The treatment of localized STS includes a combination of surgical resection and adjunctive radiotherapy – an approach that has consistently shown to increase the survival rate. Although promising, this treatment modality is not applicable in cases where patients have advanced metastatic disease. In such cases combination chemotherapy is the indicated treatment (Clark et al. 2005). This approach, however, is burdened by a limited number of effective medications available to clinicians and by poor survival outcomes.
For decades, the combination of Doxorubicin and Ifosfamide has been the mainstay of chemotherapeutic management of metastatic STS. In many patients this regimen is either not applicable due to renal and/or cardiac pathology or due to numerous side effects (Leu et al. 2004). Investigations of alternative regimens have led to the current use of Gemcitabine, in combination with Docetaxel, which has offered favorable outcomes. Studies report an overall response rate for metastatic STS that ranges from 16 to 53%, with a median overall survival that ranges from 12.1 to 17.9 months (Maki 2007). These improved response rates and survival outcomes with Gemcitabine and Docetaxel varies with the histological subtype of the sarcoma. Bay et al., demonstrated that the overall response rate in patients with advanced LMS is 24%, whereas neoplasms of other subtypes show a response rate of only 10% (Bay et al. 2006).
In this case, we presented a patient who was treated with a combination of Gemcitabine and Paclitaxel, following diagnosis of metastatic LMS. Our use of these two compounds resulted in a far better survival outcome than that which has been reported in the literature. We suspect that positive hormonal receptor expression by cells of the LMS may have contributed to the outcome we observed. The association, which has been recognized in cases of gynecologic cancers might also extend to LMS of a retroperitoneal origin. Incidence rates of LMS have been reported to mimic the age specific incidence rate of breast cancer providing further evidence of a role for sex hormones in LMS carcinogenesis (Mastrangelo et al. 2012). Studies of uterine LMS demonstrate that 21–87% and 20–80% are ER and PR receptor positive, respectively (Carvalho et al. 2009). In the case of extrauterine LMS, ER/PR is also expressed with gender defining prevalence. In women, 86% of LMS are ER positive and 86% PR positive. However, in men 22% and 33% of tumors are ER and PR positive, respectively. The expression of steroid hormonal receptors has been found to correlate with a better clinical outcome in both uterine and extrauterine sarcoma (Carvalho et al. 2009; Ioffe et al. 2009). One retrospective cohort study that included 97 patients in various stages of uterine sarcoma who received different treatment modalities, including surgery, chemotherapy and radiation therapy, indicated that patients with ER-positive uterine sarcoma have a median overall survival of 36 months, while ER negative demonstrated a median overall survival of 16 months (Ioffe et al. 2009). Carvalho et al., in their cluster analysis, similarly, found that ER expression correlated with much better survival in cases of both uterine and nonuterine LMS (Carvalho et al. 2009).
The presence of these receptors and the association between ER positivity and better clinical outcome has led to the investigation of hormonal therapy, particularly in cases of uterine sarcoma. There is also in vitro evidence that also supports this approach. For example, in Rhabdomyosarcoma, estrogen receptor beta activation mediates cell proliferation; this effect is blocked by the presence of 4’-OH Tamoxifen (Greenberg et al. 2008). Several authors have focused on the treatment of uterine LMS with Selective Estrogen Receptor Modulators (SERM), selective progesterone receptor modulators (SPRM), and/or with aromatase inhibitors. The aromatase inhibitor, anastrozole, was employed in one case as an adjuvant treatment of metastatic uterine LMS. This approach achieved an objective response of tumor regression for more than one year (Hardman et al. 2007). Although these studies show benefit with hormonal therapy, there is conflicting data. One retrospective cohort study demonstrated a low objective reponse of 9% in advanced uterine LMS that were treated with aromatase inhibitors (O'Cearbhaill et al. 2010).
Because our patient had a hysterectomy 20 years ago, it is clear that the tumor did not originate from uterus. To our knowledge, our report is the first to document the application of hormonal therapy in the setting of retroperitoneal LMS. Initiation of tamoxifen was temporally, and perhaps causally, associated with a minimal progression of this extrauterine LMS. However, our observation period was shortened because of the emergence of a second malignancy. Metastatic malignant melanoma was identified three months after the patient was treated with tamoxifen. During the 15 months she was treated with tamoxifen, there was no evidence of LMS progression. The course of her LMS remained distinct from the expected poor prognosis.