Pocket Oncology (Pocket Notebook Series), 1st Ed.

OVARIAN CANCER

Juliana Eng and Roisin O’Cearbhaill

Epidemiology

• Ovarian CA is the leading cause of death from gyn CA in the United States

• 5th most common cause of CA mortality in , ∼22240 new cases/y

• Incidence ↑ w/age; incidence rate of 57/100000  in the 8th decade

• Median age at dx is 63 y; >70% present w/advanced disease

• Fallopian tube & 1° peritoneal CA: Similar entities to ovarian CA

Risk Factors

• Advancing age, early menarche, late menopause, obesity, PCOS, nulliparity, involuntary infertility, older age at first birth (>35 y)

• ∼10% of cases are “familial”; may present earlier than sporadic cases

• Conversely, a 30–60% ↓ risk of CA associated w/younger age at pregnancy & first birth (≤25 y), OCPs, and/or breast-feeding

Etiology

• HGS CA may originate in fallopian tube fimbria as STIC (J Clin Oncol 2008;26:4160–4165)

• Clear cell & endometrioid histologies assoc w/endometriosis (ARID1A)

Genetics

• BRCA 1 or 2 Mt: AD inheritance. Most definable cause of hereditary ovarian CA esp. in AJ pop. 16–21% HGS are BRCA+. BRCA1: Lifetime risk of breast CA 85% & ovarian CA 40–60%. BRCA 2: Ovarian CA in 16–27% by age 70. Possible better prognosis: ↑ Sn to platinum-based chemo (J Clin Oncol 2012;30(21):2654–2663)

• Lynch type II: AD inheritance. Nonpolyposis colorectal CA, uterine CA, & ovarian CA; germline Mt of MMR genes (MLH1, MSH2, MLH6, PMS2). Lifetime risk of ovarian CA 5–15%.

Pathology Subtypes

• Epithelial (EOC) (95%): Serous (most common ∼75%, majority WT1+ &/or PAX 8+), mucinous, endometrioid, clear cell, transitional cell

• Germ cell (<3%, often <30 y): Dysgerminoma (like seminoma in ), endodermal sinus tumors, embryonal CA (like NSGCT in ), teratoma. Surgery + (except stage I immature teratoma/dysgerminoma) BEP × 3–4

• Sex cord stromal (<2%) heterogeneous, often early-stage, can produce androgens, estrogen: Granulosa (inhibin B as tumor marker, 5–10% assoc w/early-stage uterine CA), theca, sertoli, leydig (DICER1). Mainly surgery ± chemo (BEP or T/C). Consider RT if pelvic recur.

Clinical Manifestations

• 70% EOC tumors have spread beyond true pelvis (≥stage III) at dx

• Localized disease often asx

• Persistent, non-specific: Abd/pelvic pain/mass/bloating, urinary urgency or frequency, constipation, early satiety, dyspnea, VTE (↑ in clear cell), torsion (germ cell), rarely vaginal bleeding or paraneoplastic syndrome: Cerebellar degen, polyneuritis, DM, ↑ CA2+ (small cell)

Screening and Prevention

• Asx  at avg risk should NOT undergo ovarian CA screening

• PLCO trial: Screening w/annual transvaginal U/S (TVUS) × 4 y & CA 125 × 6 y did not ↓ ovarian CA mortality (JAMA 2011;305:2295–2303)

• In high-risk  (hereditary syndrome, BRCA1/2+) can consider multimodality screening (TVUS & CA125 q6mos starting at age 30–35 or 5–10 y earlier than earliest age of 1st ovarian CA in family), but rrBSO is most effective way to ↓ risk of ovarian/fallopian tube CA. rrBSO is recommended as soon as childbearing is complete or by age 35–40. In premenopausal BRCA+  can also ↓ breast CA risk

• OCP use in BRCA+  assoc. w/↓ ovarian CA risk (∼5%/y of OCP use)

Staging and Workup of EOC

• Laparotomy w/TAH/BSO w/comprehensive staging (inspection of all peritoneal surfaces, bx of suspicious areas/adhesions, omentectomy, pelvic & para-aortic LND & effort to achieve maximal cytoreduction) is the 1º procedure to establish dx, accurate disease extent & for maximal tumor cytoreduction

• Mucinous tumors: + appendectomy & explore upper & lower GI tract

• Optimal debulking → residual tumor <1 cm max diameter or thickness

• Ideally performed by gyn oncologist & w/“no gross residual disease”

• ↑ CA125 in 20% early-stage & 80% of advanced-stage EOC

Early Stage Adjuvant Treatment of EOC

• Low Risk: Stage IA/B: Grade 1→ no adj tx; grade 2 → consider IV taxane/carboplatin (T/C) × 3–6 cycles; grade 3/clear cell → IV T/C × 3–6

• High Risk Stage IC → adj tx w/IV T/C × 3–6 cycles; ↑ DFS & OS

Advanced Stage (II–IV) Adjuvant Treatment

• 6–8 cycles of taxane/platinum chemo.

• Stage II & stage III optimally debulked (<1 cm): IV/IP paclitaxel & IP CIS. In stage III optimally debulked pts, median PFS ↑6 mos (23.8 vs. 18), median OS ↑ 16 mos (65.6 vs. 49.7) compared w/q3wk IV Rx. ↑tox w/IP: Fatigue, pain, neuropathy, renal, IP port complications. Only ∼40% pts completed all 6 IV/IP cycles (GOG 172 NEJM 1996;354:34–43). ↑ benefit w/↑no. of IP cycles. No ↑ OS w/+ 3rd chemo drug (J Clin Oncol 2006;24:18s ASCO#5002). BEV ↑ PFS 1.7–4 mos (NEJM 2011;365:2473–2483; NEJM 2011;365:2484–2496)

• Residual disease >1 cm, stage IV, not IP candidate: Dose-dense IV T/C (wkly paclitaxel) may be superior to q3wk IV T/C. In stage II–IV (opt & subop) dose-dense IV T/C vs. q3wk T/C: ↑ PFS 11 mos (28 vs. 17) & ↑ 3-y OS by 7% (72 vs. 65%) (Lancet 2009;374(9698):1331–1338)

• Unresectable bulky disease or poor PS: Obtain bsy for dx. Neoadj chemo × 3–6 cycles → interval tumor debulking → adj chemo

• Low malignant potential: If invasive implants, consider treating as EOC

Recurrent Disease

• Majority of adv-stage recur. Platinum-refractory if <6 mos of 1º platinum

• Platinum-sensitive (recurs ≥6 mos): Platinum-based doublet (gem, liposomal dox, paclitaxel) ± 2º cytoreduction. 1st recurrence → + BEV ↑ PFS 4 mos (12.4 vs. 8.4) (OCEANS J Clin Oncol 2012;30(17):2039–2045); Serial relapses & remission w/chemo until platinum-resistance occurs.

• Platinum-resistant (<6 mos): Single-agent lipo dox, gem, topo, tax. + BEV ↑ PFS ∼3 mos (6.7 vs. 3.4) (AURELIA J Clin Oncol 2012;30 LBA5002)

• Mek inh (Selumetinib) for recurrent low grade serous (Lancet Oncol 2013;14(2):134–140)