Uterine Cancer: Part 4

Uterine Cancer
Written By Sydney Oesch

Episode Notes

Carcinosarcoma

  1. Uterine carcinosarcomas are epithelial (endometrial) cancers. Historically, they were considered to be more similar to a sarcoma and were included in many early sarcoma trials (and not included in all earlier carcinoma trials.)  Now, they are staged and treated as endometrial carcinomas.

    1. Up to ⅓ of all uterine carcinosarcomas overexpress HER2: HER2 testing is recommended for all.

  2. Epidemiology: uterine carcinosarcoma is rare, accounting for <5% of all uterine malignancies, but incidence is rising. These cancers disproportionately affect Black patients, patients with unopposed estrogen and tamoxifen exposure, and history of pelvic radiation

  3. Presentation/Prognosis: 60% are metastatic at time of presentation. 5-year survival rate is only 59% for patients with stage I-II disease, and is only 9% for patients with stage IV disease.

  4. Staging: same staging system as other endometrial carcinomas. Carcinosarcomas were included in the SENTOR trial, and as such, SLNB is the preferred method for evaluating LN in patients with apparent early stage uterine carcinosarcoma. 

  5. Treatment options:

    1. Choice of chemotherapy: carbo/taxol is preferred

      1. Ifosfamide was historically used for carcinosarcoma, based on the results of GOG 108, GOG 161

      2. GOG 232B demonstrated activity of carbo/taxol in uterine carcinosarcoma

      3. GOG261: carbo/taxol vs. taxol/ifosfamide: improved PFS, non-inferior OS, and improved toxicity with carbo/taxol

    2. Early stage disease: 

      1. Systemic therapy and postop radiation with vaginal brachytherapy or EBRT are recommended even for stage IA disease due to high risk of recurrence and poor prognosis

        1. The use of VBT/radiation therapy is mostly extrapolated from other endometrial histologies, as uterine carcinosarcomas were not traditionally included in these trials

    3. Advanced stage disease, up front:

      1. Systemic therapy

      2. Consider IO: uterine carcinosarcomas were included in the RUBY trial, but not in the GY018 trial, and as such dostarlimab is an option in patients meeting criteria

      3. Trastuzumab: results of the Fader paper were extrapolated to uterine carcinosarcoma, and trastuzumab is an option for HER2+ carcinosarcomas

    4. Systemic therapy should be started ASAP after surgery (within 3-6w)

    5. Recurrent disease:

      1. Standard recurrent therapies as for other endometrial cancers (see show notes from uterine part 3).

      2. trastuzumab-deruxtecan: based on the results of the STATICE trial, this is an option for patients with HER2 IHC >= 1+ recurrent disease

Uterine Sarcomas

  1. Epidemiology: ~3% of all uterine cancers are sarcomas

    1. Risk factors: similar to carcinosarcomas. Leiomyomas do not appear to be a precursor to uterine leiomyosarcoma.

  2. Evaluation:

    1. Preoperative MRI and biopsy may help diagnose/differentiate these from leiomyomas, but many are diagnosed postoperatively due to poor sensitivity

    2. Histopathologic evaluation: large tumors (>10cm) with prominent cellular atypia, abundant mitoses (≥10/HPF), areas of hemorrhage and necrosis.

    3. A subgroup have SMARCA4 deficiency which portends poor prognosis

    4. Staging: different than endometrial cancers

      1. ESS and uLMS: size of primary tumor matters (not DOI) for early stages

      2. Adenosarcomas do incorporate DOI

  3. Management:

    1. Surgery: similar for all subtypes.

      1. Uterine-confined disease: hysterectomy w/ or w/o BSO

        1. Unclear whether BSO influences survival in patients with newly diagnosed uterine LMS > often omitted for premenopausal patients

        2. For ESS: strongly consider a BSO due to hormonal responsiveness

      2. Extrauterine disease: optimal cytoreduction to no gross residual disease is the goal, based on limited evidence suggesting improved survival

        1. Disease not amenable to optimal cytoreduction? No benefit to surgery, and surgery may worsen prognosis if it delays time to systemic therapy

        2. LND? Reserved for patients with enlarged nodes

    2. Adjuvant Therapy?

      1. Observation recommended for all subtypes

      2. Postop: can consider observation vs. systemic therapy for completely resected stage II-III sarcomas

      3. See subtype specific recommendations below

    3. Systemic therapy for adjuvant treatment or patients not amenable to surgery

      1. For most uterine sarcoma subtypes: no study has demonstrated improved OS with combination regimens compared to doxorubicin alone.  As such, Doxorubicin, single agent, is preferred for most sarcomas.  Other combination regimens are also listed as preferred options in NCCN guidelines.

