Ovarian Cancer (Adult)

1. Clinical Overview

Summary

Ovarian cancer is the deadliest gynaecological malignancy and the fifth leading cause of cancer death in women in developed countries. [1,2] Despite accounting for only 3% of all female cancers, it causes more deaths than any other cancer of the female reproductive system, with over 70% of cases diagnosed at advanced stage (FIGO III/IV). [3]

The disease comprises three main histological categories: Epithelial (90%), Germ Cell (rare, predominantly young women), and Sex Cord-Stromal tumours. High-grade serous carcinoma (HGSC) accounts for 70% of epithelial ovarian cancers and carries the worst prognosis. [4]

Paradigm Shift in Origin: Landmark pathological studies have revolutionized our understanding of ovarian cancer pathogenesis. Most "ovarian" high-grade serous carcinomas actually originate from the fimbriated end of the fallopian tube as serous tubal intraepithelial carcinoma (STIC), subsequently exfoliating to involve the ovary and peritoneum. [5,6] This discovery has transformed risk-reducing surgery protocols.

Clinical presentation is notoriously non-specific (the "silent killer" misnomer), with symptoms mimicking benign gastrointestinal or urological conditions. The "BEAT" symptom complex (Bloating, Eating difficulty, Abdominal pain, Toilet habit changes) occurring > 12 times per month should trigger investigation in women over 50. [7]

Diagnosis relies on the Risk of Malignancy Index (RMI), which integrates CA125 level, ultrasound morphology, and menopausal status to stratify patients for specialist referral. [8] The IOTA (International Ovarian Tumour Analysis) criteria provide enhanced ultrasound-based discrimination between benign and malignant masses. [9]

Treatment follows a surgery-first paradigm for operable disease, with primary cytoreductive surgery aiming for macroscopic complete resection (R0, no visible residual disease) followed by platinum-taxane chemotherapy. [10] For advanced/unresectable disease, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery offers equivalent survival with reduced morbidity. [11]

The molecular revolution has transformed maintenance therapy: PARP inhibitors (olaparib, niraparib, rucaparib) exploit synthetic lethality in BRCA-mutated and homologous recombination deficient (HRD) tumours, dramatically extending progression-free survival. [12,13] Bevacizumab (anti-VEGF monoclonal antibody) provides additional benefit in high-risk disease. [14]

Key Facts

• Origins: 70% of HGSC originates from fallopian tube fimbriae (STIC lesions), not the ovary itself. [5,6]
• The "IBS" Red Flag: NICE guidelines mandate CA125 testing in any woman > 50 with new onset IBS symptoms, as primary IBS rarely begins after 50. [7,15]
• CA125 Limitations: Sensitivity 80% but specificity only 50% - elevated in endometriosis, fibroids, menstruation, pregnancy, heart failure, cirrhosis. [16]
• RMI Threshold: RMI > 200-250 warrants urgent referral to specialist gynae-oncology MDT. [8]
• BRCA Impact: BRCA1 mutation carriers have 40-60% lifetime ovarian cancer risk; BRCA2 carriers 10-30% risk. [17]
• Surgical Goal: Complete macroscopic resection (R0) - every 10% increase in cytoreduction improves median survival by 5.5%. [18]
• PARP Revolution: Maintenance olaparib in BRCA-mutated advanced OC: 60% progression-free at 3 years vs 27% placebo (SOLO-1 trial). [12]

Clinical Pearls

BEAT Symptoms (Sensitive but Non-Specific):

• B: Bloating (Persistent, progressive, not cyclical)
• E: Eating less / early satiety (postprandial fullness)
• A: Abdominal/Pelvic pain (constant or intermittent)
• T: Toilet changes (urinary frequency/urgency or altered bowel habit)

Key: Symptoms present > 12 times per month and represent a change from baseline. [7]

Sister Mary Joseph Nodule: Hard, irregular umbilical nodule representing peritoneal metastasis via falciform ligament. Indicates Stage IV disease. Associated with ovarian, gastric, and colorectal primaries.

Meigs' Syndrome: Classic triad of:

1. Benign ovarian fibroma (sex cord-stromal tumour)
2. Ascites
3. Pleural effusion

Mimics advanced ovarian cancer perfectly but is cured by simple tumour excision. Demonstrates that ascites + pleural effusion ≠ malignancy.

Krukenberg Tumour: Bilateral ovarian masses representing metastases from GI primary (80% gastric, signet-ring cells). Not primary ovarian cancer. Requires endoscopy to identify primary.

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2. Epidemiology

Incidence and Prevalence

Global Burden:

• 8th most common cancer in women worldwide
• 314,000 new cases and 207,000 deaths annually globally [1]
• Lifetime risk: 1 in 70-80 women (1.3%)
• Peak incidence: 60-64 years (median 63 years)
• Postmenopausal: 80% of cases [2]

Geographic Variation:

• Highest rates: Northern Europe, USA, Canada (age-standardized rate 9-12/100,000)
• Lowest rates: Asia, Africa (3-5/100,000)
• Variation reflects reproductive patterns, genetic factors, and diagnostic access [1]

Risk Factors

Genetic/Familial (Account for 20-25% of cases) [17]

Family History (No identified mutation):

• 1 first-degree relative: 3-fold increased risk
• 2 first-degree relatives: 5-fold increased risk [17]

Reproductive/Hormonal Factors

"Incessant Ovulation" Hypothesis: Cumulative ovulatory cycles increase risk through repetitive epithelial trauma and repair.

