Ovarian Cancer: Understanding Treatment Endpoints

Robert L. Coleman, MD:I think there are a couple of other questions that come up in a case like this that I think might be worthwhile to address. One is, how long do you treat? In the trials, when we looked at the use of bevacizumab in combination with chemotherapy and recurrent platinum-resistant disease, the trial didn’t have an upper limit and we just treated patients into progression.

But it does raise the question about what the endpoints are for therapy, and I usually tell patients that there are 3 endpoints. The drug works completely, so complete remission—and in that situation, what I’ll generally do is treat 2 cycles past that point to confirm that it’s a complete response. The second endpoint would be that the disease progresses upon treatment. So, in that particular setting, we would stop and obviously switch treatments. And the third endpoint would be intolerable toxicity, a dose-limiting toxicity. This would be, for instance, hearing loss or neuropathy, grade 3. These would be events where, even if the drug was working, we would have to change it. So, disease hasn’t gone away, it hasn’t developed any toxicity that’s intolerable, and there’s something still there to treat—patients could stay on this treatment indefinitely, as long as those factors are kept in mind.

And I think the caveat there is that the toxicity needs to be realistically assessed. So, sometimes the patients just want to please you and they won’t relate to you the fact that they’re having trouble buttoning their shirt. That’s an important element for completion.

Another concept that comes up that I think is relevant is, if I’ve used these drugs, are they done? I think this relates to the former plan about endpoints. Sometimes, what we see in patients that have been referred to me is that they are essentially changing their drugs every cycle because their CA 125 didn’t respond. Or, they’re changing it every other cycle when they get their CAT scans, because the tumor didn’t go away. It didn’t get worse, but it didn’t go away. I think that can lead you down a road where you’re essentially exhausting drugs without really giving them a chance to work.

The point is that if you’re following this prescription and you’re keeping the patients on it and they develop a progression on that regimen, it doesn’t necessarily mean that you can’t ever give those drugs again. I think the data are probably clearest with platinum, and I know we talked about platinum-sensitive disease. Well, platinum-sensitive disease occurs in patients who have had platinum before, and now they’re retreating them with platinum. I’ve seen a similar aspect that can occur across multiple different treatment settings, and the other one that we see is the use of bevacizumab.

Bevacizumab is a monoclonal antibody that targets VEGF. Its primary focus is going to be on the endothelial cells through the vasculature. It also has an effect on the tumor cell itself. The vasculature is a much more stable environment than the tumor, so, in that scenario, even though the tumor may mutate and progress on a specific treatment regimen, you can still target the endothelial cells because they’re relatively stable from a genomic standpoint. We’ve had some good examples in the literature where patients have been treated with a chemotherapy regimen plus bevacizumab, have developed progressive disease, and then have been maintained on bevacizumab with a different chemotherapy backbone. And it was shown that those patients who stayed on bevacizumab through the change in their chemotherapy regimen did better than the patients who just went on to chemotherapy without bevacizumab.

I think this speaks to the nuanced art of medicine, the art of treatment. When you’re thinking about the tumor and its totality—not just the tumor ball, not just the vasculature, but also the stroma, the immune function, and all of those components—it can lead you back to developing specific therapies that may include agents you’ve used before. And so, I think that is an important treatment aspect. I think that we’re continuing to develop better guidelines around it.

Transcript edited for clarity.

July 2016

• A 38-year old female presented to her gynecologist with abdominal distension, abdominal pain, fullness after eating, and increased urination frequency for 2 months
  • Pelvic examination revealed a suspicious mass on the left ovary
• Laboratory findings:
  • CA-125: 785 U/ml
  • Genetic testing forBRCA1/2, negative
• CT with contrast of the pelvis, abdomen, and chest indicated widespread peritoneal lesions
• She was referred to gynecologic oncology and underwent hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and tumor debulking; She had diffuse studding in the omentum and diaphragmatic surfaces
• Stage 3C ovarian cancer
• She achieved complete removal of gross residual disease (R0)
• Pathology, high-grade endometrioid adenocarcinoma, ovarian primary
• The patient was started on therapy with carboplatin and every-3-weekly paclitaxel

October 2016

• Post-treatment assessment revealed no evidence of disease

March 2017

• Patient complained of fatigue and chest pain
• Physical examination:
  • Lungs, moist rales bilaterally
  • Abdomen, shifting dullness
• Laboratory findings: CA-125: 1,052 U/ml
• CT imaging: left-sided pleural effusion and sclerotic lesions in the lung apical region, ascites, new hypodense lesions in the right lobe of the liver and enlarged retroperitoneal nodes were considered metastatic
• She was started on therapy with weekly paclitaxel and bevacizumab