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Table of Contents
CASE REPORT
Year : 2020  |  Volume : 7  |  Issue : 4  |  Page : 174-178

Durable response to tamoxifen and metronomic cyclophosphamide in a patient with metastatic estrogen receptor-positive uterine leiomyosarcoma


1 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
2 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

Date of Submission27-Jul-2020
Date of Decision14-Sep-2020
Date of Acceptance14-Sep-2020
Date of Web Publication1-Dec-2020

Correspondence Address:
Dr. Tom Wei-Wu Chen
Department of Oncology, National Taiwan University Hospital, No. 7, Zhongshan South Rd., Taipei
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_23_20

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  Abstract 


Uterine leiomyosarcoma is a rare uterine malignancy, but the most common type of uterine sarcoma, in which a considerable proportion of tumors express estrogen/progesterone hormone receptors. We report a case of estrogen receptor-positive uterine leiomyosarcoma with a durable response to a combination of tamoxifen and metronomic cyclophosphamide. The current landscape and potential systemic treatment for uterine leiomyosarcoma were also briefly reviewed.

Keywords: Hormone therapy, metronomic cyclophosphamide, tamoxifen, uterine leiomyosarcoma


How to cite this article:
Wu TC, Hu HW, Chen TW. Durable response to tamoxifen and metronomic cyclophosphamide in a patient with metastatic estrogen receptor-positive uterine leiomyosarcoma. J Cancer Res Pract 2020;7:174-8

How to cite this URL:
Wu TC, Hu HW, Chen TW. Durable response to tamoxifen and metronomic cyclophosphamide in a patient with metastatic estrogen receptor-positive uterine leiomyosarcoma. J Cancer Res Pract [serial online] 2020 [cited 2021 Jan 17];7:174-8. Available from: https://www.ejcrp.org/text.asp?2020/7/4/174/301909




  Introduction Top


While uterine leiomyosarcoma only accounts for 3%–7% of uterine malignancies, it is the main tumor type among uterine sarcomas, accounting for up to 80% of cases.[1],[2] However, it portends a poor prognosis. In an analysis of the National Cancer Database, even Stage I disease was associated with a 5-year overall survival (OS) rate of only 55.4%, and Stage IV disease was associated with a 5-year OS rate of 13.1% and median survival of 13.7 months.[3]

For the management of unresectable disease, the treatment options are limited. As described in the consensus guidelines such as FIGO cancer reports or NCCN guidelines, no systemic therapies have specifically been approved for uterine leiomyosarcoma.[4],[5] The recommendations consist mainly of cytotoxic chemotherapy for soft tissue sarcoma or leiomyosarcoma (e.g., trabectedin), or targeted therapy without specific molecular selection (e.g., pazopanib), both of which provide limited survival benefit. The exceptions are anti-estrogen hormone therapy for hormone receptor-positive uterine leiomyosarcoma. Regimens listed by the NCCN guidelines include aromatase inhibitors, fulvestrant, megestrol acetate, medroxyprogesterone acetate, and GnRH analogs.[5] Nevertheless, the supportive evidence mainly consists of retrospective studies or prospective studies with an extremely small number of patients. Consequently, the recommended strength of such therapies is generally lower than the strength for low-grade uterine stromal sarcoma. Even fewer studies have reported on other hormone therapies such as tamoxifen or compared different hormone agents.

A high expression of hormone receptors has been reported in uterine leiomyosarcoma, with an estrogen receptor (ER) expression of 25%–60% and progesterone receptor (PR) expression of 35%–60%.[6] In addition, considering the availability, tolerability, affordability, and convenience of hormone therapy, hormone therapy should be considered as a reasonable option, and its role and priority compared to cytotoxic chemotherapy needs to be clarified.

Metronomic chemotherapy, though not mentioned in the consensus guidelines, represents another potential therapeutic option. Case reports and small-sized studies have demonstrated some success with metronomic chemotherapy in patients with sarcoma, including leiomyosarcoma,[7] although there are also reports of conflicting results. Considering the low, nonoverlapping toxicities of metronomic chemotherapy and hormone therapy, the combination of these two modalities may be a feasible strategy with tolerable toxicity and potential additivity or synergism of efficacy, as with the experience in breast cancer.

As a demonstration of such strategy, we report a patient with metastatic ER-positive uterine leiomyosarcoma who had a deep and durable response with tamoxifen and metronomic cyclophosphamide.


  Case Report Top


A 41-year-old female was diagnosed with a uterine mass of 20 cm diameter in March 2015 with the initial presentation of heaviness of the lower abdomen. She received total abdominal hysterectomy, and the pathology revealed smooth uterine muscle of uncertain malignant potential.

