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 RoswellPark 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)

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

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

Cell cycle phase specific

Table 1-1. Cell cycle phase-specific chemotherapeutic agents

Phase of greatest activity ClassType Characteristic agents

Gap 1 (G1)Natural productEnzymeAsparaginase

HormoneCorticosteroid Prednisone

G1/S JunctionAntimetabolitePurine analogCladribine

DNA synthesis (S)AntimetabolitePyrinidine analogCytarabine,

fluorouracil,

gemcitabine

AntimetaboliteFolic acid analog Methotrexate,

AntimetabolitePurine analogthioguanine,

fludarabine

Natural productTopoisomerase 1

inhibitorTopotecan

Miscellaneous Substituted ureaHydroxyurea

Gap 2 (G)Natural productAntibioticBleomycin

Natural productTopoisomerase II

inhibitorEtoposide

Natural productMicrotubule

polymerizationPaclitaxel (Taxol)

and stablization

Mitosis (M) Natural productMitotic inhibitor Vinblastine,

vincristine

vindesine, vinorelbine

Cell cycle specific and non specific drugs

Table 1-2. Cell cycle-specific and cell cycle-nonspecific chemotherapeutic agents

ClassTypeCharacteristic agents

Cell cycle specific

Alkylating agent Nitrogen mustardChlorambucil,

Cyclophosphamide

Melphalan

Alkyl sulfonateBusulfan

TriazeneDacarbazine

Metal SaltCisplatin, carboplatin

Natural product AntibioticDactinomycin,

daunorubicin

doxorubicin

idarubicin

Cell cycle-nonspecific

Alkylating agentNitrogen mustardMechlorethamine

nitrosoureaCarmustine,

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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