Weekly Paclitaxel does not prolong progression-free survival in ovarian cancer

1. A weekly dosing regimen of Paclitaxel versus the standard dosing of Paclitaxel every 3 weeks, both administered with equal Carboplatin and Bevacizumab doses, did not show a progression-free survival benefit amongst patients with ovarian cancer.

2. Weekly Paclitaxel and Carboplatin given without Bevacizumab led to an increase in progression-free survival when compared to the 3-weekly regimen, but this outcome was still shorter than the weekly and every-3-weekly Paclitaxel, Carboplatin and Bevacizumab regimen.

Evidence Rating Level: 1 (Excellent)      

Study Rundown:  Ovarian cancer is considered to be the most lethal of the gynaecologic malignancies, given its vague and late presenting signs and symptoms. Monoclonal antibody Bevacizumab has shown activity against vascular endothelial growth factor in ovarian cancers, prolonging progression-free survival, but not overall survival. Conventional chemotherapy regimens involve Paclitaxel administered every 3 weeks, along with carboplatin. Further, dose-dense weekly Paclitaxel has demonstrated prolonged progression-free and overall survival in ovarian cancer, when compared to treatment given every 3 weeks. However, no study has compared weekly vs every-3-wk Paclitaxel and Carboplatin, with or without Bevacizumab. In carrying out such a comparison, this RCT showed no increase in progression-free survival weekly versus every-3-wk Paclitaxel (in combination with Carboplatin).  However, treatment with and without Bevacizumab in context of the above comparison did show a significant treatment difference, with Bevacizumab increasing progression-free survival. Statistically significant sequelae associated with the weekly dose-dense Paclitaxel included increased rates of grade 3/4 anemia and grade 2-4 sensory neuropathy. While a key strength of this study was being a RCT with a large number of patients across different centres, the main limitation of this study lies in the non-randomization of Bevacizumab use, and its affect on weekly vs every-3-wk Paclitaxel administration. Nevertheless, the study has important clinical implications in that it presents different treatment options for ovarian cancer patients, especially for those having increased sensitivity to paclitaxel or resistance to platinum based chemotherapies.

Click to read the study in NEJM

Relevant Reading: Incorporation of bevacizumab in the primary treatment of ovarian cancer

In-Depth [randomized controlled trial]:  This phase III randomized control trial compared two ovarian cancer treatment regimens: weekly Paclitaxel (80 mg per square meter BSA) plus Carboplatin for 6 cycles, vs every-3-wk Paclitaxel (175 mg per square meter BSA) plus Carboplatin for 6 cycles. Prior to this randomization, patients were prospectively stratified according to whether they wished to receive Bevacizumab. The primary outcome measure was progression-free survival.

A total of 692 patients with newly diagnosed, previously untreated ovarian cancer between Sept/2010 and Feb/2012 across 209 clinics in the United States, Canada, and South Korea were enrolled in the study. A total of 580 patients (84%) opted to receive Bevacizumab.  At a median follow-up of 28 months, 67% of patients were alive. The overall intention-to-treat analysis demonstrated weekly Paclitaxel did not prolong progression-free survival compared to Paclitaxel administration every 3 weeks (14.7 months vs. 14.0 months, respectively; HR for disease progression or death, 0.89; 95% [CI], 0.74 – 1.06; p=0.18).  For patients who opted to not receive Bevacizumab, weekly Paclitaxel was associated with a median progression-free survival increase of 3.9 months compared to every-3-wk Paclitaxel (14.2 months vs. 10.3 months; HR=0.62; 95% [CI], 0.40 – 0.95; p=0.03).  For patients who choose to receive, Bevacizumab, there was no difference in progression-free survival between weekly and every-3-wk Paclitaxel (14.9 months vs. 14.7 months; HR=0.99; 95% [CI], 0.83-1.2; P=0.60). In terms of side effects, patients receiving Paclitaxel weekly had a higher rate of grade 3 or 4 anemia compared to those receiving Paclitaxel every 3 weeks (36%vs.16%), and higher rates of grade 2-4 sensory neuropathy (26% vs.18%).

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