Risk Increasing:

• Nulliparity: 1.5-2x risk vs parous women
• Early menarche (less than 12 years): 1.2x risk
• Late menopause (> 52 years): 1.3x risk
• Infertility: 2-fold risk (unclear if causal or due to underlying pathology)
• Endometriosis: 2-3x risk for clear cell and endometrioid subtypes (shared pathogenesis)

Risk Reducing:

• Pregnancy: 10% risk reduction per full-term pregnancy
• Breastfeeding: 30% risk reduction if > 12 months cumulative
• Combined oral contraceptive pill (COCP): 50% risk reduction after 5 years use, protection persists > 30 years post-cessation
• Tubal ligation: 30% risk reduction (removes fallopian tube pathway)
• Hysterectomy: 30% risk reduction (mechanism unclear)

Hormonal Replacement Therapy (HRT)

• Estrogen-only HRT: 40% increased risk after 5 years (dose and duration dependent)
• Combined HRT: 20% increased risk
• Risk returns to baseline within 5 years of cessation

Other Factors

• Obesity: 1.3x risk (BMI > 30 kg/m²) - likely via unopposed estrogen from aromatization
• Talc exposure: Historical concern (perineal talc) - no convincing evidence in modern studies
• IVF: Controversial - meta-analyses show no increased risk, but borderline tumours may be increased

Protective Factors (Summary)

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3. Pathophysiology

Classification (WHO 2020 / FIGO)

1. Epithelial Tumours (90% of ovarian cancers) [4]

Type I (Low-grade, slow-growing, younger age):

• Low-grade serous carcinoma (5%)
• Mucinous carcinoma (3%)
• Endometrioid carcinoma (10%)
• Clear cell carcinoma (5%)
• Characteristics: Genetically stable, KRAS/BRAF mutations, arise from borderline tumours, confined to ovary at diagnosis, chemoresistant

Type II (High-grade, aggressive, older age):

• High-grade serous carcinoma (HGSC) (70%) - TP53 mutation in > 96%
• Characteristics: Genetically unstable, chromosomal instability, rapid growth, presents at advanced stage, chemosensitive

Epithelial Subtype Details

High-Grade Serous Carcinoma (HGSC) [5,6]

• Origin: Fallopian tube fimbriae (Serous Tubal Intraepithelial Carcinoma - STIC)
• Molecular:
  • "TP53 mutation: 96% (hallmark diagnostic feature)"
  • "BRCA1/2 dysfunction: 50% (germline 20%, somatic 30%)"
  • "Homologous recombination deficiency (HRD): 50% (BRCA-mutated + BRCA-wild-type with other HR gene defects)"
• Presentation: 70% Stage III/IV at diagnosis
• Prognosis: 5-year survival 30-40% (advanced stage)
• Chemosensitivity: High (70-80% response to platinum)

Endometrioid Carcinoma

• Association: Endometriosis (42% have concurrent endometriosis)
• Molecular: PTEN loss, PIK3CA mutation, microsatellite instability (Lynch syndrome)
• Presentation: Earlier stage (60% Stage I)
• Concurrent: 15-20% have synchronous endometrial cancer
• Prognosis: Better than HGSC (5-year survival 70-80% overall)

Clear Cell Carcinoma

• Association: Endometriosis (50% cases)
• Molecular: ARID1A mutation (50%), PIK3CA mutation (40%)
• Characteristics: Chemoresistant (response rate 10-20% vs 70% for HGSC)
• Prognosis: Good if early stage (Stage I 80% 5-year survival), poor if advanced (Stage III 20%)
• Hypercalcemia: Paraneoplastic syndrome (10% cases)

Mucinous Carcinoma

• Characteristics: Can reach massive size (> 20 cm, "basketball tumours")
• Differential: MUST exclude metastasis from GI primary (colon, appendix, pancreas) - Krukenberg tumour
• Investigation: Requires colonoscopy and CEA/CA19-9 (elevated in GI primaries)
• Molecular: KRAS mutation (60%)
• Chemoresistance: Poor response to standard platinum-taxane
• Surgery: Appendicectomy routinely performed (exclude appendiceal primary)

2. Germ Cell Tumours (less than 5%, younger women less than 30 years)

Key: Do NOT use CA125 for germ cell tumours - use AFP, β-hCG, LDH

3. Sex Cord-Stromal Tumours (less than 5%)

Molecular Pathogenesis of HGSC

Step 1: Fallopian Tube Epithelial Transformation

• STIC (Serous Tubal Intraepithelial Carcinoma) develops in fimbrial epithelium
• TP53 mutation is initiating event (loss of cell cycle checkpoint)
• "p53 signature": TP53 mutation without morphological atypia (pre-STIC lesion)

Step 2: Exfoliation and Implantation

• Malignant cells exfoliate from tube into peritoneal cavity
• Implant on ovarian surface (misattributed as "ovarian" primary)
• Seed peritoneum, omentum, diaphragm, bowel serosa

Step 3: Peritoneal Spread (Transcoelomic)

• Peritoneal fluid circulation distributes cells
• Right hemidiaphragm most common distant site (follow of peritoneal fluid flow)
• Omental cake: Omental infiltration creates solid mass

Step 4: Ascites Formation

• VEGF secretion by tumour → increased vascular permeability
• Peritoneal carcinomatosis → impaired lymphatic drainage
• Fluid accumulates (can reach 10+ litres)

Homologous Recombination Deficiency (HRD) [12,13]

Normal DNA repair pathway:

• BRCA1/2 proteins repair double-strand DNA breaks via homologous recombination (HR)
• PARP enzymes repair single-strand DNA breaks

BRCA-mutated tumours:

• Cannot repair double-strand breaks (BRCA deficient)
• Rely on PARP to repair single-strand breaks
• PARP inhibition → single-strand breaks accumulate → convert to double-strand breaks → cell cannot repair → cell death (synthetic lethality)

BRCAness: BRCA wild-type tumours with HR deficiency (RAD51, PALB2 defects) - also respond to PARP inhibitors

Routes of Spread

1. Transcoelomic (Most common): Peritoneal seeding → omentum, diaphragm, bowel serosa, liver capsule
2. Lymphatic: Para-aortic, pelvic, inguinal (via round ligament), mediastinal nodes
3. Haematogenous (Rare): Liver parenchyma, lung, bone, brain (late stage)
4. Direct extension: Bladder, rectum, pelvic sidewall

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4. Clinical Presentation

Symptoms

Early Disease (Stage I/II) - Often asymptomatic or non-specific:

• Vague abdominal discomfort
• Bloating
• Urinary frequency (pelvic mass pressure)
• Acute presentations: Ovarian torsion (sudden severe pain), cyst rupture

Advanced Disease (Stage III/IV) - BEAT symptoms:

Red Flag: Symptoms present > 12 days per month and represent change from baseline [7]

