When should bevacizumab (vascular endothelial growth factor inhibitor) be added to Neoadjuvant Chemotherapy (NACT) in a patient with advanced epithelial ovarian cancer?

When to Add Bevacizumab in Neoadjuvant Chemotherapy for Ovarian Cancer

Bevacizumab can be considered in the neoadjuvant setting before interval cytoreductive surgery, though it represents an optional rather than mandatory addition to standard carboplatin-paclitaxel chemotherapy. 1

Evidence Strength and Recommendation Grade

The most recent ESMO 2023 guidelines classify bevacizumab in the neoadjuvant setting as Level II evidence with Grade B recommendation 1, meaning:

• The evidence comes from smaller phase II trials rather than definitive phase III studies
• More than one well-designed study supports its use, but efficacy improvement is not proven with level I evidence 1
• This is a weaker recommendation compared to the Level I, Grade A recommendation for standard NACT with carboplatin-paclitaxel alone 1

Clinical Scenarios Where Bevacizumab Addition Should Be Considered

Stage III-IV Disease Undergoing NACT

• Primary indication: Patients with stage III-IV ovarian cancer who are not candidates for upfront complete cytoreductive surgery and require 3 cycles of NACT followed by interval cytoreductive surgery (ICS) 1
• Specific benefit: The ANTHALYA trial demonstrated significantly higher complete resection rates when bevacizumab was added to neoadjuvant carboplatin-paclitaxel compared to historical controls 1
• Alternative finding: The GEICO 1205/NOVA trial showed enhanced surgical operability rates, though no benefit in complete macroscopic response 1

Less Chemotherapy-Responsive Histotypes

• Low-grade serous carcinoma (LGSC): Bevacizumab has shown activity in LGSC, which typically has lower response rates to standard chemotherapy compared to high-grade serous carcinoma 1, 2
• Clear cell carcinoma (CCC): Similarly demonstrates activity in this less chemoresponsive histotype 1, 2

Practical Dosing and Timing Algorithm

Standard Neoadjuvant Regimen WITH Bevacizumab

• Chemotherapy backbone: Paclitaxel 175 mg/m² IV + Carboplatin AUC 5-6 IV every 3 weeks 1
• Bevacizumab dose: 15 mg/kg IV (or 7.5 mg/kg per ICON7 protocol) every 3 weeks 1, 2
• Duration: At least 3 cycles of bevacizumab with chemotherapy before ICS 1

Critical Surgical Timing Requirements

• Stop bevacizumab: 4-6 weeks BEFORE interval cytoreductive surgery 1
• Restart bevacizumab: At least 6-7 weeks AFTER surgery 1
• Rationale: This interval minimizes risk of wound healing complications, gastrointestinal perforation, and fistula formation 1

Post-Surgery Continuation

• When ICS is successfully performed: Complete 3 additional cycles of paclitaxel-carboplatin with or without bevacizumab 1
• When ICS is not possible and no overt progression: Give 3 additional cycles of paclitaxel-carboplatin alone [I, A] or with bevacizumab [II, B] 1

Safety Profile in the Neoadjuvant Setting

Reassuring Safety Data

• Both ANTHALYA and GEICO 1205/NOVA trials showed similar safety profiles with no increase in grade 3 hematological, gastrointestinal, or vascular adverse events compared to carboplatin-paclitaxel alone when adequate patient selection was performed 1
• Bevacizumab can be safely administered in the neoadjuvant setting with proper surgical timing intervals 1

Critical Adverse Events to Monitor

• Gastrointestinal perforation or fistula: Occurs in <3% of patients, but represents the most serious concern 1, 3
• Hypertension requiring medical therapy: Occurs at higher rates (16.5-22.9% vs 7.2% in controls) 4
• Proteinuria and neutropenia: More common with bevacizumab addition 3

Patient Selection Criteria

Appropriate Candidates

• Stage III incompletely resectable or stage IV disease requiring NACT 1
• Adequate performance status to tolerate potential bevacizumab toxicities 1
• No contraindications to bevacizumab (recent surgery, uncontrolled hypertension, bleeding diathesis) 1

Patients to AVOID Bevacizumab in NACT

• Those with recent bowel surgery or high risk of gastrointestinal perforation 1
• Patients with uncontrolled hypertension 3
• Those with recent thromboembolic events 5

Divergent Evidence and Controversy

The Upfront Treatment Debate

There is significant controversy about bevacizumab in first-line treatment generally:

• The NCCN 2012 guidelines gave bevacizumab a Category 3 recommendation (indicating >25% of panel members believe it is NOT appropriate) for upfront treatment 1, 3
• Most NCCN panel members believed bevacizumab should NOT be added upfront because GOG-0218 and ICON7 showed no overall survival benefit, only modest PFS improvement (3.8 months and 1.7 months respectively) 1, 3, 4

The ESMO 2023 Position (More Favorable)

• ESMO 2023 guidelines are more supportive than NCCN 2012, stating bevacizumab "should be considered" in stage III-IV disease with Level I, Grade A recommendation for the adjuvant setting 1
• ESMO gives bevacizumab an ESMO-MCBS score of 3 (4 in high-risk patients), indicating meaningful clinical benefit 1

Recent PAOLA-1 Data Shifting the Landscape

• Post-hoc analyses from PAOLA-1 suggest both lower-risk and higher-risk patients may derive PFS and OS benefit from bevacizumab when combined with olaparib maintenance in HRD-positive tumors 6
• This is prompting reassessment of bevacizumab's role even in lower-risk patients 6

Integration with Maintenance Strategy

Planning Ahead for PARP Inhibitor Maintenance

• BRCA1/2-mutated or HRD-positive tumors: If bevacizumab is used in NACT, plan for olaparib + bevacizumab maintenance for 2 years (ESMO-MCBS score 3, ESCAT I-A) 1
• HRD-negative tumors: Bevacizumab maintenance alone is an option (Level I, Grade A) 1
• The decision to use bevacizumab in NACT should be informed by BRCA1/2 and HRD testing performed at primary diagnosis 1

Common Pitfalls to Avoid

1. Starting bevacizumab too close to planned surgery: Always maintain the 4-6 week pre-operative window 1
2. Restarting bevacizumab too early post-operatively: Wait at least 6-7 weeks to minimize wound complications 1
3. Using bevacizumab without considering maintenance strategy: The benefit is maximized when bevacizumab continues through maintenance, not just during NACT 1, 4
4. Ignoring histotype: Bevacizumab may be particularly valuable in less chemoresponsive histotypes like LGSC and CCC 1

Practical Clinical Algorithm

For patients requiring NACT (3 cycles before ICS):

1. Assess candidacy: Stage III-IV disease, not suitable for upfront complete cytoreduction 1

2. Check contraindications: Recent surgery, uncontrolled hypertension, bleeding risk, GI perforation risk 1, 3

3. Consider adding bevacizumab IF:

   • High-risk features (stage IV or stage III with high tumor burden) 1, 2
   • Less chemoresponsive histotypes (LGSC, CCC) 1
   • Planning bevacizumab maintenance strategy 1, 2

4. Dosing: Bevacizumab 15 mg/kg every 3 weeks with paclitaxel-carboplatin for at least 3 cycles 1, 2

5. Surgical timing: Stop bevacizumab 4-6 weeks before ICS 1

6. Post-ICS: Resume bevacizumab 6-7 weeks after surgery if wound healing adequate, continue for 3 more cycles, then transition to maintenance based on molecular testing 1