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316 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 317

refractory to standard regimens. In general, these regimens may pro- In the treatment of lymphomas, the toxicity of radiation therapy to
duce organ toxicities not seen at conventional doses—including pneu- sensitive organs such as skin, lung, heart, and brain may be signifi-
monitis, cardiac failure, vascular endothelial damage, and hepatic and cantly increased by concurrent administration of anthracyclines, a
renal insufficiency—and are ordinarily reserved for patients of younger consideration that has prompted the use of radiation therapy either
age and with normal baseline organ function. before or after anthracycline antibiotics, but not concurrently. Like-
The success of chemotherapy in curing hematologic malignancy wise, bleomycin sensitizes the lungs to damage by high concentration
is incompletely understood. Although targeted therapies exploit clear of inspired O during surgery. Antiangiogenic therapies, rarely used
2
differences in biology conferred by mutations or amplification of key in hematologic malignancies, are associated with an increased risk of
genes, an explanation for the differential effects of cytotoxic drugs on bowel perforation in patients who have recently undergone intraab-
tumor versus normal tissues is less obvious. The greater susceptibility dominal surgery.
of malignant cells to drug toxicity, as reflected in the phenomenon
of leukemia remission induction, with restoration of normal marrow
function, may result from the relative resistance of normal marrow CELL KINETICS AND CANCER CHEMOTHERAPY
stem cells to drug injury. These stem cells exist in a nonreplicating The cell-killing characteristics of cancer chemotherapeutic agents
phase of the cell cycle, where they are less susceptible to damage by vary according to their mechanism of action. Many of the most effec-
DNA-directed agents, and they express genes that protect against tive agents in antileukemic therapy belong to the antimetabolite class,
chemical and hypoxic damage. In addition, there is growing evidence including cytarabine and methotrexate. These drugs kill cells most
that cancer cells lack cell-cycle checkpoints that recognize DNA dam- effectively during the DNA synthetic phase (S-phase) of the cell cycle.
age and activate repair of DNA strand breaks, base deletions, or other For these agents, a prolonged period of tumor exposure to drug is essen-
lesions induced by chemotherapy. This differential in repair capability tial so as to maximize the number of cells exposed during the vulnerable
may allow normal cells to repair damage and promote recovery from period of the cell cycle. As would be predicted, the antimetabolite drugs
chemotherapy-induced injury. are primarily active against rapidly dividing tumors such as acute leu-
kemias and intermediate and high-grade lymphomas. Other anticancer
drugs, such as the topoisomerase inhibitors and alkylating agents, do
COMBINATION CHEMOTHERAPY not require cells to be exposed during a specific phase of the cell cycle,
Most leukemias and lymphomas are highly drug sensitive, but, with the although like the antimetabolites, these drugs are generally more effec-
exception of the curability of Burkitt lymphoma (treated with cyclo- tive against actively proliferating cells as compared to resting cells. Still
phosphamide) and hairy cell leukemia (treated with cladribine), are others, most notably the nitrosoureas and busulfan, are equally toxic to
rarely, if ever, cured with single-agent chemotherapy. Combination dividing and nondividing cells, and at the same time, deplete marrow
chemotherapy forestalls the emergence of drug-resistant cells and thus stem cells. In general, the toxicity of alkylating agents is determined by
is curative in settings where individual agents are ineffective. Empiric the total dose of drug, whereas for the cell-cycle-specific drugs (such
principles have resulted from the clinical experience of the past 4 as methotrexate and cytarabine), both drug concentration and dura-
decades of combination therapy. In general, drugs selected for combi- tion of exposure determine cytocidal effect. However, for drugs that act
nation therapy should have demonstrable antineoplastic activity, or at through alternate mechanisms, such as the taxanes, myelosuppression
least biologic effects, against the tumor in question. The lone exception correlates best with the duration of exposure above a threshold plasma
may be targeted drugs that inhibit signal transduction or angiogene- concentration, which is approximately 50 to 100 nM for paclitaxel and
sis; antibodies such as trastuzumab or rituximab may exhibit limited 200 nM for docetaxel. 8
antitumor activity on their own, but may significantly augment the High-dose regimens achieve a number of worthwhile objectives
action of cytotoxic agents. Individual agents in a combination should for these agents, including an enhancement of cross-membrane trans-
7
be chosen based on their different mechanisms of action and lack of a port, saturation of anabolic pathways inside the cell, and prolongation
common mechanism of resistance such as multidrug resistance (MDR). of the period of effective drug concentration. However, achieving these
The dose-limiting toxicities of the agents chosen should not overlap; objectives is realized at the cost of increased toxicity to normal prolif-
otherwise, they could not be used together at or near full doses. The erating marrow precursor cells and may produce significant and unex-
clinical use of specific combinations should be based on preclinical evi- pected damage to normal organs, such as hepatic venoocclusive disease
dence of synergistic interaction, and single-agent activity in the disease (alkylating agents), cerebellar toxicity (certain alkylating agents and
in question. Favorable molecular or biochemical drug interactions may cytarabine [ara-C]), or pulmonary toxicity (nitrosoureas and alkylating
be dependent on specific schedules of administration. Pharmacokinetic agents). Because hematopoietic stem cells can be harvested, stored, and
interactions should be defined in initial trials of drug combinations so reinfused, dose-limiting toxicities of high-dose chemotherapy are gen-
as to avoid under- or overdosing of individual agents. erally those affecting nonhematologic organs.
Another important consideration in designing clinical protocols The choice of an appropriate dose and schedule of drug adminis-
is dose intensity, the dose administered per unit time, which should be tration depends on a number of factors: (1) the drug’s cell-cycle depen-
maintained throughout a treatment regimen. Achieving this objective dence; (2) the often empirically derived relationship between antitumor
may require the use of hematopoietic growth factors to hasten marrow effects, drug dose, and schedule; (3) pharmacokinetic behavior and the
recovery, prevent repeated episodes of febrile neutropenia, and allow need to maintain a specific drug concentration for a given period of
ontime administration of the next treatment cycle. time; (4) potential interactions with other components of the treatment
Interdigitation of chemotherapy with surgery and irradiation regimen; and (5) patient tolerance. Multiple clinical trials are required
makes it possible to take advantage of favorable cytokinetic or radi- to establish safe and effective single-agent regimens and drug combina-
osensitizing effects of chemotherapy, but drugs may enhance radia- tions. For molecularly targeted drugs, the aim is to maintain inhibition
tion or surgical toxicity to normal organs, an interaction that requires of the target for prolonged periods of time, keeping drug levels above a
careful consideration in designing a multidisciplinary regimen. Thus, threshold for toxicity to tumor cells, but balancing these considerations
5-fluorouracil and cisplatin are potent radiosensitizers used with against the potential for toxicity to normal tissues, such as skin, liver,
radiation therapy to enhance local tumor control in solid tumors. and intestinal epithelium.

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