European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion.

Eisenhauer, Elizabeth; Huinink, W.W. ten Bokkel; Swenerton, Kenneth D.; Gianni, Luca; Myles, JD; Burg, M. E. van der; Kerr, Ian G.; Vermorken, Jan B.; Buser, K.; Colombo, Nicoletta

doi:10.1200/jco.1994.12.12.2654

Cited by 582 publications

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“…As for neuromuscular toxicity, although neuropathy and myalgia/arthralgia appeared to be more severe in a phase I trial in which a shorter infusion was used (Schiller et al, 1994), the results of a randomized trial with moderate dosages of paclitaxel have not supported its schedule dependency (Eisenhauer et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

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

Kunitoh

Saijo²,

Furuse³

et al. 1998

Br J Cancer

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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%)...

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Section: Discussionmentioning

confidence: 99%

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

Kunitoh

Saijo²,

Furuse³

et al. 1998

Br J Cancer

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“…The risk of neutropenia has been significantly reduced in recent years by using shorter infusion times and the administration of granulocyte colony stimulating factors. 4,5 On the other hand, neurotoxicity cannot be prevented nor treated, can last for months, and in severe cases it may cause irreversible nerve damage. 6,7 Neurotoxicity, which has become the dose-limiting toxicity of paclitaxel, exhibits substantial interindividual variability.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

et al. 2010

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Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele) ¼ 0.55; 95% confidence interval (CI) ¼ 0.34-0.89; P ¼ 0.014 and HR (per allele) ¼ 0.51; 95%CI ¼ 0.30-0.86; and P ¼ 0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele) ¼ 1.72; 95%CI ¼ 1.05-2.82; and P ¼ 0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR ¼ 1.64 (95% CI ¼ 1.26-2.14; P ¼ 0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.

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“…A high concordance was also found in patients treated with altretamin (85%) (Rustin et al, 1997) and oxaliplatin (78%) (Dieras et al, 2002). However, in a large study of Eisenhauer et al (1994), changes in CA125 levels were not always predictive of tumour response in paclitaxel treatment of 382 patients. Overall, 49% of patients demonstrated serial decreases in CA125 levels, but only one-third of these showed a response by standard tumour measurement criteria.…”

Section: Discussionmentioning

confidence: 86%

“…Several definitions for CA125 alterations in the monitoring of ovarian carcinoma treatment have been proposed including single measurement of CA125 values (Davelaar et al, 1996), relative percentage reduction in the CA125 level (Eisenhauer et al, 1994;Rustin et al, 1996Rustin et al, , 1997Rustin et al, , 2000Bridgewater et al, 1999;Campos et al, 2001;Meyer et al, 2001;Dieras et al, 2002;Rustin, 2003), CA125 ratio at selected time intervals (Davelaar et al, 1996;de Jong et al, 1997) and exponential regression analysis of the CA125 levels Pearl et al, 1994;de Jong et al, 1997). The only definition that has been validated prospectively in different data sets is the relative percentage response definition described by Rustin et al (1996).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies identify patients in whom the effects of second-line chemotherapy on the CA125 level are in discordance with the radiographic evaluation of changes in the tumour load (Eisenhauer et al, 1994;Morgan et al, 1995;Davelaar et al, 1996). In a recent meta-analysis of 19 phase II trials including 14 different antineoplastic agents and different first-line regimens, it was found that CA125 response criteria tend to overestimate a tumour reduction when compared to WHO (World Health Organization) tumour response criteria .…”

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confidence: 99%

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Do CA125 response criteria overestimate tumour response in second-line treatment of epithelial ovarian carcinoma?

et al. 2004

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Recent studies indicate that cancer antigen 125 (CA125) response criteria tend to overestimate a tumour reduction measured by standard WHO response criteria in recurrent epithelial ovarian carcinoma. The aim of the study was to validate the recently introduced GCIG (The Gynaecological Cancer Intergroup) CA125 response criteria in predicting a tumour response measured by WHO (World Health Organization) criteria. Changes in CA125 levels (GCIG criteria) were retrospectively compared with alterations in the tumour load (WHO criteria) during second-line chemotherapy with topotecan or paclitaxel -platinum in 124 consecutive patients with recurrent or refractory disease. In patients assessable by both response criteria (n ¼ 72), the overall response rate using GCIG CA125 criteria was 57% (95% confidence interval (CI): 45 -69%) and significantly higher than the response rate of 39% (95% CI: 28 -51%) using WHO response criteria (P ¼ 0.045). The GCIG CA125 criteria had a sensitivity of 96% (95% CI: 82 -100%), a specificity of 68% (95% CI: 52 -81%) and an accuracy of 79% (95% CI: 68 -88%) in predicting a response measured by WHO criteria. In conclusion, the GCIG CA125 response criteria seem to overestimate a tumour response by WHO criteria when monitoring the efficacy of second-line chemotherapy with topotecan or paclitaxel -platinum in patients with epithelial ovarian carcinoma.

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European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion.

Cited by 582 publications

References 0 publications

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

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

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

Do CA125 response criteria overestimate tumour response in second-line treatment of epithelial ovarian carcinoma?

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