Use of doxorubicin and trabectedin in low-grade endometrial stromal sarcoma: A case report

Highlights

• •Advanced LG-ESS are often treated with hormonal therapy.
• •In cases refractory to hormonal therapies, treatment options are limited.
• •This case is the first reported instance of LG-ESS achieving partial response with doxorubicin-trabectedin therapy.

Abstract

Background

Low-grade endometrial stromal sarcoma (LG-ESS) is the most common type of endometrial stromal malignancy, yet treatment options are limited, particularly in advanced or recurrent cases that are resistant to hormonal therapy.

Case Presentation

We describe a 48-year-old patient with recurrent stage IVB LG-ESS who was treated with a combination of doxorubicin and trabectedin, followed by trabectedin maintenance; a protocol extrapolated from leiomyosarcoma treatment. Following failure to hormonal therapy, this regimen demonstrated disease stabilization, particularly in pelvic metastases.

Conclusion

Our results highlight the potential role of this chemotherapy combination in hormonal therapy-resistant LG-ESS, a malignancy with limited systemic therapeutic options. This is the first reported case of LG-ESS achieving prolonged stable disease with doxorubicin-trabectedin therapy and trabectedin maintenance. Given the manageable toxicity profile and encouraging tumor control, further studies should explore its potential role in LG-ESS management.

1. Introduction

Low-grade endometrial stromal sarcomas (LG-ESS) are the most common type of endometrial stromal tumor (EST), accounting for less than 1 % of all uterine malignancies. LG-ESS typically affects women of reproductive age, with a peak incidence between 40 and 50 years old (Conklin and Longacre, 2014, Gadducci et al., 2023).

LG-ESS is characterized by uniform cells that mimic proliferative endometrial stroma, invading the myometrium with an infiltrative growth pattern and often exhibits lympho-vascular space invasion (LVSI) (Conklin and Longacre, 2014, Gadducci et al., 2023). The diagnosis of LG-ESS relies on a combination of histological features and immunohistochemical staining, with CD10, estrogen receptor (ER), and progesterone receptor (PR) being commonly positive markers. A majority of LG-ESS cases harbor gene fusions, most commonly JAZF1-SUZ12 or PHF1 translocations, which affect transcriptional regulation through epigenetic repression (Gadducci et al., 2023).

This neoplasm typically follows an indolent clinical course, with early-stage tumours carrying a 5-year survival rate of 90 %, while advanced-stage tumors have a lower survival rate, at 40 % to 50 % (Conklin and Longacre, 2014). According to the recommendations of National Comprehensive Cancer Network (NCCN), treatment should include a hysterectomy and bilateral salpingo-oophorectomy (BSO). The data on adjuvant therapy for LG-ESS FIGO stage II to IV is very limited but given their strong expression of estrogen and progesterone receptors, they are often treated with hormonal therapy. In cases of recurrence, secondary cytoreduction or maintaining hormonal blockade therapies is preferred, and but if the tumour is unresponsive, systemic chemotherapies such as doxorubicin or gemcitabine/docetaxel have been suggested (Lewis et al., 2024). The benefit of these last-line treatments is not supported by any convincing literature on LG-ESS, but in a case where the cancer is refractory to hormonal therapies, treatment options are limited. Therefore, systemic chemotherapies commonly used in the management of other soft tissue sarcomas may be potential alternatives.

2. Case presentation

A 48-year-old female first presented with a 3-month history of pelvic and lower back pain and constipation. The patient’s first CT scans revealed an abdominopelvic mass believed to be of ovarian in origin and multiple nodules in both lungs consistent with a metastatic disease. The primary surgery consisted of an en bloc resection of the abdominopelvic mass with a hysterectomy, bilateral salpingo-oophorectomy and ileocecal resection to achieve complete abdominal cytoreduction to no gross residual disease.

Both morphology and immunohistochemistry supported the diagnosis of LG-ESS through consensus of tertiary care center gynecologic pathologists. There was extra-uterine extension and involvement of the serosa and submucosa of the ileum. On immunohistochemistry, the tumor cells showed positive expression of CD10, progesterone and estrogen receptors, and were negative for desmin, caldesmon, SMA, cyclin D1, S100, inhibin, calretinin and HMB45.

Given the metastatic unresected pulmonary nodules, the patient was started on letrozole, an aromatase inhibitor, with initial response in pulmonary lesions; the largest pulmonary nodule decreased from 30 mm to 20 mm over fourteen months. However, nine months after surgery, a 15 cm multicystic and solid right hemipelvic lesion was found on imaging, prompting a secondary cytoreduction. This mass was situated retroperitoneally and was adherent to multiple loops of the small bowel, the bladder and part of the right ureter.

A cytoreductive surgery was performed, but considered suboptimal due to multiple small bowel deposits and residual tumour on the major pelvic vessels. The resected tumor was consistent with the prior diagnosis of LG-ESS, immunohistochemistry remained consistent with the prior diagnosis. The tumour was mismatch repair (MMR) proficient. RNA sequencing fusion panel performed on the tumor tissue showed no structural rearrangements. Postoperatively, given the failure of letrozole, adjuvant treatment was changed to megestrol acetate.