Paraneoplastic Syndromes

• Hypercalcemia (clear cell carcinoma): PTHrP secretion
• Cerebellar degeneration: Anti-Yo antibodies (rare, poor prognosis)
• Dermatomyositis: Muscle weakness, heliotrope rash
• Trousseau's syndrome: Migratory thrombophlebitis (hypercoagulable state)

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5. Clinical Examination

Abdominal Examination

Inspection:

• Distension (ascites, mass)
• Sister Mary Joseph nodule: Hard umbilical mass (peritoneal metastasis)
• Cachexia (advanced disease)

Palpation:

• Pelvic mass arising from pelvis (bimanual examination more sensitive)
• Omental cake: Firm epigastric mass (omental infiltration)
• Hepatomegaly: Liver metastases (surface nodularity)
• Ascites: Shifting dullness, fluid thrill

Percussion: Shifting dullness (ascites > 1500 mL)

Auscultation: Bowel sounds (assess for obstruction in advanced disease)

Pelvic Examination

Bimanual Examination:

• Adnexal mass characteristics:
  • "Benign features: Smooth, mobile, unilateral, cystic"
  • "Malignant features: Solid, fixed, irregular, bilateral"
• Pouch of Douglas nodules: Peritoneal metastases (palpable on posterior vaginal fornix)
• Cervical excitation: If torsion suspected

Speculum: Exclude vaginal/cervical pathology

Systemic Examination

• Lymph nodes: Supraclavicular (Virchow's node - left), inguinal
• Chest: Pleural effusion (reduced breath sounds, stony dull percussion at bases)
• Legs: Deep vein thrombosis (paraneoplastic hypercoagulability)

Examination Pearls

Fixed adnexal mass: Suggests peritoneal adhesions/invasion - advanced disease Bilateral masses: Malignancy more likely (80% HGSC bilateral at diagnosis) or metastases (Krukenberg) Solid component on palpation: Increases malignancy risk 10-fold vs simple cyst

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6. Differential Diagnosis

Pelvic Mass Differential

Ascites Differential

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7. Investigations

Primary Care / Initial Assessment

1. Serum CA125 [16]

Indications (NICE Guidelines NG122): [7,15]

• Symptoms suggestive of ovarian cancer (BEAT symptoms > 12 days/month)
• New IBS symptoms in woman > 50 years
• Pelvic mass on examination

Interpretation:

• Normal: less than 35 U/mL
• Raised: > 35 U/mL → Urgent pelvic ultrasound (2-week pathway)
• Very high: > 500 U/mL → High suspicion malignancy (PPV 50%)

Causes of Elevated CA125 (Specificity only 50%):

Limitations:

• Sensitivity: 80% (20% ovarian cancers have normal CA125, especially mucinous subtype)
• False positives: Common in premenopausal women (menstruation, endometriosis)

2. Pelvic Ultrasound (Transvaginal USS) [9]

Preferred modality: Transvaginal (TVUS) for adnexal masses

Benign Features:

• Unilocular
• Smooth walls
• No solid components
• No vascularity
• less than 5 cm diameter

Malignant Features:

• Multilocular with solid components
• Papillary projections
• Irregular walls
• Ascites
• Bilateral
• Increased vascularity (Color Doppler - low resistance index)

Risk Stratification Scores

Risk of Malignancy Index (RMI) [8]

Formula: RMI = U × M × CA125

U (Ultrasound Score):

• Award 1 point each for:
  • Multilocular cyst
  • Solid areas
  • Bilateral lesions
  • Ascites
  • Intra-abdominal metastases
• U = 0 (0 features), U = 1 (1 feature), U = 3 (2-5 features)

M (Menopausal Status):

• Premenopausal = 1
• Postmenopausal = 3

Thresholds:

• RMI less than 200: Low risk (2% cancer risk) - routine gynae referral
• RMI 200-250: Intermediate risk - specialist gynae-oncology referral
• RMI > 250: High risk (75% cancer risk) - urgent 2-week cancer pathway

Example Calculation: Postmenopausal woman (M=3), complex bilateral cyst with ascites (U=3), CA125 = 150 RMI = 3 × 3 × 150 = 1350 → High risk, urgent cancer referral

Performance: Sensitivity 75-80%, Specificity 85-90%

IOTA Simple Rules [9]

International Ovarian Tumour Analysis - More sophisticated USS-based system

Benign Features (B):

• Unilocular cyst
• Solid components less than 7mm
• Acoustic shadows (suggest dermoid/fibroma)
• Smooth multilocular less than 100mm
• No blood flow

Malignant Features (M):

• Irregular solid tumour
• Ascites
• ≥4 papillary projections
• Irregular multilocular solid tumour ≥100mm
• High vascularity

Classification:

• All B, no M = Benign
• All M, no B = Malignant
• Mix of B and M = Inconclusive (use RMI or MRI)

Performance: Sensitivity 95%, Specificity 91% (superior to RMI in specialist hands)

Secondary Care / Specialist Investigations

3. CT Chest-Abdomen-Pelvis (Staging)

Indications:

• RMI > 200 or high suspicion of malignancy
• Pre-operative planning for cytoreduction

Assesses:

• Primary tumour: Size, bilaterality, invasion of adjacent organs
• Peritoneal disease: Omental cake, peritoneal deposits, disease distribution
• Ascites: Volume
• Lymphadenopathy: Para-aortic, pelvic, mediastinal nodes
• Distant metastases: Liver parenchyma, lung, pleural effusion
• Resectability: Disease in porta hepatis, mesenteric root (may preclude optimal cytoreduction)

Limitations: Cannot reliably detect disease less than 1 cm or peritoneal deposits less than 5 mm

4. MRI Pelvis

Indications:

• Characterize indeterminate adnexal masses (RMI 50-200, IOTA inconclusive)
• Young women (avoid radiation)
• Fertility preservation assessment

Superior to CT for:

• Tissue characterization (fat, blood products in dermoid cysts)
• Distinguish endometrioma vs malignancy
• Assess depth of myometrial invasion (synchronous endometrial cancer)

5. Tumour Markers (Extended Panel)

6. Genetic Testing (Germline BRCA) [17]

Indications (ALL patients with epithelial ovarian cancer should be offered testing):

