Adverse reactions paclitaxel

Taxanes such as docetaxel and paclitaxel are mitotic inhibitors, disrupting microtubule function so adverse reactions, including hypersensitivity responses, to these drugs might be expected. 

Paclitaxel is poorly water-soluble and so is conventionally administered via a poly-oxyethylated castor oil derivative, Cremo-phor EL, which is a micelle-forming vehicle. This has now been found to affect the pharmacokinetics of paclitaxel, as well as its adverse reactions, as detailed below. More recently, two new formulations have been developed albumin-bound paclitaxel (marketed as Abraxane ) and docosahexae-noic acid paclitaxel (DHA paclitaxel, marketed as Taxoprexin ). Both have different pharmacokinetics and adverse reactions from conventional paclitaxel, as discussed separately below. 

The rate of infusion also has an effect on the adverse reactions profile of paclitaxel. Shorter infusions are associated with less myelotoxicity but more acute hypersensitivity and peripheral neuropathy [22 ]. 

Hematologic Bone-marrow suppression is the most common dose-limiting adverse reaction to paclitaxel. Neutropenia occurs most commonly 8-10 days after treatment, and recovery usually occurs by days 15-21. Paclitaxel is relatively platelet sparing, and thrombocytopenia and anemia are rare [24]. There is no evidence that neutropenia is cumulative, suggesting that paclitaxel may not irreversibly damage hemopoietic stem cells [5 ]. 

Paclitaxel administered in a weekly regimen rather than the more common 3-weekly schedule has been found to be better tolerated, with less myelosuppression (as well as fewer non-hematological adverse reactions) and comparable, if not improved, efficacy [16, 53 ]. 

In a phase I study of intraperitoneal paclitaxel in patients with advanced ovarian cancer, severe abdominal pain was the dose-limiting toxicity at doses over 175 mg/rr [57 ]. Significant gastrointestinal adverse reactions have been noted in other trials of intrap eritoneal paclitaxel chemotherapy, and this has limited its usefulness as a means of administering chemotherapy via this route [58, 597]. 

In recent years, a Cremophor-free formulation of paclitaxel has been developed, with the trade name Abraxane. It uses nanoparticle albumin-bound (nab) technology as a vehicle for the delivery of paclitaxel. Abraxane is a Cremophor-free, 130-nanometer particle form of paclitaxel, which delivers paclitaxel as a suspension of albumin particles in saline. It therefore avoids the adverse reactions that are associated with Cremophor EL. It does not need premedication with glucocorticoids and antihistamines. In animals albumin-bound paclitaxel has increased and prolonged antitumor activity and more effective intratumor accumulation of paclitaxel, compared with Cremophor-based paclitaxel [93 ]. It is currently licensed for second-line treatment of metastatic breast cancer. 

Hematologic Neutropenia was the dose-limiting adverse reaction in most phase I and phase II studies of docetaxel, with a median duration to nadir counts of 7 days [132 ]. This appears to be dose-related, but not schedule-related (unlike paclitaxel). In a large phase III trial, 9.6% of patients receiving 3-weekly docetaxel 75 mg/m developed grade 3/4 neutropenia [112 ]. 

Adverse effects of paclitaxel and docetaxel are similar, being hypersensitivity reactions, bone marrow suppression, peripheral neuropathy, hair loss and cardiac arrhythmias. 

The duration of neutropenia is usually brief, and treatment delays for unresolved adverse hematological reactions on day 21 are rare. Paclitaxel-induced neutropenia does not always lead to infectious complications, and therefore a dosage reduction for... 

Observational studies In a phase Ib safety study in advanced non-small cell lung cancer, volociximab was used in combination with carboplatin and paclitaxel. Of the 29 patients who received volociximab, the most common grade 3 and above reactions were neutropenia (24%), hypnonatraemia (17%) and fatigue (10%). Three patients experienced serious adverse events [226 ]. 

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