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Adjuvant and systemic therapy for uterine adenosarcoma

TL;DR — There is no randomised evidence that adjuvant chemotherapy or radiotherapy changes survival in uterine adenosarcoma. The strongest adjuvant signal is a non-significant numerical PFS/OS improvement in Carroll’s stage I patients with sarcomatous overgrowth (PFS 46.7 vs 29.4 months, p=0.28; OS 97.3 vs 55.4 months, p=0.18) (Carroll 2014, PMID 25449308). Nathenson found no OS or local-recurrence-free survival difference for adjuvant radiation (Nathenson 2018, PMID 30044322). ESGO 2024 and French GSF/TMRG 2023 both state that adjuvant therapy is not standard in stage I without overgrowth; ESGO allows considering chemotherapy after complete resection of stage II–IV disease or after morcellation of high-grade/SO tumours (Ray-Coquard 2024, PMID 39322612; Karabajakian 2023, PMID 37202293). In recurrent/metastatic disease, a 78-patient retrospective series found doxorubicin/ifosfamide PFS 15.4 months versus 5.0 months for gemcitabine/docetaxel, with RECIST response 31.2% vs 14.3%; OS did not differ by regimen (Nathenson 2017, PMID 29445312). Hormone therapy is an option for ER/PR-positive low-grade disease; tamoxifen is discouraged (Karabajakian 2023, PMID 37202293).

A mixed-histology phase 3 adjuvant registration did include adenosarcoma (NCT00162721: radiotherapy with or without doxorubicin/ifosfamide/cisplatin), but its status is unknown, enrolment remains estimated, and no results are posted. It therefore supplies no randomised effect estimate and does not contradict the evidence statement above (ClinicalTrials.gov record rechecked 2026-09-01).

Adjuvant radiotherapy

Nathenson n=165: no difference in OS or LRFS for adjuvant radiation versus none (p=0.17 OS, p=0.076 LRFS) (Nathenson 2018, PMID 30044322). Seagle NCDB: adjuvant radiotherapy independently associated with decreased OS (Seagle 2016, PMID 27771166) — confounding by indication is the default reading, because radiation is given to worse tumours. Brooks’ mixed uterine-sarcoma SEER analysis found better 5-year relative survival for stage II–IV disease treated with radiation plus surgery versus surgery alone, not histology-specific to adenosarcoma (Brooks 2004, PMID 15047237).

ESGO pocket guidance: adjuvant radiotherapy is not recommended for stage I uterine adenosarcoma (Ray-Coquard 2024, PMID 39322612; ESGO pocket guidelines, https://www.esgo.org/media/2025/03/Pocket-Guidelines_UTERINE-sarcomas_tisk.pdf, accessed 2026-09-01). French GSF/TMRG: role of adjuvant radiotherapy is not established (Karabajakian 2023, PMID 37202293). GCIG 2014 stated that there were no trials (Friedlander 2014, PMID 25341585); the current registry shows an older mixed-histology phase 3 registration but no posted result. Nathenson’s 2018 conclusion: standard of care TAH-BSO ± lymphadenectomy and no adjuvant radiation (Nathenson 2018, PMID 30044322).

Adjuvant chemotherapy

Carroll: among stage I with SO, adjuvant therapy (chemotherapy and/or radiation as used at the time) associated with longer PFS and OS that were not statistically significant (Carroll 2014, PMID 25449308). The paper could not identify an optimal strategy. Tanner: responses to systemic treatment of measurable disease were seen with and without SO; no optimal adjuvant or systemic strategy identified (Tanner 2013, PMID 23283300). Li: 22/31 (71%) received no adjuvant therapy; 4 chemotherapy, 1 chemoradiation, 3 hormonal (Li 2022, PMID 35005157).

