Evaluating Surgery and Angiogenesis Inhibition in Recurrent Ovarian Cancer

Angeles Alvarez Secord, MD, MHSc

Although chemotherapy remains the bedrock of treatment for patients with recurrent ovarian cancer, the field is moving beyond paradigms of platinum sensitivity and resistance and relying on a multiplex classification system to better design personalized treatment strategies.

In a presentation during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma, Angeles Alvarez Secord, MD, a gynecologic cancers specialist at Duke Cancer Center and professor of Obstetrics and Gynecology at Duke University School of Medicine, discussed the available treatment modalities for patients with platinum-sensitive and -resistant recurrent ovarian cancer.

Chemotherapy and Surgery

There are mixed opinions on the value of surgery, explained Secord. Although the goal of surgery is optimal debulking, the likelihood of achieving a complete resection can be difficult to assess preoperatively. Therefore, investigators created the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score to identify patients who could achieve a complete resection during secondary cytoreduction. Predictive characteristics include a good performance score, complete resection from frontline therapy, and ascites <500 ml.

Its predictive value was prospectively validated in patients with a platinum-free interval ≥6 months in the AGO DESKTOP II trial. In the phase III AGO DESKTOP III/ENGOT ov20 study,¹ patients were randomized to surgery and platinum chemotherapy or chemotherapy alone. Not only was the median progression-free survival (PFS) superior in the surgery arm compared with the control arm by 5.6 months (19.6 months vs 14.0 months, respectively), 72.5% of patients with a positive AGO score achieved a complete resection. However, patient selection is critical as investigators later determined that the benefit of surgery was limited to patients who had a complete resection prior to recurrence.

“If you [look] to see if someone is a candidate for secondary cytoreductive surgery, and they have peritoneal carcinomatosis, you should stop because you’re not going to help them,” cautioned Secord.

Although the AGO DESKTOP III trial demonstrated the safety and effectiveness of secondary cytoreductive surgery in select patients, the approach failed to result in improved overall survival (OS) in the phase III GOG-213 trial.² In one of the two objectives of this study, patients with investigator-determined resectable platinum-sensitive disease were randomized 1:1 to receive surgery followed by platinum-based chemotherapy or platinum-based chemotherapy alone.

At a median follow-up of 34.6 months, the hazard ratio was 1.28, which translated to a median OS of 53.6 months with secondary surgery versus 65.7 months in those who received chemotherapy alone. Although investigators concluded that secondary surgery can be safely performed in this population, it did not lead to improved survival benefit.

Despite the fact that the study encouraged enrollment of only those deemed able to undergo a complete resection, the protocol was not enforced, which may have influenced the results, said Secord.

Until OS data mature from the AGO DESTOP III trial and the retrospective analysis of the GOG-213 patient population are published, Secord said that she does not offer secondary cytoreductive surgery in routine practice.

“Surgery is complicated,” said Secord. “We don’t know the answer yet, but the signs are not pointing positively to a role for cytoreductive surgery in the secondary setting.”

Chemotherapy and Bevacizumab

OCEANS

In the phase III OCEANS trial, patients with platinum-sensitive disease without prior exposure to bevacizumab (Avastin) were randomized to receive either concurrent carboplatin, gemcitabine, and bevacizumab followed by maintenance bevacizumab, or carboplatin and gemcitabine alone.

The addition of bevacizumab to chemotherapy resulted in a higher overall response rate and a complete response rate that was approximately doubled that of chemotherapy alone.³ Additionally, there was a 4-month extension in median PFS with the addition of bevacizumab at 12.4 months versus 8.4 months with chemotherapy alone (HR, 0.48; 95% CI, 0.39-0.61; P <.0001).

GOG-213

The other objective of the GOG-213 trial evaluated the addition of bevacizumab to paclitaxel/carboplatin chemotherapy and as maintenance. For the bevacizumab component of the trial, patients were randomized 1:1 to receive standard chemotherapy (n = 337) or standard chemotherapy plus bevacizumab (n = 377) every 3 weeks and continued as maintenance every 3 weeks until disease progression or toxicity.

At a median follow-up of 49.6 months, results showed a median OS of 42.2 months in the bevacizumab arm versus 37.3 months in the chemotherapy-alone arm.⁴ Response rates were expectedly higher with bevacizumab arm at 79% versus 59% with chemotherapy, mirroring prior findings from the OCEANS trial.

Notably, bevacizumab’s utility does not diminish if patients have been previously exposed to bevacizumab in the frontline setting, said Secord.

“The bottom-line is that bevacizumab works pretty much everywhere,” she added.

AURELIA

The benefit of bevacizumab has spanned to the platinum-resistant recurrent setting as well. In the AURELIA trial, women with platinum-resistant disease were randomized to receive standard chemotherapy plus bevacizumab or chemotherapy alone.

Investigators noted a striking benefit in PFS with the addition of bevacizumab of approximately 22 months versus 12 months with chemotherapy alone,⁵ said Secord. Notably, the benefit extended to all patients regardless of age, platinum-free interval, amount of measurable disease, or evidence of ascites.

“Bevacizumab is a valuable maintenance agent in platinum-sensitive or platinum-resistant disease, and safety profiles indicate that it is feasible and tolerable,” concluded Secord.

References

1. Du Bois A, Vergote I, Ferron G, et al. Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20. J Clin Oncol. 2017;35(suppl 15;abstr 5501). doi: 10.1200/JCO.2017.35.15_suppl.5501.
2. Coleman RL, Enserro D, Spirtos N, et al. A phase III randomized controlled trial of secondary surgical cytoreduction (SSC) followed by platinum-based combination chemotherapy (PBC), with or without bevacizumab (B) in platinum-sensitive, recurrent ovarian cancer (PSOC): a NRG Oncology/Gynecologic Oncology Group (GOG) study. J Clin Oncol. 2018;36(suppl 15, abstr 5501). doi: 10.1200/JCO.2018.36.15_suppl.5501.
3. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039-2045. doi: 10.1200/ JCO.2012.42.0505.
4. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicenter, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(6):779-791. doi: 10.1016/S1470-2045(17)30279-6.
5. Pujade-Lauraine E, Hilpert F, Weber B, et al; AURELIA Investigators. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). J Clin Oncol. 2012;30(suppl 18; abstr LBA5002). doi: 10.1200/jco.2012.30.18_suppl.lba5002.