• All non-mucinous epithelial ovarian cancers
• Age less than 70 years
• Family history breast/ovarian cancer

Genes Tested:

• BRCA1 (40-60% lifetime ovarian cancer risk)
• BRCA2 (10-30% lifetime ovarian cancer risk)
• Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2)
• Other: RAD51C/D, BRIP1, PALB2

Implications:

1. Treatment: PARP inhibitor eligibility (olaparib, niraparib)
2. Family: Cascade testing, risk-reducing surgery for relatives
3. Contralateral ovary: Higher risk recurrence (if fertility-sparing surgery considered)

Timing: Can test on diagnosis (blood test) or on tumour tissue (somatic mutations)

7. Ascitic Tap (if large volume ascites)

Indications:

• Confirm malignancy (cytology)
• Therapeutic drainage (symptomatic relief)
• Exclude other causes (TB, cirrhosis)

Tests:

• Cytology: Malignant cells (positive in 90% Stage III/IV)
• SAAG (Serum-Ascites Albumin Gradient): less than 11 g/L (exudative, malignancy)
• Protein: High (exudate)
• Culture: Exclude TB/spontaneous bacterial peritonitis

Investigation Algorithm (Summary)

SYMPTOMATIC WOMAN > 50 years
(BEAT symptoms > 12 days/month OR new IBS symptoms)
              ↓
          CA125 TEST
              ↓
      ┌───────┴────────┐
   less than 35 U/mL         > 35 U/mL
      ↓                 ↓
   Reassure      URGENT PELVIC USS
   Review if            ↓
   persist       CALCULATE RMI
                        ↓
              ┌─────────┴──────────┐
           RMI less than 200           RMI > 200
              ↓                    ↓
      Routine gynae        URGENT REFERRAL
      (benign likely)      Gynae-Oncology MDT
                                  ↓
                           CT STAGING
                           Genetic testing
                           MDT discussion
                                  ↓
                           TREATMENT PLAN

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8. Staging

FIGO Staging System (2014, Revised 2021)

Stage I: Confined to ovaries/fallopian tubes

Stage II: Pelvic extension or primary peritoneal cancer

Stage III: Peritoneal metastases outside pelvis and/or retroperitoneal lymph nodes

Stage IV: Distant metastases

Note: Capsule involvement (liver/spleen surface) = Stage III; Parenchymal involvement = Stage IVB

Stage Distribution at Diagnosis

Key Statistic: 70% diagnosed at Stage III/IV → Poor overall prognosis [3]

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9. Management

Management Principles

Goal:

• Curative intent: Stage I-III disease → Primary cytoreductive surgery + adjuvant chemotherapy
• Palliative intent: Stage IV or unresectable → Neoadjuvant chemotherapy → interval surgery if response

Multidisciplinary Team (MDT):

• Gynae-oncologist surgeon
• Medical oncologist
• Radiologist
• Histopathologist
• Clinical nurse specialist
• Genetics counselor

1. Surgical Management

Primary Cytoreductive Surgery (Debulking) [10,18]

Principle: Macroscopic complete resection (R0) is the single most important prognostic factor

Residual Disease Correlation with Survival:

• R0 (no visible residual): Median survival 60 months
• Optimal (less than 1 cm residual): Median survival 40 months
• Suboptimal (> 1 cm residual): Median survival 20 months
• Every 10% increase in cytoreduction → 5.5% improvement in median survival [18]

Standard Procedure Components:

Interval Cytoreductive Surgery [11]

Indications:

• Unresectable disease at presentation (imaging: mesenteric root/porta hepatis involvement)
• Poor performance status unable to tolerate extensive surgery
• Frailty (age > 75 years, multiple comorbidities)

Protocol:

1. Image-guided biopsy (IR-guided, avoid laparotomy)
2. Neoadjuvant chemotherapy (NACT) - usually 3 cycles
3. Interval surgery after cycle 3 (if response and improved performance status)
4. Adjuvant chemotherapy - further 3 cycles (total 6 cycles)

Evidence: EORTC-55971 and CHORUS trials - Equivalent overall survival to primary surgery in advanced disease, with lower morbidity (less blood loss, shorter surgery, fewer complications). [11]

2. Chemotherapy

Adjuvant Chemotherapy (Post-Surgery)

Indications:

• All Stage IC-IV epithelial ovarian cancer
• Stage IA/IB high-grade (Grade 3 or clear cell subtype)
• (Stage IA/IB low-grade can observe)

Standard Regimen: Carboplatin-Paclitaxel

Schedule: Every 21 days (3-week cycle) × 6 cycles

Neoadjuvant Chemotherapy (NACT) [11]

Same regimen: Carboplatin-Paclitaxel × 3 cycles → Interval surgery → 3 further cycles

Response Assessment: CA125 trend (should fall > 50% if platinum-sensitive), CT after 3 cycles

3. Targeted Therapy (Maintenance)

PARP Inhibitors [12,13]

Mechanism: Synthetic Lethality

• Inhibit Poly(ADP-ribose) Polymerase → blocks single-strand DNA break repair
• BRCA-mutated/HRD tumours cannot repair double-strand breaks → accumulation → cell death

Agents Available:

Eligibility:

• Complete or partial response to platinum-based chemotherapy
• BRCA mutation (germline or somatic) OR HRD-positive (genomic scar testing)
• Adequate bone marrow/renal function

Administration: Oral, daily, continued until progression or intolerance

Side Effects:

• Nausea (80%)
• Fatigue (70%)
• Anemia (40%) - may require dose reduction or transfusion
• Thrombocytopenia (30%)
• Myelodysplastic syndrome/AML (1-2%) - rare but serious long-term risk

Monitoring: FBC every 2 weeks initially, then monthly

Bevacizumab (Anti-VEGF) [14]

Mechanism: Monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF) → inhibits angiogenesis

Indication: High-risk advanced ovarian cancer (Stage IV or suboptimal Stage III)

Regimen (ICON-7 protocol): [14]

• Bevacizumab 7.5 mg/kg IV every 3 weeks
• Added to carboplatin-paclitaxel (cycles 2-6)
• Continued as maintenance for total 12 months (or until progression)

Benefit:

