Articles/Correspondence: Weekly vs. Every-3-Week Paclitaxel for Ovarian Cancer

NEJM

Correspondence

Weekly vs. Every-3-Week Paclitaxel for Ovarian Cancer

N Engl J Med 2016; 374:2602-2604June 30, 2016DOI: 10.1056/NEJMc1603849

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To the Editor:

Chan et al. (Feb. 25 issue)1 found a marginal benefit of dose-dense (weekly) chemotherapy over standard chemotherapy in a group of 112 women with ovarian cancer who did not receive bevacizumab, a subgroup that represents a mere 16% of the whole. The use of progression-free survival, instead of overall survival, in trials of ovarian-cancer therapies will exaggerate the benefit of a therapy that delays progression but has no effect on survival. The degree of exaggeration is greatest for trials, such as this one, in which the overall survival is poor, because the worse the survival is, the farther the hazard ratio associated with the intervention will fall below unity. In the present study, the 4-year survival rate was 44%; the high mortality can be attributed to the low rate of acceptance of neoadjuvant chemotherapy (13%) and the far lower rate of microscopic residual disease than gross residual disease (24% vs. 63%) after surgery. These two treatment factors are of far greater importance than is any minor modification to the chemotherapy regimen,2 and improving these should be our goal.

Steven A. Narod, M.D.
Women’s College Research Institute, Toronto, ON, Canada
steven.narod@wchospital.ca

No potential conflict of interest relevant to this letter was reported.
2 References

To the Editor:

Chan et al. report that weekly paclitaxel and carboplatin, as compared with paclitaxel and carboplatin administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. During the design of the study, the Gynecologic Oncology Group (GOG) completed protocol 218, and 84% of the patients received bevacizumab. Among patients who opted to receive bevacizumab, progression-free survival was similar in the two groups. However, among patients who opted not to receive bevacizumab, weekly paclitaxel was associated with a median progression-free survival that was 3.9 months longer than that observed with paclitaxel every 3 weeks. The Japanese Gynecologic Oncology Group (JGOG) 3016 trial1 showed significant benefit in progression-free survival and overall survival with the use of dose-dense paclitaxel and carboplatin as compared with conventional paclitaxel and carboplatin.
Given the high cost and toxic effects of bevacizumab, the lack of improvement in overall survival, and the similar progression-free survival rates with weekly paclitaxel without bevacizumab (14.2 months) and with weekly or every-3-week paclitaxel with bevacizumab (14.9 months and 14.7 months, respectively) that were observed in the GOG-0262 trial, it may be premature to adopt bevacizumab as the treatment of choice. In our opinion, using dose-dense treatment as in the JGOG 3016 trial is an excellent option, especially in developing countries.

Laís Pimenta, M.D.
Monica Dornelas, M.D.
Loureno Cezana, M.D.
Hospital Santa Rita de Cássia, Vitória, Brazil
laisguedes@yahoo.com.br

No potential conflict of interest relevant to this letter was reported.
1 Reference

The authors reply: As stated by Narod, there was a benefit noted for weekly paclitaxel over standard chemotherapy in the subgroup of patients who did not receive bevacizumab. We included bevacizumab as a prespecified stratification factor in the treatment randomization process with knowledge of its clinical activity. A secondary analysis was performed to assess the assumption of homogeneity of the treatment effect across the strata. We also believe that weekly paclitaxel does not provide a mere marginal benefit, because the magnitude of improvement (hazard ratio for disease progression or death, 0.62) in our trial was similar to that in the JGOG trial (hazard ratio for disease progression or death, 0.71), which resulted in an overall survival advantage.1
Narod also asserts that progression-free survival exaggerates the therapeutic benefit of a treatment for which there is no overall survival advantage, particularly in trials involving patients with poor overall survival. Although overall survival is an important end point, progression-free survival is widely regarded as a valid and clinically relevant end point for clinical trials involving women with advanced-stage ovarian cancer.2 The high mortality observed in this trial is due to the selection of high-risk patients with incompletely resected stage III or any stage IV epithelial cancers, as required in the initial eligibility criteria of our trial. To the contrary, our trial does not minimize the importance of primary cytoreductive surgery. Clinicians seldom change their practice on the basis of the results of a single trial. However, the findings from this current trial add supporting evidence about the benefit of weekly paclitaxel that is consistent with the findings of the JGOG ovarian-cancer trial and previous breast-cancer trials.
We appreciate the comments by Pimenta et al. on the financial advantages of weekly paclitaxel. Comparative effectiveness studies have shown that weekly paclitaxel with carboplatin has an advantage over every-3-week treatment and bevacizumab.3,4 Now, more than ever, we have many options to personalize ovarian-cancer treatments for our patients in order to improve their outcomes.

John K. Chan, M.D.
California Pacific–Palo Alto Medical Foundation, San Francisco, CA
chanjohn@sutterhealth.org
Mark F. Brady, Ph.D.
Roswell Park Cancer Institute, Buffalo, NY
Bradley J. Monk, M.D.
University of Arizona Cancer Center, Phoenix, AZ

Since publication of their article, the authors report no further potential conflict of interest.
4 References