ABSTRACT: Paclitaxel(Drug information on paclitaxel)-induced myalgias and arthralgias occur in a significant fraction of patients receiving therapy with this taxane, potentially impairing physical function and quality of life. Paclitaxel-induced myalgias and arthralgias are related to individual doses; associations with the cumulative dose and infusion duration are less clear. Identification of risk factors for myalgias and arthralgias could distinguish a group of patients at greater risk, leading to minimization of myalgias and arthralgias through the use of preventive therapies. Optimal pharmacologic treatment and possibilities for the prevention of myalgias and arthralgias associated with paclitaxel are unclear, partially due to the small number of patients treated with any one medication. The effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs) is the most frequently documented pharmacologic intervention, although no clear choice exists for patients who fail to respond to NSAIDs. However, the increasing use of weekly paclitaxel could necessitate daily administration of NSAIDs for myalgias and arthralgias and leave patients at risk for adverse effects. This concern may also limit the use of corticosteroids for the prevention and treatment of paclitaxel-induced myalgias and arthralgias. Data from case reports suggest that gabapentin(Drug information on gabapentin) (Neurontin), glutamine, and, potentially, antihistamines (eg, fexofenadine(Drug information on fexofenadine) [Allegra]) could be used to treat and/or prevent myalgias and arthralgias. Given the safety profile of these medications, considerable enthusiasm exists for evaluating their effectiveness in the prevention and treatment of paclitaxel myalgias and arthralgias, particularly in the setting of weekly paclitaxel administration.
Amelioration of the side effects of paclitaxel is essential, given its effectiveness in the treatment of several malignancies (Table 1). Historically, the dose-limiting toxicities of paclitaxel administered as a 24-hour infusion were hypersensitivity reactions and neutropenia, which are controlled largely through the use of systemic premedications and hematopoietic growth factors. Paclitaxel is also administered as a 1-or 3-hour infusion, with weekly administration recently gaining considerable popularity. Neuromuscular toxicities are frequently dose-limiting with 1-or 3-hour infusions.[1-3] The neurotoxicities of paclitaxel include sensory neuropathy, motor neuropathy, autonomic neuropathy, myopathy (ie, myalgias/arthralgias), and central nervous system effects.
Although sensory neuropathy is perceived to be the most common adverse effect, the incidence of myalgias and arthralgias closely approximates[ 5-9] or surpasses[10-13] that of sensory neuropathy. A relation ship between myalgias/arthralgias and subsequent sensory neuropathy has not been conclusively shown, but myalgias and arthralgias may be an initial symptomatic manifestation of peripheral nerve injury.
Transient myalgias and arthralgias begin 24 to 72 hours after paclitaxel administration and usually resolve in 4 to 7 days. The anatomic distribution of myalgias and arthralgias is variable, with some patients experiencing diffuse myalgias and arthralgias, and others experiencing such effects localized to large axial muscles (eg, shoulder and paraspinal muscles) or lower extremities.[4,14] There is considerable variability in the reported incidence of paclitaxel-induced myalgias and arthralgias,[5-7,9-12,15,16] potentially due to discrepancies between assessment methods and toxicity grading (Table 2).[6,9,17]
This manuscript reviews the published literature on the incidence and severity of paclitaxel-associated myalgias and arthralgias, as well as the effectiveness of medications for these adverse effects.
The pathophysiology of paclitaxelinduced neurotoxicity has been evaluated in animal models, which suggest a supportable hypothesis for the mech- anism causing sensory neuropathy. Microtubules are important in the development and maintenance of neurons, with microtubule elongation contributing to the growth of neurites. In the mature axon, microtubules have a significant role in mediating axonal transport and provide structural support for neurons. Paclitaxel is cytotoxic through polymerization and subsequent stabilization of microtubule bundles, and these processes could be expected to affect neuronal development and function.
Animal studies support this hypothesis, documenting microtubule aggregation in cultured mouse dorsal root-ganglion cells and rat Schwann cells and axons, with subsequent demyelination and loss of axoplasmic transport.[19-22] The regenerative response of axons and Schwann cells to nerve crush injuries is inhibited in rodents who have received paclitaxel.[ 23,24] It is undetermined whether myalgias and arthralgias are produced by a similar pathophysiologic process.
Several studies have been undertaken to identify risk factors for myalgias and arthralgias, with the hope of identifying a paclitaxel dose or infusion duration that minimizes these adverse effects. To date, no correlation has been observed between myalgias/arthralgias and patient parameters such as age, sex, height, prior chemotherapy, renal or hepatic function, or sites of metastases. Concurrent signs of inflammation and elevations in muscle enzyme concentrations, such as creatinine phosphokinase, have not been noted.
