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330 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 331

fibrosis. The nitrosoureas also cause nephrotoxicity, particularly after Table 22–4, which shows the fraction of the single-agent MTD that
total doses of 1200 mg/m BCNU, whereas cyclophosphamide and can be administered in combination with other drugs. As might be
2
ifosfamide cause chronic bladder toxicity, hemorrhage, and, in rare expected, this fraction is quite variable depending on the drug combi-
cases, bladder carcinomas. Urinary toxicity of the latter two agents is nations, with the average fractional MTD used in combination ranging
prevented by coadministration of mesna, a sulfhydryl that detoxifies from 0.5 to 1. Depending on the regimen, significant gastrointestinal,
acrolein at acid pH. pulmonary, hepatic, and/or renal toxicities are encountered and become
dose limiting. For these reasons, high-dose regimens are safest in
High-Dose Alkylating Agent Therapy patients who are younger (<70 years) and who have had minimal prior
The development of hematopoietic cell transplantation has made it chemotherapy and radiation therapy.
possible to administer doses of chemotherapy that would otherwise
produce life-threatening aplasia. To be of benefit, however, high- AGENTS OF DIVERSE MECHANISMS
dose therapy must employ agents that have a relatively steep dose–
response relationship. The drugs used must not have lethal extramed- BLEOMYCIN
ullary toxicity at high doses. Among the classes of cytotoxics, alkylators
have a particularly favorable linear relationship between dose and cyto- Bleomycin is a mixture of cytotoxic peptides produced by the fungus
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toxicity in experimental tumor systems. Extramedullary organ toxicities Streptomyces verticillis. Because it has antitumor activity with minimal
are infrequent until doses are increased manyfold, making them ideal marrow toxicity, it is commonly used as part of combination regimens
candidates for high-dose regimens. Depending on the agent and the (such as ABVD) to treat Hodgkin lymphoma and with cisplatin and
toxicity profile, doses may only be escalated by as little as twofold as vinblastine to treat germ cell tumors. Bleomycin acts by causing both
seen with cisplatin because of renal toxicity, or to as high as 18-fold single- and double-strand breaks in DNA. These breaks form as a con-
in the case of thiotepa (Table 22–3). 131–137 However, when agents are sequence of a bleomycin–Fe (II) complex that binds to DNA and under-
combined into a high-dose regimen, overlapping extramedullary goes redox cycling with molecular oxygen. The drug’s reactive complex
toxicities of the agents must be considered so as to avoid serious organ abstracts a proton from deoxyribose, leading to cleavage of the sugar at
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compromise (Table 22–4). 138–142 Overlapping extramedullary toxicities the 3′-carbon. In experimental tumors, resistance to bleomycin has
(particularly the risk of pulmonary or hepatic dysfunction or second- been attributed to increased tumor cell concentrations of an aminohy-
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ary leukemia) cannot be completely avoided, but rational drug selection drolase that cleaves and inactivates the drug. Some resistant cell lines
can minimize the dose reductions of the individual agents, compared to exhibit enhanced capacity to repair strand breaks, and in others, resis-
their single-agent maximum tolerated dose (MTD), while at the same tance results from decreased drug accumulation. Additional factors,
time ensuring safety of the combination regimen. This is illustrated in such as increased free radical detoxification, may also influence toxicity.
The tumor specificity of bleomycin, its severe cutaneous and pulmonary
toxicity, and its lack of toxicity to marrow and the gastrointestinal tract
may be a result of widely differing levels of metal ions and bleomycin
TABLE 22–3. Dose-Limiting Extramedullary Toxicities of hydrolase, the detoxifying enzyme, in these tissues. A polymorphism in
Single-Agent Chemotherapy the hydrolase gene, identified by SNP A1450G, may confer resistance to
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Maximum Increase Over the drug as the result of its enhanced hydrolase activity. Cell killing
Tolerated Standard Major occurs throughout the cell cycle.
Drug Dose (mg/m )* Dose † Toxicities ‡
2
Cyclophos- 7000 7.0 Cardiac Clinical Pharmacology
Bleomycin may be administered intravenously or intramuscularly in
phamide
doses of 10 to 20 U/m per week to cumulative doses of 250 U for sys-
2
Ifosfamide 16,000 2.7 Renal, CNS temic therapy, as well as intrapleurally or intraperitoneally for control
Thiotepa § 1005 18.0 GI, CNS of malignant effusions. The half-life of drug elimination from plasma
is estimated to be 2 to 3 hours. After a single intravenous injection,
Melphalan § 180 5.6 GI
more than half the dose is excreted, unchanged, in the urine within 24
Busulfan § 640 9.0 GI, hepatic hours. Bleomycin elimination may be markedly impaired in patients
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BCNU § 1050 5.3 Lung, hepatic with poor renal function; such patients are at risk of overwhelming skin
and lung toxicity. Dose reduction by 50 percent should be considered in
Cisplatin 200 2.0 Renal,
neuropathy patients with a CrCl in the range of 30 to 80 mL/min, and drug should
be withheld in the present of CrCl less than 30 mL/min.
Carboplatin § 2000 5.0 Hepatic, renal
Etoposide 3000 6.0 GI Adverse Effects
Bleomycin has minimal effects on normal marrow; however, in patients
Cytarabine 3000 10–30 Neurologic,
mucositis given other myelosuppressive drugs or who are recovering from mar-
row toxicity from these agents, additional mild myelosuppression may
BCNU, bischloroethyl nitrosourea; GI, gastrointestinal. be observed. The primary toxicities that result from bleomycin are pul-
* Independent of hematopoietic toxicity. Dose may be given over monary fibrosis and skin changes. In experimental settings, the drug
multiple days. activates the Hedgehog pathway and induces the secretion of numerous
† Fold increase. This is an approximation because standard doses may cytokines, including interleukin (IL)-6, tumor necrosis factor-α and
vary. transforming growth factor-β, by alveolar macrophages and inflam-
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‡ All drugs listed in this table cause vascular endothelial damage and matory cells, leading to collagen deposition. The risk of pulmonary
venoocclusive disease, as well as late secondary leukemias. toxicity is related to the cumulative dose administered, increasing to
§ With stem cell support. 10 percent in patients given more than 450 mg. Risk is also greater in

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