Clinical toxicities encountered with paclitaxel (Taxol).
Although paclitaxel (TAXOL) appears to be one of the most promising antineoplastic agents of the last decade, with demonstrated activity in advanced and refractory ovarian, breast, lung, and head and neck cancers, most clinical oncologists have had little experience with the agent. This is largely the result of the initially limited supply of paclitaxel and other obstacles encountered during early clinical development that restricted the drug's availability to a few investigational centers. Although a high incidence of major hypersensitivity reactions due to the Cremophor EL vehicle used in formulation disrupted and almost terminated the clinical development of paclitaxel, hypersensitivity reactions are no longer a serious problem consequent to the advent of effective premedication regimens and longer administration schemes. Instead, neutropenia is the principal toxicity of paclitaxel. At clinically relevant doses, absolute neutrophil count nadirs are severely depressed in most patients. The duration of severe neutropenia, however, is usually brief; treatment delays for unresolved hematologic toxicity are rare, and absolute neutrophil count nadirs are constant with repetitive dosing, suggesting that neutropenia is not cumulative. Asymptomatic sinus bradycardia has occurred in up to 29% of patients in phase II trials, and other cardiac disturbances, including atrioventricular conduction and bundle branch blocks, ventricular tachycardia, and possible ischemic manifestations, have been reported in approximately 3% of patients. Cardiac disturbances have primarily been noted in studies that used cardiac monitoring to more effectively detect and manage major hypersensitivity reactions. Although sinus bradycardia and conduction blocks appear to represent true toxicities, ventricular tachycardia and ischemic manifestations, which have largely been observed in patients with preexisting cardiac disease, may not be due to paclitaxel. In view of the lack of clinical significance of the cardiac effects and their infrequent occurrence, cardiac monitoring during paclitaxel is not recommended for patients without cardiac risk factors. However, until precise risk factors can be defined, patients with a significant antecedent cardiac history are generally not considered to be good candidates for paclitaxel therapy. Neurotoxicity, characterized principally by peripheral neurosensory manifestations, has generally been of mild to moderate severity, even in heavily pretreated patients at paclitaxel doses < or = 200 mg/m2. However, some patients have developed a severe sensory-motor polyneuropathy at higher doses of paclitaxel (given as a single agent or in combination with cisplatin). Patients with an antecedent peripheral neuropathy or coexisting medical illnesses associated with peripheral neuropathy (such as diabetes mellitus and substantial prior alcohol use) appear to be especially prone to developing peripheral neuropathy.(ABSTRACT TRUNCATED AT 400 WORDS)
Rowinsky
E K
EK
Johns Hopkins Oncology Center, Division of Pharmacology and Experimental Therapeutics, Baltimore, MD 21287-8934.
Eisenhauer
E A
EA
Chaudhry
V
V
Arbuck
S G
SG
Donehower
R C
RC
D000505:Alopecia / Q000139:chemically induced; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001927:Brain Diseases / Q000139:chemically induced; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity / Q000209:etiology; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis; D008954:Models, Biological; D009135:Muscular Diseases / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D012307:Risk Factors
D007073:Immunoglobulin E; D017239:Paclitaxel