Ovarian cancer

Introduction

• Lifetime risk ~1 in 70 in the US (covers ovarian, fallopian tube, and primary peritoneal cancer).
• Risk factors: age is the strongest risk factor, followed by family history. One first-degree relative raises risk from ~1 in 70 to ~1 in 20 (~5% lifetime). BRCA1/2 ovarian/tubal/peritoneal lifetime risk: BRCA1 ~39 to 58%, BRCA2 ~13 to 29% (not ~60% for both). Also Lynch syndrome (HNPCC) and genes such as BRIP1, RAD51C, RAD51D, and PALB2.
• BRCA1/2 carriers: risk-reducing bilateral salpingo-oophorectomy (RRBSO) ↓ ovarian cancer risk by ~80% and ↓ mortality by ~70%.
• All patients with ovarian cancer should be referred for genetic counseling.
• Diagnosis is made at primary surgery or by pretreatment tissue biopsy; before neoadjuvant chemo, histologic confirmation (core biopsy preferred) is required. Cytoreduction means surgery to remove all sites of cancer within the abdominal cavity. It is optimal (<1 cm residual tumor) or suboptimal (>1 cm residual disease).
• Staging: FIGO system. Stage I: limited to ovaries and/or fallopian tubes. IA = one ovary or tube; IB = both ovaries or tubes (capsules intact, no surface tumor, negative washings). Primary peritoneal cancer cannot be stage I.
• IC mnemonic: the Capsule is cracked. IC1 = surgical spill (spi11), IC2 = capsule rupTWOred, IC3 = malignant cells in ascites/washings.

Staging (AJCC / FIGO)

Epithelial ovarian cancer histology

5 main subtypes of epithelial ovarian cancer:

1. High-grade serous: presents at advanced stage.
2. Endometrioid carcinoma: age 40 to 50, diagnosed early stage, usually positive for CK7, PAX8, CA-125 and ER+.
3. Clear cell carcinoma: high-grade tumors, more responsive to RT.
4. Mucinous carcinoma: rare; rule out a GI primary (EGD and colonoscopy); inspect the appendix and remove it if abnormal or suspicious (routine removal of a grossly normal appendix is not mandatory). Check CA 19-9 and CEA. Chemo options include carboplatin/paclitaxel or a GI regimen (FOLFOX or CAPOX) +/- bevacizumab; the GI approach is not proven superior.
   • Krukenberg tumor (mucinous mimic, not an epithelial ovarian subtype): metastatic disease to the ovaries composed of mucin-rich signet-ring cells; most common primary is the stomach.
5. Low-grade serous carcinoma.

• Pearl: Lynch syndrome is associated with endometrioid ovarian carcinomas, clear cell cancers, and serous carcinomas.

Molecular associations:

• TP53 mutations: typically high-grade serous ovarian cancer.
• CTNNB-1 (beta-catenin) and PTEN: most common in ovarian endometrioid carcinoma.
• KRAS and BRAF: frequent in low-grade serous tumors, exceptionally rare in high-grade cancers.

Principles of ovarian surgery (NCCN)

• Epithelial ovarian confined to an ovary or the pelvis (stage IA to IIA):
  • Maximum cytoreduction of all pelvic disease; evaluate for occult disease in the upper abdomen or retroperitoneum.
  • Ascites or peritoneal lavage for cytology; biopsy suspicious lesions, or random biopsies if none.
  • BSO and hysterectomy with omentectomy, keeping an encapsulated mass intact during removal. Consider USO or BSO with uterine preservation (fertility).
  • Bilateral para-aortic and bilateral pelvic node dissection.
• Newly diagnosed invasive epithelial ovarian cancer involving pelvis and upper abdomen (stage ≥IIB):
  • Maximum cytoreduction, remove all gross disease. Optimal = residual <1 cm; suboptimal = >1 cm deposits.
  • Ascites for cytology; remove all involved omentum.
  • Resect suspicious/enlarged nodes if possible; resection of clinically negative nodes is not required.
  • Additional procedures for optimal cytoreduction (any stage): bowel resection, appendectomy, stripping of the diaphragm or other peritoneal surfaces, splenectomy, partial cystectomy and/or ureteroneocystostomy, partial hepatectomy, partial gastrectomy, cholecystectomy, and/or distal pancreatectomy.
  • Low-volume residual disease favors IP therapy; consider placing an IP catheter at initial surgery.