        1. Gemcitabine/docetaxel

          1. Hensley 2002, GOG 131G, GOG87L, Hensley 2009, SARC002

          2. GeDDiS trial: doxorubicin alone vs. gem/docetaxel. PFS and OS equivalent between two regimens, but doxorubicin less toxic than combo, with less dose delays and reduction

        2. Other options: doxorubicin/ifosfamide, doxorubicin/dacarbazine

      2. Leiomyosarcomas: Doxorubicin/trabectedin: LMS-04. PFS doubled (6 vs. 12m) with addition of trabectedin, OS data not yet mature.

        1. 96% of patients in combo group had ≥grade III AE.

        2. Based on this data, this is now a preferred, first line therapy for patients with uLMS who can tolerate the regimen

      3. Biomarker-directed therapies

        1. NTRK gene fusion: larotrectinib or entrectinib

        2. SMARCA4 deficient: consider clinical trials

  4. Subtypes and subtype-specific adjuvant therapy

    1. Leiomyosarcoma (most common)

      1. Express smooth muscle markers: desmin, smooth muscle actin, or caldesmon

      2. Adjuvant therapy

        1. Completely resected, uterine-confined disease? Observation is recommended, based on the results of: GOG20, Hensley 2009, SARC005, GOG277

          1. Radiation? Not recommended, based on the results of EORTC 55874

        2. Advanced disease: doxorubicin/trabectedin as above is specific to uLMS

      3. Recurrent disease

        1. Trabectedin, single-agent: preferred based on results of SAR-3007

        2. Other options

          1. Pazopanib: based on results of PALETTE trial

          2. Eribulin: based on Study 309

          3. Pembrolizumab for TMB-H tumors

          4. PARPi for patients with BRCA mutation

    2. Endometrial stromal sarcoma

      1. Low grade: 

        1. JAZF1, PHF1, EPC1 gene fusions

        2. Present at an earlier stage

      2. High grade: 

        1. Also have fusion proteins

        2. Strong Cyclin D1 positivity

      3. Adjuvant options: consider anti-estrogen therapy (if ER/PR positive) consider EBRT

        1. Aromatase inhibitors preferred regimen

        2. Ovarian suppression for premenopausal patients with ovaries

      4. Recurrence: hormonal therapy first choice, or systemic therapy options for recurrent sarcoma

    3. Undifferentiated uterine sarcoma

      1. Characterized by infiltrative sheets of epithelioid and/or spindle cells. Usually a diagnosis of exclusion.

    4. Adenosarcoma: benign, glandular epithelial component in conjunction with the malignant sarcomatous component. Low grade, relatively good prognosis.

      1. Without sarcomatous overgrowth

        1. Adjuvant options: consider anti-estrogen therapy (if ER/PR positive) consider EBRT

          1. Aromatase inhibitors preferred regimen

          2. Ovarian suppression for premenopausal patients with ovaries

      2. With sarcomatous overgrowth: if sarcomatous tissue is >25% of the tumor. Worse prognosis and increased risk of recurrence

    5. Perivascular epithelioid cell neoplasm (PEComa)

      1. Can be benign or malignant

      2. Adjuvant therapy: albumin-bound sirolimus

    6. Inflammatory myofibroblastic tumor (IMT)

      1. Can be benign or malignant

      2. Often have ALK rearrangements, may respond to ALK inhibitors

Uterine Part 4 Reference List

1.       Cusimano MC, Vicus D, Pulman K, et al. Sentinel lymph node biopsy versus lymphadenectomy for high-grade endometrial cancer staging (SENTOR trial): A prospective multicenter cohort study. Gynecol Oncol. 2020;159:2. doi:10.1016/j.ygyno.2020.06.003

2.       Walker JL, Piedmonte MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol. 2009;27(32):5331-5336. doi:10.1200/JCO.2009.22.3248

3.       Omura GA, Blessing JA, Major F, et al. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study. https://doi.org/101200/JCO1985391240. 2016;3(9):1240-1245. doi:10.1200/JCO.1985.3.9.1240

