Current Treatment Issues Associated With Advanced Cervical Cancer and Metastatic Ovarian Cancer

PracticeUpdate: Dr. Tewari, would you please provide us with your analysis of the GOG 240 trial?

Dr. Tewari: The GOG 240 is a phase III randomized clinical trial for which the non-platinum chemotherapy doublet question regarding the superiority of topotecan–paclitaxel was first presented at the SGO 44th Annual Meeting in March.1 The main objective was to determine whether non-platinum chemotherapy doublets were superior to platinum-based therapy for women with recurrent and metastatic cervical cancer. The bottom line was that the non-platinum chemotherapy doublet of topotecan plus paclitaxel was not superior to the platinum-based therapy, but it wasn’t inferior either.

There remain few options in patients with recurrent and metastatic cervical cancer. Platinum-based therapies continue to be the standard. However, most patients with locally advanced cervical cancer are exposed to platinum with their primary therapy, and many who relapse are platinum-resistant. Their response rates to platinum-based salvage therapy are lower, which is why we wanted to study non–platinum based therapy.

Although the non–platinum based therapy did not improve overall survival, which was the primary endpoint of that study, it did promise some benefit to dubzh726zhhns9ydqmg7some patients because the toxicity profiles of the two regimens are different. I think, based on these results, a non-platinum chemotherapy doublet using topotecan plus paclitaxel is a treatment alternative for some patients, especially if they have been previously exposed to platinum and/or have toxicity assessments that would indicate that they wouldn’t tolerate platinum.

PracticeUpdate: In your opinion, what three studies presented at the SGO meeting in March would the community oncologist find most valuable?

Dr. Tewari: The three main studies of particular interest for community oncologists are, in my opinion, all related to ovarian cancer. A study by Rob Bristow demonstrated that most women in the United States with ovarian cancer are not undergoing surgery by people trained to do the operation.2

Most of the study patients were not treated according to the National Comprehensive Cancer Network (NCCN) guidelines. In addition, the study indicated that patients with stage I and II disease who were not treated according to the guidelines had worse survival rates compared with those who were. Survival was worse as well for patients with advanced-stage cancers who weren’t treated according to the guidelines.

It is really unfortunate because, basically, only one-third of the patients studied were referred to and treated by gynecologic oncologists who were considered to be high-volume surgeons. High-volume surgeons were characterized as having completed more than 10 to15 cases per year in institutions doing more than 20 cases per year. That was a very important finding, and it made the front page of the New York Times.

PracticeUpdate: Were most of these patients seeing gynecologic oncologists or gynecologists?

Dr. Tewari: Most of them were treated by gynecologists. You know, it is difficult to determine whether the issue is lack of access to gynecologic oncologists, the refusal of the gynecologist to refer the patient, or that the gynecologist did not think that the patient had cancer.

The second key presentation at SGO 2013 was long-term follow-up of two phase III randomized trials of intraperitoneal intravenous chemotherapy in women with ovarian cancer.3

Those studies were published in 2001 and 2006 and, now, with 9 to 10 years of follow-up, data reveal the sustained superiority of intraperitoneal intravenous chemotherapy.

Unfortunately, intraperitoneal therapy has still not caught on throughout the country for various reasons—there are concerns about complications, it is labor intensive, and there’s a lack of training. In the world of ovarian cancer—other than the original paclitaxel–platinum study from 1996 (GOG 111), which compared cisplatin plus cyclophosphamide vs cisplatin plus paclitaxel—we have not had any studies that have shown improvement in overall survival except for intraperitoneal therapy. Still, these results with continued follow-up have demonstrated that the improvement in overall survival has been sustained.

The third study that I find important looked at ancillary data from GOG 218, which was the up-front bevacizumab study.4

Dr. Eskander and colleagues evaluated whether time to initiation of chemotherapy from the point of surgery was important. And what they found was that there was a window of opportunity of 25 days wherein if chemotherapy was not initiated, outcome was worse. The timing was much more important in the group of patients who had microscopic residual disease.

Because surgery is so important in this group of patients, we need to have some mechanism whereby chemotherapy can be instituted quickly, because this group of patients is the most sensitive.

We don’t know the reasons for the delays in therapy. Delays may have been due to postoperative complications, the referral process, or getting to a medical oncologist if the gynecologic oncologist wasn’t doing the chemotherapy. It’s hard to tell, but the point is that often we miss that window of opportunity.

PracticeUpdate: Did the patients receive bevacizumab during that 25-day window of opportunity?

Dr. Tewari: No. Bevacizumab wasn’t given with the first cycle of chemotherapy. The first cycle was just platinum–paclitaxel. Bevacizumab was administered with the second cycle, which occurred 21 days after the first.

PracticeUpdate: Do you think that is because patients who were not familiar with the trial thought that perhaps they were getting bevacizumab first and they wanted to hold off?

Dr. Tewari: That’s a very good question. I don’t know the answer to that. You know, once patients are enrolled in a study, things start happening—meaning they get placed on a calendar.

PracticeUpdate: And then, maybe, the investigator, just not being savvy on the bevacizumab, would say, “Oh, we’ll just hold off and wait for 4 weeks to get started.”

Dr. Tewari: Right. That’s a very good point.

PracticeUpdate: In community practice, sometimes, the gynecologic oncologists does the surgery and will weigh-in on systemic therapy, which is given by the medical oncologist.

Dr. Tewari: I think it’s great when medical oncologists do the chemo. Although, in my own experience, if patients on whom I’ve operated are on a health plan in which I’m not going to do the chemo, the insurance authorizations can take a while to get. I’ll refer my patients to a medical oncologist and they’ll come back and tell me, “Oh, I’m not going to get in for 4 weeks.”

PracticeUpdate: How do you feel about using progression-free survival (PFS) as an endpoint in these patients?

Dr. Tewari: Unless we have a drug that can cure the disease, PFS is the endpoint we have to use just because ovarian cancer is pretty chemo-sensitive. And so, patients end up getting multiple different lines of therapy—second line, third line, fourth line, and we can’t control for that. So, in the bevacizumab studies, PFS has to be our endpoint; the overall survival question is too broad and there are too many different regimens that are given.

PracticeUpdate: Is there anything else that you want to add?

Dr. Tewari: No. I think that there are many other minor points, but the major takeaways from the meeting are the ovarian cancer findings. In addition, the non–platinum chemotherapy doublet is important.

PracticeUpdate: Are there any up-and-coming studies to keep an eye out for?

Dr. Tewari: Yes. Data from the SGO 2013 meeting concerning GOG 252 should be reported within the year. It is a study on ovarian cancer treated with dose-dense weekly paclitaxel and up-front and maintenance bevacizumab.

In addition, there is an ovarian trial led by John Chan (GOG 262) that focuses on whether dose-dense weekly paclitaxel improves survival in this group of patients. Both arms in the trial receive bevacizumab, so bevacizumab is not really the main question.

GOG 249 is an up-front adjuvant therapy study for patients with high-risk endometrial cancer. These stage-I patients have lymphovascular-space invasion, deep myometrial invasion, and high-grade lesions. They are randomized to vaginal brachytherapy plus adjuvant chemotherapy or pelvic radiotherapy.

And then, we come back to GOG 240. The bevacizumab question of this trial will be presented at the American Society of Clinical Oncology (ASCO) 2013 annual meeting in June.