What are the treatment options for a patient with a wild type ovarian tumor?

Treatment of Wild-Type Ovarian Tumors

For patients with BRCA wild-type high-grade non-mucinous ovarian cancer, treatment consists of maximal cytoreductive surgery performed by a gynecologic oncologist followed by platinum-based combination chemotherapy (carboplatin plus paclitaxel), with genomic instability testing at diagnosis to guide first-line maintenance therapy decisions for advanced stage disease. 1, 2, 3

Initial Diagnostic and Molecular Testing Requirements

• All patients with high-grade non-mucinous tubo-ovarian carcinoma require BRCA mutation testing (both germline and somatic) at diagnosis, regardless of stage 1
• For BRCA wild-type patients with FIGO stage III-IV disease, genomic instability testing is mandatory as it provides critical predictive information for first-line maintenance therapy decisions 1
• The genomic instability test must be clinically validated in large cohorts or phase III trials 1
• An adequate surgical specimen or image-guided biopsy of treatment-naive tumor is required, containing at least 30% tumor cells 1

Primary Surgical Management for Wild-Type Disease

Complete cytoreductive surgery is the cornerstone of treatment and must be performed by a gynecologic oncologist (Category 1 recommendation). 2

Standard Surgical Procedure Components:

• Total abdominal hysterectomy and bilateral salpingo-oophorectomy via paramedian or midline incision 2
• Complete infracolic omentectomy 2
• Appendectomy (mandatory for all cases, especially mucinous histology) 2, 4
• Pelvic and para-aortic lymph node assessment with resection of suspicious/enlarged nodes 2
• Peritoneal biopsies from multiple sites including diaphragm, paracolic gutters, bladder peritoneum, and pelvic cul-de-sac 2
• Ascites collection or peritoneal washings for cytologic examination 2

Surgical Goals and Outcomes:

• The primary goal is complete resection of all visible disease (R0 resection), which doubles median survival from 17 to 39 months compared to suboptimal cytoreduction 2
• Each 10% increase in maximal cytoreduction correlates with a 5.5% increase in median survival 2
• Optimal cytoreduction is defined as residual disease <1 cm, though complete macroscopic resection is strongly preferred 2

Neoadjuvant Chemotherapy Approach for Wild-Type Disease

For patients who are poor surgical candidates or when optimal cytoreduction appears unlikely, neoadjuvant chemotherapy with interval debulking surgery should be considered. 2

Indications for Neoadjuvant Approach:

• Advanced age, frailty, or poor performance status 2
• Significant medical comorbidities 2
• Advanced disease unlikely to be optimally cytoreduced at primary surgery 2

NACT Protocol:

• 3-4 cycles of upfront platinum-based chemotherapy 2
• Interval debulking surgery with goal of maximal cytoreduction 2
• 3-4 additional cycles of postoperative chemotherapy 2

Systemic Chemotherapy for Wild-Type Ovarian Cancer

All patients except those with stage IA grade 1 tumors require adjuvant platinum-based combination chemotherapy. 2, 3

Standard Chemotherapy Regimens:

• Carboplatin 300 mg/m² IV on day 1 every 4 weeks combined with cyclophosphamide 600 mg/m² IV on day 1 every 4 weeks for 6 cycles 3
• Alternative single-agent carboplatin: 360 mg/m² IV on day 1 every 4 weeks 3
• For advanced disease (stage II-IV): 6-8 cycles total 2
• For stage I disease (excluding stage IA grade 1): 3 cycles may be adequate 2

Dose Adjustment Criteria:

• Intermittent courses should not be repeated until neutrophil count is at least 2,000 and platelet count is at least 100,000 3
• For patients with creatinine clearance 41-59 mL/min: reduce dose to 250 mg/m² 3
• For patients with creatinine clearance 16-40 mL/min: reduce dose to 200 mg/m² 3

Maintenance Therapy Considerations for Wild-Type Disease

Genomic instability testing results directly inform maintenance therapy decisions in BRCA wild-type patients with advanced disease. 1

• Patients with positive genomic instability (homologous recombination deficiency) may benefit from PARP inhibitor maintenance despite being BRCA wild-type 1
• There are no validated predictive markers of primary resistance to platinum or PARP inhibitors at diagnosis 1

Special Considerations for Grade 1 (Low-Grade) Wild-Type Tumors

Grade 1 low-grade serous or endometrioid carcinomas often respond poorly to chemotherapy and require a modified treatment approach. 1

Treatment Algorithm for Low-Grade Disease:

• Stage IA or IB: Postoperative observation and monitoring 1
• Stage IC to II: Options include (1) intravenous carboplatin with paclitaxel or docetaxel, (2) observation (category 2B), or (3) hormone therapy including anastrozole, letrozole, leuprolide, or tamoxifen (category 2B) 1
• Stage III to IV: First-line chemotherapy regimens or hormone therapy (category 2B) 1

Fertility-Sparing Options (Early Stage Only)

For young patients with stage IA disease who desire fertility preservation, unilateral salpingo-oophorectomy with preservation of uterus and contralateral ovary may be considered, but comprehensive surgical staging must still be performed. 2

• Approximately 30% of patients are upstaged with complete staging, making thorough evaluation essential 2
• This approach is only appropriate for stage IA disease with favorable histology 2

Critical Pitfalls to Avoid in Wild-Type Disease Management

• Never perform incomplete staging: If initial surgery was inadequate, restaging laparotomy should be performed as soon as possible 2
• Surgery must be performed by a gynecologic oncologist: This significantly improves outcomes (Category 1 evidence) 2
• Do not omit appendectomy: For mucinous tumors, appendectomy is absolutely mandatory as 8% have appendiceal involvement and primary appendiceal cancer frequently mimics ovarian cancer 2, 4
• Avoid permanent colostomy when performing bowel resection for cytoreduction 2
• Do not delay molecular testing: Genomic instability testing should be performed at diagnosis in advanced-stage wild-type disease to inform maintenance therapy decisions 1