What is the recommended first‑line systemic therapy for a newly diagnosed adult woman with stage IV epithelial ovarian cancer, and what are the treatment options for recurrence based on the platinum‑free interval?

Chemotherapy for Metastatic Ovarian Cancer

First-Line Treatment for Stage IV Epithelial Ovarian Cancer

The standard first-line treatment is paclitaxel (175 mg/m²) plus carboplatin (AUC 5-6) every 3 weeks for six cycles, with bevacizumab added for high-risk stage IV disease, followed by risk-stratified PARP inhibitor maintenance therapy based on BRCA1/2 and HRD status. 1

Initial Chemotherapy Regimen

• Administer paclitaxel 175 mg/m² plus carboplatin AUC 5-6 every 3 weeks for six cycles as the backbone chemotherapy 1
• For frail patients with poor performance status, use weekly dosing: paclitaxel 60 mg/m² plus carboplatin AUC 2 1
• Add bevacizumab 15 mg/kg every 3 weeks during chemotherapy and continue as maintenance for stage IV disease or stage III with suboptimal cytoreduction, as this improves progression-free survival with an ESMO-MCBS score of 4 in high-risk patients 1, 2

Mandatory Molecular Testing

• Order germline and somatic BRCA1/2 mutation testing plus HRD status at diagnosis before initiating treatment to guide maintenance therapy selection 1
• This testing is essential as it determines eligibility for PARP inhibitor maintenance, which significantly impacts survival outcomes 1

Maintenance Therapy Algorithm

For BRCA1/2-mutated tumors after complete or partial response:

• Olaparib monotherapy for 2 years (ESMO-MCBS score: 4, highest benefit) 1
• Alternative: Niraparib for 3 years (ESMO-MCBS score: 3) 1
• Alternative: Olaparib plus bevacizumab for 2 years if bevacizumab was used in first-line (ESMO-MCBS score: 3) 1

For BRCA1/2-wild-type/HRD-positive tumors:

• Niraparib for 3 years (ESMO-MCBS score: 3) 1
• Alternative: Olaparib plus bevacizumab for 2 years (ESMO-MCBS score: 3) 1

For HRD-negative tumors:

• Bevacizumab maintenance 1
• Alternative: Niraparib for 3 years after complete or partial response 1

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Treatment of Recurrent Disease

Assessment Before Treatment Selection

Evaluate these specific factors to determine platinum eligibility: 1

• Response to prior platinum therapy (progression during vs. after platinum) 1
• Treatment-free interval from last platinum (TFIp), though the traditional 6-month cutoff is no longer rigidly applied 1
• BRCA1/2 mutation status 1
• Prior PARP inhibitor exposure 1
• Residual neurotoxicity from prior taxanes 3
• Prior bevacizumab exposure 3
• Performance status and patient preferences 1

Platinum-Eligible Recurrent Disease

For patients who did not progress during or immediately after platinum therapy:

Surgical Evaluation

• Refer all patients with first relapse to a gynecological oncology center to assess candidacy for secondary cytoreductive surgery if TFIp >6 months 1
• Surgery is recommended only for patients with positive AGO score: complete resection at primary surgery (or FIGO stage I-II), ECOG performance status 0, and ascites <500 ml 1
• The DESKTOP III trial demonstrated OS and PFS benefit when complete resection (R0) is achievable 1

Systemic Therapy Options

Preferred regimen for rapid response or if not previously exposed to PARP inhibitors:

• Carboplatin plus pegylated liposomal doxorubicin (PLD) plus bevacizumab (ESMO-MCBS score: 3), followed by bevacizumab maintenance until symptomatic progression 1, 3
• This combination has superior safety profile compared to carboplatin-paclitaxel, with lower rates of severe neurotoxicity and hypersensitivity reactions 3
• Alternative platinum doublets: carboplatin plus gemcitabine or carboplatin plus paclitaxel, both with bevacizumab 1

If PARP inhibitor-naïve and achieve response to platinum doublet:

• Add PARP inhibitor maintenance after completing chemotherapy: 1
  • Olaparib for BRCA1/2-mutated (ESMO-MCBS score: 2) 1
  • Niraparib regardless of BRCA1/2 status (ESMO-MCBS score: 3) 1
  • Rucaparib regardless of BRCA1/2 status (ESMO-MCBS score: 3) 1
• Continue PARP inhibitor until disease progression or next treatment line, as benefit beyond progression is not established 1

Critical caveat: Avoid repeating carboplatin-paclitaxel if completed within the past 12 months due to cumulative neurotoxicity from both agents 3

Platinum-Ineligible Recurrent Disease

Patients are considered platinum-ineligible if they have: 1

• Progression during platinum therapy 1
• Early symptomatic progression post-platinum (expected resistance) 1
• Platinum intolerance/hypersensitivity 1
• Unacceptable quality of life concerns with platinum 1

Treatment Algorithm for Platinum-Resistant Disease

First-line platinum-resistant therapy:

• Weekly paclitaxel plus bevacizumab (ESMO-MCBS score: 4, highest benefit for platinum-resistant disease) 1, 4
• Alternative: Pegylated liposomal doxorubicin plus bevacizumab 1, 4
• Alternative: Topotecan plus bevacizumab 1, 4
• Continue bevacizumab until symptomatic progression 1

Single-agent options if bevacizumab contraindicated:

• Weekly paclitaxel 1
• Pegylated liposomal doxorubicin 1
• Topotecan 1
• Gemcitabine 1

For platinum intolerance with TFIp >6 months:

• Trabectedin plus PLD (ESMO-MCBS score: 2; EMA approved, not FDA approved) 1

Critical recommendation: Integrate palliative care early in the treatment pathway for all platinum-resistant patients, as this improves quality of life and may improve overall survival 1, 4

Special Histologic Considerations

For low-grade serous carcinoma (LGSC):

• Hormonal therapy with anti-estrogen agents after first-line platinum-based chemotherapy 1
• For recurrent LGSC after platinum and hormone therapy, consider trametinib (MEK inhibitor) 1

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Key Clinical Pitfalls to Avoid

• Do not rigidly apply the 6-month platinum-free interval cutoff, as many factors influence TFIp and response to platinum rechallenge; patients with TFIp <6 months may still respond to platinum combinations 1
• Monitor for platinum hypersensitivity reactions, which affect ~5% of patients and increase with multiple exposures; desensitization protocols exist for successful re-introduction 1
• Do not continue bevacizumab or PARP inhibitors beyond progression unless in the context of a clinical trial, as benefit has not been demonstrated 1
• Avoid intraperitoneal chemotherapy and HIPEC in first-line treatment outside of clinical trials, as they are not considered standard of care due to controversy about benefit versus toxicity 1