DISCUSSION
In the present study, the clinical characteristics and treatment outcomes of 71 patients with recurrent uterine leiomyosarcoma treated at our institution were analyzed. To our knowledge, the current study is one of the largest studies to evaluate the clinical characteristics and treatment outcomes of women with recurrent uLMS in a single center to data. We found that secondary cytoreductive surgery is an important treatment choice for recurrent uLMS and time to fist recurrence within 12 months is an independent predictor of decreased 5-year OS in patients who received SCS. These findings suggested that it’s important to identify the suitable candidate for SCS.
Uterine leiomyosarcoma is the most frequent malignant gynecologic mesenchymal tumor, often develops distant metastases and local recurrence.(Mbatani et al , 2018) Because of their low incidence and the lack of prospective studies, it is very difficult to reach conclusions as to the best disease management recommendations for recurrent uLMS. Treatment recommendations are made according to the site and nature of the recurrence for recurrent uLMS. Emerging evidence suggested that optimal surgical resection for recurrent uLMS may provide an opportunity for long-term survival in a select patient population.(Leitao et al , 2002; Giuntoli et al , 2007; Bacalbasa et al , 2015; Villalaín-González et al , 2017; Nakamura et al , 2018; Bizzarri et al , 2019; Cybulskaet al , 2019) The survival advantage was seen not only in patents with pulmonary metastases but also patients with extrapulmonary metastases.(Giuntoli et al , 2007) In the present study, we found secondary cytoreduction surgery in patients with first recurrent uLMS was associated with a significant improvement in overall survival. Recently, some studies showed cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) was a promising treatment modality for uterine sarcoma patients with peritoneal dissemination.6–8 It’s important to identify the suitable candidate for SCS.
The time to first recurrent since initial diagnosis affects the survival. Patients with uLMS who experience longer time to recurrence may have improved survival outcomes following metastasectomy.(Leitao et al , 2002) In the present study, patients experienced first recurrence after initial diagnoses within 12 months had a significantly worse 5-year OS than those after 12 months, which was an independent predictor of worse survival.
Site governs local control, distant recurrence-free and disease-specific survival for completely resected locally recurrent sarcoma without metastasis.(Stojadinovic et al , 2002) Patients with single site recurrence are more likely to receive SCS and achieve a complete resection with no residual disease than those with multiple sites recurrences. We found patients with multiple recurrent locations were more likely to receive systematic therapy and had a worse survival, which in accordance with other studies. Similarly, patients with residual tumors after cytoreductive surgery had a tendency towards a worse survival than those without in the present study.
Furthermore, Bartosch et al found the most frequent distant metastatic sites were lung (67.7%).(Bartosch et al , 2017) We found lung was also the most common distant metastatic site in our study. But it’s not that bad for some patients, especially for those with lung-only recurrence. We found patients with lung-only recurrence had a tendency towards better 5-year OS than those without.
uLMS also have a high tendency for local recurrent in pelvic and abdominal cavity after initial treatment. Since it is difficult to discriminate between benign uterine fibroids and uterine sarcomas preoperatively, most uterine sarcomas are often found incidentally after primary hysterectomy or myomectomy.(Hosh et al , 2016) Tumor fragmentation/morcellation might be used which was associated with significantly higher risk of recurrence and a nearly 4-fold increase in peritoneal recurrence.(Pedra Nobre et al , 2021) Since nearly all patients received primary myomectomy in other centers, we could not determining how many patients received morcellation clearly in the present study.
Radiotherapy can be recommended for patients with recurrent uterine sarcoma based on tumor resectability and patients’ prior radiotherapy exposure. For patients with local recurrent, all recurrences are localized either in the vagina or in or directly proximal to the vaginal stump that is negative for distant metastatic disease. Radiotherapy or surgery treatment are reasonable choices. Concurrent radiotherapy shows good local effectiveness with a good long-term survival for local recurrence.(Kortmann et al , 2006) A combined modality approach with perioperative EBRT, surgery, and IORT for locally advanced or recurrent uterine sarcoma resulted in excellent local disease control with acceptable toxicity, even in patients with positive resection margins. (Barney et al , 2012) 8.5% patients had vaginal cuff recurrent in our study and 3 of them received pelvic radiotherapy in our study.
Further adjuvant systemic therapy should be considered for patients with recurrent leiomyosarcoma after initial surgical treatment or radiotherapy. Systemic therapy is also important medical choice for patients with distant metastasis.
Leoimyosarcoma is extremely aggressive and responds poorly to traditional chemotherapeutics. Docetaxel/gemcitabine, doxorubicin, and ifosfamide are all reasonable options for advanced or recurrent disease with response rates ranging from 17% to 36%.(Seddon et al , 2017; Mbatani et al , 2018) Gemcitabine and docetaxel have demonstrated the highest objective response rates as first-line or second-line treatment for metastatic disease, with an OS of 14.7 months in second-line treatment.(Hensley et al , 2008) Gemcitabine-docetaxel remains a standard first-line treatment for uLMS.(Hensley et al , 2015) Recently, new drugs such as trabectedin and eribulin have showed promising therapeutic effect for patients with recurrent uLMS. (Pautier et al , 2015; Schöffskiet al , 2016) The most common chemotherapy regimens for recurrent uLMS were doxorubicin-based regimens and docetaxel/gemcitabine in our study.
Target therapy are important choice for patients with recurrent sarcoma. In recent years, targeted therapies such as pazopanib and olaratumab achieved a highly significant improvement in survival for patients with metastatic uLMS.(van der Graafet al , 2012; Tap et al , 2016) Larotrectinib is highly active treatment especially for patients with TRK fusions.(Hong et al , 2020) The potential role of immunotherapy is being assessed in current uLMS clinical trials. Doxorubicin in combination with pembrolizumab is a promising combination worthy of further study, especially in certain sarcoma subtypes.(Pollack et al , 2020; Livingston et al , 2021) Endocrine therapy is also an important treatment for recurrent sarcoma. Aromatase inhibitors can be considered for ER/PR-expressing uLMS.(George et al , 2014)
There are two limitations to our study. The current study was retrospective, and the primary treatment was not assigned at randomized. All patients with recurrent uLMS in this study came from our single center. Therefore, caution is required when interpreting our results.