Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting.

Abstract

Taxol and cisplatin doses of 250 mg/m2 and 75 mg/m2, respectively, can be administered repetitively with G-CSF to untreated and minimally pretreated patients. However, these doses are not recommended for patients with pre-existing neuropathies until additional experience in high-risk patients is obtained. Although this Taxol dose is nearly 85% higher than the dose that can be combined with cisplatin in the absence of G-CSF, this high-dose regimen should not be used outside the investigational setting until a dose-response relationship has been demonstrated for Taxol in randomized clinical trials.

Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin

“…Neuropathy has also been reported as a dose-dependent side-effect of treatment with paclitaxel (Taxol) (Lipton et al, 1989;Gerven et al, 1994). As expected, trials on combination chemotherapy of cisplatin and paclitaxel found a high incidence of peripheral neuropathy (Rowinsky et al, 1991;Rowinsky et al, 1993;Chaudhry et al, 1994).…”

“…Neuropathy has also been reported as a dose-dependent side-effect of treatment with paclitaxel (Taxol) (Lipton et al, 1989;Gerven et al, 1994). As expected, trials on combination chemotherapy of cisplatin and paclitaxel found a high incidence of peripheral neuropathy (Rowinsky et al, 1991;Rowinsky et al, 1993;Chaudhry et al, 1994).Peripheral neurotoxicity has been reported as a frequent, but usually mild side-effect of docetaxel in several phase I and phase II studies (Bissett et al, 1993;Extra et al, 1993;Aamdal et al, 1994;Fossella et al, 1994;Francis et al, 1994a;Francis et al, 1994b;Smyth et al, 1994;Chevallier et al, 1995; Hilkens et al, 1996;New et al, 1996). The neurotoxic effects of docetaxel in combination Chemotherapy was administered in 3-weekly regimens.…”

“…The incidence of neuropathy was disproportionately higher than expected with either paclitaxel or cisplatin alone at similar single and cumulative doses. In a study of 32 patients treated with higher doses paclitaxel (135-350 mg m-2 per cycle) and cisplatin (75-100 mg m-2 per cycle), 75% developed a neuropathy (Rowinsky et al, 1993). It was suggested that the neuropathy was mainly due to paclitaxel.…”

“…In view of their partly non-overlapping side-effects and their activities in a wide range of tumour types, developing combination chemotherapy regimens, including both taxoids and platins, is of major interest (Rowinsky et al, 1991;Rowinsky et al, 1993;Chaudhry et al, 1994). An important dose-dependent side-effect of cisplatin is the development of peripheral neuropathy, mainly affecting thick-fibre-mediated sensory qualities (Thompson et al, 1984;Roelofs et al, 1984;Gerritsen van der Hoop et al, 1990a;Vecht et al, 1991; Hilkens et al, 1994).…”

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

“…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.…”