Thomas C. Krivak, MD; John K. Chan, MD; Cecelia H. Boardman, MD; and Ashley Farione, PA-C, review the optimal approach to maintenance therapeutic options for a patient with stage III, high-grade serous epithelial ovarian cancer.
Thomas C. Krivak, MD: This patient, undergoes TAH/BSO [total abdominal hysterectomy/bilateral salpingo-oophorectomy], lymph node dissection, tumor debulking. She gets optimally debulked to microscopic disease. She gets treated with carboplatin and paclitaxel. She has some fatigue, some grade 1 cytopenias with chemotherapy rounds 4 and 5. They’re monitoring her blood counts. Platelet count recovers within 2 months after finishing chemotherapy. After completion of chemotherapy, she’s in clinical remission, complete response [CR]. CA [cancer antigen]-125 is normal, CT scan is normal, physical examination is normal. Weight is about 198 lb, and she’s homologous recombination deficient [HRD], or HRD positive, with respect to her tumor testing.
Again, looking at this patient, we’ve talked about BRCA2 mutations. Now we’re going into the BRCA wild-type, HRD-positive group. What are the therapeutic options for this patient? What clinical trials are available? How do we determine what therapy we’re going to use? For this patient, Dr Chan, what do you think about? What would you want to use for development of the maintenance strategy for this patient?
John K. Chan, MD: Backing up to the testing, you said, yes, it’s clearly confusing for the patient with respect to testing. But I was just thinking this is probably when Myriad Genetics came out with their myChoice test. At first with the MyRisk test, only 10% of our patients would get a benefit, and so 90% of the time I’m kind of disappointed with the test. But now with the myChoice test showing that 50% of the patients are positive, that means half the time I’m able to give the patients some encouraging news about how they’re going to respond, and also that their prognosis is going to be better. The testing is more complex, but it did add significantly to how we design better treatments for them and also how their prognosis may change based on the associated results of this test. With respect to patients like this, she’s got wild type and an HRD-positive disease. I don’t believe she started on bevacizumab; this patient would get single-agent niraparib in my practice.
Cecelia H. Boardman, MD: But certainly, if you had started bev [bevacizumab] during her primary chemotherapy, you also have the option to do bevacizumab plus olaparib for her. It gives you another option, and so you’ve got some choices, which again, it goes back to the fact that it’s amazing and wonderful that we have these options.
Thomas C. Krivak, MD: To me, John, just like you said, we’re now going from maybe being able to help 15% to 20% of the patients, 10%, now to 50%. I always think that there’s only so much time in our clinic visits to digest all the treatment options, explain it, molecular options, and explain it. We’re trying to get through a lot of information quickly, but the bottom line is that we are impacting a number of our patients because these patients are having these molecular abnormalities that will increase their response rates and have a better prognosis for them.
To me, this patient wasn’t started on bevacizumab, and so niraparib is the treatment of choice for her with respect to that. It’s once-a-day dosing. Obviously, if she would have bad thrombocytopenia, if she’d get started on niraparib, have hypertension, switching over to olaparib, or olaparib and bevacizumab, could be done. We have these choices. Again, what we’re trying to do is develop a treatment plan that she’d be able to get through long term, whether it’s 2 or 3 years. Again, not significant ascites, not stage IV disease. But I’m just curious, do you guys look at extent of disease to say at the time of surgery if you’re going to use bevacizumab, and would you want to stop bevacizumab and put them on single-agent niraparib for this case? Or would you say this patient has done very well, recovered her counts, and wouldn’t worry about that too much? Do you guys think about extent of disease, tumor burden, things like that, clinical factors? Cecilia?
Cecelia H. Boardman, MD: Absolutely. Certainly the patient who has pleural effusion, has large volume ascites, significant upper abdominal disease, that weighs into my decision about whether they’re going to get bevacizumab. I’m a bevacizumab believer. I’m not afraid of bevacizumab, so I will use it in those patients. And then as I said, there were recently some data presented at ESMO [European Society for Medical Oncology annual meeting] that looked at the PAOLA trial, and then looked at patients who were not necessarily clinically meeting those indicators for bevacizumab, in other words, optimal stage III. And when you looked at them with combination therapy, they didn’t meet the median PFS [progression-free survival]. The extended survivorship was quite impressive. It’s caused me to rethinkwhen I might actually think about combination for a patient like this, even though she’s an optimal stage III. We have wonderful options, and then talking to the patient about what that means in terms of time in the chair, and office visits, and logistics in the maintenance phase is also important.
Thomas C. Krivak, MD: Yes. You bring up an important point about the low-risk, high-risk groups in that study. What I point out when I see that, for the high-risk groups, the Kaplan-Meier curves were lower than the low risk who were treated with combination therapy. But when you look at that low-risk group that didn’t receive combination therapy, they did poorly, and we’re saying they’re low risk. Again, that’s why I think maintenance therapy is very important and adding combination therapy, bevacizumab with other agents. Again, I know we’re talking about olaparib and bevacizumab, but there are data with OVARIO, a phase 2 trial, with Avastin and niraparib. We had that open at our institution and we enrolled somewhere between 13 and 15 patients, and they did very well. And the AVANOVA trial is a combination of bevacizumab with niraparib. A lot of these medications can be combined safely.
