What is ovarian cancer, including its risk factors, signs and symptoms, FIGO (Federation Internationale de Gynecologie et d'Obstetrique) staging, management options such as surgical, chemotherapy (using medications like carboplatin and paclitaxel), and radiotherapy approaches, and risk assessment?

Ovarian Cancer: Comprehensive Overview

Definition and Epidemiology

Ovarian cancer is a malignant neoplasm arising from the ovary, with epithelial ovarian cancer being the most common type (90% of cases), while germ cell tumors and sex cord stromal tumors account for the remaining 10%. 1 The disease predominantly affects women over age 50, with peak incidence in the eighth decade of life at 57 per 100,000 women annually. 1 The average lifetime risk is 1.3% in the general population. 2

Risk Factors

High-Risk Genetic Factors

• BRCA1 mutations confer a 40% lifetime risk by age 70, while BRCA2 mutations carry an 18% risk 2
• Lynch syndrome (hereditary nonpolyposis colorectal cancer) increases lifetime risk to 12%, particularly for endometrioid, clear cell, and papillary serous carcinomas 1
• Family history with ≥2 first-degree relatives with ovarian cancer significantly elevates risk 1

Reproductive and Hormonal Risk Factors

• Nulliparity and refractory infertility increase risk 3
• Increased lifetime ovulatory cycles (theory of incessant ovulation) 3
• Possibly past clomiphene use 2

Protective Factors

• Oral contraceptive use for 5 years reduces risk by approximately 50%, even in women with family history 3
• Multiparity 3
• Tubal ligation or hysterectomy 3
• Prophylactic bilateral salpingo-oophorectomy in high-risk women (BRCA1/2 mutations) reduces risk of ovarian, fallopian tube, primary peritoneal, and breast cancers 1

Signs and Symptoms

Clinical Presentation

Symptoms are typically nonspecific and include bloating, pelvic or abdominal pain, difficulty eating or early satiety, and urinary symptoms (urgency or frequency), especially when new and occurring >12 days per month. 1 Abdominal pain is the most common presenting symptom. 2

• Subacute pelvic pain and feeling of pelvic pressure from pelvic mass 1
• Menstrual irregularities 1
• Ascites (associated with worse prognosis) 1

Special Presentations by Histologic Type

• Granulosa cell tumors produce inhibin and may cause clinical manifestations from hormonal activity 1
• Sertoli-Leydig cell tumors produce androgens, causing virilization in 70-85% of patients 1

Critical Caveat

These symptoms have limited sensitivity and specificity for early-stage disease, and routine screening using these symptoms is not recommended. 1 Most epithelial ovarian cancers (70%) are diagnosed at stage III or IV. 4

FIGO Staging System

Overview

The FIGO (International Federation of Gynecology and Obstetrics) staging system, updated in 2014, provides a unified classification for ovarian, fallopian tube, and primary peritoneal cancers. 5 The AJCC (American Joint Committee on Cancer) has approved this system, effective for cases recorded after January 1,2017. 1

Stage Definitions

• Stage I: Disease limited to the ovaries 5

  • IA: One ovary, capsule intact, no surface tumor
  • IB: Both ovaries, capsules intact, no surface tumor
  • IC: Subdivided into IC1 (surgical spill), IC2 (capsule rupture or surface tumor), IC3 (malignant ascites or positive washings)

• Stage II: Pelvic extension 5

  • IIA: Extension to uterus/fallopian tubes
  • IIB: Extension to other pelvic tissues

• Stage III: Peritoneal implants outside pelvis and/or retroperitoneal lymph nodes 5

  • IIIA: Subdivided based on microscopic vs macroscopic peritoneal disease
  • IIIB: Macroscopic peritoneal disease ≤2 cm
  • IIIC: Peritoneal disease >2 cm and/or regional lymph node involvement

• Stage IV: Distant metastases 5

  • IVA: Pleural effusion with positive cytology
  • IVB: Parenchymal and extra-abdominal metastases

Diagnostic Workup

Preoperative Assessment

Before surgery, obtain abdominal-pelvic CT or MRI, chest imaging, serum CA-125, complete blood count, and renal/hepatic function tests. 5