Approximately following the secondary cytoreduction, imaging showed a slight regression in the lung nodules (e.g. the previously 20 mm nodule was 18 mm), but recurrence of the pelvic soft tissue mass, showing a 4.3 x 2.1 cm lesion at the level of the vaginal cuff, as well as a 10.1 x 6.5 x 9.6 cm solid mass at the level of the right pelvis. The disease progression confirmed the failure of megestrol acetate, leading to its discontinuation. The patient was then started on six cycles of doxorubicin (60 mg/m²) every 3 weeks combined with trabectedin (1.1 mg/m²), followed by trabectedin maintenance at the same dose and frequence (Fig. 1). This treatment regimen came from data extrapolated from the LMS-04 clinical trial, studying the effects of the combination on uterine leiomyosarcoma(Pautier et al., 2024). This was well tolerated, without side effects. Treatment was delayed once by a week due to a high white blood count (22.1 x 10⁹/L).

Fig. 1.

Growth curve of the right pelvic solid mass following suboptimal resection and doxorubicin/trabectedin treatment with trabectedin maintenance. Growth curve of the right pelvic solid mass following the suboptimal resection of a recurring abdominal tumor. Time is in months following the operation. Mass sizes are volumes calculated from approximations made by radiologists from all available CT images from follow ups. The green line represents the time the patient was started for six cycles of doxorubicin (60 mg/m²) every 3 weeks combined with trabectedin (1.1 mg/m²). The red line represents the end of the combination of doxorubicin and trabectedin and the initiation of trabectedin maintenance at the same dose and frequence. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

After 3 cycles of doxorubicin-trabectedin, imaging showed interval decrease of the lung nodules and the vaginal cuff mass (3.6 x 2.6 cm), but a small interval increase of the pelvic sidewall mass (10.1 x 8.2 x 10.1 cm) (Fig. 2A). It showed increase necrosis within the mass, which could have been attributed to treatment response or to the tumor outgrowing its blood supply. At that time, the patient had lower extremity symptoms consistent with a mass abutting the right sciatic nerve as well as a mass compressing the right external iliac vein seen on imaging. The decision was made to reassess 6 weeks later. The following CT scan also showed stable lung metastases and stable pelvic mass with unchanged necrotic component.

Fig. 2.

Abdominal LG-ESS masses after doxorubicin-trabectedin therapy and trabectedin maintenance. CT images showing the reduction of the solid pelvic mass (blue arrows) and the vaginal cuff mass (green arrows). A) CT scan after 3 cycles of doxorubicin and trabectedin. The larger pelvic mass measures 10.1 x 8.2 x 10.1 cm and the vaginal cuff mass measures 3.6 x 2.6 cm. B) CT scan 4 months after completion of the 6 cycles of doxorubicin-trabectedin combination and initiation of trabectedin maintenance (4 cycles). The larger pelvic mass measures 8.0 x 5.4 x 8.4 cm and the vaginal cuff mass measures 3.5 x 2.8 cm. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

The patient completed her 6 cycles of doxorubicin–trabectedin combination and imaging showed mild increase in size of the lung metastases (eg. the previously 18 mm nodule was now 20 mm), but a decrease in size of the pelvic metastases (the right pelvic mass was 8.3 x 6.0 x 8.6 cm). After 4 cycles of maintenance trabectedin, there was growth of a new 2 mm lung nodule, but further decrease in the size of the right pelvic mass (8.0 x 5.4 x 8.4 cm) (Fig. 2B). Six months following the end of chemotherapy, there was marginal size increase of the implant abutting the vagina (3.9 x 3.3 x 3.1 cm, previously 3.5 x 2.8 x 3.1 cm), with the right pelvic mass being stable in size. Decision was made to continue the maintenance trabectedin, which was well tolerated by the patient as she did not experience toxicity, and it significantly slowed tumor growth. To treat the pelvic implants, the tumor board agreed on giving 5 fractions of stereotactic body radiation therapy for local control which was well tolerated. At the time of submission, the patient completed 18 cycles of maintenance trabectedin and maintained a ECOG of 0.

3. Discussion

The reviewed case is on the use of doxorubicin-trabectedin with trabectedin maintenance for the treatment of a recurrent stage IVB LG-ESS. This treatment plan provides insights into the management of an LG-ESS due to its rapid growth on hormonal therapy. In the current literature, there are no reports of partial response or stable disease of this presentation of LG-ESS to this chemotherapy regimen.

