Anya Litvak and Martee L. Hensley
• 200000 cases/y worldwide; most common gynecologic malignancy in developed countries; second most common in developing countries. Usu presents at an early stage w/abnl uterine bleeding 2° to unopposed estrogen in peri-/postmenopausal women w/avg age of 61. African-American women p/w more advanced stage disease & higher incidence of aggressive histology.
Etiology and Clinical Manifestations
• RF: Mostly related to unopposed estrogen: Exogenous (tamoxifen, HRT) or endogenous (obesity, PCOS, early menarche, late menopause, nulliparity). ↑ risk w/age, HTN, DM; HNPCC carries 40–60% of lifetime risk of developing endometrial CA; OCPs may ↓ risk
• Sx: Postmenopausal vaginal bleeding (75–80%), abdominal/pelvic pain, cough, wt loss
Characteristic Genetic Mutations
• PTEN loss (40–83%), KRAS (10–46%), p53 (20%) MIS, ER/PR receptors, B-catenin, MLH1
• Refer to genetics if <55 y w/significant FHx of uterine/CRC or known LS. May benefit from prophylactic TAH/BSO (NEJM 2006;354(3):261–269).
Screening and Prevention
• Screening: ACS recommends yearly screening w/endometrial bx at age 35 for women w/HNPCC. If using tamoxifen, need to evaluate all abnl bleeding but no clinical data justifies routine screening. All postmenopausal vaginal bleeding needs to be evaluated as 15% have endometrial carcinoma
Workup and Staging
• W/u: Transvaginal US & endometrial bx/aspirate curettage + endocervical sample. Hysteroscopy if high suspicion & endometrial bx neg; CXR, CT scan of the abd/pelvis; surgical staging required if medically stable to undergo surgery. Standard surgical staging w/total abdominal hysterectomy, bilateral salpingooophorectomy, washings, pelvic & para-aortic lymph node sampling/dissection, & exam of entire abdominal cavity.
• FIGO Staging: Stage I (80%): Tumor limited to the corpus uteri; Stage IA w/<50% myometrial invasion, Stage IB w/>50% myometrial invasion, Stage II (11%): Uterine cervical extension, Stage III (6%): Local & parametrial involvement, Stage IV (2%) other organ invasion including bladder/rectum (Stage IVA) or inguinal lymph node involvement/distant met (Stage IVB)
Management: Depends on surgical stage, grade, & histologic subtype
Management: Stage IA Disease, Low Risk
• Surgery: TAH/BSO w/complete surgical staging. Adjuvant Rx not necessary.
• Radiation: Consider for nonsurgical candidates
• Endocrine Rx w/progestin & discontinue: Acceptable for some pts who want to preserve fertility
Management: Stage IB–Stage II Disease, Intermediate Risk
• Surgery: TAH/BSO w/complete surgical staging including washings & LN evaluation
• Adjuvant Radiation: Vaginal ± pelvic RT. GOG 99 showed that radiation ↓ rate of local recurrence (GOG 99 Gynecol Oncol 2004;92:740). PORTEC 2 showed that intravaginal brachytherapy has = RR & OS compared to whole pelvic radiation w/↓ tox (PORTEC 2 Lancet 2010;375(9717):816)
• Chemotherapy: Unclear if chemotherapy adds benefits in stage IB–stage II disease. Consider for high-grade/high-risk histologies
Management: Stage III/IVa Disease, High Risk:
• Multimodality Rx: Optimal adjuvant tx yet to be defined
• Surgery: TAH/BSO w/complete surgical staging
• Adjuvant Chemotherapy: Platinum-based chemotherapy should be considered for pt w/residual disease <2 cm; adjuvant doxorubicin (dox)/CIS showed ↑ DFS & 5-y OS as compared to whole abdominal RT although ↑ tox (GOG 122 JCO 2006;24(1):36). Other options for chemotherapy: Platinum-based doublets (cis/dox; carbo/paclitaxel) or TAP (cis, dox, paclitaxel)
• Adjuvant Radiation: Pelvic & Vaginal RT, unclear if ↑ oncologic benefit in stage III/IVa disease
• Chemoradiation: Concurrent CIS +RT followed by carbo/taxol for nonsurgical pts
Management: Stage IV & Recurrent Disease:
• Debulking surgery: Controversial; considered for recurrent pelvic/intra-abdominal disease for highly selected pts
• Chemotherapy: Cis, carbo, paclitaxel, dox, ifosfamide, topotecan all w/overall 20–35% RR. Dox/Cis w/↑RR & PFS but = OS compared to dox alone (JCO 2004;22(19):3902). Cis/dox/paclitaxel/G-CSF vs. Dox/Cis ↑ RR, PFS, & OS slightly but ↑ tox as compared to cis/dox (GOG 177 JCO 2004;22(11):2159). If <6 mos after receiving prior platinum-based regimen, can consider single agent dox/paclitaxel
• Endocrine Rx: 10–30% RR. FIGO grade 1–2, long disease free interval, & ER/PR receptor positivity ↑probability of response. Can use in minimally symptomatic disease. If progress, should switch to chemotherapy
• Experimental: Arzoxifene (SERM), angiogenesis inhibitors (bevacizumab, VEGF TRAP, cediranib, brivanib), EGFR inhibitors/TKIs (lapatinib, gefitinib), MTOR inhibitors (everolimus/temsirolimus), & angiokinase inhibitors currently in clinical trials