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

drug interactions of the various agents. Antineoplastic chemotherapy
Inherited genetic variations in drug-metabolizing enzymes may lead to an is a complex undertaking, with the potential for serious or fatal side
increased risk of drug toxicity and may alter the antitumor response. The most effects. Patients are best served if their treatment is based on evidence
important of these familial syndromes affecting treatment of leukemia is the from clinical trials, which define optimal doses, schedules, and drug
deficiency of thiopurine methyltransferase, which slows the elimination of combinations. The specific protocol chosen for treatment should be
6-mercaptopurine (6-MP) and leads to unanticipated toxicity during mainte- appropriate not only for the stage and histology of the tumor but should
nance chemotherapy for acute lymphocytic leukemia. Pharmacokinetic moni- consider individual patient comorbidities, age, and susceptibility to
toring has a standard role in the use of certain therapies, particularly high-dose specific potential toxicities. Thus, bleomycin is not a safe choice for a
methotrexate, and in the evaluation of new drugs or new drug combinations. patient with serious underlying renal or lung disease, nor is doxorubicin
an appropriate drug for use in a patient with a history of congestive
To ensure appropriate dosing, and management of toxicity, there is no substi- heart failure; even in patients with normal cardiac or pulmonary func-
tute for therapy based on standard protocols and peer-reviewed clinical trials. tion, total dose limits should be respected for these agents. Even though
Adherence to protocols ensures that the pharmacologic variables affecting clinical trials define the benefits and risks of a cohort of patients of a
drug disposition can be taken into account early in the course of treatment defined age range and physiology, these results may not be easily extrap-
and that serious untoward events can be avoided while maintaining effective olated to patients at the extreme ends of the spectrum.
therapy. Depending on the major route of drug clearance, doses should be
modified for renal or hepatic dysfunction (Table 22–1). Changes in the
dose and schedule of a drug (dose-dense chemotherapy) offer poten-
tially greater antitumor effects, but often lead to unique toxicities. With
the development of techniques for marrow or blood stem cell storage
The leukemias and lymphomas have been the initial testing ground for
cancer chemotherapy. Because of their rapid rates of proliferation, lack of and replacement of marrow after chemotherapy, potentially lethal doses
surgical treatment options, ready access to malignant cells, and availabil- of chemotherapy can be administered in an attempt to cure malignancies
ity of mouse models of leukemia, the hematologic malignancies drew the
attention of early investigators interested in treating cancer with drugs.
The first evidence for activity of a chemical antitumor agent came in 1942, TABLE 22–1. Dose Modification in Patients with Renal or
from the experimental work and subsequent clinical trials conducted by
Goodman, Gilman, and colleagues at Yale, and their observation that Hepatic Dysfunction
nitrogen mustard caused tumor regression in a patient with Hodgkin Renal dysfunction (creatinine clearance <60 mL/min)
lymphoma. Six years later, Sidney Farber, a pathologist at Children’s Reduce dose in proportion to reduction in creatinine clearance.
1
Hospital in Boston, made the even more startling discovery of remission Drugs
induction by aminopterin and then methotrexate in acute lymphocytic
leukemia (ALL). His work ushered in the modern era of chemother- 1. Methotrexate
apy. Over the next 20 years, clinical trials in these diseases established 2. Cisplatin
2
the basic principles of cyclic combination therapy and dose intensifica- 3. Carboplatin
tion, developed effective strategies for management of infectious and 4. Bleomycin
3
hemorrhagic complications, and led to the cure of these diseases with 5. Etoposide
chemotherapy. High-dose chemotherapy with marrow reconstitution
has further extended the cure rate in leukemias and lymphomas. As our 6. Hydroxyurea
understanding of the biologic and molecular basis for malignancy has 7. Deoxycoformycin
advanced, the concept of molecularly targeted therapy achieved its first 8. Fludarabine phosphate
striking success with the development of imatinib mesylate for chronic 9. Cladribine
myelogenous leukemia (CML). Studies of relapsing patients on imatinib 10. Topotecan
4
provided the first clear evidence for target mutation as a mechanism of 11. imatinib
clinical drug resistance. The first effective use of a monoclonal antibody,
5
rituximab, has extended the cure rate for patients with large cell lympho- 12. Dasatinib (likely, but no guidelines available)
mas, and the first clear demonstration of drug-induced differentiation by 13. Lenalidomide
all-trans retinoic acid (ATRA) has led to a remarkable improvement in Hepatic dysfunction
the cure rate of acute promyelocytic leukemia (APL). Other unique non- For bilirubin >1.5 mg/dL reduce initial dose by 50%.
6
cytotoxic drugs with unusual mechanisms of action, such as L-asparagi- For bilirubin >3.0 mg/dL reduce initial dose by 75%.
nase, thalidomide, and bortezomib, have become valuable components
of regimens for specific kinds of hematologic malignancies. Molecular Drugs
studies of the abnormalities in pathways that control proliferation and 1. Amsacrine
survival lymphomas and leukemias have revealed distinct subsets of dis- 2. Doxorubicin
ease have identified new therapeutic targets. 3. Daunorubicin
4. Vincristine
BASIC PRINCIPLES OF CANCER 5. Vinblastine
CHEMOTHERAPY 6. Paclitaxel and docetaxel
7. Mitoxantrone
The safe and effective use of chemotherapy in clinical practice requires 8. Gleevec
a thorough understanding of the basic aspects of drug action as well as 9. Dasatinib
knowledge of the important clinical toxicities, pharmacokinetics, and

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