How about starting maintenance therapy? What do you guys think is the ideal timing for starting maintenance therapy, do you like 4 weeks, 8 weeks, 12 weeks? What do you folks think? Wait till they recover and the patients want to start, or is there a time you say, ‘Listen, I want you to take maybe 6 weeks off, and then let’s get you back started on treatment?” How do you guys approach that? How about you, Dr Chan?
John K. Chan, MD: Yes, that’s a good one. Generally, I start the discussion with these patients, I usually get a completion CT scan after they finish their chemotherapy, so I bring them in to start the discussion. Generally, that is about 3 to 4 weeks after they finish their last cycle of chemotherapy. It’s already been a month since they’ve seen me, they get a CT scan and they get some results, some encouraging data showing that their disease is in complete remission. Then by the time you discuss the HRD, bring them back for a second discussion with respect to their ability to access these drugs, and they finally decide to go for maintenance therapy, which most of them will as long as we sit down with them, discuss with them some of the benefits and the strategies and also the prevention of the risks associated with these drugs. Most of our patients go for the maintenance therapy. And by the time insurance gets there and they finally get their drug, it’s probably about 8 weeks.
Cecelia H. Boardman, MD: That’s a great point, John, and I was going to bring that up. I start the discussion about a PARP inhibitor at cycle 1, cycle 2, but start to discuss it further at cycle 4, cycle 5. And I go ahead and put that insurance authorization request in around that time because for some patients, it may take time to get insurance authorization, and then a benefits assessment, what their co-pay is going to be. I do not have a dispensing pharmacy, so I’ve got to go to a third-party pharmacy for dispensing of drugs, that also builds in a delay. Like you, I get a post-treatment CT and bring them back at about 4 weeks post treatment. But then we see where we are from the insurance authorization and delivery of drugs standpoint. For me, we wind up starting patients somewhere between 6 and 8 weeks. I get a little nervous if it’s longer than that because I worry if they do have any residual disease, is it going to start to creep? But we certainly know that we have up to 12 weeks to start.
The other thing is, obviously, this is a patient who’s a complete responder, but even in a partial response patient we can flip them onto a PARP. That’s why I don’t wait until cycle 6 and the post-treatment CTs to have a conversation about maintenance therapy. We have the ability, based on those trials, somewhere between 20% and 30% of the patients were partial response patients. I feel comfortable even starting the discussion in cycle 4 because I know they’re going to a PARP no matter what.
Thomas C. Krivak, MD: Ashley, going back to some of that conversation, do you think patients are accepting of this? How about fatigue, this patient had some fatigue, what do you think you’d say to some of these folks about managing fatigue and having them get ready for their PARP maintenance treatment?
Ashley Farione, PA-C: Most of them are eager to get started on the PARP at some point because they know they’re continuing the therapy and they’re still going to be on treatment, so their disease will tentatively be under some type of treatment. As far as the fatigue goes, a lot of times I encourage them to do a balance of napping as well as exercising. And a lot of the time the patients say they are so tired that they can’t walk or move, which you hear quite a bit. But I still try to encourage them that it will help if they try to take a daily walk or something. Then I try to have them take naps in between, things like that. That’s how I deal with the fatigue, and sometimes they listen, sometimes they don’t and they come back, and we have the same conversation again, but I keep encouraging it.
But for the most part, like I said about the PARP, they are ready to get started on it. And as with you too, we start early on introducing the idea that we’re going to send this out for testing, we’re going to get you set up to see if you qualify for maintenance afterward. Early on in their treatment they are given the idea that we’re going to continue maintenance, so it’s not a big surprise at the end that they’re going to be starting on something.
Thomas C. Krivak, MD: Yes, early intervention and education is key.
Cecelia H. Boardman, MD: We spend a lot of time talking about fatigue management, and so I spend a lot of time talking to patients about sleep hygiene and making sure they’re getting good quality sleep at night to try to improve their fatigue during the day. I agree with Ashley, exercise certainly can be helpful, dedicated physical therapy to do strength and conditioning, walking, yoga, those are very helpful. Then there are those select patients with whom I will talk about medication to improve their fatigue, so low-dose dexamethasone, anywhere from 1 to 8 mg in the morning. And some patients I’ll even talk to about low-dose Ritalin in the morning to combat fatigue. But I spend a lot of time initially talking about sleep hygiene, and it’s amazing to me how many patients don’t put away their electronic devices, sleep with the television on, don’t adjust the environment in their bedroom. So looking at sleep hygiene is an important strategy for fatigue management.
Thomas C. Krivak, MD: Very good points.
Transcript Edited for Clarity