New Chemotherapy Strategy Emerges in Ovarian Cancer

Jonathan S. Berek, MD, MMS

Professor and Director, Women’s Cancer Center, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA

A study evaluating first-line chemotherapy dosing strategies for treating patients with advanced epithelial ovarian cancer has delivered practice-changing findings, and ongoing trials are likely to provide further clarity on the comparative benefits of routes of administration, according to Jonathan S. Berek, MD, MMS.

The noteworthy results stem from Japanese Gynecologic Oncology Group (JGOG) trial 3016, which established a significant survival benefit for patients who received dose-dense weekly paclitaxel plus carboplatin versus the conventional dosing schedule for those two drugs.¹

“It’s a very important study,” said Berek, professor and director, Stanford Women’s Cancer Center at Stanford Cancer Institute in California, in an interview. “This trial demonstrates, at least within the context of this large, well-performed, prospective randomized trial, that the dose-dense (every week) intravenous chemotherapy regimen is preferable to the standard (every 3 weeks) intravenous regimen. Therefore, it is, as we say, a game-changer.”

Berek, who served as the discussant of the JGOG 3016 trial results at the American Society of Clinical Oncology (ASCO) annual meeting in June, said there are at least four prospective trials under way worldwide that should shed further light on whether the chemotherapy regimen is best delivered through intravenous (IV) or intraperitoneal (IP) administration.

Lead investigator Noriyuki Katsumata, MD, PhD, of the Department of Medical Oncology at the Nippon Medical School, Musashikosugi Hospital, Kawasaki, Japan, presented the JGOG 3016 follow-up data at ASCO. (The trial also is known as the NOVEL study).

The long-term results involve the experiences of 631 patients with stage II—IV epithelial ovarian, fallopian tube, or primary peritoneal cancers.

Participants were randomized to receive either the dose-dense regimen of carboplatin AUC 6.0 on day 1 and paclitaxel 80 mg/m² on days 1, 8, and 15 versus the standard regimen of carboplatin AUC 6.0 and paclitaxel 180 mg/m² on day 1. Treatments were repeated every 21 days for six cycles, with patients who responded eligible for three additional cycles.

After 6.4 years’ follow-up, the 312 patients who received dose-dense therapy achieved a median progression-free survival (PFS) of 28.2 months versus a median PFS of 17.5 months for the 319 patients who received the standard regimen (HR = 0.76, 95% CI [0.62-0.91]; P = .0037).

The median overall survival (OS) had not yet been reached in the dose-dense group, while the OS among those treated conventionally was 62.2 months. At five years, the survival rate was 58.7% in the dose-dense group, compared with 51.1% in the standard-treatment group (HR = 0.79, 95% CI [0.63-0.99]; P = .039).

Key Statistics in JGOG 3016 Trial, at 6.4 Years’ Follow-Up¹

Treatment

Patients (No)

Median PFS

Median OS

Dose-Dense

312

28.2 mo

Not reached

Conventional

319

17.5 mo

62.2 mo

P value

.0037

.039

PFS indicates progression-free survival; OS, overall survival.

A subgroup analysis indicated that patients with clear-cell and mucinous carcinomas, who made up 15% to 17% of patients, did not show a statistically significant advantage with either treatment strategy. More than 80% of the patients in each arm had serous adenocarcinomas and other types.

“Neither dose-dense nor conventional treatment seemed effective against clear-cell or mucinous ovarian cancers, which suggests that other treatment strategies are needed,” Katsumata said in his presentation.

While the study provides insight into dosing strategies, questions remain unanswered about the impact of the route of administration, Berek indicated. Participants in both groups in the JGOG 3016 study received IV chemotherapy.

In 2006, the National Cancer Institute recommended a combination of IV and IP chemotherapy following surgical debulking for women with advanced ovarian cancer after the Gynecologic Oncology Group (GOG) study 172 found the combination more effective than the standard regimen delivered via IV.²

Berek, however, noted that a dose-dense regimen of paclitaxel was used in the IV/IP arm of GOG 172. He said that made it difficult to determine whether it is a dose-dense regimen, the route of administration, or both that result in superior outcomes.

“If you look at the survival data from the dosedense carboplatin/paclitaxel, which is intravenous, not intraperitoneal, the survivals are very similar to the survivals seen in the intraperitoneal regimen. So one might argue that it might not be because it’s given directly into the peritoneal cavity. It might be because the paclitaxel is given more frequently,” said Berek. “Future studies will hopefully answer the question: How does intravenous dose-dense carboplatin-paclitaxel compare to intraperitoneal chemotherapy using cisplatin or carboplatin plus paclitaxel?”

Berek said a dose-dense regimen given intravenously offers a good option for patients in light of issues that have arisen with IP regimens. “The adoption of intraperitoneal therapy is not universal,” he said. “In fact, probably fewer than half of patients have been treated with that anyway for a variety of reasons. And so this [dose-dense regimen] represented a suitable alternative to intraperitoneal therapy.”

While clinical trials continue, Berek believes that clinicians should discuss the treatment options with their patients. He said there might be valid reasons for certain patients to receive conventional therapy but that “what we don’t recommend as a routine, as a standard, any longer is the every-third-week regimen.”

References

1. Katsumata N, Yasuda M, Isonishi S, et al. Long-term follow-up of a randomized trial comparing conventional paclitaxel and carboplatin with dose-dense weekly paclitaxel and carboplatin in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: JGOG 3016 trial. Presented at: American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, IL. Abstract 5003.
2. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34-43.