• Transvaginal ultrasound with Doppler studies is the most useful initial imaging modality 6, 2
• For young patients with suspected germ cell tumors: serum hCG, AFP, and LDH 1
• Inhibin for suspected granulosa cell tumors 1
• Consider CEA and CA 19-9 if mucinous tumor suspected 5
• Preoperative karyotype for pre-menarche girls with suspected gonadoblastomas (associated with dysgenetic gonads) 1

Important Limitation

CA-125 is not elevated in all patients and should not be used alone for diagnosis. 2 Transvaginal ultrasound combined with CA-125 lacks sufficient sensitivity and specificity for routine screening. 1

Surgical Management

General Principles

Surgery must be performed by a trained gynecologic oncologist with extensive experience, as data show improved survival when surgery is performed by experienced specialists. 7, 5 All procedures should be performed via midline or para-median laparotomy for adequate staging. 7, 5

Comprehensive Surgical Staging Requirements

All patients require comprehensive surgical staging including: 7, 5

• Peritoneal washings for cytological analysis
• Thorough visual and palpable examination of entire abdominal cavity
• Biopsy of diaphragmatic peritoneum
• Paracolic gutter biopsies
• Pelvic peritoneum biopsies
• Infracolic omentectomy
• Appendicectomy 1
• Systematic pelvic and para-aortic lymph node sampling or dissection

Note: For germ cell tumors, thorough surgical staging is not indicated as all patients require chemotherapy regardless. 1 For sex cord stromal tumors, retroperitoneal evaluation is not mandatory due to very low incidence of retroperitoneal metastases in early stage. 1

Early-Stage Disease (FIGO IA-IIA)

Standard Surgery for Postmenopausal Women or Those Not Desiring Fertility

Total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendicectomy, and complete staging as described above. 1

Fertility-Sparing Surgery

For young patients with stage IA/IB, grades 1-2, non-clear cell histology, unilateral disease, unilateral salpingo-oophorectomy with complete staging is acceptable. 1

• Wedge biopsy of contralateral ovary only if not normal on inspection 1
• For germ cell tumors, unilateral salpingo-oophorectomy with preservation of contralateral ovary and uterus is adequate even in advanced disease due to chemotherapy sensitivity 1
• For sex cord stromal tumors at stage I, conservative surgery is appropriate in young patients 1
• No systematic ovarian biopsy needed if contralateral ovary macroscopically normal 1

Special Considerations

• Endometrial curettage must be performed for granulosa cell tumors to rule out concomitant uterine cancer 1
• Stage I tumors with dense adhesions should be upstaged and treated as stage II due to similar relapse rates 1

Advanced-Stage Disease (FIGO IIB-IV)

Maximal upfront surgical cytoreduction with the goal of no residual disease (R0 resection) is the standard approach. 1, 7, 5 Surgery includes:

• Total abdominal hysterectomy
• Bilateral salpingo-oophorectomy
• Omentectomy
• Removal of all visible disease
• May require bowel resection (rectosigmoid), but avoid permanent colostomy 1
• Pelvic and para-aortic lymphadenectomy plus bowel resection if complete tumor resection achievable 1

Interval Debulking Surgery

For patients who did not undergo maximal initial cytoreduction, interval debulking surgery should be performed after 3 cycles of chemotherapy in those responding or with stable disease, followed by 3 additional cycles. 1

Second-Look Surgery

There is no evidence for survival benefit from second-look surgery. 1

Inadequate Initial Surgery

If a patient presents after inadequate surgery, restaging operation should be undertaken as soon as possible. 1 Restaging after laparoscopy must include resection of trochar tracks. 1

Chemotherapy Management

Early-Stage Disease Requiring Adjuvant Therapy

Indications for Adjuvant Chemotherapy

Surgery alone is adequate for stage IA/IB, well-differentiated (grade 1), non-clear cell histology. 1, 7

Adjuvant chemotherapy is required for: 1, 7

• Stage IA/IB poorly differentiated (grade 2-3)
• Stage IA/IB with dense adhesions
• Stage IA/IB clear cell histology
• All grades stage IC and IIA

