Uterine Cancer: Part 3

Uterine Cancer
Written By Sydney Oesch

Episode Notes

  1. High risk EC definition: 

    1. Stage III disease or higher, regardless of histology or grade

    2. Serous/clear cell histology, regardless of stage

    3. Grade III deeply invasive endometrioid carcinoma

  2. Workup and staging

    1. Workup: CT C/A/P, molecular sub-typing, ER testing, CA-125

    2. Staging/surgery: Hysterectomy, Bilateral Salpingo-opherectomy, cytoreduction

      1. LN evaluation: not necessary if clinically advanced disease (if positive LN would not upstage the patient)

      2. Cytoreduction to no residual disease is standard of care, based on observational/retrospective data demonstrating improved survival in optimally cytoreduced patients

    3. 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).

      1. Medical stability for surgery must be considered

  3. Adjuvant treatment for surgically managed patients

    1. Systemic therapy recommended for all patients with ≥stage III disease

      1. Consider systemic therapy for high risk early stage disease (example: serous carcinoma, stage IB grade III, stage II disease)

      2. Choice of therapy

        1. SOC: Carbo/taxol based on results of GOG209 (non inferiority trial of carboplatin/paclitaxel vs. paclitaxol/adriamycin/cisplatin)

    2. Radiation?

      1. Radiation vs. chemo

        1. GOG 122: whole abdomen radiation vs. chemo(cisplatin/doxorubicin): chemo alone had improved PFS and OS

      2. Chemoradiation vs. radiation

        1. 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.)

          1. Molecular analysis: greatest benefit in p53 mutated cancers, with benefit at all stages

        2. LUNCHBOX trial: chemoradiation (cisplatin/radiation followed by 4 cycles carbo/taxol) vs. carbo/taxol x 3 cycles >EBRT >carbo/taxol x 3 cycles

          1. No difference in PFS or OS, trial closed due to futility analysis

      3. Chemoradiation vs. chemo

        1. GOG 258: chemoradiation did not improve PFS or OS compared to chemo alone. Recurrence patterns different in different arms.

      4. 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.

  4. Primary treatment for patients not undergoing primary surgery

    1. Options per NCCN

      1. EBRT w/ or w/o brachytherapy w/ or w/o systemic therapy

      2. Systemic therapy alone

        1. Systemic therapy recommended for patients with distant metastases

        2. Consider neoadjuvant chemo (no prospective data in uterine cancer)

      3. Re-evaluation for surgery as appropriate 

  5. Immunotherapy: dostarlimab and pembrolizumab category I choice for adjuvant treatment of advanced EC, in addition to SOC carbo/taxol, for patients meeting inclusion criteria

    1. 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). 

      1. Carbo/taxol +/- Dostarlimab with dostarlimab maintenance. 

      2. Improved PFS in overall population, with increased benefit in dMMR population.

      3. Carcinosarcoma cases included

    2. NRG-GY018: stage III or IVA with measurable disease, stage IVB with or without measurable disease, and any recurrent EC.

      1. Carbo/taxol +/- pembrolizumab with pembrolizumab maintenance

      2. Improved PFS in overall population, with increased benefit in dMMR population.

      3. No carcinosarcoma cases included

    3. DUO-E: immunotherapy + PARPi. Stage III-IV EC or recurrent EC with ≥12 months since last treatment

      1. Carbo/taxol +/- durvalumab, a PD-L1 inhibitor, and a third arm with carbo/taxol/durvalumab + olaparib (a PARP-inhibitor). No PARPi alone arm.

      2. Improved PFS in both the durvalumab AND durvalumab+PARPi arms compared to carbo/taxol in overall population.

        1. pMMR tumors derived significant benefit from addition of olaparib

        2. dMMR tumors did not derive additional benefit from adding olaparib to durvalumab.

  6. Other targeted therapies: up front 

    1. Trastuzumab + carbo/taxol in HER2 positive serous tumors

    2. Oral selinexor: SIENDO trial. Improved PFS in audited analysis. P53 wild type patients derived most benefit.

  7. Treatment of recurrent disease

    1. Locoregional recurrences

      1. EBRT+/- VBT (if no prior radiation)

      2. Systemic therapy

      3. Surgical resection

    2. Distant recurrence

      1. Systemic therapy

        1. Platinum-based regimens

          1. Consider single agent therapy if significant side effects

        2. Consider addition of IO

          1. KEYNOTE-158: basket trial for MSIH/dMMR patients

        3. lenvatinib/pembrolizumab: for pMMR tumors. Based on KEYNOTE-775 trial. Improved PFS and OS compared to investigator’s choice chemotherapy. 