The patient had an abdominal recurrence after a complete abdominal resection, and a suboptimal secondary cytoreduction. Despite ER and PR positivity, hormonal therapy (letrozole and megestrol acetate) was ineffective in controlling the abdominal tumor growth, although it had some effect on the lung metastases, underscoring the limitations of hormonal therapy in certain LG-ESS cases. A retrospective comparative study analyzed hormonal therapy for LG-ESS of different stages and found comparable efficacy for megestrol acetate and letrozole (Saab et al., 2024). For adjuvant treatment, letrozole is typically preferable due to its better tolerability. However, in the context of treatment at the first recurrence of disease, the study found a significant improvement in overall survival with megestrol acetate, for 27.46 years, compared to the use of letrozole, for 7 years. In another case series of 8 patients with recurrent LG-ESS treated with progestins, complete response occurred in 4 patients (50 %) and stable disease in 2 (25 %) (Chu et al., 2003). When hormonal therapy fails, few alternatives exist, making systemic chemotherapy an acceptable second-line option (Lewis et al., 2024). NCCN recommendations also include radiation therapy in advanced and recurrent cases of pelvic extra-uterine LG-ESS (Gadducci et al., 2023, Koh et al., 2015).

The absence of large or prospective trials on systemic therapies for LG-ESS often requires the use of soft tissue sarcoma treatment regimens. A trial on the combination of doxorubicin-trabectedin with trabectedin maintenance, LMS-04, gave very promising results for its use in advanced leiomyosarcoma (Pautier et al., 2024). An objective tumor response rate of 36 % was seen in patients in the doxorubicin-trabectedin group, as opposed to a 13 % in the group given doxorubicin alone, as well as a median progression-free survival that nearly doubled for the combination group (Pautier et al., 2022). While systemic treatment is not a standard of care in LG-ESS, doxorubicin is known to induce DNA damage in soft tissue sarcomas such as high-grade ESS (Koh et al., 2015). Doxorubicin has been reported in a few cases of LG-ESS refractory to hormonal therapy. A patient with recurrent LG-ESS, for whom both an aromatase inhibitor and medroxyprogesterone acetate were ineffective, obtained partial response to seven cycles of doxorubicin (50 mg/m²) and ifosfamide (2 g/m²) and stable disease with pazopanib. In another case of recurrent LG-ESS refractory to tamoxifen, the patient was treated with 2 cycles of doxorubicin (30 mg/m²) and ifosfamide (3 g/m²) with complete response of the lung metastasis and partial response of the abdominal mass, followed by secondary cytoreduction. The patient was in complete remission 5 years post-surgery (Ihnen et al., 2007). Trabectedin is usually used as a second-line treatment for patients with soft tissue sarcoma unresponsive to doxorubicin or ifosfamide. In a cohort of patients with advanced soft tissue sarcomas, trabectedin treatment achieved an objective response rate of 48 % (Samuels et al., 2013). This justifies the use of doxorubicin and trabectedin for the aforementioned case of a rapidly growing LG-ESS.

Our results are particularly noteworthy as they provide the first documented instance of stable disease (19 % reduction in tumour size) in a case of advanced LG-ESS treated with doxorubicin-trabectedin and trabectedin maintenance. The combination regimen provided overall durable stable disease for at least 18 months while maintaining a good quality of life for the patient. Notably, while initial scans showed increased pelvic mass size, further evaluation revealed extensive necrosis, which suggests that the chemotherapy was effectively targeting tumor viability. The patient’s lung metastases remained stable for an extended period, and the pelvic lesions demonstrated a delayed response, shrinking over time with trabectedin maintenance. Given the poor response of LG-ESS to conventional chemotherapy, these results suggest that trabectedin maintenance may play a crucial role in prolonging disease control in cases refractory to hormonal therapy.

4. Conclusion

This case represents the first reported instance of LG-ESS achieving stable disease for at least 18 months with doxorubicin-trabectedin therapy and trabectedin maintenance. The treatment demonstrated meaningful tumor control despite prior hormonal therapy failure. While no data directly supports this combination’s superiority over doxorubicin alone in LG-ESS, the continued diminution of the pelvic tumor size in trabectedin maintenance suggest its potential benefit in similar cases. Further similar case studies are warranted to explore its efficacy in this rare malignancy.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

CRediT authorship contribution statement

Délya Valcourt-Gendron: Writing – review & editing, Writing – original draft, Visualization, Validation, Formal analysis, Data curation, Conceptualization. Basile Tessier-Cloutier: Writing – review & editing, Writing – original draft, Investigation, Data curation, Conceptualization. Xing Zeng: Writing – review & editing, Writing – original draft, Formal analysis, Conceptualization. Reitan Ribeiro: Writing – review & editing, Writing – original draft, Conceptualization. Shuk On Annie Leung: Writing – review & editing, Writing – original draft, Conceptualization. Victoria Mandilaras: Writing – review & editing, Writing – original draft, Conceptualization. Lili Fu: Writing – review & editing, Writing – original draft, Conceptualization. Tuyet Nhung Ton Ton Nu: Writing – review & editing, Writing – original draft, Conceptualization. Lara Richer: Writing – review & editing, Writing – original draft, Conceptualization. Lucy Gilbert: Writing – review & editing, Writing – original draft, Conceptualization. Laurence Bernard: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Methodology, Formal analysis, Data curation, Conceptualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.