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Patients with partially Platinum-sensitive recurrent ovarian cancer: extension of Platinum-free interval does not improve efficacy


The idea that a non-Platinum therapy might artificially extend the Platinum-free interval, thereby improving outcomes in ovarian cancer patients who experience recurrence between 6 and 12 months after responding to Platinum-based therapy, was first proposed more than 20 years ago.
Despite a lack of prospective data with respect to this non–Platinum-therapy approach, the idea has been used successfully to market non-Platinum chemotherapy agents such as Paclitaxel, Topotecan, Pegylated liposomal Doxorubicin ( PLD ), and more recently, PLD-Trabectedin for use before reinitiating Platinum chemotherapy.

In fact, a 2007 retrospective analysis ( SOCRATES ) showed that 35% of patients with recurrence at 6-12 months after Platinum-based therapy were treated with a non-Platinum single agent before re-treatment with a Platinum-based therapy, and that the approach has been used as the control arm in multiple phase III trials that included patients with a Platinum-free interval of 6-12 months.
The findings indicate that the unproven hypothesis has been adapted into clinical practice, but the investigators were unable to demonstrate an advantage with the approach and concluded that further investigation was warranted.

MITO-8, a multi-organization collaborative effort, was designed to test whether artificial prolongation of the Platinum-free interval with a single-agent non-Platinum treatment would improve overall survival in recurrent partially Platinum-sensitive ovarian cancer patients.

In 107 such patients randomized to the experimental arm, receiving a non–Platinum-based chemotherapy first to prolong the Platinum-free interval, followed by Platinum-based chemotherapy after progression – the median time from previous Platinum to randomization was 8 months, and from randomization to Platinum, 7.8 months.
Median overall survival, the primary endpoint of the study, was 21.8 months.

In 108 patients randomized to immediate standard therapy with Platinum-based chemotherapy followed by non-Platinum therapy, median time from previous Platinum to randomization was 8 months, and overall survival was 24.5 months ( hazard ratio favoring Platinum chemotherapy, 1.38 ); the difference in overall survival was not statistically significance.

A secondary endpoint of progression-free survival after the second treatment was 12.8 months in the experimental arm, vs. 16.4 months in the Platinum-based chemotherapy arm ( adjusted HR, 1.41 ). This difference was statistically significant.

No differences with respect to safety or toxicity were seen between the groups.

MITO-8 subjects were women with ovarian cancer recurring between 6 and 12 months after previous Platinum-based chemotherapy.
The patients had received no more than two prior lines of chemotherapy, had good performance status, and had normal organ function.

Non–Platinum-based therapy used in the study included Pegylated liposomal Doxorubicin, except during a period of the study when the agent was in short supply and other single agents were used, including Gemcitabine and Topotecan. Most patients, however, received Pegylated liposomal Doxorubicin.

Platinum-based therapy was Carboplatin plus Paclitaxel or, in patients with neurotoxicity at baseline, Carboplatin plus Gemcitabine.

Enrollment began in 2009, but was temporarily suspended in 2011 because of the Pegylated liposomal Doxorubicin shortage.
In 2012, the amendment to allow other non–Platinum-based chemotherapies to be used was approved at most sites and enrollment resumed.
However, accrual slowed and enrollment was closed in 2015.
The study was stopped early, and the final analysis was conducted in March 2016 when events plateaued. ( Xagena )

Source: Annual Meeting of the American Society of Clinical Oncology ( ASCO ), 2016

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