4.       Reed NS, Mangioni C, Malmström H, et al. Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874). Eur J Cancer. 2008;44(6):808-818. doi:10.1016/J.EJCA.2008.01.019

5.       Homesley HD, Filiaci V, Markman M, et al. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(5):526-531. doi:10.1200/JCO.2006.06.4907

6.       Wolfson AH, Brady MF, Rocereto T, et al. A gynecologic oncology group randomized phase III trial of whole abdominal irradiation (WAI) vs. cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol Oncol. 2007;107(2):177-185. doi:10.1016/J.YGYNO.2007.07.070

7.       Powell MA, Filiaci VL, Rose PG, et al. Phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group study. J Clin Oncol. 2010;28(16):2727-2731. doi:10.1200/JCO.2009.26.8326

8.       Powell MA, Filiaci VL, Martee ;, et al. Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial. J Clin Oncol. 2022;40:968-977. doi:10.1200/JCO.21

9.       Leitao MM, Zivanovic O, Chi DS, et al. Surgical cytoreduction in patients with metastatic uterine leiomyosarcoma at the time of initial diagnosis. Gynecol Oncol. 2012;125(2):409-413. doi:10.1016/J.YGYNO.2012.02.014

10.    Kapp DS, Shin JY, Chan JK. Prognostic factors and survival in 1396 patients with uterine leiomyosarcomas. Cancer. 2008;112(4):820-830. doi:10.1002/CNCR.23245

11.    Hensley ML, Ishill N, Soslow R, et al. Adjuvant gemcitabine plus docetaxel for completely resected stages I-IV high grade uterine leiomyosarcoma: Results of a prospective study. Gynecol Oncol. 2009;112(3):563-567. doi:10.1016/J.YGYNO.2008.11.027

12.    Hensley ML, Wathen JK, Maki RG, et al. Adjuvant therapy for high-grade, uterus-limited leiomyosarcoma: results of a phase 2 trial (SARC 005). Cancer. 2013;119(8):1555-1561. doi:10.1002/CNCR.27942

13.    Hensley ML, Enserro D, Hatcher H, et al. JOURNAL OF CLINICAL ONCOLOGY Adjuvant Gemcitabine Plus Docetaxel Followed by Doxorubicin Versus Observation for High-Grade Uterine Leiomyosarcoma: A Phase III NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol. 2018;36:3324-3330. doi:10.1200/JCO.18.00454

14.    Pautier P, ITALIANO A, PIPERNO-NEUMANN S, et al. Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2022;23(8):1044-1054. doi:10.1016/S1470-2045(22)00380-1

15.    Hensley ML, Blessing JA, Mannel R, Rose PG. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol. 2008;109(3):329-334. doi:10.1016/J.YGYNO.2008.03.010

16.    Maki RG, Wathen JK, Patel SR, et al. Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Alliance for Research Through Collaboration Study 002. https://doi.org/101200/JCO2006104117. 2016;25(19):2755-2763. doi:10.1200/JCO.2006.10.4117

17.    Seddon B, Strauss SJ, Whelan J, et al. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 2017;18(10):1397-1410. doi:10.1016/S1470-2045(17)30622-8

18.    Tap WD, Wagner AJ, Schöffski P, et al. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas The ANNOUNCE Randomized Clinical Trial Supplemental content. JAMA. 2020;323(13):1266-1276. doi:10.1001/jama.2020.1707

19.    Van Der Graaf WTA, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): A randomised, double-blind, placebo-controlled phase 3 trial. The Lancet. 2012;379(9829):1879-1886. doi:10.1016/S0140-6736(12)60651-5

20.    Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. New England Journal of Medicine. 2022;386(5):437-448. doi:10.1056/NEJMOA2108330/SUPPL_FILE/NEJMOA2108330_DATA-SHARING.PDF

21.     Demetri GD, Von Mehren M, Jones RL, et al. JOURNAL OF CLINICAL ONCOLOGY Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol. 2015;34:786-793. doi:10.1200/JCO.2015.62.4734

22.      Hensley ML, Blessing JA, Degeest K, Abulafia O, Rose PG, Homesley HD. Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: A Gynecologic Oncology Group phase II study. Published online 2008. doi:10.1016/j.ygyno.2008.02.024

23.      Sutton G, Brunetto VL, Kilgore L, et al. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol. 2000;79(2):147-153. doi:10.1006/GYNO.2000.6001

Sydney Oesch
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Uterine Cancer: Part 3