• ICON-7: PFS benefit +2 months overall (19 vs 17 months), +5 months in high-risk group
• No overall survival benefit in most trials

Side Effects:

• Hypertension (30%) - requires monitoring/treatment
• Proteinuria (20%) - check urine dipstick each cycle
• GI perforation (2%) - absolute contraindication if bowel involvement
• Bleeding (epistaxis common, severe rare)
• Impaired wound healing (avoid surgery within 6 weeks)
• Thromboembolic events

Current Use: Reserved for high-risk disease due to limited benefit, toxicity, and cost

Management Algorithm

SUSPECTED OVARIAN CANCER
(High RMI, imaging suggestive)
            ↓
    CT CHEST-ABDO-PELVIS
    Genetic testing (BRCA)
            ↓
    MDT DISCUSSION
            ↓
   ┌────────┴─────────┐
OPERABLE             UNRESECTABLE
(Resectable to       (Bulky disease,
less than 1cm residual)       poor PS, frail)
   ↓                      ↓
PRIMARY              IMAGE-GUIDED BIOPSY
CYTOREDUCTIVE               ↓
SURGERY              NEOADJUVANT CHEMO
(TAH-BSO-            (Carbo-Taxol × 3)
Omentectomy)               ↓
   ↓                 REASSESS (CA125, CT)
ADJUVANT                   ↓
CHEMOTHERAPY         Response? PS improved?
(Carbo-Taxol × 6)          ↓
   ↓                 INTERVAL CYTOREDUCTIVE
Complete/partial     SURGERY
response?                  ↓
   ↓                 ADJUVANT CHEMO
MAINTENANCE          (× 3 further cycles)
THERAPY                    ↓
   ↓                 MAINTENANCE THERAPY
BRCA-mutated/HRD?
   ↓
Olaparib/Niraparib
(if response)
   ↓
SURVEILLANCE
(CA125, imaging)

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10. Complications

Disease-Related Complications

Malignant Bowel Obstruction

Incidence: 25-50% of advanced ovarian cancer patients (terminal phase)

Mechanism:

• Carcinomatosis peritonei: Multiple serosal deposits → luminal narrowing, impaired motility
• Less commonly: mechanical obstruction by tumour mass

Presentation: Nausea, vomiting, colicky abdominal pain, absolute constipation, abdominal distension

Management:

• Imaging: AXR (dilated bowel loops), CT (transition point, exclude simple mechanical cause)
• Conservative/Palliative (if terminal disease, poor prognosis):
  • NG tube decompression
  • "Antiemetics: Haloperidol, cyclizine, levomepromazine"
  • "Antisecretory: Octreotide (reduces GI secretions)"
  • "Corticosteroids: Dexamethasone (reduce peritoneal oedema)"
  • Venting gastrostomy (if prolonged, refractory vomiting)
• Surgical: Bypass/resection/stoma (only if localized obstruction, good performance status, life expectancy > 3 months)

Prognosis: Median survival 3-6 months if malignant obstruction in recurrent disease

Malignant Ascites

Management:

• Paracentesis: Therapeutic drainage (symptom relief)
• Indwelling peritoneal catheter: If recurrent, frequent drainage needed (PleurX catheter)
• Diuretics: Usually ineffective (exudative, not transudative)
• Chemotherapy: If platinum-sensitive recurrence

Venous Thromboembolism (VTE)

Incidence: 20% of ovarian cancer patients (hypercoagulable state)

Prevention:

• Perioperative: LMWH + TED stockings (extended prophylaxis 28 days post-major surgery)
• Chemotherapy: Consider primary prophylaxis if high risk

Treatment: Therapeutic LMWH (or DOAC) - indefinite in active cancer

Treatment-Related Complications

Chemotherapy Toxicity

Surgical Complications

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11. Prognosis and Outcomes

Overall Survival

Overall 5-year survival: 45% (all stages combined) [2]

Prognostic Factors

Favorable:

• Early stage (I/II)
• Complete cytoreduction (R0)
• Low-grade histology
• BRCA-mutated (paradoxically better prognosis - platinum-sensitive, PARP inhibitor response)
• Good performance status
• Platinum-sensitive recurrence (progression > 6 months after last platinum)

Unfavorable:

• Advanced stage (III/IV)
• Suboptimal cytoreduction (> 1 cm residual)
• High-grade serous histology
• Clear cell histology (chemoresistant)
• Platinum-resistant recurrence (progression less than 6 months after last platinum)
• Ascites
• Poor performance status (ECOG ≥2)

Recurrence

Incidence: 70% of advanced-stage disease recurs within 3 years

Patterns:

• Peritoneal: Most common (80%)
• Lymph node: 20%
• Distant (liver parenchyma, lung): 15%

Classification (Treatment-Free Interval):

• Platinum-sensitive: Recurrence > 6 months after last platinum → re-treat with platinum (60-70% response rate)
• Platinum-resistant: Recurrence less than 6 months → Non-platinum agents (paclitaxel, topotecan, gemcitabine, PLD - response rate 10-20%)
• Platinum-refractory: Progression during platinum therapy → Poor prognosis, palliative care

Treatment of Recurrence:

• Platinum-sensitive: Re-challenge with platinum doublet (carboplatin-gemcitabine, carboplatin-PLD) ± bevacizumab → PARP inhibitor maintenance
• Platinum-resistant: Single-agent chemotherapy (weekly paclitaxel, topotecan, PLD), consider clinical trials
• Secondary cytoreduction: Only if platinum-sensitive recurrence, single-site disease, complete resection achievable

Surveillance (After completion of primary treatment):

• CA125: Every 3 months (years 1-2), every 4-6 months (years 3-5)
• Clinical review: Every 3-4 months
• Imaging: Not routine (unless symptomatic or rising CA125)

Note: Early detection of recurrence (asymptomatic CA125 rise) does NOT improve survival - early treatment vs waiting for symptoms gives the same outcome

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12. Prevention and Screening

Primary Prevention (Risk Reduction)

Chemoprevention

Combined Oral Contraceptive Pill (COCP):

• 50% risk reduction after 5 years use
• Protection persists > 30 years after cessation
• Mechanism: Ovulation suppression ("incessant ovulation" hypothesis)
• Benefit vs risk: Must balance against VTE/breast cancer risk (small)