Along with recurrence of symptoms including heaviness of the lower abdomen, poor appetite, and body weight loss, a computed tomography (CT) scan in February 2017 revealed an 8-cm mixed solid and cystic right ovarian mass, diffuse peritoneal seeding, retrocaval lymphadenopathy, and bilateral pleural effusion with right pleural nodules. She received suboptimal debulking surgery consisting of right salpingo-oophorectomy, cytoreduction, infracolic omentectomy, and excision of the intestinal and peritoneal tumors, and multiple residual tumors with maximal diameter of 1.5 cm were noted over the colon, small intestine, and peritoneal wall.

The pathology showed well-differentiated leiomyosarcoma with moderate nuclear atypia and increased mitotic activity (5 mitoses/10 high-power fields). Immunohistochemically, the tumor cells were positive for smooth muscle actin, H-caldesmon, focally positive for desmin, CD10, p53, but negative for cytokeratin (AE1/AE3) and p16. The Ki-67 index was 5%–10%. Moreover, there was moderate to strong ER staining in 75%–90% of the tumor cells [Figure 1].
Figure 1: Pathology showed (a) spindle cells arranged in vague fascicles (b) frequent mitoses; (c) Ki-67 index around 5%–10%; (d) moderate to strong estrogen receptor staining in 75%–90% of the leiomyosarcoma tumor cells

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Four weeks after surgery, tamoxifen 20 mg QD and metronomic cyclophosphamide 50 mg QD were initiated. There were initial responses of the peritoneal, pleural, and right internal mammary lymph node tumors, and the sizes of the tumors were stable in a follow-up CT scan in April 2020 [Figure 2]. The regimen was quite tolerable, without any events related to dose delay, interruption, or reduction up to now.
Figure 2: Serial postoperative computed tomography (March 2017–April 2020) showing: (a-c) One of the peritoneal masses gradually shrank from postoperative 4 cm × 41 mm to 32 cm × 26 mm, along with resolution of the ascites. (d-f) Postoperatively, there was a pleural mass of 55 mm × 26 mm and pleural effusion, and both lesions were no longer detectable in April 2020

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  Discussion Top


We report a patient with metastatic uterine leiomyosarcoma and extraordinary ongoing response of at least 38 months. This certainly exceeds the expected outcome of patients with uterine leiomyosarcoma, and the outcome was even better than most of the reported extraordinary responders.[8],[9] Although it is not possible to make any definite conclusion or solid scientific argument from a single case report, this may suggest the potential use of this approach in the clinical practice and provide potential clues for further research.

Several cytotoxic chemotherapeutic agents have been proven to be effective in uterine leiomyosarcoma, but with a limited response rate and unsatisfactory survival. The combination of gemcitabine/docetaxel raised interest, as early reports showed a response rate of up to 50% and time to progression of 5.6 months.[10] However, a randomized phase 3 study (gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas [Geddis]) did not show a significant advantage of gemcitabine/docetaxel combination.[11] In the leiomyosarcoma and uterine leiomyosarcoma subgroups, the hazard ratios of progression-free survival (PFS) were around one.[11] The subgroup analysis provides tangential data that gemcitabine/docetaxel may be as effective as doxorubicin in uterine leiomyosarcoma. This efficacy was also demonstrated in other studies. A phase 3 study of chemotherapy-naïve uterine leiomyosarcoma patients comparing gemcitabine/docetaxel with or without bevacizumab showed that although the addition of bevacizumab did not bring additional benefit, the control arm of gemcitabine/docetaxel combination achieved a response rate of 31.5%, PFS of 6.2 months, and OS of 26.9 months.[12] In recent years, several agents have been approved for late-line advanced soft-tissue sarcoma. The subgroup of uterine leiomyosarcoma patients retrieved from registration studies showed a best response rate of around 10%, PFS of 1.5–4 months, and OS of 9.4–17.5 months [Table 1].[13],[14],[15] In spite of expanding treatment options, the efficacy is far from satisfactory.
Table 1: Efficacy of selected regimens for leiomyosarcoma/uterine leiomyosarcoma patients in recent phase II/III studies

