Frontline Data for Newly Diagnosed Ovarian Cancer Leave Much to Be Discerned

Jessica L. Berger, MD

Before considering intraperitoneal (IP) chemotherapy or dose-dense chemotherapy for a patient with newly diagnosed advanced ovarian cancer, their fitness should be established, said Jessica L. Berger, MD, as both approaches carry more toxicity than that of a standard weekly intravenous (IV) approach.

If a patient is medically fit enough, the decision of whether to pursue IP chemotherapy or dose-dense chemotherapy may depend on whether they underwent an optimal or suboptimal cytoreduction, she added.

Beyond risk status—which, if high, might warrant the use of bevacizumab (Avastin)—available data still do not provide a clear directive. For example, the phase III GOG-172 trial showed a benefit in progression-free survival (PFS) and overall survival (OS) with IP chemotherapy versus IV chemotherapy. Yet, data from the phase III GOG-252 trial failed to show any benefit to IP chemotherapy versus IV chemotherapy. The latter may have been due to the fact that all patients in the trial also received bevacizumab (Avastin).

“Ovarian cancer is a very challenging disease to treat. We have invested a lot in trials for IP administration, dose-dense administration, different drugs, and targeted agents. Yet, we keep making modest incremental improvements,” said Berger. “We’re going to have to work smarter instead of just throwing more chemotherapy at patients.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer, Jessica Layne Berger, MD, a gynecologic oncologist at the University of Pittsburgh Medical Center Hillman Cancer Center, evaluated the treatment approaches available for patients with newly diagnosed advanced ovarian cancer.

OncLive: What options are available in the frontline treatment of patients with newly diagnosed advanced ovarian cancer?

Berger: Platinum- and taxane-based chemotherapy are standard of care for these patients. The question of how to deliver [these approaches] is still up in the air. We can give [chemotherapy] in a standard every-3-week fashion. We can give it in a dose-dense fashion to get a higher dose intensity over that 3-week period. We can give it regionally with IP chemotherapy. Or, we can give it weekly without increasing the dose density to try to make it more tolerable for patients.

Could you expand on the role of IP chemotherapy and how it compares with dose-dense chemotherapy and IV chemotherapy?

IP chemotherapy has been investigated in multiple trials over the last 20 years. We were investigating this before taxanes. People were excited about it because it made sense. Delivering chemotherapy intravenously and into the belly cavity where the tumors are was thought to enhance the treatment effects; however, this is not without increased toxicity.

Most trials have shown a survival benefit [with IP chemotherapy]. We were very excited about GOG-172, which showed a significant survival advantage with IP administration. However, this is a difficult regimen to receive; patients have a hard time with the full doses. Only 40% of patients in that trial were able to receive the full 6 cycles of their IP regimen. That made it hard, so we dropped the dose. Supportive care was improved so some patients could still receive it.

In many of these trials, patients in the IP arms received more chemotherapy over the 3-week period than patients in the control arm who received every-3-week chemotherapy. That raised the question of whether the IP administration was more dose-dense [based]. That’s when the dose-dense trials came out.

The dose-dense trial in Japan showed a significant survival advantage as well, which was very exciting. We wanted to replicate that [success] in the United States, so we undertook GOG-262 to try to confirm those results. Unfortunately, there was no survival benefit observed in that trial. The survivals [between the arms] were equivalent. However, that trial was a bit limited due to the co-administration of bevacizumab in an uncontrolled fashion. When we just look at the patients who received chemotherapy, the survival curves start to separate. Would we have gotten a survival benefit without bevacizumab? Perhaps, but we don’t know the answer to that question. Both dose-dense and IP chemotherapy are a little bit harder to tolerate. However, both approaches seem to help compared with every-3-week dosing. Which one you prefer to use often depends on your own bias. Some are still really excited about regional therapy while others are not.

How do you approach treatment selection for these patients?

Most of the IP trials were done in patients who had been optimally cytoreduced; that's the population it has been studied in best. The Japanese investigators who conducted the dose-dense trial did a subgroup analysis of patients who had an optimal cytoreduction compared with those who had been suboptimally cytoreduced.

The suboptimally cytoreduced patients seem to have a unique benefit from dose-dense chemotherapy. Their survival curves widen more than the optimally cytoreduced patients. Dose-dense therapy is probably more exciting for that population, whereas IP chemotherapy is more exciting for the optimally cytoreduced population. Both populations have to have a pretty good performance status and are willing to put up with a little extra toxicity in order to receive more intense chemotherapy as opposed to the every-3-week regimen.

How do the toxicity profiles compare between these approaches?

IP chemotherapy comes with many gastrointestinal (GI) adverse events. In the trials, patients had many port complications. Port complications are common, so you need a specialized port into the abdomen for that type of treatment. Dehydration, electrolyte abnormalities, abdominal pain, and GI toxicities are higher with IP chemotherapy. With dose-dense chemotherapy, we see a higher risk of anemia—much more than we see with every-3-week dosing.

Is there any ongoing research on these approaches?

We were eagerly awaiting the results of GOG-252, which have just been published. That trial looked at dose-dense chemotherapy compared with IP, and investigators also included an arm with a dose-dense regimen that included IP carboplatin.

Unfortunately, there was no difference in survival curves between any of the arms. Admittedly, GOG-252 used a slightly lower dose of cisplatin, so we couldn’t compare [that with] the regimen from GOG-172. It was slightly dose reduced, and every patient received bevacizumab. Bevacizumab is confounding our results. Would we have seen a difference if the patients did not get bevacizumab? Maybe. Would we have seen a difference if patients received the full dose of IP chemotherapy? Maybe.

What is the role of bevacizumab in this space? What are some of the key trials exploring its use in the upfront setting?

Bevacizumab was investigated in GOG-218 and ICON7. Both trials used bevacizumab concurrently with chemotherapy and as maintenance therapy afterward. GOG-213 was a 3-arm trial; 1 arm did not incorporate maintenance therapy. If you compare the control arm with the maintenance bevacizumab arm, there was a difference in PFS. However, it was a modest benefit; it only provided about a 4-month PFS benefit and no overall survival benefit. Likewise, ICON7 did not show a survival benefit. Subset analyses of those trials have suggested that high-risk patients, patients with residual disease, or those with inoperable cancers might benefit from the addition of bevacizumab. However, those findings haven't been confirmed in phase III trials.