Uterine Cancer: Part 3
Episode Notes
High risk EC definition:
Stage III disease or higher, regardless of histology or grade
Serous/clear cell histology regardless of stage
Grade III deeply invasive endometrioid carcinoma
Workup and staging
Workup: CT C/A/P, molecular subtyping, ER testing, CA-125
Staging/surgery: Hyst, BSO, cytoreduction
LN evaluation: not necessary if clinically advanced disease (if positive LN would not upstage the patient)
Cytoreduction to no residual disease is standard of care, based on observational/retrospective data demonstrating improved survival in optimally cytoreduced patients
Which patients might not be suitable for primary surgery? those in whom optimal cytoreduction seems unlikely (some visceral metastases, vaginal, bladder, bowel/rectal, nodal or parametrial involvement may not be surgically resectable).
Medical stability for surgery must be considered
Adjuvant treatment for surgically managed patients
Systemic therapy recommended for all patients with ≥stage III disease
Consider systemic therapy for high risk early stage disease (example: serous carcinoma, stage IB grade III, stage II disease)
Choice of therapy
SOC: Carbo/taxol based on results of GOG209 (non inferiority trial of carboplatin/paclitaxel vs. paclitaxol/adriamycin/cisplatin)
Radiation?
Radiation vs. chemo
GOG 122: whole abdomen radiation vs. chemo(cisplatin/doxorubicin): chemo alone had improved PFS and OS
Chemoradiation vs. radiation
PORTEC III: chemoradiation vs. radiation alone after surgical intervention. Post-hoc survival analysis with OS benefit in chemoradiation group (only in stage III disease and serous cancers.)
Molecular analysis: greatest benefit in p53 mutated cancers, with benefit at all stages
Updated 10 yr analysis October 2025: 10 yr OS benefit in the all-comer population (74.4 vs. 67%) with chemoRT vs. RT alone. RFS also improved in all comers. However, the majority of the benefits arise from the p53-mutated population, who had a disproportionately high improvement with chemoRT (10 yr OS 53% vs. 37%, HR 0.52). NSMP ER-negative patients also derived a benefit in exploratory analyses; POLEmutated and dMMR patients did not derive a benefit from the addition of chemo.
With these results, the strongest evidence for adding chemo to RT is for patients with p53 mutation
LUNCHBOX trial: chemoradiation (cisplatin/radiation followed by 4 cycles carbo/taxol) vs. carbo/taxol x 3 cycles >EBRT >carbo/taxol x 3 cycles
No difference in PFS or OS, trial closed due to futility analysis
Chemoradiation vs. chemo
GOG 258:
Patient population: stage III-IVA or other high risk EC.
Intervention: chemotherapy vs. chemoradiation
Results: chemoradiation did not improve PFS or OS compared to chemo alone. Recurrence patterns different in different arms.
Takeaway? Addition of radiation and chemoradiation to chemotherapy alone does not appear to improve PFS or OS, but can reduce the risk of locoregional recurrences.
Primary treatment for patients not undergoing primary surgery
Options per NCCN
EBRT w/ or w/o brachytherapy w/ or w/o systemic therapy
Systemic therapy alone
Systemic therapy recommended for patients with distant metastases
Consider neoadjuvant chemo (no prospective data in uterine cancer)
Re-evaluation for surgery as appropriate
Immunotherapy: dostarlimab and pembrolizumab category I choice for adjuvant treatment of advanced EC, in addition to SOC carbo/taxol, for patients meeting inclusion criteria
RUBY Trial: EC not amenable to curative therapy (stage IIIa-IIIc measurable disease, stage IIIC1 with high risk histologies regardless of measurable disease, stage IIIC2-stage IV disease regardless of measurable disease, or recurrent EC).
Carbo/taxol +/- Dostarlimab with dostarlimab maintenance (up to 3 years treatment).
Improved PFS in overall population, with increased benefit in dMMR population.
Updated OS data August 2024: data immature, but there was a significant OS benefit in the dMMR population. pMMR population did not derive an OS benefit.
Carcinosarcoma cases included
NRG-GY018: stage III or IVA with measurable disease, stage IVB with or without measurable disease, and any recurrent EC.
Carbo/taxol +/- pembrolizumab with pembrolizumab maintenance (up to 2 years treatment)
Improved PFS in overall population, with increased benefit in dMMR population.
