Thomas Herzog, MD
Clinical trials of intraperitoneal (IP) chemotherapy, hyperthermic intraperitoneal chemotherapy (HIPEC), and dose-dense regimens, while conflicting, have helped evolve the ovarian cancer field in the frontline setting, explained Thomas Herzog, MD.
As the field continues to evolve, physicians hope to augment these developments with a better understanding of biomarkers and patients’ genomic signatures.
The frontline setting most recently saw an advance with the June 2018 FDA approval of bevacizumab for use in combination with carboplatin and paclitaxel, followed by bevacizumab monotherapy, for the treatment of women with advanced ovarian cancer following initial surgical resection.
In an interview during the 2018 OncLive®
State of the Science SummitTM
on Ovarian Cancer, Herzog, professor of Obstetrics and Gynecology, deputy director, University of Cincinnati Cancer Institute, traced the therapeutic evolution of frontline treatment for patients with ovarian cancer.
OncLive: What progress have we seen with frontline therapies in ovarian cancer?
: We owe all the progress we've made in ovarian cancer to clinical trials. It was those clinical trials over a decade ago that allowed us to adopt paclitaxel into the care of women with ovarian cancer. That has significantly improved survival. Phase III trials have made a difference in taking a very cumbersome inpatient regimen and making it a very convenient outpatient regimen. Those trials allowed us to substitute cisplatin, which had a lot of toxicities with carboplatin, as well as take the paclitaxel infusion time from 24 hours to 3 hours. That's been extremely helpful.
If we then look at what else clinical trials have done, it was about trying to improve survival beyond that. Over a decade ago, our standard was carboplatin/paclitaxel every 3 weeks. Then people questioned whether giving maintenance therapy improved survival. SWOG-9701/GG-178 showed an improvement in progression-free survival (PFS). The endpoints were set up so that if there was a difference in PFS or overall survival (OS), they stopped the trial. In that case, we never had the OS data because of the number of crossovers and so forth.
GOG-212 was designed with a novel taxane, as well as regular paclitaxel, versus observation in patients who had a complete response after initial treatment. That trial did not show an advantage for giving 1 year of an extra taxane, regardless of whether it was the novel taxane or the traditional taxane. We took that off the table.
The next thing we looked at was this concept of dose-dense therapy. Could we give a higher dose over a shorter period of time and improve outcomes? Japanese researchers came out with a trial that showed an improvement in PFS in 2 widely read papers. Then, they had a final analysis on their OS that showed a significant improvement. We thought that we should be giving dose-dense chemotherapy, so most people moved to that.
Then GOG-262 was an attempt to somewhat mimic that trial. The problem was that we allowed bevacizumab to be used. It was given as an option, and over 80% of patients chose to be on it. Patients were randomized to dose-dense versus no dose-dense [chemotherapy], but they were able to choose whether they went on to bevacizumab. The overall results of that trial absolutely contradicted the results of the Japanese trial, which showed that dose-dense therapy was beneficial.
The small unplanned subgroup analysis showed that if patients did not have bevacizumab, there was an apparent improvement in outcomes if they had dose-dense therapy. That left everyone confused.
We then had the MITO-7 trial, which didn't show any difference in outcome. However, they fractionated the carboplatin, so people didn't know what to [make of those results]. Then, the ICON8 data came out, which showed that there was no difference; it was negative. Bevacizumab was not part of that. Looking at that, most people believed that dose-dense therapy was probably OK to give. Adding in the patient experience of having to come in on a weekly basis, the extra cost, and in many cases, more toxicity, it was decided that for most people dose-dense therapy is no longer as avant-garde as it was. We see more neurotoxicity, for example, which can be a long-term side effect.
People then looked at other ways of improving survival. The biggest area there has been IP chemotherapy. Three phase III trials showed an improvement in outcome with a 20% to 30% improvement in PFS or OS by giving some of the regimen directly into the peritoneal cavity through a catheter. The idea behind that was that you can give a much higher concentration and, therefore, achieve a more favorable pharmacokinetic result. People were impressed with the data; however, use never exceeded 15% in the United States. This was largely due to concerns about toxicity. It took a lot more time without additional reimbursement to compensate for that.