Risk-Reducing Surgery

Bilateral Salpingo-Oophorectomy (RRSO)

Indications:

• BRCA1 mutation: Recommend age 35-40 years (or when childbearing complete)
• BRCA2 mutation: Recommend age 40-45 years
• Lynch syndrome: Age 40 years (or concurrent with hysterectomy for endometrial cancer risk)

Risk Reduction:

• Ovarian cancer: 80-95% risk reduction (not 100% - residual risk primary peritoneal cancer)
• Breast cancer: 50% risk reduction (in premenopausal women - removes ovarian estrogen)

Complications:

• Surgical menopause: Vasomotor symptoms, osteoporosis, cardiovascular risk, sexual dysfunction
• HRT: Can be used (does NOT negate benefit in BRCA carriers)

Opportunistic Salpingectomy

• Removal of fallopian tubes during hysterectomy/sterilization procedures (leave ovaries)
• Rationale: Remove STIC source while preserving ovarian function
• Risk reduction: Estimated 50-70% ovarian cancer risk reduction
• Increasingly standard practice in benign gynae surgery

Screening (Population)

UKCTOCS Trial (UK Collaborative Trial of Ovarian Cancer Screening):

• Largest ovarian cancer screening trial (202,000 women)
• Compared annual CA125 + TVUS vs TVUS alone vs no screening
• Follow-up: 14 years

Results:

• Earlier stage detection: Yes (shift to Stage I/II)
• Mortality reduction: NO (HR 0.96, p=0.58)
• Conclusion: Population screening does NOT reduce ovarian cancer mortality

Why Screening Fails:

• Rapid progression: HGSC grows rapidly - window between detectable and advanced disease is narrow
• Lead-time bias: Earlier detection doesn't mean lives saved
• Overdiagnosis: Borderline tumours detected and treated unnecessarily

Current Recommendation: Population screening NOT recommended (NICE, USPSTF, ACOG)

Exception: High-risk women (BRCA carriers) - Consider annual TVUS + CA125 from age 30 until RRSO performed (evidence limited, but offered)

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13. Hereditary Ovarian Cancer Syndromes

BRCA1/2-Associated Ovarian Cancer [17]

Inheritance: Autosomal dominant

Lifetime Risks:

Ovarian Cancer Characteristics:

• Earlier age: Mean diagnosis 10 years younger than sporadic (age 50-55)
• Better prognosis: Platinum-sensitive, better response to chemotherapy
• PARP inhibitor sensitivity: Hallmark - synthetic lethality

Family Implications:

• 50% inheritance risk to offspring
• Cascade testing: All first-degree relatives should be offered genetic counseling
• Male carriers: Increased prostate/pancreatic cancer risk, can transmit to daughters

Management:

• Surveillance: Annual CA125 + TVUS from age 30 (limited evidence)
• Risk-reducing surgery: RRSO at age 35-40 (BRCA1) or 40-45 (BRCA2)
• Chemoprevention: COCP (discuss risks/benefits)

Lynch Syndrome (HNPCC)

Genes: MLH1, MSH2, MSH6, PMS2 (mismatch repair genes)

Lifetime Ovarian Cancer Risk: 10-15%

Associated Cancers:

• Colorectal: 50-80% risk (early onset, right-sided)
• Endometrial: 40-60% risk
• Gastric, small bowel, hepatobiliary, urinary tract: 5-10%

Ovarian Cancer Characteristics:

• Endometrioid and clear cell subtypes more common
• Earlier age: Mean diagnosis age 45-50

Management:

• Colonoscopy: Every 1-2 years from age 25
• Endometrial surveillance: Annual endometrial biopsy from age 30-35 (or TVUS)
• Risk-reducing surgery: Hysterectomy + BSO at age 40 (or when childbearing complete)

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14. Evidence and Guidelines

Key Guidelines

Landmark Studies

1. SOLO-1 Trial (2018) [12]

Question: Does maintenance olaparib improve outcomes in BRCA-mutated advanced ovarian cancer?

Design: RCT, 391 patients with newly diagnosed BRCA-mutated Stage III/IV, response to platinum chemotherapy

Intervention: Olaparib 300 mg BD orally vs placebo (Duration: 2 years or until progression)

Results:

• Median PFS: 56 months (olaparib) vs 13 months (placebo) - HR 0.30
• 3-year PFS: 60% vs 27%
• Game-changing result - quadrupled progression-free survival

Impact: Established olaparib as standard 1st-line maintenance for BRCA-mutated ovarian cancer

2. PRIMA Trial (2019) [13]

Question: Does niraparib benefit extend beyond BRCA-mutated to all HRD tumours?

Design: RCT, 733 patients with advanced ovarian cancer (response to platinum), including BRCA wild-type

Intervention: Niraparib vs placebo (maintenance)

Results:

• HRD-positive (including BRCA wild-type): Median PFS 21 months vs 10 months
• Overall population: Median PFS 13 vs 8 months
• Benefit even in non-HRD patients (smaller)

Impact: Expanded PARP inhibitor use to all HRD tumours, not just BRCA-mutated

3. EORTC-55971 / CHORUS Trials (2010, 2015) [11]

Question: Is neoadjuvant chemotherapy non-inferior to primary surgery for advanced ovarian cancer?

Design: RCT comparing primary debulking surgery → chemotherapy vs neoadjuvant chemotherapy (3 cycles) → interval surgery → chemotherapy (3 cycles)

Results:

• Overall survival: Equivalent (EORTC: 29 vs 30 months; CHORUS: 24 vs 22 months)
• Surgical morbidity: Lower in NACT group (less blood loss, shorter surgery, fewer complications)
• Optimal cytoreduction rate: Higher after NACT (80% vs 40%)

Impact: Established NACT as acceptable for unresectable disease, frail patients, poor PS

4. ICON-7 Trial (2011) [14]

Question: Does bevacizumab improve outcomes in advanced ovarian cancer?