Guideline positions:

Body Stage I, no SO Stage I with SO / high-grade Stage II–IV resected
ESGO/EURACAN/GCIG 2024 Adjuvant endocrine therapy not recommended; adjuvant RT not recommended; post-operative chemotherapy not standard Chemotherapy not standard for stage I; can be considered after morcellation of high-grade/SO Adjuvant chemotherapy can be considered as an option because of poor prognosis
French GSF/TMRG 2023 Complete surgery; role of hormone therapy, chemotherapy, adjuvant RT not established SO defines grade/risk Same: role not established
GCIG 2014 Surgery; no reported adenosarcoma-specific trial evidence SO worse outcome No reported histology-specific result
Nathenson reviews 2016/2018 (PMID 27718181; PMID 30169984) Observation for low-risk “Candidates for aggressive therapy with adjuvant chemotherapy” — reviewer’s inference Insufficient data to recommend routinely

The ESGO “can be considered” for stage II–IV and for morcellated high-grade/SO tumours is graded as an option, not a standard, in the pocket guideline (Ray-Coquard 2024, PMID 39322612). There is no regimen with a comparative adjuvant claim.

Recurrent and metastatic chemotherapy

Nathenson 2017, n=78 recurrent/metastatic. Median OS from recurrence 1.8 years. OS influenced by pathology on recurrence (p=0.035) and by surgery for first recurrence (26.3 vs 15.1 months), not by chemotherapy (p=0.58), palliative radiation (p=0.58) or hormonal therapy (p=0.15) (Nathenson 2017, PMID 29445312).

Among those who received first-line chemotherapy (RECIST 1.1):

Regimen Response (CR+PR) Median PFS
Doxorubicin-based (pooled) 31.2% —
Doxorubicin/ifosfamide — 15.4 months
Other doxorubicin-based — 6.5 months
Gemcitabine/docetaxel 14.3% 5.0 months
Platinum-based — 5.7 months

OS from start of first-line chemotherapy did not differ significantly among regimens (Nathenson 2017, PMID 29445312). The PFS ranking of doxorubicin/ifosfamide is a retrospective, non-randomised observation in a rare tumour; it is the best comparative number the field has and is still not a trial.

French GSF/TMRG: for high-grade inoperable or metastatic disease, standard chemotherapies are doxorubicin-based combinations; an integrated surgical plus medical approach should also be considered (Karabajakian 2023, PMID 37202293). Benson and Miah’s uterine-sarcoma perspective lists doxorubicin, trabectedin, gemcitabine-based chemotherapy, eribulin and pazopanib as agents with activity in uterine sarcoma as a class, not as adenosarcoma-specific results (Benson 2017, PMID 28919822). Trabectedin and pazopanib adenosarcoma literature is case-level (search this session: 3 trabectedin hits, 1 pazopanib hit).

A single patient with uterine adenosarcoma was treated with trastuzumab plus lapatinib for an ERBB2 mutation in a 17,878-patient solid-tumour sequencing programme, as one of four ERBB2-mutated patients who had tumour shrinkage (Cousin 2018, PMID 29941010). That is an n=1 histology-agnostic anecdote.

Hormonal therapy

Hormone-receptor expression is common in typical low-grade adenosarcoma and is often lost with sarcomatous overgrowth (Gallardo 2009, PMID 18941402). Ioffe’s mixed uterine-sarcoma series: ER-positive in 63%, associated with improved OS, and 14/18 patients treated with hormone therapy for recurrent/progressive disease had stable disease or response (Ioffe 2009, PMID 19767065) — mixed histologies. Nathenson 2017: hormonal therapy did not influence OS in the 78-patient recurrent adenosarcoma series (p=0.15) (Nathenson 2017, PMID 29445312).

French GSF/TMRG: in advanced inoperable or metastatic low-grade adenosarcoma with ER/PR overexpression, hormone therapy is an option (Karabajakian 2023, PMID 37202293). ESGO: endocrine therapy with an aromatase inhibitor, progestogen or GnRH analogue should be offered for recurrent/metastatic ER/PR-positive low-grade uterine adenosarcoma; tamoxifen should not be administered because of potential agonist effect; adjuvant endocrine therapy is not recommended for stage I (Ray-Coquard 2024, PMID 39322612).

FUCHSia (NCT03926936) enrolled ER-positive low-grade gynecologic cancers including “low grade adenosarcoma without sarcomatous overgrowth,” n=17 actual, completed 2022; results were not retrieved as a PubMed-indexed primary paper in this session. Elacestrant (NCT07467772) is recruiting ER-positive uterine sarcomas including adenosarcoma, estimated n=30.