No carcinosarcoma cases included
OS and exploratory analysis published May 2025
OS data immature, HR not yes statistically significant
PFS significant in both pMMR and dMMR groups
AtTEnd: phase III RCT, carbo/taxol +/- atezolizumab (until progression/toxicity)
Patients: advanced/recurrent EC or carcinosarcoma, no prior systemic therapy
Results: PFS improved in overall population (NR vs. 6.9m). PFS not improved in the pMMR population. OS data immature.
KEYNOTE-B21: Immunotherapy for high risk EC with less advanced stage
Patients: EC/carcinosarc with FIGO 2009 stage I-II, high grade/-53 mutated w/ myometrial invasion or stage III-IV of any histology/grade. POLE mutated tumors excluded. All patients with no residual disease after surgery
Intervention: carbo/taxol +/- pembrolizumab (up to 1 yr treatment)
Radiation allowed in either arm
Results
DFS HR 1.02, median not reached in either arm. OS data immature
Pre-planned exploratory analysis: dMMR patients w/ significant improved DFS with addition of pembro, pMMR with no benefit.
No other subgroup derived benefit including stage III/IV tumors
Ongoing studies
KEYNOTE-C93: pembro vs. chemo alone in advanced EC
DOMENICA: advanced or recurrent dMMR tumors, dostarlimab vs. carbo/taxol
DUO-E: immunotherapy + PARPi. Stage III-IV EC or recurrent EC with ≥12 months since last treatment
Carbo/taxol +/- durvalumab, a PD-L1 inhibitor, and a third arm with carbo/taxol/durvalumab + olaparib (a PARP-inhibitor). No PARPi alone arm.
Improved PFS in both the durvalumab AND durvalumab+PARPi arms compared to carbo/taxol in overall population.
pMMR tumors derived significant benefit from addition of olaparib
dMMR tumors did not derive additional benefit from adding olaparib to durvalumab.
LEAP-001: Phase III RCT
Patients: newly diagnosed stage III-IV or recurrent EC
Intervention: len/pem vs. carbo/taxol
Outcomes: neither PFS nor OS improved, but grade 3+ AE higher in len/pem group when compared with chemo alone.
Other targeted therapies: up front
Trastuzumab + carbo/taxol in HER2 positive serous tumors
Fader 2018: randomized phase II trial
Outcomes: PFS (18m vs. 9m) and OS (NR vs. 24m) improved
Oral selinexor: SIENDO trial. Improved PFS in audited analysis. P53 wild type patients derived most benefit. Not yet FDA approved
Upcoming: XPORT-EC-042: selinexor maintenance in p53 mutated tumors
Treatment of recurrent disease
Locoregional recurrences
EBRT+/- VBT (if no prior radiation)
GOG 238: RCT for patients with mostly low grade pelvic confined recurrent EC to EBRT w/ brachy boost +/- the addition of concurrent weekly cisplatin.
PFS was not significantly different between the two arms. Acute toxicity was higher in the CisRT arm compared to RT alone.
Systemic therapy
Surgical resection
Distant recurrence
Systemic therapy
Platinum-based regimens
Consider single agent therapy if significant side effects
Consider addition of IO
KEYNOTE-158: basket trial for MSIH/dMMR patients
lenvatinib/pembrolizumab: for pMMR tumors. Based on KEYNOTE-775 trial. Improved PFS and OS compared to investigator’s choice chemotherapy.
Statistical analysis planned in pMMR and overall population
FDA approval is for pMMR tumors
Larotrectinib/entrectinib: for NTRK fusion mutation
Hormonal therapy
HER2 directed therapy
Carbo/taxol/trastuzumab for uterine serous carcinoma and uterine carcinosarcoma that is HER2 ≥2+
Trastuzumab-deruxtecan for recurrent EC that is ≥2+ IHC, regardless of histology. This regimen recently got accelerated FDA approval for recurrent solid tumors with IHC 3+
PI3K, mTOR inhibitors
GOG248: temsirolimus +/- megace/tamoxifen. Combination arm closed early due to excess DVT risk, single arm temsirolimus had ORR 22%.
GOG 3007: everolimus/letrozole vs. tamoxifen/megace. ORR 22 vs. 25%. Chemo-naive patients with improved PFS w/ everolimus/letrozole.
letrozole/abemaciclib: evaluated in a phase II trial, ORR 30%.
Surgical resection/targeted radiation for isolated disease
Ongoing trials
ADCs:
ASCENT-GYN-01, TROFUSE-OO5: both evaluating sacituzumab as an ADC.
Uterine Part 3 Reference List
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Updated as of January 2026