Bevacizumab's Value in Recurrent Ovarian Cancer

Robert L. Coleman, MD:This patient was treated with a regimen that was investigated formally in a phase III study. It was reported by Eric Pujade-Lauraine a couple of years ago in theJournal of Clinical Oncology. And what they did in that trial, which I thought was really well done, is they looked at what would be considered an acceptable physician-choice chemotherapy in the setting. So, that was the one with doxorubicin, weekly paclitaxel, or topotecan in a couple different schedules.

And they randomized that physician’s choice to that drug or that drug plus bevacizumab. And what was neat about this particular trial is that they actually capped the accrual for each of those chemotherapy arms. So, if you think about it, although it was 360 or so patients, there essentially were 3 trials, all with about 120. And each of them were then equally balanced between the 2 groups. And what they showed is that for the whole group that was being studied, the whole 360 group, there was an improvement in response rate and an improvement in the primary endpoint, which was progression-free survival.

There has been a subsequent study that came from Andres Poveda that looked at the individual chemotherapy subcomponents. And what they showed was that in each of the subcomponents—so the topotecan arm, the doxorubicin arm, and the paclitaxel arm—each of those showed an improvement over their expected response rate and progression-free survival.

So, I think we have pretty good confidence that adding bevacizumab to chemotherapy in this way, as this patient received, would be an acceptable and actually maybe a preferred choice because she has ascites.

I mentioned ascites as a complication, or as a factor, of recurrent disease. She obviously presented with ascites and now has ascites as a recurrent feature. One of the things we know about ascites is that it appears to be not only just the overproduction, let’s say, of fluid in the abdominal cavity, but it’s also kind of the reduction in the outflow. So, if you think about the water into a tub and out of a tub, the faucet is actually turned on more because the cancer environment is promoting development of leaky blood vessels. So, more volume in. The drain is being also blocked because we know that these tumor cells that are in the fluid actually accumulate in the exit points, which the predominate of which is a lymphostatic uptake area over the liver, which frequently has metastatic deposits. So, both of those together can lead to this acceleration of fluid in the abdomen.

Interestingly, that process is under tight regulation with vascular endothelial growth factor, which is the primary target of bevacizumab. So, in a patient like this, we would expect that she would get some relief, if nothing else, just from the bevacizumab that controls some of those tumor-related symptoms.

The unique aspect of the AURELIA trial was this idea of controlling symptoms. As you can imagine, when you take 2 drugs that each individually have side effects and you put them together, it’s unlikely there are going to be less side effects, right? So, the AURELIA trial was one where they built in a quality-of-life patient-reported outcomes metric where they captured it at the first assessment cycle, which is week 8 or 9 in the design of the trial. And they had really good data for that.

And one of the things they found in that was that even though there, yes indeed, were more side effects with the combination of the drugs, the patients actually had better patient-reported outcomes. So, here you have a situation of a more toxic drug that’s producing better patient-reported outcomes. And what that tells you is that the drug is active and the patient population is symptomatic. In the case that we’re talking about here, this is a woman who has abdominal bloating and has the symptoms of metastatic disease, and is going to be put on a drug therapy that is actually going to address that. So, even with the higher potential for bone marrow suppression, hypertension, and kidney issues that come with that combination, what we saw in the trial was that it actually led to an improvement in their overall functionality. That’s a critical piece of data that’s important to consider when treatment regimens are being looked at in a patient who is in need of therapy.

Another common question I get is, “Well, how long do I need treatment?” It’s a very good question as well. And I usually tell patients that there are 3 kind of standard endpoints: progression, complete resolution, or intolerance. And if you don’t hit one of those 3, you essentially can stay on the drug because it means that it’s working, there’s something to treat, and it’s not too toxic.

So, in the trial that I mentioned earlier, the AURELIA trial, the trial was actually written to give chemotherapy plus or minus bevacizumab until progression. And so, that would be a reasonable thing to do because most of the patients who have a relatively short-time interval—what we call the platinum-free or treatment-free interval from frontline disease—generally will progress on whatever therapy we give them. We know that historically, and it was true also in the AURELIA trial. So, in general, we’re treating those patients into one of those 3 endpoints.

Now, there is a situation, and this happens occasionally, where a patient is actually getting a very good response—not complete, but a good response—but they’re running into toxicities that are due to chemotherapy. And that sometimes needs some customization. Obviously, there are dose modifications that can be done like reduction, or we can space out the chemotherapies. But sometimes we just need to stop the chemotherapy. So, for instance, if a patient—hope to heal like this patient—had a white blood cell count that was difficult or having a long time to recover, we could just drop the topotecan. Or if it was paclitaxel and they had issues with neuropathy, then we would just essentially consider either some changing it or switching it or stopping it.

So, in those situations, we would essentially go into a maintenance therapy, which would be a single agent, like bevacizumab, and I’ve certainly done that. But I think what we try to do is to take the active regimen, which we think is the combination, and then give that as long as we don’t reach one of those 3 endpoints that I mentioned.

Transcript edited for clarity.

December 2016

• A 38-year old female presented with bloating and pain
• PMH: unremarkable
• FH: no malignancy
• Abdominal/pelvic CT scan: pelvic mass (9-cm) arising from the right ovary, omental cake (15-cm), and extensive peritoneal carcinomatosis
• CA-125: 1027 U/mL
• The patient was diagnosed with stage IIIC epithelial ovarian cancer
• She underwent hysterectomy, bilateral salpingo-oophorectomy, and omentectomy
  • Scattered residual peritoneal nodules (<1 cm) remained following surgery
• Following surgery, treated with 6 cycles of IP/IV carboplatin/paclitaxel
  • After 6 cycles of therapy, CA-125 level declined to 2.5 U/mL
  • Symptoms were ameliorated

March 2017

• Patient reported bloating and abdominal pain
• Lab results showed elevated CA 125 (985 U/mL)
• CT scan confirmed recurrence with ascites and visible disease (2-cm peritoneal mass)
• She was treated with bevacizumab and topotecan for 4 cycles
  • Patient had good response therapy
  • After 4 cycles, she was switched to bevacizumab maintenance

October 2017

• Patient returned with complaint of abdominal pain
• CT scan revealed ascites and several 1- to 2-cm peritoneal masses in the pelvis and upper abdomen