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As a considerable proportion of uterine leiomyosarcomas express estrogen and/or PRs, hormone therapy has also been used. The most studied agents are aromatase inhibitors, although the published results were generally retrospective or small in size. A single-arm phase 2 study at Dana-Farber Cancer Institute treated 27 patients with a median of two prior lines of systemic treatment with letrozole 2.5 mg QD. Although there were no responders and the median duration of treatment was only 2.2 months, 54% of the patients had stable disease, with a 12-week PFS rate of 50% and 3/27 patients sustained on treatment for more than 24 weeks.[18] Another randomized phase 2 study for adjuvant therapy of uterine leiomyosarcoma at MD Anderson Cancer Center, which was closed early due to slow recruitment, reported a 24-month PFS of 100% in the letrozole arm compared with 40% in the observation arm, although only nine patients were recruited.[19] In a retrospective analysis at Cedar-Sinai Medical Center, ER positivity was identified as a potential prognostic factor, and among 18 ER-positive uterine sarcoma patients with recurrent or progressive disease, 14 achieved an objective response or stable disease with hormone treatment.[20] Among the ER-positive uterine leiomyosarcoma subgroup, five patients received hormone therapy (mainly aromatase inhibitors), of whom one patient had a partial response and four patients had stable disease. The largest cohort was reported by Memorial Sloan Kettering Cancer Center with 34 advanced uterine leiomyosarcoma patients, of whom 71% were ER-positive. The patients received letrozole, anastrozole, or exemestane, and the response rate was 9%, median PFS was 2.9 months, and 1-year PFS rate was 28%.[21] In the 16 hormone receptor-positive uterine leiomyosarcoma patients in a study from Royal Marsden Hospital, the response rate was 12.5%. If patients with stable disease for more than 6 months were included, the clinical benefit rate was 62.5%. In addition, the median PFS at the first-line setting was 14 months.[6]

The utility of other hormone therapy in this indication was generally based on evidence of case report level. Responders with metastatic uterine leiomyosarcoma to medroxyprogesterone acetate were reported early in 1990s,[22],[23] and a preclinical model has also supported this phenomenon.[24] Several studies have reported the use of megestrol acetate for hormone receptor-positive uterine leiomyosarcoma, however the response was not clearly described.[25],[26] Besides ER/PR antagonism, activity of GnRH agonist has also been reported in a case report.[27] Although a responder to fulvestrant with ER-expressed endometrial stromal sarcoma has been reported,[28] no reported cases of the use of fulvestrant in uterine leiomyosarcoma were found in a PubMed search (last search date: June 1, 2020). An ongoing phase 2 trial (FUCHSia, NCT03926936) is evaluating fulvestrant for recurrent/metastatic ER-positive gynecological malignancies, including uterine leiomyosarcoma.

In our case report, tamoxifen was administered as the hormone therapy. Tamoxifen is not listed as a treatment option for uterine leiomyosarcoma in the NCCN guidelines,[5] and it has been discouraged in some review articles.[29],[30] These suggestions were based on concerns of an association between tamoxifen and the occurrence of uterine sarcoma.[31],[32] However, while the association between long-term tamoxifen use and endometrial malignancy has been well established, the association between tamoxifen and uterine sarcoma is based on case reports and cohort studies with statistically nonsignificant trends. Moreover, the possible association with occurrence does not guarantee that there is no therapeutic role of tamoxifen. Moreover, there have been reports of the use of tamoxifen in the treatment of uterine leiomyosarcoma. A case at Cedar-Sinai was treated with tamoxifen monotherapy and was reported to have stable disease.[20] In another patient with metastatic uterine leiomyosarcoma refractory to doxorubicin/dacarbazine/ifosfamide, the addition of tamoxifen induced a good partial response.[33] The durable response of our case may serve as further evidence to consider tamoxifen in this indication.

Metronomic chemotherapy may be another potential treatment option. In a study enrolling 26 elderly patients with various tissue types of soft tissue sarcoma including leiomyosarcoma, the combination treatment of metronomic cyclophosphamide and prednisolone yielded a response rate of 26.9% and a median PFS of 6.8 months.[7] In other cancer types such as breast cancer, the combination of metronomic chemotherapy and hormone therapy was more receptive. Due to nonoverlapping toxicities, the combination has been reported to be highly tolerated and to have promising efficacy.[34],[35] Our report is the first reported case to use this combination strategy in ER-positive uterine leiomyosarcoma, with an extraordinary duration of response which was better than expected considering the efficacy of each component.


  Conclusion Top


In conclusion, we presented a case of uterine leiomyosarcoma with ER expression who had a deep and durable response to a combination of tamoxifen and metronomic cyclophosphamide. When treating uterine leiomyosarcoma, a pathologic examination of hormone receptors should be mandatory. Subsequently, tamoxifen should not be excluded as an option of hormone therapy for hormone receptor-expressing uterine leiomyosarcoma. Finally, a combination of metronomic chemotherapy and hormone therapy may be a strategy worth further exploration.

Ethical approval

This study is approved by the IRB of National Taiwan University Hospital (IRB approval project number: 202007062W). The patient informed consent was waived by the IRB.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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