        4. Larotrectinib/entrectinib: for NTRK fusion mutation

        5. Hormonal therapy

        6. HER2 directed therapy

          1. Carbo/taxol/trastuzumab for uterine serous carcinoma and uterine carcinosarcoma that is HER2 ≥2+ 

          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+

        7. PI3K, mTOR inhibitors

          1. GOG 248: temsirolimus +/- megace/tamoxifen. Combination arm closed early due to excess DVT risk, single arm temsirolimus had ORR 22%.

          2. GOG 3007: everolimus/letrozole vs. tamoxifen/megace. ORR 22 vs. 25%. Chemo-naive patients with improved PFS w/ everolimus/letrozole.

          3. letrozole/abemaciclib: evaluated in a phase II trial, ORR 30%.

      2. Surgical resection/targeted radiation for isolated disease


References

1.       Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2004;22(11):2159-2166. doi:10.1200/JCO.2004.07.184

2.       Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol. 2009;112(3):543-552. doi:10.1016/J.YGYNO.2008.11.014

3.       Miller DS, Filiaci VL, Mannel RS, et al. Carboplatin and Paclitaxel for Advanced Endometrial Cancer: Final Overall Survival and Adverse Event Analysis of a Phase III Trial (NRG Oncology/GOG0209). Journal of Clinical Oncology. 2020;38(33):3841. doi:10.1200/JCO.20.01076

4.       Randall ME, Filiaci VL, Muss H, et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2006;24(1):36-44. doi:10.1200/JCO.2004.00.7617

5.       Matei D, Filiaci V, Randall ME, et al. Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer. New England Journal of Medicine. 2019;380(24):2317-2326. doi:10.1056/NEJMOA1813181/SUPPL_FILE/NEJMOA1813181_DATA-SHARING.PDF

6.       de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(3):295-309. doi:10.1016/S1470-2045(18)30079-2

7.       de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;20(9):1273-1285. doi:10.1016/S1470-2045(19)30395-X

8.       Leon-Castillo A, De Boer SM, Powell ME, et al. Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy. Journal of Clinical Oncology. 2020;38(29):3388. doi:10.1200/JCO.20.00549

9.       Barlin JN, Mahar B, Ata A, et al. Lunchbox trial: A randomized phase III trial of cisplatin and irradiation followed by carboplatin and paclitaxel versus sandwich therapy of carboplatin and paclitaxel followed by irradiation then carboplatin and paclitaxel for advanced endometrial carcinoma. Gynecol Oncol. 2024;180:63-69. doi:10.1016/J.YGYNO.2023.11.012

10.    Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. New England Journal of Medicine. 2023;388(23):2145-2158. doi:10.1056/NEJMOA2216334

11.    Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. New England Journal of Medicine. 2023;388(23):2159-2170. doi:10.1056/nejmoa2302312

12.    Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. Journal of Clinical Oncology. 2020;38(1):1. doi:10.1200/JCO.19.02105

13.    Colombo N, Lorusso D, Herráez AC, et al. 726MO Outcomes by histology and prior therapy with lenvatinib plus pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer (Study 309/KEYNOTE-775). Annals of Oncology. 2021;32:S729-S730. doi:10.1016/j.annonc.2021.08.1169

14.    Slomovitz BM, Filiaci VL, Coleman RL, et al. GOG 3007, a randomized phase II (RP2) trial of everolimus and letrozole (EL) or hormonal therapy (medroxyprogesterone acetate/tamoxifen, PT) in women with advanced, persistent or recurrent endometrial carcinoma (EC): A GOG Foundation study. Gynecol Oncol. 2018;149:2. doi:10.1016/j.ygyno.2018.04.012

15.    Rimel BJ, Enserro D, Bender DP, et al. NRG-GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer. Cancer. 2024;130(8):1234-1245. doi:10.1002/CNCR.35151

16.    Fader AN, Roque DM, Siegel E, et al. JOURNAL OF CLINICAL ONCOLOGY Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu. Published online 2018. doi:10.1200/JCO

17.    Westin SN, Moore K, Chon HS, et al. Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial. Journal of Clinical Oncology. 2024;42(3):283. doi:10.1200/JCO.23.02132

Sydney Oesch
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