of
one or more drugs followed by several days or
weeks without treatment.
This gives normal cells time to recover from
the drug’s side effects.
Each drug is given on a schedule that is
carefully set up to make the most of its
anticancer actions and minimize side effects.

62. Pre-chemotherapy assessment
Essential Prerequisites:
Definitive Diagnosis- histology
Accurate staging
Work up
Detailed history: Age, Occupation, Duration
of symptoms, Weight loss, PMHx, FSHx,
drug rxn.
Physical Examination: Lymphadenopathy,
tumour size, Organomegaly, States of the
heart & lungs, Bone involvement,
metastasis, Ht, Wt, BSA

63. Pre-chemotherapy assessment
Investigations
Hematologic – FBC, ESR, BM biopsy
Biochemical – LFT, E/U/Cr
Imaging – CXR, USS, Bone scan, CT, MRI,
ECHO
Tumour markers

64. Pre-chemotherapy assessment
Counseling
 Nature of cancer and stage
 Treatment options
 Nature of prescribed chemotherapy
 Side effects and management
 Possible outcome of treatment
 Consent
Optimization
 Fluid & Electrolytes
 Blood if anaemic
 Antibiotics when indicated
 G-CSF

65. Monitoring
Tumor markers
Tumor size
Imaging: CT, USS, bone scan
Hematological indices
Hb >12g/dl
WBC > 3.0 x 109
/l
Neutrophils > 1.5 x 109
/l
Platelets > 100 x 109
/l

66. Definition of terminologies

67. Definition of terminologies
Induction: High-dose, usually combination,
chemotherapy given with the intent of
inducing complete remission when initiating
a curative regimen.
Consolidation: Repetition of the induction
regimen in a patient who has achieved a
complete remission after induction, with the
intent of increasing cure rate or prolonging
remission

68. Intensification: Chemotherapy after
complete remission with higher doses of
the same agents used for induction or with
different agents at high doses with the
intent of increasing cure rate or remission
duration.
Maintenance: Long-term, low-dose, single
or combination chemotherapy in a patient
who has achieved a complete remission,
with the intent of delaying the regrowth of
residual tumor cells.

69. Adjuvant: A short course of high-dose,
usually combination chemotherapy in a
patient with no evidence of residual cancer
after surgery or radiotherapy, given with the
intent of destroying a low number of
residual tumor cells.
Neoadjuvant: Adjuvant chemotherapy
given in the preoperative or perioperative
period.

70. Palliative: Chemotherapy given to control
symptoms or prolong life in a patient in
whom cure is unlikely.
Salvage: A potentially curative, high-dose,
usually combination, regimen given in a
patient who has failed or recurred following
a different curative regimen

71. Remission: Decrease or disappearance of
signs and symptoms of cancer, although
cancer may still be present.

72. Response
Complete response: disappearance of all
evidence of disease and no appearance of
new disease confirmed at ≥4wks
Partial response: a reduction by at least 50%
in the sum of the products of the two longest
diameters of all lesions, with no appearance of
new disease, confirmed at ≥4wks
Progression: ≥25% growth of existing disease
or appearance of new disease during
chemotherapy.

73. Stable disease: Neither partial response
nor progression criteria met (no change)

74. Resistance to chemotherapy

75. Resistance to chemotherapy
Primary resistance: Absence of response
on first exposure to currently available
standard agents
Acquired resistance: Absence of response
which develops in an originally drug-
sensitive tumor type

76. Resistance to chemotherapy
Mechanism
Increased expression of an MDR1 gene coding
for a transmembrane P-glycoprotein by tumor
cells, resulting in increased efflux of the drug
Alterations in drug uptake or transport (e.g.
anthracyclines)
Increased repair of drug-induced nucleic acid
damage (e.g., platinum drugs)

77. Cancer cells may mutate and develops
mechanisms for drug inactivation
Development of resistant clones of cancer
cells
Sanctuary sites(brain/testes)

78. Side effects/Toxicities

79. Side effects of cancer
chemotherapy and toxicities
Although chemotherapy is given to kill
cancer cells, it also damages normal cells.
The normal cells most likely to be damaged
are those that divide rapidly, for instance
Bone marrow/blood cells
Cells of hair follicles
Cells lining the digestive tract
Cells lining the reproductive tract

80. Side effects/Toxicities
General
Bone marrow
Leukopenia & resulting
infections
 Thrombocytopenia
 Immunosuppression
 Anemia
GI
Oral & intestinal
ulcerations
Diarrhoea
Others
Hair Follicles -
Alopecia
Wounds - impaired
healing
Gonads - menstrual
irregularities including
premature menarche;
impaired
spermatogenesis
Fetus - Teratogenesis)

81. Side effects/toxicities
Renal toxicity: Cisplatin, Methotrexate
Hepatic toxicity: 6-MP, Busulfan,
Cyclophosphamide
Pulmonary toxicity: Bleomycin, Busulfan,
Procarbazine
Cardiac toxicity: Doxorubicin, Daunorubicin

82. Neurotoxicity: Vincristine, Cisplatin, Paclitaxel
Immunosuppression: Cyclophosphamide,
Cytarabine, Dactinomycin, Methotrexate
Hemorrhagic cystitis: cyclophosphomide
Pancreatitis: asparaginase
Leukemia: procarbazine

83. Prevention and management of
side effects and toxicities
Nausea & Vomiting
5-HT3 receptor antagonist-Ondasetron,
Ganisetron
dexamethasone
Anaemia
Erythropoietin
Blood transfusion
Immunosupression:
Colony stimulating factor
Broad-spectrum antibiotics
BM transplant

84. Prevention and management of
side effects and toxicities
Chemoprotective agents
Mesna: reduces bladder irritation
Leucovorin: minimizes toxic effects on other
body cells when given with methothrexate
Amifostine: reduces the level of renal injury
Desrazoxane: reduces the effect of
chemotherapy on the heart.
Secondary tumors: Careful follow-up

85. Extravasation injury refers to the damage
caused by the leakage of solutions from the
vein into the surrounding tissue spaces.
Depending on the substance that is
extravasated into the tissue, the degree of
injury can range from a very mild skin
reaction to severe necrosis.
Extravasation of vesicants is a medical
emergency

87. Chemotherapy Safety
Safe drug storage
Minimal personnel exposure
Protective clothing
Safety precautions during drug
reconstitution and administration
Patient care after chemotherapy
Proper cytotoxic waste disposal

88. Advancements
Liposomal formulations
Targeted therapy, Angiogenesis inhibitors
Monoclonal antibodies
Continued Research into safer ways of
treating cancer

89. THANK YOU FOR THE
AUDIENCE

91. References
 Cancersbiology.blogspot.com/2012/07/definition-of-
cancer.html
 Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology Instructor: Dr. Donald
Kufe
 American Cancer society: Chemotherapy principles
 Postgraduate surgery Al-fallouji
 Cancer management: a multidisciplinary approach; Chp.3;
Principles of chemotherapy; Ray Page, DO, PhD, and
Chris Takimoto, MD, PhD
 Cancer Chemotherapy; (ppt) Prof. Clement A. Adebamowo,
BM ChB Hons. (Jos), FWACS, FACS, D.Sc. (Havard)