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Basic Princi ples of Cancer Chemotherapy

Cancer Established Treatment Modalities

Uncontrolled Multiplication & Spread of abnormal forms of body’s own cell Surgery
2nd most commonest cause of death (1st – CVD) Radiotherapy
1:3 people diagnosed with cancer during lifetime Chemotherapy (Cytotoxics – damage/kill cells)(Inhibit cell division)

Cellular Basis
Cancer arise from loss of control in normal growth
In normal tissue, rates of new growth & old cell death in balance
In cancer, balance is disrupted
Disruption causes
Uncontrolled cell growth
Loss of cell ability to apoptosis

Cancer Chemotherapy
Use of Drugs that are selectively toxic
Intended only for cancer cells
Leaving normal cells unharmed
Not possible to attack only malignant cells
Cytotoxic agents damage/ interfere with DNA synthesis
Cancer – Resistance to Apoptosis (kill all rapidly dividing cells)
Normal cell turns cancerous (1≥ Mutation takes place in DNA) All other (normal) cells affected as well
Inherited Most drugs – Antiproliferative (affect cell division)
Acquired Treatment is directed towards DNA, its precursors, anywhere in pathway
Main genetic lesions Functions of DNA
Inactivation – Tumour Suppressor Gene
Activation – Proto-Oncogene → On cogene DNA
Pathogenesis ↓
RNA
↓
Protein

Indications for Chemotherapy

Disseminated neoplasm & Not amendable to surgery
Adjuvant Neoadjuvant Maintainance
Following surgery/ Given prior to surgical ↓ dose Chemo
radiation treatment
Attacks Shrinks size Prolong remission
Micrometastases

Characteristics of Ideal Chemotherapy

Safe, Effective, Discriminating
Action limited to cancer cells only
Only few Side Effects
Return patient to former state of health
Characteristics of Cancer Cells
Uncontrolled proliferation
Dedifferentiation & Loss of function
↑ Dose Intermittent Therapy
Invasiveness
More effective than Continuous therapy
Metastases
Allow normal tissues to Recover from toxicity between doses
Tumour cells also recover
Goal of Cancer Treatments
Curative Control of Disease Palliative To prevent tumour Regrowing to its original size, ↑ dose is administered in the
next course
Total eradication of Stop cancer from Alleviation of symptoms
cancer cells enlarging/ spreading & avoidance of toxicity
Dose Calculation
Curable cancers Extend survival ↑ Quality of life
Testicular tumour Bases of Body Surface Area
Drugs may not lengthen
Wilm’s tumour Individuals have varying PK (Pharmacokinetics), PD (Pharmacodynamics)
life
Have Narrow Therapeutic Index
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Cell Cycle Combination Therapy

Growth cycle of a cell is the major determinant of Cancer cells – Heterogenous & Respon d differently to Different drugs
responsiveness to chemotherapy Different Toxicity & Mechanism of Action (MOA )
(overcome limited cell kill of individual anti cancer agents)
Measure of cell growth = cell cycle Advantages
Prevent development of drug Resistance (↓ Chance to develop – 2 drugs)
4 Major Phases of cell cycle ↑ Cancer cell kill (Different MOA)
G1 ↓ Toxicity (Use drugs that do not have Overlapping Toxicities)
S Principles for Combination Therapy
G2 Each drug should be active when used alone (against any particular CA)
M Drugs combined should have different MOA
Drugs combined should have different Toxic Effects Profile
Minimal Cross-Resistance between drugs
Hodgkin’s Non-H odgkin’s Testicular CA Breast CA
MOPP CHOP PVB CMF
Anticancer Drugs & Cell Cycle Mechlorethamine Cyclophosphamide Platinol Cyclophosphamide
Rapidly dividing cells - ↑ susceptible to Anticancer drugs (cisplatin)
Non-proliferating cells (G0 phase) – Not affected (Generally) Oncovin Hydroxydaunorubicin Vinblastine Methotrex ate
Cell-cycle spe cific (CCS) Cell-cycle Non-s pecific (CCNS) (vincristine)
Effective only in Replicating cells Kill tumour cells Procarbazine Oncovin Bleomycin Fluorouracil
(Not in G0 – resting phase) (Cycling & G0 resting phase) (vincristine) (+/- tamoxifen)
Prednisone Prednisone
Effective in ↑ Growth Fraction Effective for ↓ Growth Fraction
ABVD CAF
(↑ Rapid cell turn-over, ↑ effe ctive) (usually solid tumours)
Adriamycin Cyclophosphamide
Effective also in ↑ Growth Fraction (doxorubicin)
malignancies Bleomycin Adriamycin
Generally ↑ active in Haematology Most toxic in cycling cells Vinblastine Fluorouracil
malignancies – relatively large Dacarbazine
proportion of cells are proliferating Hodgkin’s lymphoma
(↑ Growth Fraction) MOPP induce remission in 80% of patients (Replaced by ABVD due to S/E)
When given individually, induce remission in only <40%
ABVD is as effective as MOPP, with ↓ S/E of Sterility & 2° Malignancy (Leukaemia)
May alternate MOPP with ABVD if neoplasm become resistant

