Clinical Pharmacology and Therapeutics

370 CANCER CHEMOTHERAPY
Table 48.2: Multiple mechanisms of acquired tumour drug resistance
Table 48.4: Emetogenic potential of commonly used cytotoxic drugs
Mechanism
Examples
Severe Moderate Low
1. Reduced intracellular drug
concentration
(i) increased drug efflux Anthracyclines (e.g.
(MDR-1, Pgp and related doxorubicin), vinca alkaloids
proteins)
(e.g. vincristine), taxanes
(paclitaxel), podophyllotoxins
(etoposide)
(ii) decreased inward transport Antimetabolites –
methotrexate, nitrogen
mustards
2. Deletion of enzyme to Cytosine arabinoside;
activate drug
5-fluorouracil
3. Increased detoxification 6-Mercaptopurine, alkylating
of drug
agents
4. Increased concentration of Methotrexate, hydroxyurea
target enzyme
5. Decreased requirement for L-Asparaginase
specific metabolic product
6. Increased utilization of Antimetabolites (e.g.
alternative pathway
5-fluorouracil)
7. Rapid repair of drug- Alkylating agents (e.g.
induced lesion
mustine, cyclophosphamide
and cisplatin)
8. Decreased number of Hormones,
receptors for drug
glucocorticosteroids
Doxorubicin Lomustine, carmustine Bleomycin
Cyclophosphamide Mitomycin C Cytarabine
(high dose) Procarbazine Vinca alkaloids
Dacarbazine Etoposide Methotrexate
Mustine Ifosfamide 5-Fluorouracil
Cisplatin Taxanes Chlorambucil
Camptothecins
Mitozantrone
antagonists NK1 antagonist; see Chapter 34) which are tailored
to the emetogenic potential of the chemotherapy to be
administered. It may also be necessary to give the patient a
supply of as-needed medication for the days after chemotherapy.
No prophylactic anti-emetic treatment is 100% effective,
especially for cisplatin-induced vomiting.
EXTRAVASATION WITH TISSUE NECROSIS
Tissue necrosis, which may be severe enough to require skin
grafting, occurs with extravasation of the following drugs:
doxorubicin, BCNU, mustine, vinca alkaloids and paclitaxel.
Careful attention to the correct intraluminal location of vascular
catheters for intravenous cytotoxic drug administration is
mandatory.
Table 48.3: Common adverse effects of cytotoxic chemotherapy
Immediate
Delayed
1. Nausea and vomiting 1. Bone-marrow suppression
predisposing to infection,
bleeding and anaemia
2. Extravasation with tissue 2. Alopecia
necrosis
3. Agent-specific organ toxicity
3. Hypersensitivity reactions (e.g. nervous system –
peripheral neuropathy with
vinca alkaloids, taxanes)
4. Psychiatric morbidity and
cognitive impairment
5. Infertility/teratogenicity
6. Second malignancy
Sometimes vomiting may be anticipatory and this may be
minimized by treatment with benzodiazepines. It is often
routine to use two- or three-drug combinations as prophylactic
anti-emetic therapy (e.g. glucocorticosteroids 5HT 3
BONE MARROW SUPPRESSION
There are two patterns of bone marrow recovery after suppression
(see Figure 48.3), namely rapid and delayed. The
usual pattern is of rapid recovery, but chlorambucil, BCNU,
CCNU, melphalan and mitomycin can cause prolonged
myelosuppression (for six to eight weeks). Support with blood
products (red cells and platelet concentrates) and early antibiotic
treatment (see below) is crucial to chemotherapy, since
aplasia is an anticipated effect of many effective regimens. The
availability and use of recombinant haematopoietic growth
factors (erythropoietin (Epo), granulocyte colony-stimulating
factor (G-CSF), granulocyte macrophage colony-stimulating
factor (GM-CSF)), to minimize the bone marrow suppression
caused by various chemotherapeutic regimens is a clear-cut
advance in supportive care for patients undergoing cancer
chemotherapy. In the future, the availability of additional
haematopoietic growth factors, e.g. interleukin-3 (IL-3),
thrombopoietin (Tpo) and interleukin-11, may further
enhance the ability to minimize cytotoxic induced bone marrow
suppression. Vincristine, bleomycin, glucocorticosteroids
and several of the recently developed molecularly