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Hormonal Treatment of Metastatic Endometrial Stromal Sarcomas Discussion

Under standard conditions, the cycling of endometrium is controlled and regulated by the steroid hormones oestrogen and progesterone. These hormones bind to their respective receptors, which are expressed in various isoforms. Progesterone has isoforms alpha and beta, which are primarily expressed in normal endometrium. Primary LGESS express both isoforms, but alpha is the dominant isoform. In recurrent LGESS, alpha levels are reduced and the beta becomes increased. Generally, 80% of LGESS express oestrogen alpha receptors and the beta is not detected.5

This is the basis and evidence

for the fact that LGESS arise in the setting of oestrogen stimulation. Clinicians have noticed that recurrences occur more frequently in patients who are on exogenous forms of oestrogen such as tamoxifen.6,7

however, recommends radiotherapy for all resected uterine sarcomas stage I–II, except for LGESS.2

One study reported on 21 women with

LGESS; 15 received radiotherapy following surgery, with an overall local control rate of 93.8%. The authors conclude that the combination of surgery and radiotherapy may be the most effective strategy.17

Nonetheless, it is difficult to interpret these data given the small number of patients, the indolent behaviour of these tumours and the retrospective nature of these studies. The available data seem to indicate that adjunctive radiation does not confer any significant survival benefit for early-stage LGESS.


Therefore, it is often recommended that the ovaries be removed at the time of surgery and progestins or aromatase inhibitors be utilised to decrease oestrogen levels. This is only applicable to LGESS, as undifferentiated endometrial sarcomas tend to lose expression of OR and PR, raising the possibility of a different pathway or pathogenesis compared with LGESS.5

In a study performed by Ioffe

et al., OR and PR were expressed in 76% of their cases of LGESS and all undifferentiated endometrial sarcomas showed no expression.3


Endometrial sarcomas are initially treated with surgery. The recommended surgical therapy is total hysterectomy with bilateral salpingo-oophorectomy.9

Surgery is also advocated for debulking of

Oophorectomy serves the purpose of removing the trophic production of oestrogen in pre-menopausal patients. In one study, there was 100% recurrence in patients who retained their ovaries versus 43% in those who had them removed.9


there are studies that challenge the effectiveness of oophorectomy in preventing the recurrence of LGESS.15

The role of regional lymph-node

dissection in LGESS also remains controversial. Lymph-node dissection is generally not recommended for stage I LGESS.16

Although there

Negative margins for a surgically resected tumour are important, as shown in studies by Nordal et al., but there are other important prognostic factors, such as tumour grade, tumour diameter and menopausal status.9


Studies in the early 1990s by Berchuck et al. showed a 57 and 40% response rate to chemotherapy and radiation therapy, respectively.10

LGESS recur in up to 50% of patients as reported in the literature; tumours are most likely to recur in the pelvis, abdomen and lungs.5,6,8 The benefits of radiation therapy are still unclear. There are a number of studies suggesting a survival advantage and improved local control.2

Adjuvant radiation prevents local recurrence in the pelvis but clearly does not prevent recurrences at distant sites.5


is no significant difference in overall survival or in disease-free survival comparing those who undergo post-operative pelvic radiation and those who do not.9

Various recommendations have been made in

terms of the use of radiation therapy in the adjuvant setting. The National Cancer Institute (NCI) recommends adjuvant radiotherapy for stage I–III but not for stage IV, which is treated with systemic chemotherapy. The National Comprehensive Cancer Network (NCCN),


are data indicating that the rate of lymph-node involvement may be higher than previously thought, this remains controversial. In one retrospective study, lymph-node metastases were seen in five of 15 patients with LGESS, while another study showed no metastasis in seven patients.2

Hormonal Therapy

As with other neoplasms of the female genital tract, LGESS often express OR and PR, which serve as potential targets for therapy. Instead of using chemotherapy or radiation therapy, which often have deleterious side effects, hormonal agents have a more favourable therapeutic index. Many anecdotal reports in the literature appear to support this approach. Although some reports question the effectiveness of hormonal treatment,19

the majority of studies

demonstrate a measurable benefit. In general, LGESS express OR and PR more than undifferentiated endometrial sarcomas, but not all tumours express OR and PR. Therefore, it is recommended that all endometrial sarcomas be evaluated for OR and PR expression.20 Endometrial sarcomas often lose OR and PR expression in metastases and can also switch to different isoforms, making tumours unresponsive to hormonal therapy, resulting in treatment failure.5


are no prospective studies examining the use of hormonal therapy in the treatment of LGESS due to the rarity of the tumour; however, a number of retrospective studies have been published attesting to the effectiveness of hormonal therapy in the treatment of LGESS. In a study completed by the current authors, 13 patients with LGESS were identified and six had metastatic or recurrent disease. All but one patient underwent surgical resection and all six patients with metastases had tumours that tested positive for OR and PR. All six were treated with megestrol acetate initially for a period of one to four years. Two patients were then changed to maintenance with medroxy- progesterone acetate; one patient was lost to follow-up. Three patients with persistent disease were changed to aromatase inhibitors: one to


recurrence and for residual tumours after pelvic radiation and chemotherapy.2,8–10,12

There are various case reports and retrospective studies with small patient populations quoting successful treatments utilising chemotherapy. The chemotherapy regimens vary, generally including platinum drugs, taxanes, ifosfamide and doxorubicin. Berchuck et al. published a study showing a 50% response rate to doxorubicin in their patient population.10

Of all the data on chemotherapy agents, most

indicate a favourable response to regimens that include doxorubicin. In spite of this demonstrated response to chemotherapy, most studies show no advantage in progression-free survival or overall survival.2

At this time, the data do not support the use of radiation or chemotherapy in the adjuvant setting; as summarised by Haberal et al., there appears to be no difference in recurrence rates between those who receive and those who do not receive adjuvant therapy.9

The role of chemotherapy in the treatment of LGESS remains unclear. There is discordance in the literature pertaining to chemotherapy treatment of LGESS. Most studies report on patients with advanced-stage disease, often combining undifferentiated endometrial sarcomas with LGESS. In one study, 21 patients with advanced, recurrent or metastatic endometrial sarcomas were treated with ifosfamide and there was an overall response rate of 33.3%.18

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