A Textbook of Clinical Pharmacology and Therapeutics

370 CANCER CHEMOTHERAPY

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 prophyl-
actic anti-emetic therapy (e.g. glucocorticosteroids5HT 3

antagonistsNK1 antagonist; see Chapter 34) which are tai-

lored 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 chemother-

apy. 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 vascu-

lar catheters for intravenous cytotoxic drug administration is

mandatory.

BONE MARROW SUPPRESSION

There are two patterns of bone marrow recovery after sup-

pression (see Figure 48.3), namely rapid and delayed. The

usual pattern is of rapid recovery, but chlorambucil,BCNU,

CCNU, melphalanand mitomycin can cause prolonged

myelosuppression (for six to eight weeks). Support with blood

products (red cells and platelet concentrates) and early antibi-

otic 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 mar-

row suppression. Vincristine, bleomycin, glucocorticos-

teroids and several of the recently developed molecularly

Table 48.2:Multiple mechanisms of acquired tumour drug resistance

Mechanism Examples

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

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

Table 48.4:Emetogenic potential of commonly used cytotoxic drugs

Severe Moderate Low

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