What is the indication for adding bevacizumab (anti-angiogenic agent) to neoadjuvant chemotherapy (NACT) in a patient with ovarian clear cell carcinoma?

Bevacizumab in Neoadjuvant Chemotherapy for Ovarian Cancer

Bevacizumab can be considered in the neoadjuvant setting for stage III-IV ovarian cancer, including clear cell carcinoma, primarily to potentially improve surgical outcomes, though survival benefit remains unproven. 1

Primary Indication

The ESMO-ESGO consensus guidelines provide clear direction on bevacizumab use in neoadjuvant chemotherapy (NACT):

• Bevacizumab in the neoadjuvant setting can be considered, although additional improvement in efficacy is not proven with level I evidence (Level of evidence: II, Strength of recommendation: B, with 97.5% consensus). 1

• The primary rationale is potential improvement in surgical outcomes, not survival benefit. 1

Evidence Base for Neoadjuvant Use

Two phase II randomized trials (ANTHALYA and GEICO 1205/NOVA) evaluated bevacizumab with NACT:

• Patients received 4 cycles of neoadjuvant carboplatin/paclitaxel with or without at least 3 cycles of bevacizumab (15 mg/kg) followed by interval debulking surgery (IDS). 1

• ANTHALYA trial showed significantly higher complete resection rates with bevacizumab compared to historical controls. 1

• GEICO 1205/NOVA trial showed no benefit in complete macroscopic response but found enhanced surgical operability rates. 1

• Both trials demonstrated similar safety profiles with no increase in grade 3 hematological, gastrointestinal, or vascular adverse events when adequate patient selection was performed. 1

Specific Considerations for Clear Cell Carcinoma

• Bevacizumab has shown activity in all histological subtypes of ovarian cancer, including less chemotherapy-responsive types like clear cell carcinoma (CCC). 2

• Clear cell carcinoma is notoriously chemotherapy-resistant, and bevacizumab represents one of the few agents with demonstrated activity in this histotype. 2

• Recent data from the INOVA trial showed sintilimab combined with bevacizumab achieved a 40.5% objective response rate in relapsed/persistent ovarian clear cell carcinoma, demonstrating bevacizumab's activity in this histotype. 3

• A phase II study of gemcitabine, cisplatin, and bevacizumab for recurrent CCC showed 61.1% overall response rate, further supporting bevacizumab's efficacy in clear cell histology. 4

Practical Administration Guidelines

Timing relative to surgery is critical for safety:

• Bevacizumab must be stopped 4-6 weeks before interval cytoreductive surgery. 1

• Bevacizumab can be restarted at least 4-6 weeks (preferably 6-7 weeks) after IDS (Level of evidence: II, Strength of recommendation: B, with 100% consensus). 1

• The ANTHALYA trial used 4-5 weeks before and 7 weeks after surgery, while GEICO 1205/NOVA used 6 weeks before and 6 weeks after. 1

Dosing regimen:

• Standard dose is 15 mg/kg every 3 weeks in combination with carboplatin (AUC 5-6) and paclitaxel (175 mg/m²). 1, 2

• Alternative dose of 7.5 mg/kg every 3 weeks can be considered. 1

When to Consider Adding Bevacizumab to NACT

Consider bevacizumab in neoadjuvant setting when:

• Patient has stage III-IV ovarian cancer (including clear cell carcinoma) planned for NACT followed by interval debulking surgery. 1, 2

• Goal is to maximize complete cytoreduction rates at interval surgery. 1

• Patient has adequate performance status and no contraindications to bevacizumab (no inflammatory bowel disease, no planned large bowel resection). 1

• When interval cytoreductive surgery is not possible and there is no overt disease progression, three additional cycles of paclitaxel-carboplatin with bevacizumab are recommended. 1, 2

Important Safety Caveats

Patient selection is critical to minimize serious adverse events:

• Previous inflammatory bowel disease and large bowel resections at surgery are significantly associated with increased gastrointestinal adverse events. 1

• Most common serious adverse events include gastrointestinal perforation (1.1%), hemorrhage (0.8%), and fistula formation (0.7%). 1

• Common manageable toxicities include grade 2 hypertension and grade 3 proteinuria. 1

• Risk of thromboembolic events and mucocutaneous bleeding exists. 1

Alternative Considerations

• The 2016 ASCO/SGO guidelines note that NACT trials tested only every-3-week IV carboplatin and paclitaxel, and weekly paclitaxel regimens in the neoadjuvant setting should be formally tested in future trials. 1

• Intraperitoneal chemotherapy after NACT and ICS remains investigational with insufficient data for formal recommendation. 1