CONSIDERATIONS IN CANCER CHEMOTHERAPY
The existence of the
blood-brain barrier is an important consideration in the chemotherapy of
neoplastic dis-eases of the brain or meninges. Poor drug penetration into the
CNS has been a major cause of treatment fail-ure in acute lymphocytic leukemia
in children. Treatment programs for this disease now routinely em-ploy
craniospinal irradiation and intrathecally adminis-tered methotrexate as
prophylactic measures for the prevention of relapses. The testes also are
organs in which inadequate antitumor drug distribution can be a cause of
relapse of an otherwise responsive tumor.
The multidrug transporter
P-glycoprotein is ex-pressed in the endothelial lining of the brain and testis
but not in other organs and is thought to be a major component of the
blood-brain and blood-testis drug barriers.
Although the effects of
various schedules are not al-ways predictable, drugs that are rapidly
metabolized, excreted, or both, especially if they are phase specific and thus
act on only one portion of the cell cycle (e.g., cytarabine), appear to be more
effective when adminis-tered by continuous infusion or frequent dose
fraction-ation than by high-dose intermittent therapy. On the other hand,
intermittent high-dose treatment of Burkitt’s lymphoma with cyclophosphamide is
more ef-fective than fractionated treatment, since cyclophos-phamide acts on
all phases of the cell cycle and almost all of the tumor cells in that disease
are actively prolif-erating.
The classic example of schedule dependency is cy-tarabine, a
drug that specifically inhibits DNA synthesis and is cytotoxic only to cells in
S-phase. Continuous in-fusion or frequent administration of cytarabine
hy-drochloride is superior to intermittent injection of the drug. Bleomycin is
another drug for which continuous infusion may increase therapeutic efficacy.
Administration of some
anticancer drugs by contin-uous infusion has
been shown to improve their thera-peutic index through selective reduction of
toxicity with retained or enhanced antitumor efficacy.
In addition to the usual
intravenous or oral routes, some anticancer agents have been administered by
regional intraarterial perfusion to increase drug delivery to the tumor itself
and at the same time diminish systemic tox-icity. Thus, patients with
metastatic carcinomas of the liver and little or no disease elsewhere (a common
oc-currence in colorectal cancer) can be treated with a con-tinuous infusion of
fluorouracil or floxuridine through a catheter implanted in the hepatic artery.
of various agents has been used for patients with malignant pleural or
peri-toneal effusions. Intraperitoneal
instillations of cisplatin, etoposide, bleomycin, 5-fluorouracil, and
interferon are well tolerated and are being evaluated in patients with ovarian
carcinomas, in whom the tumor is frequently re-stricted to the peritoneal
Other routes of
administration can be employed in certain situations. Methotrexate and
cytarabine are given intrathecally or
intraventricularly to prevent
re-lapses in the meninges in acute lymphocytic leukemia and to treat
carcinomatous meningitis. Thiotepa and bleomycin have been administered by
intravesical in-stillation to treat early bladder cancers. Fluorouracil can be
applied topically for certain skin cancers.
Antineoplastic drugs may
participate in several types of drug interactions. Methotrexate, for example,
is highly bound to serum albumin and can be displaced by sali-cylates,
sulfonamides, phenothiazines, phenytoin, and other organic acids. The induction
of hepatic drug-metabolizing enzymes by phenobarbital may alter the metabolism
of cyclophosphamide to both active and in-active metabolites. Mercaptopurine
metabolism is blocked by allopurinol, an occurrence that may result in lethal
toxicity if the dosage of mercaptopurine is not re-duced to one-fourth of the
usual dosage. Methotrexate is secreted actively by the renal tubules, and its
renal clearance may be delayed by salicylates.
Procarbazine exhibits an
interesting interaction with ethanol, resulting in headaches, diaphoresis, and
facial erythema; patients taking this drug should be fore-warned to abstain
from alcohol. Procarbazine is also a monoamine oxidase (MAO) inhibitor and may
potenti-ate the effects of drugs that are substrates for this en-zyme.
The biliary and renal
excretion of some drugs (e.g., anthracyclines, vinca alkaloids, dactinomycin,
etopo-side) by the P-glycoprotein multidrug transporter can be inhibited by
other drugs that are also transported by P-glycoprotein.