Treatment

• Early-stage:
  • Stage IA or IB, grade 1 or 2: surgery alone, no adjuvant chemo (observation).
  • Stage IA or IB grade 3, any IC, or clear cell: generally surgery followed by adjuvant chemo ×3 to 6 (histology-specific; observation acceptable for completely staged IA clear cell and selected IC low-grade serous/mucinous).
    • Adjuvant chemo ↑ OS by ~8% and ↑ DFS by ~10%. 3 vs 6 cycles: same OS, non-significant ↑ DFS with 6 cycles.
  • Stage ≥II: adjuvant chemo ×6, +/- bevacizumab.
• Advanced stage III to IV: start with gyn-onc evaluation and cross-sectional imaging; diagnostic laparoscopy is an optional tool to assess resectability or obtain tissue.
  • Resectable: cytoreductive surgery followed by adjuvant carboplatin/taxane ×6.
  • Unresectable: neoadjuvant chemo ×3 → surgery → adjuvant chemo to complete 6 cycles total.
    • Selected stage III patients at interval cytoreduction after neoadjuvant carboplatin/paclitaxel: cisplatin HIPEC at surgery ↑ OS (OVHIPEC-1). Not a universal component of optimal cytoreduction (not proven for primary CRS or stage IV).
    • Base further therapy on response and operability: if responding or stable, continue platinum-based therapy (surgery may be deferred). Only progression on platinum establishes platinum-refractory disease; unresectability alone does not.

First-line therapy

• Carboplatin/paclitaxel ×6 (GOG-158; GOG-172 was IV vs IV/IP cisplatin-based, not carboplatin).
• +/- bevacizumab q3 weeks followed by bevacizumab maintenance (ICON-7 and GOG-218): ↑ PFS, same OS.
• GOG-172 IP regimen improved PFS and OS vs IV (more toxicity, worse QOL during treatment); GOG-252 found no PFS benefit from IP when all arms got bevacizumab. Results are regimen- and trial-specific. IP is contraindicated in suboptimal cytoreduction (poor penetration into larger tumors); IP evidence (GOG-172) was in optimally debulked stage III with residual nodules <=1 cm (not only microscopic disease); benefit is greatest with smallest residual.
• Q3 weeks preferred; can be given weekly (dose-dense JGOG3016, more cytopenias; MITO-7, better tolerated in the elderly).
• If mucinous histology: carboplatin/paclitaxel or a GI regimen, FOLFOX (5-FU/oxaliplatin) or CAPOX (capecitabine/oxaliplatin), +/- bevacizumab; the GI approach is not proven superior.

Maintenance therapy

• No OS benefit with bevacizumab maintenance; bevacizumab can ↓ ascites.
• Bevacizumab is started concurrently with chemotherapy and continued as maintenance (GOG-218, ICON7); initiating it only after chemo is not the pivotal-trial regimen; PARP inhibitors are given only after completion of adjuvant chemo.
• First question when deciding maintenance: was bevacizumab used with primary therapy?
• No bevacizumab (adjuvant chemo alone): olaparib for BRCA1/2 mutated; niraparib for HRD-positive disease (FDA label restricted to HRD-positive Mar 2026); rucaparib (ATHENA-MONO) is NCCN-listed but not FDA-approved in 1L.
  • BRCA1/2 wt (or unknown): observe (if in CR) or rucaparib; niraparib only if HRD-positive.
  • BRCA1/2 mutated: observe (if stage II), olaparib, rucaparib, or niraparib.
• Received bevacizumab during primary therapy:
  • BRCA1/2 wt (or unknown) and HRD negative (HR proficient): bevacizumab alone.
  • BRCA1/2 wt and HRD positive: bevacizumab + olaparib, or bevacizumab alone.
  • BRCA1/2 mutated: bevacizumab + olaparib, olaparib, rucaparib, or niraparib.
  • Data are limited for PARP inhibitor maintenance in stage II disease.
  • DUO-O (Harter Ann Oncol 2025; NCT03737643): 1L newly-diagnosed advanced HGSOC without tBRCA mutation; induction paclitaxel/carboplatin + bevacizumab ± durvalumab, then maintenance bev + durva ± olaparib. HRD-positive cohort: mPFS 37.3 vs 23.0 mo (HR 0.49) with durva+olap+bev vs bev alone. All-comers non-tBRCA: mPFS 24.2 vs 19.3 mo (HR 0.63). Not FDA-approved for ovarian cancer (interim OS HR 0.95; Harter Ann Oncol 2025). The Jun 14, 2024 durvalumab approval was for dMMR endometrial cancer (DUO-E), not ovarian.