No relationship has been found between myalgias/arthralgias and the pharmacokinetic characteristics of paclitaxel (ie, peak plasma concentration, area under the plasma concentration vs time curve, duration of paclitaxel concentration > 0.1 μM). Moreover, concurrent administration of cisplatin(Drug information on cisplatin), which is known for its neurotoxicity, does not appear to affect the severity of myalgias and arthralgias.[ 4,26] The relationships between paclitaxel-induced myalgias and arthralgias and factors such as single dose, cumulative dose, and duration of infusion have all been evaluated.[3,6,8,9,11,14,16,25,27,28]
Increasing single doses of paclitaxel are positively correlated with the incidence and severity of myalgias and arthralgias. Mild and self-limiting myalgias and arthralgias usually occur at doses less than 170 mg/m2. Initial data from case series and phase I/II trials suggested that myalgias and arthralgias are more common at doses greater than 190 mg/m2.[4,8,25,27,28]
The incidence of myalgias and arthralgias of any grade increased from 54% to 67% in 391 patients with ovarian cancer who received paclitaxel at 135 mg/m2 or 175 mg/m2, respectively (P = .01). Eisenhauer et al designed this study such that women were randomized in a bifactorial design to receive either 135 mg/m2 or 175 mg/m2 as a 3-hour or 24-hour infusion, leading to the creation of four treatment groups.
In 599 patients with metastatic non-small-cell lung cancer (NSCLC), grade 3/4 myalgias and arthralgias occurred in 1% of those receiving paclitaxel at 135 mg/m2 IV (over 24 hours) with cisplatin, compared to 7% of those receiving paclitaxel at 250 mg/m2 IV (over 24 hours), cisplatin, and granulocyte colonystimulating factor (G-CSF, Neupogen).[ 27] The incidence of myalgias and arthralgias of any grade was 23% and 14% in 198 patients with NSCLC who received carboplatin(Drug information on carboplatin) (Paraplatin) with a 3-hour infusion of paclitaxel, 175 mg/m2 or 225 mg/m2, respectively.[ 29] The difference in incidence of myalgias and arthralgias between these two groups was not statistically significant (P > .05).
Thus, available data suggest a higher incidence and severity of myalgias and arthralgias when higher single doses of paclitaxel are administered, with the incidence rising at single paclitaxel doses greater than or equal to 135 mg/m2.
The relationship between paclitaxel- induced myalgias and arthralgias and cumulative dose is unclear. A retrospective analysis of neuromuscular toxicity in 247 patients treated with paclitaxel revealed a Spearman's correlation coefficient of 0.218 (P = .0006) for myalgias and arthralgias and total paclitaxel dose. A wide range of cumulative paclitaxel doses (median: 630 mg/m2, range: 35 to 3,150 mg/m2) were administered over a 3-hour infusion every 3 weeks. Of the 85 patients who experienced grade 2 or 3 myalgias and arthralgias, 80 (94%) had at least grade 1 and 68 (80%) had at least grade 2 symptoms after the first course, indicating that myalgias and arthralgias occur during early treatment cycles in most patients who suffered more severe myalgias and arthralgias.
A case series in 27 patients re- ported a similar pattern in those who experienced sensory neuropathy following paclitaxel administration (135-300 mg/m2). Although data from Kunitoh et al suggests a weak association between cumulative paclitaxel dose and myalgias and arthralgias, these adverse effects also have an early onset, suggesting that the total dose is not a critical risk factor for developing myalgias and arthralgias.
At equivalent paclitaxel doses, the length of infusion does not appear to relate to the incidence of myalgias and arthralgias,[6,11] despite initial reports suggesting that shorter infusions (ie, 1 to 3 hours vs 24 hours) led to an increased risk. Eisenhauer et al reported that the overall incidence of myalgias and arthralgias was 64% with a 3-hour infusion vs 58% with a 24-hour infusion in 391 ovarian cancer patients who were randomized to one of four arms (ie, 135 mg/m2 3-hour infusion, 135 mg/m2 24-hour infusion, 175 mg/m2 3-hour infusion, 175 mg/m2 24-hour infusion). The incidence was collapsed across doses.
Similar findings were observed in 557 patients with breast cancer who participated in the National Surgical Adjuvant Breast and Bowl Project (NSABP) B-26 study, which was a randomized, controlled trial of 3-hour or 24-hour infusion of paclitaxel, 250 mg/m2. Myalgias and arthralgias occurred in 82% of patients who received a 3-hour infusion and in 87% of those receiving a 24-hour infusion.[ 6] The incidence of grade 3/4 myalgias and arthralgias (19% in both groups) was not affected by length of infusion.
No published trials have compared 1-hour paclitaxel infusions with 3-or 24-hour infusions. A phase II trial of 100 patients with NSCLC who received paclitaxel, 225 mg/m2 over 1 hour, followed by carboplatin suggests that the incidence and severity of myalgias and arthralgias is similar to that seen with 3-and 24-hour infusions.[ 3] Of 94 evaluable patients, 63% experienced grade 1/2 myalgias and arthralgias and 5% had grade 3/4 symptoms. These results suggest that the length of paclitaxel infusion is not associated with significant differences in the incidence of myalgias and arthralgias; however, 1-hour infusion data are limited. Prospective trials gaining additional information about these potential risk factors and identifying novel risk factors are needed.