Various chemotherapeutic agents have been previously evaluated, and cisplatin, carboplatin, paclitaxel, and topotecan are considered active agents for recurrent cervical cancer (Table 4).13,19,31,32 The most effective regimens for treating recurrent or metastatic cervical cancer include cisplatin and/or paclitaxel.7–10 The median response rate for paclitaxel monotherapy was 25% and progression-free survival for paclitaxel-containing regimens was 3.5 months. Recent randomized trials from GOG-240 demonstrated that a topotecan+paclitaxel+bevacizumab regimen was not inferior to a cisplatin+paclitaxel+bevacizumab regimen. No significant difference in overall survival was seen; however, the trend for response rate (45% vs. 27%) and overall survival (14.3 vs. 12.7 mo) suggest that the cisplatin+paclitaxel+bevacizumab regimen is superior.32 In addition, a phase III randomized trial (JCOG-505) showed that the response rate (63% vs. 59%) and overall survival (17.5 vs. 18.3 mo) were similar between carboplatin+paclitaxel and cisplatin+paclitaxel regimens.30 These studies, therefore, endorse the importance of paclitaxel in the management of recurrent cervical cancer.
As prior cisplatin chemotherapy during initial treatment may decrease cisplatin sensitivity in the recurrent setting, other nonplatinum chemotherapy agents may be potential options. Our study explored the utility of modified dose-dense paclitaxel monotherapy in recurrent cervical cancer and found that this regimen was associated with better survival compared with nonpaclitaxel regimens. Patients who received prior cisplatin-based treatment may be good candidates for single-agent paclitaxel. Furthermore, our dose-dense regimen, which skips day 22 administration, has proven to be well tolerated despite the fact that half of patients (47%) were undergoing their third or fourth lines of chemotherapy. Because we did not examine the classic dose-dense paclitaxel regimen (day 1, 8, 15, and 22), it remains unknown if similar findings will be seen in the classic regimen and merits further investigation. However, the response rate of modified dose-dense paclitaxel monotherapy (29.4%) was higher than the rate identified for conventional every 3 week paclitaxel monotherapy in our systematic review (median 25%).
Our study highlights the potential efficacy of salvage chemotherapy with dose-dense paclitaxel monotherapy in recurrent cervical cancer. The National Comprehensive Cancer Network guidelines have given category 1 evidence for bevacizumab, when used in combination with cisplatin and paclitaxel, and this has become the standard of care as first-line therapy for recurrent cervical cancer (www.nccn.org/professionals/physician_gls/pdf/cervical.pdf). Therefore, potential patient candidates for modified dose-dense paclitaxel monotherapy in this setting include women who are not able to tolerate this combination therapy, women who developed adverse events to cisplatin, and women who have contraindications to bevacizumab use. Of note, in our study, all patients treated with modified dose-dense paclitaxel monotherapy recurred before bevacizumab was approved by the United States Food and Drug Administration in August 2014, (www.cancer.gov/about-cancer/treatment/drugs/fda-bevacizumab) and thus, our study patients were rarely exposed to bevacizumab.
The main limitation of our study is its retrospective nature and possible confounding variables. Regardless, the majority of patients treated with modified dose-dense paclitaxel in this study were receiving it as second-line or third-line therapy, and nonetheless, were noted to have a relatively longer survival after recurrence compared with patients in the GOG 240 or JCOG-505 trials.30,32 In our study, using a pooled analysis including any line of chemotherapy (salvage therapy and maintenance therapy) may have influenced the results. As evidenced by the phase II GOG trials, response rates for second-line chemotherapy range from 0% to 20% at best.13,58–60 A relatively high response rate for modified dose-dense paclitaxel monotherapy in this study warrants consideration of patient selection bias. Although the appropriate study design is to perform a comparison of each treatment line, ideally prospectively, our limited sample size did not permit this approach. Because the majority of our study population was Hispanic, generalizability to different population remains unknown. Lastly, we used the date of hospice transfer due to terminal cancer stage as the survival endpoint because we not able to follow-up the final survival status after hospice transfer. Although this allocation can result in time-lead bias, we believe that hospice transfer can be a surrogate marker for survival endpoint due to minimal life-expectancy after hospice transfer.27
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