A Textbook of Clinical Pharmacology and Therapeutics

COMMONCOMPLICATIONS OFCANCERCHEMOTHERAPY 369

Cytotoxic cancer chemotherapy is primarily used to induce
and maintain a remission or tumour response according to the
following general principles. It often entails complex regi-
mens of two to four drugs, including pulsed doses of a cyto-
toxic agent with daily treatment with agents with different
kinds of actions. Knowing the details of such regimens is not
expected of undergraduate students and graduate trainees in
oncology will refer to advanced texts for this information.

• Drugs are used in combination to increase efficacy, to inhibit
  the development of resistance and to minimize toxicity.


• Drugs that produce a high fraction cell kill are preferred.


• Drugs are usually given intermittently, but in high doses.
  This is less immunosuppressive and generally more
  effective than continuous low-dose regimens.


• Toxicity is considerable and frequent blood counts and
  intensive clinical support are essential.


• Treatment may be prolonged (for six months or longer)
  and subsequent cycles of consolidation or for relapsed
  disease may be needed.

RESISTANCE TO CYTOTOXIC DRUGS

Drug resistance may be primary (i.e. a non-responsive

tumour) or acquired. Acquired tumour drug resistance results

from the selection of resistant clones as a result of killing sus-

ceptible cells or from an adaptive change in the neoplastic cell.

The major mechanisms of human tumour drug resistance are

summarized in Table 48.2. The ability to predict the sensitivity

of bacterial pathogens to antimicrobial substances in vitro pro-

duced a profound change in the efficacy of treatment of infec-

tious diseases. The development of analogous predictive tests

has long been a priority in cancer research. Such tests would

be desirable because, in contrast to antimicrobial drugs, anti-

cancer agents are administered in doses that produce toxic

effects in most patients. Unfortunately, currently, clinically

useful predictive drug sensitivity assays against tumours do

not exist.

COMMON COMPLICATIONS OF CANCER

CHEMOTHERAPY

Chemotherapeutic drugs vary in adverse effects and there is

considerable inter-patient variation in susceptibility. The most

frequent adverse effects of cytotoxic chemotherapy are sum-

marized in Table 48.3.

NAUSEA AND VOMITING

Cytotoxic drugs cause nausea and vomiting to varying

degrees (see Table 48.4). This is usually delayed for one to

two hours after drug administration and may last for 24–48

hours or even be delayed for 48–96 hours after therapy. The

mechanisms of chemotherapy-induced vomiting include

stimulation of the chemoreceptor trigger zone (in the floor of

the fourth ventricle) and release of serotonin in the gastro-

intestinal tract – stimulating 5-HT 3 receptors which also stim-

ulate vagal afferents leading to gastric atony and inhibition of

peristalsis.

Table 48.1:Classification of common traditional cytotoxic drugs according
to their effect on the cell cycle

Predominantly cell cycle Predominantly cell cycle

phase-non-specific phase-specific

Actinomycin D Etoposide

Busulfan 5-Fluorouracil

Carmustine (BCNU) Camptothecins – irinotecan

Chlorambucil Capecitabine

Cyclophosphamide Cytosine arabinoside

Dacarbazine (DTIC) Gemcitabine

Daunomycin Methotrexate (MTX)

Doxorubicin 6-Mercaptopurine (6-MP)

Ifosfamide Taxanes –

Lomustine (CCNU) paclitaxel/docetaxel

Melphalan 6-tioguanine

Mitomycin C Vinca alkaloids

Mitoxantrone

Nitrogen mustard

CCNU,cis-chloroethylnitrosourea; BCNU, bis-chloroethylnitrosourea.

Key points

Principles of cytotoxic chemotherapy

• Cytotoxic drugs kill a constant percentage of cells – not
  a constant number.


• Cells have discrete periods of the cell cycle during which
  they are sensitive to cytotoxic drugs.


• Cancer chemotherapy slows progression through the
  cell cycle.


• Cytotoxic drugs are not totally selective in their toxicity
  to cancer cells.


• Cell cytotoxicity is proportional to total drug exposure.


• Cytotoxic drugs should be used in combination.

Key points

Combination chemotherapy

• Develop combinations in which the drugs have:
  
  
  • individual antineoplastic actions;
  
  
  • non-overlapping toxicities;
  
  
  • different mechanisms of cytotoxic effects.
  
  
  
  


• The dose and schedule used must be optimized.


• Combination therapy is better than single drug therapy
  because:
  
  
  • there is improved cell cytotoxicity;
  
  
  • heterogeneous tumour cell populations are killed;
  
  
  • it reduces the development of resistance.