Epithelial ovarian cancer carries a poor prognosis because of the advanced stage at diagnosis and narrow chemotherapeutic options. Patients with stage IV disease have an expected 5-year overall survival rate of less than 20 percent (Gynecol Oncol 2007;105:84-89).
The standard of care for advanced, stage IIIc or IV, epithelial ovarian cancer includes primary cytoreductive surgery (PCS) followed by adjuvant platinum and taxane-based regimen. PCS aims to resect all visible disease, defined as complete cytoreduction, but achieving optimal cytoreduction-defined as residual disease < 1cm-also improves survival outcomes compared with suboptimal cytoreduction (Obstet Gynecol 2006; 107:77-85).
Patients with extensive disease or poor performance status, however, can be deemed unfit for PCS, so to increase the rate of cytoreduction for these patients, neoadjuvant chemotherapy followed by surgery-known as interval cytoreductive surgery (ICS)-provides an alternative strategy. In the neoadjuvant setting, chemotherapy consists of a platinum and taxane-based treatment, the same as the adjuvant regimen.
Bartles and others conducted a meta-analysis that showed neoadjuvant chemotherapy with ICS resulted in less morbidity and mortality and improved complete cytoreduction compared to PCS, but it did not impart a survival benefit (Gynecol Oncol 2019;doi: 10.1016/j.ygyno.2019.07.011.)
Vascular endothelial growth factor (VEGF), a potent contributor to angiogenesis, promotes ovarian cancer progression; thus, it emerges as a treatment target. In patients with advanced ovarian cancer, bevacizumab, an anti-VEGF antibody, combined with carboplatin and paclitaxel (BCP) prolonged progression-free survival compared to carboplatin and paclitaxel (CP) (N Engl J Med 2011;365:2473-2483). Whether adding bevacizumab in the neoadjuvant setting would boost benefits without leading to surgical complications-such as wound dehiscence and digestive fistulas-began to be examined in 2014.
Four trials studied BCP in the neoadjuvant setting for patients with advanced ovarian cancer who were unfit for PCS.
Study Details
Salani and others investigated neoadjuvant treatment in nine patients, five with stage IIIC and four with stage IV disease, deemed unfit for PCS. The trial studied the maximum-tolerated dose (MTD) of weekly paclitaxel when given with carboplatin and bevacizumab and the feasibility of ICS (Int J Gynecol Cancer 2014;24:682-686).
The MTD was not reached because no patient experienced toxicities leading to treatment delay. Investigators identified paclitaxel 80 mg/m2 as the feasible dose.
All the patients qualified for surgery and achieved optimal cytoreduction and 77.8 percent achieved complete cytoreduction-no microscopic residual disease.
After neoadjuvant treatment, patients proceeded to surgery at a minimum of 42 days after the last bevacizumab dose, and no intraoperative complications were reported.
Petrillo and others carried out a case-controlled study to assess the perioperative outcomes of IDS, progressive-free survival, and toxicity in advanced ovarian cancer. The study compared 25 patients with high-grade serous ovarian cancer treated with BCP to 50 patients treated with CP. ICS was performed 4 weeks after the last chemotherapy dose (Ann Surg Oncol 2015;22 Suppl 3:S952-8).
The BCP group experienced fewer cases of recurrent disease, 32 percent compared with 70 percent in the control group (P=0.001). Upon analysis, the absence of residual disease at IDS and bevacizumab treatments were prognostic for longer PFS (P=0.001). BCP compared to CP prolonged progression-free survival, 18 months versus 10 months (P=0.001), which was statistically significant.
For adverse events, neither group amassed a detectable difference. Grade 3 or 4 occurred at a frequency of 36 percent in the BCP arm and 28 percent in the control arm, which wasn't statistically significant. And there was no difference in surgical complications. One death did occur, however, because of gastrointestinal perforation in the BCP arm.
A phase IV, sub-group analysis of 79 patients described the influence of neoadjuvant BCP on the feasibility of ICS and safety (Gynecol Oncol 2017;144:256-259).
For those undergoing ICS, 86.5 percent of patients reached optimal cytoreduction, and 63.5 percent achieved complete cytoreduction.
The median interval between the last bevacizumab treatment and IDS was 38 days. Safety data reported no post-operative deaths, and 38 percent experienced post-operative adverse events: the most frequent being fever and blood transfusion, both 4 percent. And wound healing complications arose in 3 percent of patients.
In a phase II study, Rouzier and others compared the complete resection rate (CRR)-defined as the removal of all macroscopic residual tumor-at ICS after BCP or CP (Eur J Cancer 2017;70:133-142).
A total of 95 patients enrolled in the study, 58 and 37 patients in the BCP and CP groups, respectively. The patients in the BCP group received 3 cycles of BCP and 1 cycle of CP only (cycle before ICS), and those in the CP group received 4 cycles of CP. After surgery, both groups received 4 cycles of CP and up to 26 cycles bevacizumab.
Accounting for all patients (those ineligible and eligible for IDS), the BCP group achieved a CRR of 58.6 percent compared with 51.4 percent in the CP group. And for patients who underwent IDS, the BCP and CP group reached a CCR of 85.5 percent and 86.4 percent, respectively.
Adverse events between the groups were comparable with serious events occurring at a rate of 25 percent in the BCP group and 38 percent in the CP group, grade >= 3 events appearing at a rate 63 percent and 62 percent, and postoperative complications arising at a rate of 28 percent and 36 percent, respectively.
Conclusion
Although PCS remains the preferred treatment for patients with advanced ovarian cancer, some patients will be unsuitable candidates for surgery because of extensive cancer burden or performance status, and in these patients, neoadjuvant chemotherapy-carboplatin and paclitaxel-followed by IDS delivers an effective alternative.
Adding bevacizumab to carboplatin-paclitaxel in the neoadjuvant setting followed by ICS may improve optimal and complete cytoreduction and may also extend PFS without jeopardizing safety. While uncommon, patients with a history of inflammatory bowel disease or diffuse bowel involvement may be at increased risk of gastrointestinal perforation when treated with bevacizumab. With limited treatment options for advanced ovarian cancer, BCP followed by ICS offers a compelling alternative for a select group of patients.
Vincent Vidaurri is a contributing writer.