Uterine sarcomas—Recent progress and future challenges

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Abstract

Uterine sarcomas are a group of rare tumours that provide considerable challenges in their treatment. Radiological diagnosis prior to hysterectomy is difficult, with the diagnosis frequently made post-operatively. Current staging systems have been unsatisfactory, although a new FIGO staging system specifically for uterine sarcomas has now been introduced, and may allow better grouping of patients according to expected prognosis. While the mainstay of treatment of early disease is a total abdominal hysterectomy, it is less clear whether routine oophorectomy or lymphadenectomy is necessary. Adjuvant pelvic radiotherapy may improve local tumour control in high risk patients, but is not associated with an overall survival benefit. Similarly there is no good evidence for the routine use of adjuvant chemotherapy. For advanced leiomyosarcoma, newer chemotherapy agents including gemcitabine and docetaxel, and trabectedin, offer some promise, while hormonal therapies appear to be more useful in endometrial stromal sarcoma. Novel targeted agents are now being introduced for sarcomas, and uterine sarcomas, and show some indications of activity. Non-pharmacological treatments, including surgical metastatectomy, radiofrequency ablation, and CyberKnife® radiotherapy, are important additions to systemic therapy for advanced metastatic disease.

Introduction

In 2006, uterine cancer was only the thirteenth commonest cancer in the UK, and only the fourth commonest cancer in women in the UK, with an incidence of 18.1 per 100,000, accounting for 7045 cases [1]. Uterine sarcomas are especially rare, comprising only 8.4% of uterine cancers [2]. Nevertheless, there has in recent years been significant progress in the more accurate classification, staging and management of patients with uterine sarcoma. Despite the rarity of this tumour, in the last two years several review articles have been published on the current management of uterine sarcomas [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Thus, the emphasis of this article is not to repeat previous reviews, but rather to highlight recent progress, emerging evidence, and future challenges of relevance and interest to both oncologists and radiologists (Table 1).

Section snippets

Pathology

The current World Health Organisation classification of tumours of the female genital tract classifies uterine mesenchymal tumours into smooth muscle and endometrial stromal tumours [13]. Smooth muscle tumours are benign or malignant neoplasms composed of cells showing smooth muscle differentiation arising within the myometrium. They are divided into benign leiomyoma, smooth muscle tumour of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). Endometrial stromal tumours arise from

Clinical presentation and diagnosis

The clinical presentation of uterine sarcomas is non-specific. The peak incidence is between 50 and 65 years of age. The classical history is often of a rapidly growing uterine mass, and additional symptoms may include pelvic or abdominal pain and vaginal bleeding. However, the diagnosis of uterine sarcomas is frequently unexpected, discovered incidentally on histopathology review following hysterectomy, often for fibroids (benign leiomyomas) [30]. Of those patients undergoing hysterectomy for

Prognostic factors and staging

Prior to treatment, newly diagnosed cancers will be staged to define tumour extent. An effective staging system will define individual stages that will accurately stratify patients into clinically meaningful groups, with distinct outcomes and prognosis, which will in turn guide management. The staging of uterine sarcomas has for many years now been unsatisfactory. Until recently the 1988 International Federation of Gynaecology and Obstetrics (FIGO) staging system for uterine corpus cancer was

Surgical management for early stage disease

Primary management for early stage operable uterine sarcomas is surgical, with total abdominal hysterectomy with or without bilateral salpingoophorectomy [68]. Surgery is the most important component of treatment, and indeed the absence of primary surgery [57], [62] or incomplete cytoreduction [30], [69] has been shown to be independent prognostic factors.

Involvement of pelvic lymph nodes in LMS is infrequent (Table 6), and is usually associated with visible enlargement of the lymph nodes

Adjuvant radiotherapy

Until recently, evidence on the role of adjuvant radiotherapy in uterine sarcomas had been limited to retrospective non-comparative case series. Papers have not clearly described outcomes for individual histological subtypes, have frequently included CS, and have not differentiated between ESS and UES. This has made assessment of the potential benefit of radiotherapy in particular sarcoma subtypes difficult to quantify. However, in the last two years, a phase III study and three population

Adjuvant chemotherapy

The pattern of relapse in uterine sarcomas, particularly in the higher grade LMS and EUS, is mostly distant metastases, often with locoregional disease [63], [83]. Hence, the use of adjuvant chemotherapy to reduce local and distant relapses and improve cure rates has been attractive. However, there are only limited data available to support the use of adjuvant chemotherapy specifically for uterine sarcoma. An early randomised study in the 1980s found that adjuvant doxorubicin compared with

Chemotherapy for metastatic disease

In soft tissue sarcoma generally, standard first line chemotherapy for metastatic disease has been unchanged for three decades and remains doxorubicin with or without ifosfamide [92], [93]. A large number of phase II studies of single chemotherapy agents have been carried out in metastatic uterine sarcomas and specifically LMS, evaluating a range of agents over the last two decades. Some of these have been active (doxorubicin, response rate (RR) 25% [94], ifosfamide RR 17.2% [105], gemcitabine

Hormone therapy – adjuvant and metastatic treatment

The incidence of hormone receptor positivity in LMS and ESS has been discussed earlier (Section 2). Given the low toxicity profile of hormonal therapies as compared with chemotherapy, their use in uterine sarcomas in both the adjuvant and advanced settings has been the subject of some considerable interest amongst both clinicians and patients.

The use of adjuvant hormonal therapy after primary surgery in ESS has been reported in a number of studies. A retrospective series of 22 patients with ESS

Novel targeted agents

The few effective chemotherapy agents, and their associated toxicities, have meant that identifying new targeted agents effective in uterine sarcomas is an important priority. Increasing numbers of targeted agents are being introduced into clinical use, and indeed one of the earliest examples that provided proof of principle in solid tumours was in sarcoma, when the receptor tyrosine kinase inhibitor imatinib mesylate was shown to be clearly effective in the previously treatment resistant

Surgery and locally ablative therapies for metastatic disease

The role of surgery and locally ablative therapies for metastatic disease in uterine sarcomas depends upon the extent of disease and the aims of treatment. Pulmonary metastatectomy has become a standard intervention with potentially curative intent in selected patients with lung metastases [147]. Recent series’ of patients who have undergone pulmonary metastatectomy for soft tissue sarcoma metastases have indicated a survival benefit for surgery, with 5 year overall survival rates of 18–38%.

Conclusions

Uterine sarcomas are a rare group of tumours, and it is this rarity that makes their management challenging. There is a lack of data, and in particular a lack of randomised controlled trials, to guide management of these patients, which leaves a reliance on information derived from small retrospective case series. Recently this has been overcome to some degree by utilising large population based databases, which have provided important insights into treatments. In addition, useful information

Acknowledgement

This work has been supported by UCLH/UCL Comprehensive Biomedical Research Centre.

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