Design: RCT, 1,528 patients with high-risk disease (Stage III suboptimal or Stage IV)

Intervention: Carboplatin-paclitaxel ± bevacizumab 7.5 mg/kg (cycles 2-6, then maintenance to 12 months)

Results:

• Overall population: PFS +2 months (19 vs 17 months), no OS benefit
• High-risk subgroup (Stage IV / suboptimal III): PFS +5 months, OS +7 months

Impact: Bevacizumab approved for high-risk disease, but limited adoption (toxicity, cost, modest benefit)

5. UKCTOCS (2016)

Question: Does population screening for ovarian cancer reduce mortality?

Design: RCT, 202,000 women aged 50-74, 14-year follow-up

Results:

• Stage shift: Yes (more Stage I/II detected in screening arms)
• Mortality reduction: NO (HR 0.96, p=0.58)
• False positives: Led to unnecessary surgeries (50 surgeries per cancer detected)

Impact: Population screening NOT recommended - No mortality benefit, harms from overdiagnosis

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15. Patient and Layperson Explanation

What is ovarian cancer?

Ovarian cancer is a disease where cells in the ovaries (the organs that produce eggs) start to grow out of control. Most ovarian cancers actually start in the fallopian tubes (the tubes connecting ovaries to the womb) and then spread to the ovaries and the lining of the tummy (peritoneum).

Why is it called the "silent killer"?

This is actually a misleading term. Ovarian cancer does cause symptoms, but they are vague and easy to dismiss - bloating, feeling full quickly, tummy pain, and needing to pee more often. These symptoms are so common in everyday life that they don't raise alarm bells until the cancer has spread.

The real problem: There's no good screening test (like a smear test for cervical cancer), and by the time symptoms are severe enough to investigate, the cancer has often spread.

Why was my cancer found so late?

70% of ovarian cancers are diagnosed at Stage III or IV (advanced stage) because:

• The ovaries are deep in the pelvis - tumours can grow large without being felt
• Symptoms mimic common conditions (IBS, bladder problems)
• There's no screening programme (screening doesn't save lives in ovarian cancer)

What is "debulking" surgery?

Ovarian cancer spreads like sand sprinkled inside your tummy. The surgery aims to remove every visible grain of sand - the ovaries, womb, fatty apron (omentum), and any areas where the cancer has spread.

Why so extensive? The less cancer left behind, the better chemotherapy works. Studies show that complete removal of all visible disease doubles survival time.

Recovery: This is major surgery - expect 6-8 weeks recovery, possible stoma (bag), and intensive care initially.

Why do I need genetic testing (BRCA)?

We test for the BRCA gene (the "Angelina Jolie gene") because:

1. Treatment: If you have BRCA mutation, we can use PARP inhibitor drugs (olaparib, niraparib) that specifically kill BRCA-mutated cancer cells - these drugs have quadrupled the time before cancer comes back in trials
2. Family: Your blood relatives (children, siblings, parents) have 50% chance of carrying the gene - they can have preventative surgery or enhanced screening
3. Contralateral ovary: If we're considering leaving one ovary (fertility preservation), we need to know your risk

All patients with ovarian cancer should be offered testing - it's not just for people with family history.

What is a PARP inhibitor?

PARP inhibitors (olaparib, niraparib, rucaparib) are tablet chemotherapy you take daily at home. They work by exploiting a weakness in BRCA-mutated cancer cells:

• Normal cells have two ways to repair damaged DNA
• BRCA-mutated cancer cells have lost one repair pathway (BRCA)
• PARP inhibitors block the second pathway
• Cancer cell cannot repair DNA → dies
• Normal cells (with working BRCA) are unaffected

This is called "synthetic lethality" - two defects together are lethal, but each alone is survivable.

Results: In SOLO-1 trial, women taking olaparib after chemotherapy had 60% still disease-free at 3 years vs 27% on placebo - a game-changer.

Side effects: Tiredness, nausea, low blood counts (may need dose reduction or breaks)

Will I lose my hair?

Yes, with standard chemotherapy (carboplatin-paclitaxel). Hair loss starts 2-3 weeks after first cycle and is complete (scalp, eyebrows, eyelashes, body hair).

Good news: Hair always regrows after chemotherapy finishes (often curlier or different color initially)

Scalp cooling: Can reduce hair loss in some patients (not always available, limited success)

What are my chances?

Honest answer: Ovarian cancer is serious, but survival is improving:

However: New drugs (PARP inhibitors, bevacizumab) are changing these statistics - women treated in 2020s are living longer than these older figures suggest.

Will it come back?

Unfortunately, yes - 70% of advanced ovarian cancers recur within 3-5 years, even after complete treatment.

However:

• Recurrence is treatable - many women live years with recurrent disease
• PARP inhibitors are dramatically extending the time before recurrence
• Each recurrence can be treated (platinum chemotherapy, PARP inhibitors, other drugs)

How is recurrence detected?

CA125 blood test - a protein made by ovarian cancer cells. Checked every 3 months after treatment.

Important: Studies show that early detection of recurrence doesn't improve survival - treating when CA125 rises vs waiting for symptoms gives the same outcome. Some women choose not to have CA125 monitoring to avoid anxiety.

What if I have a family history?

You should be referred to genetics if you have:

• 2 relatives with ovarian cancer
• 1 relative with ovarian cancer less than 50 years
• Breast cancer less than 40 years in family
• Male breast cancer in family
• Jewish ancestry (higher BRCA rates)

Genetic testing can identify BRCA/Lynch syndrome mutations → options for risk-reducing surgery (remove ovaries/tubes at age 35-45) which cuts cancer risk by 80-95%.

