Neuromuscular toxicities of paclitaxel 210 mg m-2 by 3-hour infusion

Abstract

Summary We retrospectively analysed neuromuscular toxicity associated with paclitaxel 210 mg m-2 given by 3-h infusion in 247 patients. The severity correlated significantly with total cumulative dose, but could not be predicted by the pretreatment clinical variables or by pharmacokinetic parameters. The toxicity tended to occur in early treatment cycles.Keywords: paclitaxel; peripheral neuropathy; myalgia; arthralgia; pharmacokinetics; risk factor Peripheral neuropathy and myalgia/arthralgia are among the significant toxicities of paclitaxel. It has been reported that neuropathy associated with paclitaxel by a 24-h injection is dependent upon total cumulative dosage, and no known risk factors have been identified (Wiemik et al, 1987;Chaudhry et al, 1994). Little information is available on the pharmacokinetics and this toxicity. There are also few reports of neuromuscular toxicity of the drug given by shorter infusion, the currently preferred method of administration (Gianni, 1995).The aim of this retrospective analysis was to evaluate the risk factors for neuromuscular toxicity associated with paclitaxel by a 3-h infusion. Pharmacodynamics were also analysed in patients in whom pharmacokinetic data were available. PATIENTS AND METHODSA retrospective analysis was performed on four phase II trials of paclitaxel at a dose of 210 mg m-2 given as a 3-h infusion. Two trials included patients with non-small-cell lung cancer, one trial patients with breast cancer and the other trial patients with ovarian cancer. A summary of the patient characteristics is given in Table 1.Paclitaxel was supplied by Bristol-Myers Squibb (Tokyo, Japan) as a solution containing 30 mg of the drug in 5 ml of 50% polyoxyethylated castor oil (Cremophor EL) and 50% dehydrated alcohol. Each patient received 210 mg m-2 paclitaxel diluted in 500 ml of 5% glucose in a 3-h i.v. infusion, every 3 weeks.Adverse reactions to paclitaxel were graded according to the toxicity criteria of the Japan Society for Cancer Therapy (Japan Society for Cancer Therapy, 1993).Pharmacokinetic analysis was performed during the first course of the treatment in 50 patients. Heparinized blood samples for the measurement of plasma paclitaxel concentration were collected before the infusion and at 5, 15 and 30 min, and 1, 2, 3, 4, 6, 12, 24 Spearman's correlation coefficient was used to determine the correlation between two variables. The difference in the grade of toxicity between the two groups was evaluated using the Mann-Whitney U-test. RESULTSThe median number of paclitaxel chemotherapy cycles was three (range 1-15), and the median cumulative dose of the drug was 630 mg m-2 (range 35-3150 mg m-2).Peripheral neuropathy was grade 0 in 51 (21%), grade I in 120 (49%), grade 2 in 64 (26%) and grade 3 in 12 (5%) patients; no patient suffered grade 4 neuropathy. The neuropathy was predominantly sensory, and only five patients (four with grade 2 and one with grade 3) experienced motor neuropathy. The severity of myalgia/arthralgia was grade 0 in 88 (36%), grade 1 in 74 (30%)...

Abnormal muscle afferent function in a model of Taxol chemotherapy-induced painful neuropathy

“…Although as a clinical entity, neuropathic muscle pain has been largely neglected, many forms of peripheral neuropathy manifest persistent, sometimes debilitating, and often difficult to treat pain in skeletal muscle (Bradley et al 1970;Gardner 1972;Kunitoh et al 1998;Marchettini et al 2006;Peltier and Russell 2006;van de Glind et al 2007;Vittadini et al 2001). We have recently observed mechanical hyperalgesia in skeletal muscle in three models of painful peripheral neuropathy, namely CIPN induced by two chemotherapeutic drugs that have CIPN as dose-limiting side effects, paclitaxel (Alessan- Fig.…”

“…It also induces painful peripheral neuropathy (Tanner et al 1998a,b) as a major dose-limiting side effect; the incidence of this form of peripheral neuropathy is often Ͼ50% and approaches 90% with some dosage regimens (Cavaletti et al 1995;Rowinsky 1993). Paclitaxel containing chemotherapeutic regimens often also produce a pain syndrome characterized by intense myalgias (Jacobson et al 2003;Kunitoh et al 1998), which can persist for months (Kunitoh et al 1998). We recently demonstrated, in an established model of paclitaxel CIPN, persistent muscle pain, manifest as mechanical hyperalgesia, comparable in time course with, and sharing underlying mechanisms with, paclitaxel-induced cutaneous mechanical hyperalgesia (Alvarez et al 2011).…”

“…WHEREAS THE CONCEPT OF NEUROPATHIC muscle pain has received remarkably little attention, a number of reports describe muscle pain as a prominent symptom in patients with diverse forms of peripheral neuropathy (Bradley et al 1970;Gardner 1972;Kunitoh et al 1998;Marchettini et al 2006;Peltier and Russell 2006;van de Glind et al 2007;Vittadini et al 2001). However, the muscle pain experienced by these patients can be incapacitating and resistant to treatment (Jacobson et al 2003).…”

Docetaxel-carboplatin as first line chemotherapy for epithelial ovarian cancer

“…No patients were removed from protocol therapy as a direct result of this side-effect, and troublesome functional neuronal impairment -CTC grade II/III toxicity -was reported in less than 6% of all patients. Peripheral sensorineural and motor toxicity is the principal non-myelogenous toxicity of paclitaxel, occurring in up to 80% of patients (Kunitoh et al, 1998), and is dependent upon the cumulative dose and schedule of administration (Rowinski et al, 1993). As a single agent, docetaxel produces neuropathy in only 11% of treated patients (New et al, 1996), and unlike paclitaxel neuropathy, which may manifest early during treatment, docetaxel-induced neuropathy generally does not appear until cumulative doses of docetaxel exceeding 600 mg/m 2 (Hilkens et al, 1996).…”

A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules

“…Drug was not detectable in samples taken after this time. Patients 12,16,25, and 27 were omitted from the calculation of summary pharmacokinetic parameters as there were insufficient data to estimate individual parameters. Patients 9,17, and 20 were omitted from the calculation of summary pharmacokinetic parameters as spuriously high values for conjugated taxanes were found in samples obtained just before the second cycle of treatment.…”