Cancer Cure Rates

50% of patients with CA can be cured (17% by chemotherapy)
CA Chemotherapy curative for
Testicular CA
Diffuse Large Cell Lymphoma
Hodgkin’s Lymphoma
Choriocarcinoma
Childhood Tumours
(ALL, Burkitt’s Lymphoma, Wilm’s Tumour, Embryonal Rhabdomyosarcoma)
Initial Surgery + Chemotherapy Difficult for CA Chemotherapy
Growth Fraction curative for to be curative
Ratio of Proliferating cells to cells in G0 Early stage Breast CA Colon CA
↑ Proliferating cells, ↓ G0 cells = ↑ Growth Fraction Osteogenic sarcoma Lung CA
↓ ProliferaƟng cells, ↑ G0 cells = ↓ Growth FracƟon
Growth Fraction & Tumour size Problems in Chemotherapy
As Tumour size ↑, Growth FracƟon ↓ Resistance
• ↓ O2 & Nutrient 1° Acquired
• Eg. Growth Fraction <10% in slow-growing Colon & Lung carcinoma Absence of response on 1st Mutation
Debulking (surgery, radiotherapy) can stimulate remaining cells into active exposure
proliferation Eg. Non-Small cell CA of Lung, Colon Particularly with prolonged
• ↑ SuscepƟbility to cancer Chemotherapy suboptimal drug dose
Solid cancer Tumours Disseminated cancers
↓ Growth FracƟon ↑ Growth FracƟon Mechanism of Resistance Multidrug Resistance
Respond p oorly to Chemotherapy Respond well to Chemotherapy ↓ Uptake of Drugs Associated with ↑ expression of
Need to be removed by Surgery Deletion of enzyme to Activate Drug normal gene (MDR1 gene) for cell
↑ Detoxification of Drug surface glycoprotein
Log Kill Hypothesis ↑ Concentration of Target enzyme (P-glycoprotein)
Chemotherapeutic agents kill a Constant Fraction of cells (1st order kinetics) Rapid repair of Drug-Induced Le sion
(rather than a specific number of cells ) ↓ No. of Rece ptors for Drug MDR1 gene – involved in drug Efflux
RED ↑ Drug Efflux Results – Pumping of drugs Out of
Untreated patients cell through P-glycoprotein
DARK BLUE Toxicity
Late Rx (to take) Damage DNA, initiate apoptosis
Infrequent sched uling Affect rapidly dividing normal cells – toxicity (side effects)
LIGHT BLUE • Hyperuricaemia & Tumour Lysis Syndrome (TLS)
Early Rx (to take) • Extravasation of IV drugs
↑ Intensive Combination Chemo • Nausea, Vomiting (CTZ stimulation)
GREEN • BM suppression
Early Surgery
• Impaired Immune response
Followed by Adjuvant Chemo (Myelosuppression ↓ WBC)
Amount of cells before Therapy determines the success of Chemotherapy • Alopecia (reversible)
Better results achieved with • Reproductive function (Impair Gametogenesis) (Teratogenic 1st trimester)
Early Treatment Treatment induced Tumours
Small Tumours Anticancer agents are also Mutagens (particularly, alkylating agents)
Intensive Treatment Acute Non-Lymp hocytic Leukaemia (eg. AML)
Combination Che motherapy
Early Surgical Removal – followed by Adjuvant Chemo (for solid tumours)