The rationale for weekly paclitaxel in the treatment of breast cancer is that more frequent delivery of more moderate doses may achieve greater efficacy than larger doses given less often through more sustained exposure of dividing tumour cells to cytotoxic drugs.
Weekly paclitaxel has been used successfully in the treatment of advanced breast cancer, as a single agent therapy, in combination therapy, with radiotherapy and with immunomodulating drugs, such as trastuzumab. Many of the patients in these studies have received previous chemotherapy regimens. Nevertheless, response rates of up to 86% have been achieved with weekly paclitaxel therapy, up to 87% with combination therapy and up to 100% combined with radiotherapy. Paclitaxel given in combination with trastuzumab has shown response rates of 50 to 82% in patients with HER2-positive tumours.
Paclitaxel is associated with moderate toxicity. Its main dose limiting toxicities are neutropenia and peripheral neuropathy, but these are generally manageable
The evidence for the above regimen comes from a phase II multicentre trial conducted by Perez et al to determine the efficacy and safety of weekly paclitaxel 80 mg/m2 in metastatic breast cancer.r
A total of 212 patients were enrolled into the study; 90% had received prior chemotherapy.
The primary end point was response rate and secondary end points included time to progression and overall survival.
Weekly paclitaxel versus 3 weekly paclitaxel, with trastuzumab in metastatic Breast Cancerr
The Cancer and Leukaemia Group B (CALGB) conducted a randomised phase III trial (CALGB 9840) to determine whether weekly paclitaxel (100 mg/m2 initially, modified to 80 mg/m2 after initial weeks of therapy) is more effective and less toxic than 3 weekly paclitaxel (175 mg/m2). Trastuzumab, having demonstrated improved outcomes of paclitaxel therapy for human epidermal growth factor receptor-2 (HER-2) positive patients, was subsequently incorporated into the trial.
A total of 577 patients were enrolled into CALGB 9840 trial. An additional 158 patients from the CALBG 9342 trial bringing the combined sample to 735, were included in the analysis. The primary end point was response rate (RR); secondary end points were time to progression (TTP), overall survival (OS) and toxicity.
One of the main differences of the 2 trials was that only 16.5% patients in CALBG 9840 trial received prior chemotherapy compared with 75% in CALBG 9342. This has the potential to bias the results in favour of the weekly schedule.
After a median follow-up of 336 days, the overall response rate was 21.5%, with 41.8% of patients having disease stabilisation. Median time to progression was 4.7 months and overall survival was 12.8 months.r
The table below summarises the RR of the combined sample (CALGB 9840 + CALGB 9342) and the limited sample (CALGB 9840).r
© Journal of Clinical Oncology 2008
Median TTP for patients receiving weekly versus 3 weekly paclitaxel was 9 months versus 5 months (HR=1.43; p < 0.0001). Adjustments were made for line of therapy given the differences between the CALGB 9840 and 9342 patient population.
(A) TTP by paclitaxel schedule (combined sample) (B) TTP by trastuzumab use in HER-2 nonoverexpressors (limited sample)r
© J Clin Oncol 2008
The overall survival of the 3 weekly to weekly paclitaxel in the combined sample, after adjusting for line of therapy, had a hazard ratio of 1.28 (p = 0.0092)
Adverse event data was presented for the limited sample only (CALGB 9840). Although grade 3 or worse granulocytopenia was more frequent with 3 weekly versus weekly paclitaxel (15% vs 9%; p = 0.017), febrile neutropenia requiring hospitalisation was infrequent with either schedule
Grade 2 and 3 sensory neuropathy was encountered in 24% of patients receiving weekly paclitaxel versus 12% receiving 3 weekly paclitaxel (p = 0.0046). This increase in incidence is inflated as a result of the excess neuropathy encountered in the first 116 patients who received 100 mg/m2 paclitaxel for the first 6 infusions. Also a prospective analysis showed that this increase in neurotoxicity did not affect the quality of life scores.
2 treatment-related deaths occurred, attributable to pneumonia, in patients randomly assigned to weekly paclitaxel alone.r
Haematological Toxicity r
© J Clin Oncol 2008
Non Haematological Toxicity
© J Clin Oncol 2008