Paclitaxel(Drug information on paclitaxel) in Metastatic Breast">Weekly 1-Hour Paclitaxel in Metastatic Breast Cancer
Experience With Shorter Infusions
Although paclitaxel exposure duration seems to be an important determinant of cell kill, many oncologists perceive prolonged continuous infusions to be cumbersome and inconvenient. Theoretically, one might approximate the pharmacokinetics of prolonged paclitaxel infusion by more frequent administration of the agent, which can also increase the delivered dose density. Pharmacodynamic studies have linked pharmacologic parameters, such as time above a specific threshold plasma paclitaxel concentration and neutropenia, with toxicity. However, little is known about pharmacologic correlates of antitumor activity.
Recently, several investigators have begun to explore short 1-hour infusions of paclitaxel. Hainsworth et al compared a triweekly 1-hour infusion vs split-dose paclitaxel for three consecutive daily 1-hour infusions every 3 weeks in 164 patients with advanced refractory cancers. In this study, no serious hypersensitivity reactions occurred, and activity in various solid tumor types was noted.
Loeffler et al  studied a weekly paclitaxel 1-hour infusion in 50 patients, all of whom had previously received chemotherapy. Initial doses of 40 mg/m² weekly for six cycles, followed by a 3-week off-treatment interval, were escalated up to 90 mg/m² weekly, without grade 3 or 4 neutropenia. Responses were seen in 20 (40%) of the 50 patients, including partial responses in 3 of 6 patients with breast cancer.
The tolerability of a weekly 1-hour schedule has been confirmed in further studies by Klaassen et al and in ovarian cancer at our institution.
An Active, Tolerable Regimen
Motivated by these experiences, in addition to preclinical data demonstrating that paclitaxel can inhibit basic fibroblast growth factor and vascular endothelial growth factor-induced angiogenesis, we recently initiated a phase II and pharmacologic study of paclitaxel, 100 mg/m² via a 1-hour weekly infusion, in patients with metastatic breast cancer. Patients who have not received extensive prior therapy (one or two prior regimens that may include anthracyclines in the metastatic or adjuvant setting) are eligible for inclusion. Intrapatient dose escalation or reduction according to tolerance is addressed in the trial design.
To date, 16 patients have received 215 weekly infusions of paclitaxel (median, 13 per patient; range, 7 to 22). The initial dose was 100 mg/m²; actual median delivered dose intensity is 95 mg/m²/wk thus far. Granulocyte colony-stimulating factor was not given prophylactically, nor was its administration necessary to maintain weekly dosing.
Preliminary data suggest that this is both an active and tolerable regimen. No episodes of febrile neutropenia have been encountered. In the absence of dose-limiting or cumulative myelosuppression, paclitaxel doses were increased to 110 to 120 mg/m²wk in the first nine patients. Unfortunately, this strategy resulted in grade 3 neurosensory and neuromotor toxicity in five of nine patients; hence subsequent escalation above 100 mg/m² was abandoned. Other grade 3 or 4 toxicities that have been observed are neutropenia (14%) and headache (7%).
Thus far, responses have been noted in 6 of 15 evaluable patients (40%; 95% CI, 16% to 68%), including one complete response (cutaneous chest wall disease) and five partial responses (liver, lung, lymph nodes, and skin). Plasma paclitaxel concentration assayed by high-performance liquid chromatography in 14 patients reveal a median peak concentration (Cmax) of 4.75 µM (range, 2.73 to 6.76 µM), median area under the curve of 17.23 µM-h (9.34 to 22.35 µM-h), and t½beta of 12.35 h (8.3 to 25.0 h).
Patient accrual continues to better estimate the proportion of responses to this promising schedule of paclitaxel administration.
QOL and Outcome Assessment
The therapeutic goals in the management of metastatic breast cancer are being extended beyond classic bidimensional measurement of tumor response to include relief of tumor-related symptoms and maintenance or enhancement of QOL. With this in mind, we performed a parallel prospective and comprehensive assessment of these parameters in conjunction with our clinical trials of the 24-hour paclitaxel infusion with G-CSF in previously treated patients.
Patients completed a series of validated instruments designed to capture the many dimensions that contribute to global QOL. Questionnaires were completed prior to paclitaxel therapy and at 9-week (three-cycle) intervals during therapy. We found QOL assessment to be feasible in patients with advanced cancer receiving investigational therapy in a phase II clinical trial setting.
Although limited by sample sizes, our single-institution experience suggests a potential palliative benefit afforded by paclitaxel in patients with responsive disease (complete or partial response) or minor response. Multivariate analysis, using logistic regression models, also demonstrates the independent prognostic value of baseline scores of two QOL instruments in predicting survival. These instruments are the Global Distress Index, a 10-item subscale of the recently validated Memorial Symptom Assessment Scale (MSAS), and the Functional Living Index-Cancer (FLIC).
Since chemotherapy-related symptoms (eg, myalgia and arthralgia) are often transient, we have obtained frequent prospective measurements of pain in parallel with paclitaxel/G-CSF therapy of metastatic breast cancer. This exploratory analysis demonstrated the ability to capture short-lived episodic symptoms--in this case, attributable to paclitaxel and/or G-CSF--that would not have been captured with less frequent assessment. We are encouraged by ongoing investigations addressing these important issues in parallel with ongoing randomized phase III trials of paclitaxel alone and in combination (eg, Eastern Cooperative Oncology Group [ECOG] protocol 1193).
We are presently addressing the issue of cost/charges of medical care relative to the standard outcome measurements of response, survival, toxicity, and QOL. Consenting patients receiving single-agent paclitaxel for metastatic breast cancer are followed prospectively, with classic assessment of tumor response and toxicity. In addition, patients complete the MSAS and Functional Assessment of Cancer Therapy-Breast (FACT-B) instruments at regular intervals to capture parallel longitudinal QOL changes. Health-care expenditures incurred during the treatment period are evaluated prospectively by administrative collaborators within our institution, using existing computerized data systems. This nonrandomized effort is designed to examine the relationship between tumor response, palliation, and costs in the treatment of advanced breast cancer.