Western Regional Blog – BC, YK, AB, NWT and Nunavut
“Our primary study hypothesis was that the experimental weekly schedule could produce an improvement in health-related quality of life, compared with the standard schedule.”
Following the successful completion of other randomized trials performed by our cooperative group MITO (Multicentre Italian Trials in Ovarian cancer),1,2 we planned a large randomized phase III trial (MITO-7) for patients with advanced ovarian cancer eligible for first-line chemotherapy, with the aim of comparing a weekly schedule of carboplatin and paclitaxel versus the standard, every 3–week schedule of the same drugs. The results of this study were recently published in The Lancet Oncology.
The accrual in the MITO-7 trial was completed between 2008 and 2012, thanks to a cooperation among GINECO (Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens et du sein), MANGO (Mario Negri Gynecologic Oncology), ENGOT (European Network of Gynaecological Oncological Trial Groups), and GCIG (Gynecologic Cancer InterGroup)—the trial involved 67 institutions in Italy and France. This was a great cooperative effort, especially considering that MITO-7 was a completely academic, nonprofit trial, without any external funding source.
Our primary study hypothesis was that the experimental weekly schedule could produce an improvement in health-related quality of life, compared with the standard schedule. When the trial started, MITO-7 had a planned sample size of 400 patients in order to demonstrate a clinically relevant difference in primary outcome, which was quality of life measured by the Functional Assessment of Cancer Therapy Ovarian Trial Outcome Index over the first 9 weeks of treatment. We strongly believe in quality of life as a relevant endpoint in this setting because the standard combination of carboplatin plus paclitaxel is a quite toxic treatment, particularly causing hair loss, neurotoxicity, and fatigue.
The protocol was designed in order to guarantee a similar planned dose intensity of both drugs in the two study arms, and each administration in the weekly arm was carboplatin AUC 2 and paclitaxel 60 mg/m2. During the conduction of the study, the scientific community discussed with great interest the results of a Japanese phase III study comparing the standard every 3–week schedule of carboplatin and paclitaxel with a dose-dense schedule made by every 3–week carboplatin (AUC 6) plus weekly dose-dense paclitaxel (80 mg/m2).4 In that population of Japanese patients, the experimental dose-dense schedule produced higher toxicity, but was associated with a substantial improvement in efficacy—in detail, prolongation ≥ 10 months in median progression-free survival (28.0 months vs 17.2 months; HR, 0.71; 95% CI, 0.58–0.88; P = .0015), along with a significantly better overall survival. Although the MITO-7 experimental schedule was different from the schedule tested in the Japanese trial (in our study, we were using weekly carboplatin and a lower dose of paclitaxel), we decided that our ongoing study represented a great opportunity to confirm in a Western population the positive results obtained in Japan, and we amended MITO-7, adding progression-free survival as a co-primary endpoint. Due to this amendment, the sample size of the trial was increased from 400 to 810 patients, with 80% statistical power to demonstrate a 6-month improvement in median progression-free survival, corresponding to a hazard ratio of 0.75.
Unfortunately, and differently from the Japanese experience, the MITO-7 trial did not show a significant difference in progression-free survival between the two schedules of carboplatin plus paclitaxel. However, the outcomes in the two arms were quite similar, although we cannot formally claim the noninferiority of the weekly schedule because the study was designed to show superiority of the experimental arm. In detail, after a median follow-up of 22.3 months, median progression-free survival was 17.3 months with the standard, every 3–week schedule and 18.3 months with the weekly treatment (HR, 0.96; 95% CI, 0.80–1.16; P = 0.66). Consistent with our hypothesis, the weekly schedule produced significantly fewer side effects (hematologic toxicity, vomiting, neuropathy, and hair loss were more frequent and severe in the every 3–week arm), and the experimental treatment was associated with a significantly better quality of life. During the first 9 weeks of treatment, which was the period of observation for our primary endpoint, the standard treatment produced a significant worsening of quality of life after each every 3–week administration, while patients’ quality of life was much less affected by the weekly schedule.
On one hand, we were disappointed that the MITO-7 results did not confirm the impressive difference in progression-free survival observed in the Japanese trial. This could be attributed to chance or to several differences between the two trials (different doses of paclitaxel, different schedule of paclitaxel, different ethnicity), which we extensively discussed in The Lancet Oncology paper. On the other hand, however, while waiting for the results of a couple of ongoing trials (GOG 262 and ICON-8), we believe that the results obtained with the weekly schedule in terms of toxicity and quality of life represent a result of great clinical value and make this schedule a potential alternative for first-line treatment in clinical practice. As already acknowledged in the discussion of the paper, however, compliance with planned treatment was slightly better in the every 3–week schedule, witnessing that, even if less toxic and better tolerated than the standard, the weekly regimen remains a challenging treatment. Furthermore, we recognize that the adoption of a weekly schedule in clinical practice might represent a logistical problem for the organization of gynecological cancer units, due to the tripled number of hospital admissions for chemotherapy administration.
In the commentary accompanying the publication of our paper, Sven Mahner and Alexander Burges state that the MITO-7 data will not only increase the understanding of specific treatment effects on quality of life but will also serve as an example for future study designs.5 As for future research, considering the favorable tolerability and quality of life profile that has been demonstrated in the MITO-7 trial, the weekly schedule of carboplatin plus paclitaxel could represent an ideal chemotherapy backbone for combination with biological agents.