Recommended Regimen

Carboplatin AUC 5-7 mg/mL/min + paclitaxel 175 mg/m² IV over 3 hours every 3 weeks for 3-6 cycles. 7, 5, 8, 9

Advanced-Stage Disease (FIGO IIB-IV)

Standard First-Line Chemotherapy

Carboplatin AUC 5-7.5 mg/mL/min + paclitaxel 175 mg/m² IV over 3 hours every 3 weeks for 6 cycles. 1, 7, 5, 8, 9

Alternative FDA-approved regimen: Paclitaxel 135 mg/m² IV over 24 hours followed by cisplatin 75 mg/m². 9

Premedication Requirements

All patients must receive premedication to prevent severe hypersensitivity reactions: 9

• Dexamethasone 20 mg PO at 12 and 6 hours before paclitaxel
• Diphenhydramine 50 mg IV 30-60 minutes before paclitaxel
• Cimetidine 300 mg or ranitidine 50 mg IV 30-60 minutes before paclitaxel

Treatment Initiation Criteria

Do not initiate or repeat treatment until neutrophil count ≥1,500 cells/mm³ and platelet count ≥100,000 cells/mm³. 9

Dose Modifications

Reduce dose by 20% in subsequent courses for patients experiencing severe neutropenia (neutrophils <500 cells/mm³ for ≥1 week) or severe peripheral neuropathy. 9

Recurrent Disease

Carboplatin is indicated for palliative treatment of recurrent ovarian carcinoma after prior chemotherapy, including cisplatin-treated patients. 8 However, patients who progressed during cisplatin therapy may have decreased response rates. 8

Special Histologic Subtypes

Clear Cell Carcinoma

Adjuvant chemotherapy may be omitted for adequately staged IA or IB disease, but is recommended for stages IC2, IC3, and II. 7

High-Risk Mucinous Carcinoma

Adjuvant platinum-based chemotherapy should be offered for stage I-II disease. 7

High-Grade Endometrioid Carcinoma

Adjuvant platinum-based chemotherapy is recommended following complete surgical resection with systematic lymph node dissection. 7

Critical Timing Consideration

Completing 6 cycles of chemotherapy within ≤21 weeks is associated with better outcomes; periods >21 weeks are associated with worse prognosis (HR 81.24 for PFS, 9.57 for OS). 10 Maximal efforts should be made to maintain on-schedule administration. 10

Radiotherapy

Radiotherapy is not a standard treatment modality for epithelial ovarian cancer. The guidelines reviewed do not recommend radiotherapy as part of standard management for ovarian cancer. 1 Treatment relies on surgical cytoreduction and platinum-based chemotherapy.

Risk Assessment and Prognostic Factors

Established Prognostic Factors

The most important prognostic factors determining treatment and outcomes are: 1, 5

1. FIGO stage (most important) 1
2. Volume of residual disease after initial surgery 1
3. Histological type (non-mucinous and non-clear cell have better prognosis) 1, 5
4. Degree of differentiation (especially for early-stage disease) 1, 5
5. Age (younger age associated with better outcomes) 1, 5
6. Performance status 1, 5
7. Absence of ascites 1, 5

Stage-Specific Survival

Five-year survival rates by stage are: 3

• Stage I: 93%
• Stage II: 70%
• Stage III: 37%
• Stage IV: 25%

Surgical Outcome Impact

Optimal debulking surgery (≤1 cm residual disease) versus suboptimal debulking (>1 cm) significantly impacts outcomes, with HR of 14.38 for PFS and 11.83 for OS. 10

Early-Stage Favorable Prognostic Factors

For stage I disease, favorable factors include: 1

• Low grade
• Absence of dense adhesions
• Minimal ascites
• Subgroups IA/IB versus IC
• Cell type other than clear cell

Screening and Prevention

Randomized data do not support routine screening for ovarian cancer in the general population, and no professional society recommends it due to significant harms from unnecessary procedures. 1

For high-risk women (BRCA mutations, family history), some physicians use CA-125 monitoring and endovaginal ultrasound, but prospective validation remains elusive. 1

Women with genetic syndromes increasing risk should be offered genetic counseling and consideration of prophylactic bilateral salpingo-oophorectomy. 1, 2