What “no defined role” means

Nathenson and Conley’s 2018 review: “There is no defined role for adjuvant or neoadjuvant chemotherapy or radiation” (Nathenson 2018, PMID 30169984). That sentence is a statement of absence of comparative evidence, not a statement that adjuvant therapy has been tested and found equivalent to observation. Carroll’s non-significant numerical benefit in stage I SO is the entire positive comparative signal and is compatible with no effect (Carroll 2014, PMID 25449308). Writing this as equipoise that has been tested would overstate the evidence.

Open questions

  • Would a multi-institutional comparison of adjuvant doxorubicin-based chemotherapy versus observation in stage I SO be feasible? Carroll’s p=0.28 is the hypothesis-generating result (PMID 25449308). The barrier is rarity, not lack of a question.
  • Does ER/PR status predict hormone-therapy benefit in adenosarcoma specifically? Ioffe is mixed sarcoma (PMID 19767065); Nathenson 2017 found no OS effect of hormonal therapy in recurrent adenosarcoma (PMID 29445312).
  • What did FUCHSia (NCT03926936) show in the adenosarcoma subset? Completed; not PubMed-indexed as of this session’s searches.

References

  1. Carroll A, et al. Uterine adenosarcoma: an analysis on management, outcomes, and risk factors for recurrence. Gynecol Oncol. 2014;135:455-61. PMID 25449308
  2. Nathenson MJ, et al. The Importance of Lymphovascular Invasion in Uterine Adenosarcomas. Int J Gynecol Cancer. 2018;28:1297-1310. PMID 30044322
  3. Nathenson MJ, Conley AP. Prognostic factors for uterine adenosarcoma: a review. Expert Rev Anticancer Ther. 2018;18:1093-1100. PMID 30169984
  4. Nathenson MJ, et al. Treatment of Recurrent or Metastatic Uterine Adenosarcoma. Sarcoma. 2017;2017:4680273. PMID 29445312
  5. Nathenson MJ, et al. Uterine Adenosarcoma: a Review. Curr Oncol Rep. 2016;18:68. PMID 27718181
  6. Seagle BL, et al. Survival of women with Mullerian adenosarcoma: A National Cancer Data Base study. Gynecol Oncol. 2016;143:636-641. PMID 27771166
  7. Tanner EJ, et al. Management of uterine adenosarcomas with and without sarcomatous overgrowth. Gynecol Oncol. 2013;129:140-4. PMID 23283300
  8. Li JY, et al. Clinicopathologic characteristics and oncologic outcomes in adenosarcoma of gynecologic sites. Gynecol Oncol Rep. 2022;39:100913. PMID 35005157
  9. Brooks SE, et al. SEER analysis of 2677 cases of uterine sarcoma 1989-1999. Gynecol Oncol. 2004;93:204-8. PMID 15047237
  10. Friedlander ML, et al. GCIG consensus review for mullerian adenosarcoma of the female genital tract. Int J Gynecol Cancer. 2014;24:S78-82. PMID 25341585
  11. Karabajakian A, et al. Uterin adenosarcoma: French Guidelines. Bull Cancer. 2023;110:836-843. PMID 37202293
  12. Ray-Coquard I, et al. ESGO/EURACAN/GCIG guidelines for the management of patients with uterine sarcomas. Int J Gynecol Cancer. 2024;34:1499-1521. PMID 39322612
  13. Gallardo A, Prat J. Mullerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases. Am J Surg Pathol. 2009;33:278-88. PMID 18941402
  14. Ioffe YJ, et al. Hormone receptor expression in uterine sarcomas: prognostic and therapeutic roles. Gynecol Oncol. 2009;115:466-71. PMID 19767065
  15. Benson C, Miah AB. Uterine sarcoma - current perspectives. Int J Womens Health. 2017;9:597-606. PMID 28919822
  16. Cousin S, et al. Targeting ERBB2 mutations in solid tumors: biological and clinical implications. J Hematol Oncol. 2018;11:86. PMID 29941010