PARP inhibitor first-line maintenance trials (by BRCA/HRD)

• BRCA1/2 mutations have better response to platinum-based chemo.
• Olaparib (SOLO1): advanced (stage III/IV) high-grade endometrioid or serous with germline/somatic BRCA1/2; mPFS 56 vs 13.8 mo.
• Olaparib + bevacizumab (PAOLA1): benefit only in BRCA1/2 or HRD; PFS 22.1 vs 16.6 mo in all comers; HRD-negative mPFS 16.6 vs 16.2 (no benefit). Olaparib is the only PARP inhibitor given with bevacizumab for maintenance.
• Rucaparib (ATHENA): ↑ PFS regardless of BRCA1/2 or HRD status.
• Niraparib (PRIMA): ↑ mPFS 13.8 vs 8.2 mo overall (21.9 vs 10.4 mo in HRD-positive); FDA 1L label restricted to HRD-positive disease in Mar 2026.
• Veliparib (VELIA): ↑ PFS in BRCA1/2 and HRD-positive patients.

Recurrence

• Do not treat rising CA-125 without imaging evidence of disease progression.
• Second-look laparotomy is no longer standard of care for diagnostic purposes.
• Platinum sensitive (recurrence ≥6 months after completing first-line platinum-based therapy):
  • Consider secondary debulking. Per the DESKTOP trial, ascites, initial suboptimal debulking, and diffuse carcinomatosis are indications against repeat debulking. DESKTOP III used a positive AGO score: ECOG 0, complete resection at initial surgery, and ascites <500 mL. Select for likelihood of complete secondary resection, not a lesion count.
  • Platinum-based chemotherapy for 6 cycles: carboplatin/paclitaxel, carbo/gemcitabine, or carbo/liposomal doxorubicin (good if neuropathy).
  • If PR or CR to chemo, add maintenance:
    • If progressed on bevacizumab maintenance, continue bevacizumab after completing chemo.
    • If progressed on chemo alone and bevacizumab was not used, PARP inhibitor maintenance for BRCA-mutated disease only per current FDA labels (olaparib or rucaparib for germline/somatic BRCA; niraparib for germline BRCA).
• Platinum resistant (progressing within <6 months of completing first-line platinum-based therapy):
  • Single-agent chemotherapy: liposomal doxorubicin, topotecan, etoposide, docetaxel, paclitaxel.
  • Bevacizumab combines with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan (AURELIA), not every salvage agent; use after prior bevacizumab progression is a separate decision.
  • Late-line PARP inhibitor treatment (non-maintenance) indications were withdrawn in 2022: olaparib (BRCA-mutated, SOLO3) and rucaparib (BRCA-mutated, ARIEL4) because of OS detriment, and niraparib (HRD-positive after ≥3 prior regimens, single-arm QUADRA) on the overall late-line data.
  • Mirvetuximab soravtansine-gynx (Elahere), a folate receptor α (FRα) ADC with DM4 maytansinoid. FDA accelerated Nov 14, 2022 (SORAYA: ORR 31.7%, mDOR 6.9 mo); full approval Mar 22, 2024 based on MIRASOL (Moore NEJM 2023; PMID 38055253) vs investigator-choice chemo in FRα+ platinum-resistant ovarian ca; mOS 16.5 vs 12.7 mo (HR 0.67), mPFS 5.6 vs 4.0 mo, ORR 42% vs 16%. Indication: FRα+ platinum-resistant epithelial ovarian/fallopian tube/primary peritoneal ca, 1 to 3 prior lines (FRα ≥75% by VENTANA FOLR1 RxDx). Class AEs: ocular toxicity (keratopathy, blurred vision; mandate ophthalmology eval, prophylactic topical corticosteroid drops, and lubricating drops (vasoconstrictor pre-infusion drops are for tisotumab vedotin, not mirvetuximab)) and peripheral neuropathy. Investigational in platinum-sensitive disease, not current FDA indications (PICCOLO (single-arm phase II of mirvetuximab monotherapy in FRα-high, ≥3rd-line platinum-sensitive disease, ORR 51.9%); GLORIOSA with bevacizumab maintenance in FRα+ platinum-sensitive disease); GLORIOSA: ongoing phase 3 of mirvetuximab + bevacizumab vs bevacizumab maintenance in FRα-high platinum-sensitive recurrent disease; efficacy (PFS) not yet reported.
  • Pembrolizumab + weekly paclitaxel (± bevacizumab; KEYNOTE-B96, Colombo Lancet 2026) after 1 to 2 prior lines: CPS ≥1 mPFS 8.3 vs 7.2 mo (HR 0.72), mOS 18.2 vs 14.0 mo (HR 0.76). FDA Feb 10, 2026 for PD-L1 CPS ≥1.
  • Relacorilant (selective glucocorticoid receptor antagonist) + nab-paclitaxel (ROSELLA), no biomarker selection: mOS 16.0 vs 11.9 mo (HR 0.65) vs nab-paclitaxel alone. FDA Mar 25, 2026 after 1 to 3 prior regimens (at least one with bevacizumab).
  • Check NGS for dMMR and NTRK fusions.
• Surveillance: H&P and pelvic exam q3mo ×3 yrs, then q4 to 6mo until 5 yrs, then annually. Monitoring with CA-125 has no OS or QOL advantage.

