PRINCIPLES OF CANCER CHEMOTHERAPY

12/17/2014 [email protected] 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 tumoursby 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/Mand 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 AGENTCyclophosphamide,chlorambucil, thiothepa, melphalan etc

Interferes with cross linkage of DNA

MyelosupressionHemorrhagic cystitisSkin rashFlu-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-AsparaginaseNitrosoureaCis-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

MelanomaRenal cell caNeuroblastomaNHL

Interferon Enhance NK-cells Re-expression of HLA gene

Kaposi’s sarcomaMultiple myelomaLeukemia

BCG Stimulate immune response

CIS of the bladder,


TARGET THERAPY MECHANISM OF ACTION CILNICAL USES

SMALL MOLECULES GefitinibErlotinib

Inhibits EGFR tyrosine kinase thereby inhibiting growth of cancer cells

Non-small cell cancer of the lungs

MONOCLONAL ANTIBODIESTrastuzumab(Herceptin)Rituximab(mabthera)Bevacizumabcetuximab

Selectively kill tumour cellsexpressing certain receptors

Trastuzumab is use Her-2positive breast cancer


HORMONE CLINCAL USES

ANTI-ANDROGENSFlutamideoestrogen

Use with gosereline in the treatment of metastatic prostate cancer

ANTI-ESTROGENTamoxifenPure anti-oestrogen (fasodex)

Breast cancer

SELECTIVE AROMATASE INHIBITORSAnastrozole

2nd line in ER/PR +ve breast ca

AMINOGLUTETHIMIDE Breast and adrenal ca

PROGETINSMedroxyprogesterone acetate

Breast and endometrial

LHRH analogueGoserelin

Prostate and breast ca

CORTICOSTEROIDSDexamethasoneprenisolone

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 - Dead31


• Physical examination

– The extent of primary and metastatic disease via the general and thorough systemic examination

– Body surface area

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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


TREATMENTNU

MB

ER

OF

CE

LLS

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.


TREATMENTNU

MB

ER

OF

CE

LLS

KEY:

Normal cells

Tumour cells

Rx RxRx

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

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– 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.

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PRINCIPLES OF CANCER CHEMOTHERAPY