Is Neoadjuvant Chemo Justified in Ovarian Cancer?

Thomas Herzog, MD

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, MD, clinical director of the University of Cincinnati Cancer Institute.

“There’s growing use of neoadjuvant chemotherapy. It’s gone from less than 10% in the 1990s all the way up to well over 35% now, if you look at registries,” Herzog said in a presentation at the 33rd Annual Chemotherapy Foundation Symposium.

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

The phase III EORTC 55971 trial (N Engl J Med. 2010;363[10]:943-953) randomized 670 patients with stage IIIc or IV 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, with a hazard ratio (HR) for death of 0.98 (90% CI, 0.84-1.13; P = .01). 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% of patients in the neoadjuvant chemotherapy arm, the residual tumor was <1 cm following interval debulking surgery compared with 41.6% of patients in the primary cytoreduction arm. Rates of postoperative death (<28 days after surgery) were 0.7% versus 2.5%, respectively.

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

“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 >10 cm), resulting in poorer outcomes.

Herzog also discussed the phase III CHORUS trial, which randomized 550 women with stage III/IV ovarian cancer in a 1:1 ratio to primary surgery followed by 6 cycles of chemotherapy, or to 3 cycles of neoadjuvant chemotherapy followed by surgery and then 3 more cycles of chemotherapy (Lancet. 2015;386[9990]:249-257).

Neoadjuvant chemotherapy was shown to be noninferior, with an HR for death of 0.87 (95% CI, 0.72-1.05). 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% of patients in the neoadjuvant chemotherapy arm, the residual tumor was <1 cm following interval debulking surgery compared with 41% of patients in the primary cytoreduction arm. Rates of postoperative death (<28 days after surgery) were 0.3% versus 6% respectively.

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

CHORUS also included an R0 (no residual disease) analysis. Thirty-nine percent of patients in the neoadjuvant/interval debulking arm had R0, compared with 17% 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 R0 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 $5600 savings with neoadjuvant chemotherapy versus primary debulking surgery in patients aged ≥65 with advanced ovarian cancer.

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