Making the Case for Neoadjuvant Chemotherapy in Ovarian Cancer

Neoadjuvant chemotherapy is increasingly used in advanced ovarian cancer, even though it has not been shown to improve survival versus primary cytoreduction, according to Thomas J. Herzog, clinical director of the University of Cincinnati Cancer Institute.

“There’s growing use of neoadjuvant chemotherapy. It’s gone from less than 10 percent in the 1990s all the way up to well over 35 percent now, if you look at registries,” Herzog said in a presentation at the 33rd Annual Chemotherapy Foundation Symposium, a meeting of over 1,000 physicians and other oncology professionals in New York City.

At the meeting, Herzog reviewed key studies examining whether this increased use of neoadjuvant chemotherapy versus primary surgery is justified.

The phase 3 EORTC 55971 trial (N Engl J Med. 2010;363[10]:943-953) randomized 670 patients with stage 3c or 4 ovarian cancer to either primary debulking surgery followed by platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy followed by debulking surgery (“interval debulking surgery”).

Neoadjuvant chemotherapy was shown to be noninferior. The median overall survival (OS) was 30 versus 29 months in the neoadjuvant chemotherapy versus primary debulking arms, respectively.

Outcomes were improved with neoadjuvant chemotherapy in several areas. In 80.6 percent of patients in the neoadjuvant chemotherapy arm, the residual tumor was less than 1 cm following interval debulking surgery compared with 41.6 percent of patients in the primary cytoreduction arm. Rates of postoperative death (fewer than 28 days after surgery) were 0.7 percent versus 2.5 percent, respectively.

Toxicities were also lower following interval (neoadjuvant arm) versus primary debulking, including grade 3/4 hemorrhage (4.1 percent vs 7.4 percent), infection (1.7 percent vs 8.1 percent) and venous complications (0 vs 2.6 percent).

“So if you’re arguing for neoadjuvant chemo [over primary surgery], that’s quite impressive in terms of the outcomes,” said Herzog. He noted, however, that the results did not translate into a universal embrace of neoadjuvant chemotherapy because the 30-month median OS is much lower than historical results with upfront surgery.

Herzog said that one of the arguments used to explain the survival disparity was that patients in EORTC 55971 had higher volume disease (almost two-thirds of patients had lesions greater than 10 cm), resulting in poorer outcomes.

Herzog also discussed the phase 3 CHORUS trial, which randomized 550 women with stage 3/4 ovarian cancer in a one-to-one ratio to primary surgery followed by six cycles of chemotherapy, or to three cycles of neoadjuvant chemotherapy followed by surgery and then three more cycles of chemotherapy (Lancet. 2015;386[9990]:249-257).

Neoadjuvant chemotherapy was shown to be noninferior. The median OS was even lower than in EORTC 55971 at 24.1 versus 22.6 months with upfront chemotherapy versus primary surgery, respectively.

In 73 percent of patients in the neoadjuvant chemotherapy arm, the residual tumor was less than 1 cm following interval debulking surgery compared with 41 percent of patients in the primary cytoreduction arm. Rates of postoperative death (less than 28 days after surgery) were 0.3 percent versus 6 percent respectively.

Grade 3/4 adverse events (14 percent vs 24 percent), infection (3 percent vs 6 percent) and venous complications (0 vs 2 percent), were all lower following interval versus primary debulking.

CHORUS also included an analysis of no residual disease. Thirty-nine percent of patients in the neoadjuvant/interval debulking arm had no residual disease, compared with 17 percent in the primary surgery arm.

According to Herzog, this is the crux of the neoadjuvant chemotherapy versus primary cytoreduction debate.

“We see less morbidity and mortality. But we’ve not been able to solve what is going on biologically that when we get [no residual disease] in the neoadjuvant setting, it doesn't translate into the survival advantage that we see with primary debulking surgery and that's really where our next set of studies needs to take us.”

Herzog said ongoing studies, including the NCIC CTG OV.21 and MRC-UK ICON8 trials, are hoping to add further clarity to the use of neoadjuvant chemotherapy in ovarian cancer.

In the meantime, beyond the clinical data, Herzog also described available cost data that may influence treatment selection. An article recently published in the American Journal of Obstetrics and Gynecology described a model demonstrating a $5,600 savings with neoadjuvant chemotherapy versus primary debulking surgery in patients aged 65 years or older with advanced ovarian cancer.