Download Clinical Applications of Antineoplastic Chemotherapy

Clinical Applications of Antineoplastic Chemotherapy
Chemotherapy
5th-6th decades of 20th century
Subsequent integration into treatment protocols
Limitations due to resistance, toxicity
Understanding of mechanisms through which the drugs work
History
Paul Erlich coined the term chemotherapy
George Clowes at Roswell Park developed rodent lines to test potential drugs
Alkylating agents – First class
Product of a secret gas programme by USA
1943 use in Hodgkin’s lymphoma
Sidney Farber – folic acid analogs
Cure of childhood leukaemia and HD-1960
Work with solid tumors – disappointing
Nearly 90% drug cures occur in 10% cancer types
Felt that this was related to tumor characteristics and drug resistance
Tumor features
 Cancer cells do not divide at faster rate than normal cells
 Greater number of cells dividing
 Slow growing tumors – less responsive
 Faster growing tumors – more responsive and curable
 Highly aggressive cancer – almost incurable
e.g. Non-Hodgkin’s lymphoma
Diffuse large cell lymphoma - curable in advanced stages (more aggressive)
Indolent lymphoma - responds to treatment but likely incurable in advanced stages
(low grade)
Increase in growth fraction - negative response to Rx-? emergence of resistance
Normal cells
Never develop resistance
Resistance of tumor cells associated with sensitivity of normal cells
Bone marrow and GIT cells are most vulnerable
Chemotherapy options
 Induction for advanced disease
 As adjunct to local treatment
 Primary treatment for localized disease when local treatment is not possible
 Direct instillation to sanctuary sites or site direct perfusion (CNS therapy for acute
leukaemia)
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Chemotherapy – Options
 Induction
 Adjuvant
 Neoadjuvant
 Palliation
Induction chemotherapy
Primary treatment of cancer (before surgery)
No alternative treatment exists (leukaemia)
Adjuvant chemotherapy
Use of systemic treatment after local therapy (minimal tumor bulk)
Use based on risk of recurrence (presence of microscopic disease)
Use based on response of similar tumors at advanced stage
Primary chemotherapy
Neoadjuvant
Used in tumors where alternative treatment is available but is less acceptable
Allows organ preservation (osteogenic sarcoma/breast cancer)
Can assess efficacy of treatment
End points in evaluating response
 Partial response (PR)
 Complete response (CR)
 Relapse free survival (RFS)
 Freedom from progression (FFP)
Combination chemotherapy – Rationale for use
Single drugs at tolerable doses unable to cure cancer
Allows maximum cell kill with tolerable host toxicity
Allows range of drug interaction with tumor cells with different genetic abnormalities
May prevent or slow development of drug resistance
Only drugs known to be effective as single agents used
Drugs causing CR preferred
Select drugs whose toxicities do not overlap
Optimize dose and schedules
Keep interval dosing consistent
Shortest possible time for sensitive tissue recovery
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Bone marrow function – effects of chemotherapy
 Storage compartment exists
 Supplies cells to PB for 8-10 days
 Events in PB lag 7days behind BM
 Day 9-10 fall in PB counts
 Nadir-Day 14-18
 Recovery –Day 21
 Completed recovery – Day 28
Chemotherapy effects
Cell death can be due to direct effect
Agent may trigger differentiation
May cause apoptosis (programmed cell death)
Cell death may not take place at time of drug exposure
Only a proportion of cells die
Chemotherapy-assumptions
All tumor cells are equally sensitive
Drug accessibility and sensitivity-independent of location of cells and host factors
Cell sensitivity remains constant
Evidence to the contrary
Tumor growth – depends on:
Cell cycle time
Growth fraction
Total number of tumor cells
Intrinsic cell death
Phases in cell cycle
G0 – resting
G1 – RNA and protein synthesis
S – DNA synthesis
G2 – RNA and protein synthesis
M – Mitosis
As cells mature they differentiate (BM, GIT cells – cell cycle 24-48 hrs)
Thus their sensitivity to chemotherapy
Phase and cell cycle specificity of drugs
Phase specific drugs
Cell cycle specific
Cell cycle non-specific
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Cell cycle phase specific
Table 1-1. Cell cycle phase-specific chemotherapeutic agents
Phase of greatest activity
Class
Type
Gap 1 (G1)
Natural product
Hormone
Antimetabolite
Antimetabolite
Enzyme
Asparaginase
Corticosteroid
Prednisone
Purine analog
Cladribine
Pyrinidine analog Cytarabine,
fluorouracil,
gemcitabine
Folic acid analog
Methotrexate,
Purine analog
thioguanine,
fludarabine
Topoisomerase 1
inhibitor
Topotecan
Substituted urea
Hydroxyurea
Antibiotic
Bleomycin
Topoisomerase II
inhibitor
Etoposide
Microtubule
polymerization
Paclitaxel (Taxol)
and stablization
Mitotic inhibitor
Vinblastine,
vincristine
vindesine,
vinorelbine
G1/S Junction
DNA synthesis (S)
Antimetabolite
Antimetabolite
Natural product
Gap 2 (G)
Miscellaneous
Natural product
Natural product
Natural product
Mitosis (M)
Natural product
Characteristic agents
Cell cycle specific and non specific drugs
Table 1-2. Cell cycle-specific and cell cycle-nonspecific chemotherapeutic agents
Class
Type
Characteristic agents
Cell cycle specific
Alkylating agent
Nitrogen mustard
Natural product
Alkyl sulfonate
Triazene
Metal Salt
Antibiotic
Chlorambucil,
Cyclophosphamide
Melphalan
Busulfan
Dacarbazine
Cisplatin, carboplatin
Dactinomycin,
daunorubicin
doxorubicin
idarubicin
Cell cycle-nonspecific
Alkylating agent
Nitrogen mustard
nitrosourea
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Mechlorethamine
Carmustine,
lomustine
Drug resistance
 Natural
 Acquired
Categories of resistance
Kinetic
Biochemical
Pharmacologic
Kinetics and resistance
Relates to cycle and phase specificity
Overcome by reducing tumor bulk
Use of combinations to include drugs affecting resting cells
Schedule drugs to prevent phase escape
Biochemical resistance
Inability to convert drug to active form
Decrease drug uptake
Increased efflux
Changes in intracellular target
Increased inactivation
Increased rate of repair of damage DNA
bcl-2 overexpression (blocks apoptosis)
p53 mutations
MDR-drug efflux
Use of agents to rescue normal cells so allowing use of higher doses of chemotherapy
Pharmacologic resistance
Poor or erratic absorption
Increased excretion
Increased catabolism
Drug interactions
Poor transport of agents into some tissues (entry of drugs into CNS)
Future
Understand molecular basis of cancer
Understand differences between normal and malignant cells
Current chemotherapy regimens may be a crude beginning
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