A Textbook of Clinical Pharmacology and Therapeutics

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
Mitoxantrone
Nitrogen mustard
Vinca alkaloids
CCNU, cis-chloroethylnitrosourea; BCNU, bis-chloroethylnitrosourea.
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 regimens
of two to four drugs, including pulsed doses of a cytotoxic
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.
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.
COMMON COMPLICATIONS OF CANCER CHEMOTHERAPY 369
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.
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 susceptible
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 produced
a profound change in the efficacy of treatment of infectious
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, anticancer
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 summarized
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 gastrointestinal
tract – stimulating 5-HT 3 receptors which also stimulate
vagal afferents leading to gastric atony and inhibition of
peristalsis.