What is the role of bevacizumab (Avastin) in the treatment of a patient with advanced ovarian cancer?

Bevacizumab in Advanced Ovarian Cancer

Bevacizumab (15 mg/kg every 3 weeks) combined with carboplatin and paclitaxel for six cycles, followed by bevacizumab maintenance for up to 15 months, is recommended for patients with advanced ovarian cancer (stage III-IV) who have poor prognostic features, specifically stage IV disease or suboptimal debulking (residual disease >1 cm after surgery). 1

Patient Selection Criteria

High-risk patients who benefit most from bevacizumab include:

• Stage IV disease 1
• Stage III disease with residual tumor >1 cm after debulking surgery 1
• Presence of ascites 2

The ICON-7 trial demonstrated that bevacizumab provides greater benefit in this "high-risk" population, with interim analysis showing prolonged overall survival in this subgroup. 1

Dosing and Duration

First-line regimen:

• Bevacizumab 15 mg/kg IV every 3 weeks 1, 3
• Combined with carboplatin (AUC 5-6) and paclitaxel (175 mg/m²) 3
• Continue bevacizumab during chemotherapy (6 cycles) and as maintenance for up to 15 months total or until progression 1

The European Medicines Agency approved bevacizumab at 15 mg/kg based on the GOG-218 trial, while ICON-7 used 7.5 mg/kg. 1 The higher dose (15 mg/kg) is the licensed and recommended dose. 1

Maintenance Therapy Strategy

After completing first-line chemotherapy with bevacizumab, maintenance therapy depends on molecular status:

• BRCA1/2-mutated tumors: Olaparib plus bevacizumab for 2 years (ESMO-MCBS score of 3, ESCAT I-A) 3
• BRCA wild-type/HRD-positive tumors: Olaparib plus bevacizumab for 2 years (ESMO-MCBS score of 3, ESCAT I-A) 3
• HRD-negative tumors: Bevacizumab maintenance alone 3

Recurrent Disease Settings

Platinum-sensitive recurrence (>6 months from last platinum):

• Bevacizumab 15 mg/kg with carboplatin and gemcitabine OR carboplatin and paclitaxel, followed by bevacizumab maintenance 1, 2

Platinum-resistant recurrence (<6 months from last platinum):

• Bevacizumab with single-agent chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) for patients who received ≤2 prior chemotherapy regimens 1, 2
• The AURELIA trial (MO22224) demonstrated median PFS of 6.8 months with bevacizumab plus chemotherapy versus 3.4 months with chemotherapy alone (HR 0.38, p<0.0001) 2

Critical Safety Considerations and Contraindications

Absolute contraindications to bevacizumab:

• Clinical signs or symptoms of gastrointestinal obstruction 4
• History of abdominal fistulae, gastrointestinal perforation, or intra-abdominal abscess within 6 months 4
• Evidence of rectosigmoid involvement or bowel involvement on imaging 4
• Recent peritoneal debulking surgery (particularly concerning given the high rate of gastrointestinal perforation observed in ovarian cancer patients) 1

Surgical timing requirements:

• Stop bevacizumab at least 6 weeks (2 half-lives) before any elective surgery 1
• Do not restart bevacizumab until at least 6-8 weeks postoperatively 1

Common serious adverse events requiring monitoring:

• Gastrointestinal perforation (7.1% of treatment-related deaths) - rare but critical 1
• Hemorrhage (23.5% of treatment-related deaths) 1
• Hypertension (significantly increased risk) 1
• Arterial thromboembolic events, especially in patients ≥65 years 1
• Wound healing complications (13% vs 3.4% when given during major surgery) 1
• Neutropenia (12.2% of treatment-related deaths) 1

Neoadjuvant Setting

For patients receiving neoadjuvant chemotherapy before interval cytoreductive surgery:

• Bevacizumab can be added to neoadjuvant carboplatin and paclitaxel (strength of evidence II, B) 3
• If interval cytoreductive surgery is not possible and no disease progression occurs, give three additional cycles of paclitaxel-carboplatin with bevacizumab 3

Efficacy Data

The GOG-218 and ICON-7 trials both met their primary endpoint of improved progression-free survival with bevacizumab maintenance. 1 However, no overall survival benefit was observed in GOG-218, and mature survival data from ICON-7 showed OS benefit only in the high-risk subgroup. 1

Treatment-related mortality is increased with bevacizumab (RR 1.33,95% CI 1.02-1.73, p=0.04), which must be weighed against the progression-free survival benefit. 1

Histologic Considerations

Bevacizumab has demonstrated activity across all histological subtypes of ovarian cancer, including less chemotherapy-responsive types such as low-grade serous carcinoma and clear cell carcinoma. 3 This is particularly relevant since these subtypes typically have poor response to platinum-based chemotherapy alone. 1

Practical Implementation

The FDA approved bevacizumab for stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with carboplatin and paclitaxel, followed by bevacizumab as a single agent, for patients following initial surgical resection. 1 This represents the standard indication in the United States as of February 2019. 1