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16. References

Primary Sources

1. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. PMID: 33538338. DOI: 10.3322/caac.21660

2. Torre LA, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68(4):284-296. PMID: 29809280. DOI: 10.3322/caac.21456

3. Doubeni CA, et al. Diagnosis and Management of Ovarian Cancer. Am Fam Physician. 2016;93(11):937-944. PMID: 27281837.

4. Kurman RJ, Shih IM. The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded. Am J Pathol. 2016;186(4):733-747. PMID: 27012190. DOI: 10.1016/j.ajpath.2015.11.011

5. Kindelberger DW, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol. 2007;31(2):161-169. PMID: 17255760. DOI: 10.1097/01.pas.0000213335.40358.47

6. Labidi-Galy SI, et al. High grade serous ovarian carcinomas originate in the fallopian tube. Nat Commun. 2017;8:1093. PMID: 29061967. DOI: 10.1038/s41467-017-00962-1

7. NICE Guideline NG122. Ovarian cancer: recognition and initial management. 2011 (Updated April 2024). Available at: https://www.nice.org.uk/guidance/ng122

8. Jacobs I, et al. A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol. 1990;97(10):922-929. PMID: 2223684. DOI: 10.1111/j.1471-0528.1990.tb02448.x

9. Timmerman D, et al. Simple ultrasound-based rules for the diagnosis of ovarian cancer. Ultrasound Obstet Gynecol. 2008;31(6):681-690. PMID: 18504770. DOI: 10.1002/uog.5365

10. Bristow RE, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20(5):1248-1259. PMID: 11870167. DOI: 10.1200/JCO.2002.20.5.1248

11. Vergote I, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943-953. PMID: 20818904. DOI: 10.1056/NEJMoa0908806

12. Moore K, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018;379(26):2495-2505. PMID: 30345884. DOI: 10.1056/NEJMoa1810858

13. González-Martín A, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2019;381(25):2391-2402. PMID: 31562799. DOI: 10.1056/NEJMoa1910962

14. Perren TJ, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496. PMID: 22204725. DOI: 10.1056/NEJMoa1103799

15. Hippisley-Cox J, Coupland C. Identifying women with suspected ovarian cancer in primary care: derivation and validation of algorithm. BMJ. 2011;344:d8009. PMID: 22217555. DOI: 10.1136/bmj.d8009

16. Moss EL, et al. The role of CA125 in clinical practice. J Clin Pathol. 2005;58(3):308-312. PMID: 15735166. DOI: 10.1136/jcp.2004.018077

17. Kuchenbaecker KB, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017;317(23):2402-2416. PMID: 28632866. DOI: 10.1001/jama.2017.7112

18. Chang SJ, et al. Survival impact of complete cytoreduction to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis. Gynecol Oncol. 2013;130(3):493-498. PMID: 23747291. DOI: 10.1016/j.ygyno.2013.05.040

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17. Examination Focus

Common Exam Questions

1. General Practice / Primary Care

Q: 55-year-old woman presents with new onset bloating and IBS-like symptoms for 6 weeks. What is your next step?

A: Check serum CA125. NICE guidelines (NG122) state that any woman > 50 years with new onset IBS symptoms must have CA125 tested, as primary IBS rarely begins after age 50. If CA125 > 35 U/mL, arrange urgent pelvic ultrasound (2-week pathway). [7,15]

2. Gynaecology / MRCOG

Q: What is the Risk of Malignancy Index (RMI) formula and threshold for urgent referral?

A:

• Formula: RMI = U × M × CA125
• U (ultrasound): 0, 1, or 3 based on features (multilocular, solid, bilateral, ascites, mets)
• M (menopause): 1 (pre) or 3 (post)
• Threshold: RMI > 200-250 warrants urgent gynae-oncology referral
• RMI > 250 has 75% positive predictive value for malignancy [8]

Q: What is the origin of high-grade serous ovarian carcinoma?

A: Most HGSC originates from the fimbriated end of the fallopian tube as Serous Tubal Intraepithelial Carcinoma (STIC), NOT from the ovarian surface epithelium. This explains why risk-reducing salpingectomy (removing tubes, keeping ovaries) reduces ovarian cancer risk by 50-70%. [5,6]

3. Oncology

Q: Explain the mechanism of PARP inhibitors in BRCA-mutated ovarian cancer.

A: Synthetic lethality:

• BRCA proteins repair double-strand DNA breaks via homologous recombination
• PARP enzymes repair single-strand breaks
• BRCA-mutated cancer cells cannot repair double-strand breaks
• PARP inhibition → single-strand breaks accumulate → convert to double-strand breaks
• Cancer cell has no repair mechanism → accumulates DNA damage → cell death
• Normal cells (intact BRCA) are unaffected

SOLO-1 trial: Maintenance olaparib after platinum chemotherapy → 60% progression-free at 3 years vs 27% placebo (median PFS 56 vs 13 months). [12]

4. Pathology

Q: What tumour markers would you request in a 25-year-old with a large ovarian mass?

A: Germ cell tumours are most common in young women (less than 30 years). Check:

• AFP (alpha-fetoprotein) - yolk sac tumour, immature teratoma
• β-hCG (beta-human chorionic gonadotropin) - choriocarcinoma, dysgerminoma
• LDH (lactate dehydrogenase) - dysgerminoma

NOT CA125 (epithelial tumour marker, less relevant in young women).

5. Surgery

Q: What is the surgical goal in ovarian cancer cytoreduction? What is the prognostic impact?

A:

• Goal: Macroscopic complete resection (R0) - no visible residual disease
• Optimal cytoreduction: less than 1 cm residual (if R0 not achievable)
• Suboptimal: > 1 cm residual

Prognostic impact: [10,18]

• R0: Median survival 60 months
• Optimal (less than 1 cm): Median survival 40 months
• Suboptimal (> 1 cm): Median survival 20 months
• Every 10% increase in cytoreduction → 5.5% improvement in median survival

Components: TAH-BSO, omentectomy, peritoneal strippings, lymph node assessment, ± bowel resection/diaphragm stripping to achieve R0.

6. Genetics

Q: What are the lifetime ovarian cancer risks for BRCA1 and BRCA2 mutation carriers, and when should risk-reducing surgery be offered?

A:

• BRCA1: 40-60% lifetime ovarian cancer risk
• BRCA2: 10-30% lifetime ovarian cancer risk

Risk-reducing bilateral salpingo-oophorectomy (RRSO): [17]

• BRCA1: Age 35-40 years (or when childbearing complete)
• BRCA2: Age 40-45 years
• Risk reduction: 80-95% (not 100% - residual primary peritoneal cancer risk)
• Also reduces breast cancer risk by 50% (premenopausal)

HRT can be used post-RRSO (does not negate protective effect in BRCA carriers).

High-Yield Facts for Exams

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists and follow local guidelines. This content is designed for postgraduate medical education and examination preparation (MRCOG, FRANZCOG, gynae-oncology training).