Borderline and low-grade serous tumors

• Borderline tumors (low malignant potential): surgery, 5-yr OS >95%. Observation after surgery if no low-grade serous carcinoma component.
• Low-grade serous carcinoma:
  • Observation if stage IA or IB.
  • Stage IC: observation vs anti-estrogen vs chemo ×3 to 6.
  • Stage II to IV: adjuvant chemo ×6.
  • Consider maintenance hormonal therapy after chemotherapy.
  • At recurrence, repeat surgery and check NGS for BRAF V600E (dabrafenib + trametinib; trametinib is a MEK inhibitor that improved PFS in recurrent LGSOC regardless of BRAF/KRAS, GOG-281/LOGS; binimetinib (MILO/ENGOT-ov11) did not meet its primary endpoint), KRAS (avutometinib + defactinib, FDA accelerated approval May 8, 2025 for KRAS-mutated recurrent LGSOC after prior systemic therapy), and NTRK (entrectinib or larotrectinib).
• Mucinous tumors: borderline mucinous tumors are managed with surgery alone; for invasive mucinous carcinoma, carboplatin/paclitaxel or a colorectal backbone (FOLFOX or CAPOX), the latter not proven superior.

Malignant Sex Cord-Stromal Tumors (MSCST)

• Granulosa cell tumors: FOXL2 mutation in nearly all adult-type (<10% in pediatric type); ↑ inhibin B (used to diagnose and monitor). Produce estrogen → ↑ endometrial lining → endometrial cancer. Vascular and prone to rupture (abdominal pain, hemoperitoneum). Treatment: surgery (H-BSO; fertility-sparing if confined to ovary); carboplatin/paclitaxel for stage II to IV. If not a surgical candidate, platinum-based chemo. At relapse: surgical resection vs platinum-based chemo vs bevacizumab; hormonal therapy (leuprolide) can be considered.
• Sertoli-Leydig cell tumors (androgen-producing): age <40, >90% stage I; surgery preferred. Platinum-based chemo for poorly differentiated tumors and advanced/recurrent disease.
• Thecoma: pure stromal tumor in post-menopausal women, produces estrogen, benign. Treat with surgery followed by observation.
• Steroid cell tumor: pure stromal, benign or malignant. Treat with surgery. Observe low-grade stage I low-risk; adjuvant chemo if malignant/poorly differentiated and >IC.
• Gynandroblastoma.
• Fibroma.

Ovarian Malignant Germ Cell Tumors (OMGCT)

• 2% to 3% of ovarian cancers; adolescent age.
• Dysgerminomas are most common. More likely confined to one ovary, good prognosis. Fertility-preserving surgery has good outcomes (no hysterectomy needed). Stage IA/IB: observe. Stage IC: selected pure dysgerminoma may be surveilled after complete staging. Stage II to IV: platinum-based chemo (BEP). ↑ LDH; a minority of pure dysgerminomas mildly elevate beta-hCG (syncytiotrophoblastic giant cells) without being mixed; AFP should be normal (elevated AFP suggests another germ-cell component).
• Other OMGCT: yolk sac tumors (endodermal sinus tumors), immature teratoma (malignant; mature cystic/dermoid and most monodermal teratomas are benign), embryonal cell tumors, polyembryoma, nongestational choriocarcinomas, and mixed germ cell tumors.
• No adjuvant chemotherapy for stage IA/IB dysgerminomas or stage I grade 1 immature teratomas. NCCN accepts observation for pediatric/adolescent patients with stage IA embryonal carcinoma and stage IA yolk sac tumors.
• Adjuvant treatment: BEP (bleomycin, etoposide, cisplatin) ×3 to 4 cycles for the other germ cell tumor types.
• Relapse after initial chemotherapy: TIP (paclitaxel, ifosfamide, cisplatin), or VIP/VeIP (cisplatin, ifosfamide, and either etoposide or vinblastine); in platinum-resistant patients, high-dose chemotherapy with stem-cell rescue may cure some.
• Fertility preservation.
• Dermoid cyst (mature cystic teratoma): benign, common (most common ovarian germ cell tumor; malignant transformation rare), arises from a totipotential germ cell (primary oocyte) and can contain mature tissue (hair, skin, teeth). Observation after surgical removal; no adjuvant chemo. More common in childbearing years; associated with mature teratomas.
• Cystadenomas: cysts developing from ovarian tissue, may be filled with liquid/mucus.