Paclitaxel toxicity

Bergmann TK, Green H, Brasch-Andersen C et al (2011) Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer. Eur J Clin Pharmacol 67 693-700... 

The finding in two of these studies - that the toxicity of taxanes was not reduced by amifostine does not support earlier in vitro data where amifostine protected normal tissue from paclitaxel toxicity. ... 

Four to six cycles of doublet chemotherapy with cisplatin or carboplatin plus docetaxel, gemcitabine, paclitaxel, or vinorelbine are recommended as first-line chemotherapy for patients with unresectable stage III or IV NSCLC. No combination was found to be superior tolerance of expected toxicities may contribute to the decision. 

Other suggested mechanisms for the increased radiosensitization seen with both paclitaxel and docetaxel include an increased alpha component of DNA damage and the fact that docetaxel is toxic for S-phase cells that are maximally radiation resistant (41,42). 

Socinski et al. have reported on their phase I/II experience with dose-escalated thoracic radiation in the setting of a combined modality approach to locally advanced NSCLC (55,64). Two cycles of carboplatin and paclitaxel (AUC 6 and 225 mg/m2/3h q21d) were followed on d 43 by weekly carboplatin and paclitaxel (AUC 2 and 45 mg/ m2/3h x 6) and thoracic radiotherapy (TRT), 50 Gy was delivered to the prechemotherapy tumor volume and areas of suspected microscopic spread in the mediastinum with a 1.0-2.0 cm margin. Boost volumes included the primary tumor volume and all radiographically positive nodes with a 1.0 cm margin. The total dose of radiation was escalated through four cohorts of patients 60,66,70,74 Gy without reaching any of the planned toxicity endpoints. The overall response to the therapy was 50% (3% CR, 47%... 

A similar small phase II trial from Germany has reported on seven patients receiving concurrent chemoradiation for transitional cell carcinoma of the bladder with cisplatin and paclitaxel (96). The authors conclude that this combination is at least feasible given an acceptable acute toxicity profile and reasonable efficacy. Another small series is reported by Nichols et al. (97) where eight patients received radiation with concurrent paclitaxel and carboplatin in an attempt at bladder preservation. Three of the patients remain free of distant metastases, and local recurrence has occurred in three. 

Single-agent activity of paclitaxel was initially evaluated by the Eastern Cooperative Oncology Group (ECOG) in a select cohort of 34 patients with unresectable, recurrent, or metastatic disease (34). The overall response rate was 40% (4 CR, 8 PR). Myelosuppression was the primary toxicity. The median survival was 9.2 mo with a 1-yr survival of 33%. 

Hoffman and colleagues evaluated the effects of a 1 h weekly infusion of paclitaxel (20 mg/m2, escalating by 10 mg/m2 increments) with conventional radiotherapy (35). The MTD was 30 mg/m2/wk with the dose-limiting toxicity being mucositis. 

A randomized phase II trial comparing weekly methotrexate (MTX, 40-60 mg/m2) vs triweekly paclitaxel (175-225 mg/m2 by 3-h or 24-h infusion) in the recurrent or metastatic setting was prematurely closed as a result of toxicity and minimal response (76). 

After phase I trials had determined the safety of paclitaxel doses of 45-50 mg/m2/ wk and carboplatin of AUC 2/wk concurrent with standard RT of 66 Gy/7 wk, phase II trials yielded encouraging survival results (69). Acute esophageal grade III or greater toxicity was high (30-50%) however, most patients fully recovered from these acute effects. Choy extended the experience with concurrent radiation and paclitaxel/ carboplatin using hyperfractionated radiation to 69.6 Gy and observed a 1-yr survival of 63% (70). 

There has been widespread acceptance of some of the new generation ChT agents like paclitaxel and carboplatin because of their more favorable toxicity profile and... 

In addition, Safran et al. (13) presented preliminary data on preoperative chemoradiotherapy using paclitaxel (Taxol) inpatients having T2-T4 N0-N3 adenocarcinoma. They found an overall response rate of 63% with acceptable toxicity. 

Other potential radiation sensitizers for cervical cancer are being explored in phase I and II trials. Paclitaxel has been combined with cisplatin in several small phase I studies. Pignata et al. (29) found that 50 mg/m2 per week of paclitaxel could be combined with weekly cisplatin (30 mg/m2) and radiation therapy with acceptable toxicity, although 10 of 18 patients in their study had grade 3-4 hematologic toxicity. Chen etal. (30) also were able to give weekly paclitaxel at a dose of 50 mg/m2 (in this case combined with 50 mg/m2 of cisplatin every three weeks) with tolerable toxicity and minimal delay in planned radiation therapy. In both studies, the dose-limiting side effect appeared to be diarrhea. It should be noted that the total dose of cisplatin delivered in these trials was lower than that used in the most successful prospective trials of cisplatin or cisplatin and fluorouracil (Table 3). 

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