GYNECOLOGIC CANCERS (NS REED, SECTION EDITOR)

A Review of Treatment of Uterine Leiomyosarcomas

Nicholas Reed

Published online: 18 October 2013# Springer Science+Business Media New York 2013

Abstract Uterine leiomyosarcomas are rare but challengingtumours. They occur most commonly around or shortly afterthe menopause. Their clinical behaviour is very variable,from highly aggressive to very indolent. Most are diagnosedunexpectedly and thus initially operated on by generalgynaecologists. This article discusses the important surgicalissues and the role of adjuvant treatments such as radiotherapyand chemotherapy. Important new international trials areopening to address these issues. Relapsed disease is usuallyincurable, but a subgroup of patients may benefit fromrepeated surgical procedures, hormones and ablative thera-pies. The choice of drugs for chemotherapy is discussed.New approaches with targeted agents have yet to establishthemselves in treatment of leiomyosarcomas.

Keywords Uterine . Leiomysarcoma . Adjuvant .

Chemotherapy . Radiotherapy

Introduction

Uterine leiomyosarcomas (LMS) are relatively uncommoncancers most commonly arising in the perimenopausal woman.Much has been written in the historical literature about therelationship to fibroids, but it is really quite rare to find an LMSarising in a fibroid, although it is not uncommon to findassociated fibroids. Further details on the incidence can befound in historical review articles [1–3]. Uterine LMS are mostcommonly diagnosed after surgery usually performed inpatients with menstrual disorders or “fibroids” when the finalanalysis of the hysterectomy specimen reveals a smoothmuscletumour, and hence the patient will be referred to the tumourboard or multidisciplinary team for further management.

Historically, they were divided into carcinosarcomas, alsoknown as malignant mixed mesodermal tumours, LMS andendometrial stromal sarcomas, but now it is more appropriate todiscuss high-grade and low-grade sarcomas [4–6]. Traditional-ly, they were thought to be three separate entities, but newtechnologies have blurred these distinctions. This probablymakes a lot of sense practically, although the old terms are stillfrequently used in clinical usage.

Smooth muscle tumours of the uterus range from those ofunknown malignant potential, through to high-grade LMSwith a very aggressive pattern of relapse and spread. However,it is clear that there is a significant spectrum, and furthermorethere is some overlap with the other uterine sarcomas as theymay have mixed appearances or molecular profiling which isheterogeneous. The future will lie with molecular typing todetermine the classification, and this also has the potential todirect new therapeutic options. In a recent article, Mehineet al. [7•] discussed the genomics of smooth muscle tumoursof the uterus, and may give some clues to why multipleleiomyomas may develop in the same patient.

It is also important to stress that there are differences inbehaviour between uterine and extrauterine LMS, and this hasbeen reviewed in a recent article [8•]. It would appear that apartfrom age at presentation being younger in uterine LMS, there arefew differences. Historically, gastrointestinal stromal tumourswere sometimes labelled as LMS but the use of c-kit and othermolecular markers has allowed this important distinction to bemade as they require a very different management approach.

Diagnosis and Staging

The primary diagnosis is unlikely to be made on imaging.Patients may be identified as having fibroids, but sincefibroids are common and LMS are rare, the chance of identi-fying a fibroid with a malignant transformation is unusual [9].A transvaginal ultrasound examination may have been done,but is likely just to show a “fibroid”. The diagnosis is usually

N. Reed (*)Beatson Oncology Centre, Gartnavel General Hospital,1053 Great Western Road, Glasgow G12 0YN, UKe-mail: nick.reed@ggc.scot.nhs.uk

Curr Oncol Rep (2013) 15:581–587DOI 10.1007/s11912-013-0350-4

onlymade at the time of surgery, and therefore detailed imagingis performed postoperatively. The whole topic of imaging of alluterine sarcomas was nicely reviewed by Shah et al. [10].Surgery is often performed by a general gynaecologist andmay often be just a “simple hysterectomy”, especially if thepatient has been referred with menstrual disorders or fibroids.In younger women, ovarian preservation may be performed, sothe patient needs to be referred to the tumour board or multi-disciplinary team for discussion of reoperation, restaging andfurther management.

Is it necessary to complete surgery and if so what type?Arguments abound about the need for completion bilateralsalpingo-oophorectomy, omentectomy and nodal dissection.Amant [11] and others have reviewed the literature, and itwould appear that there is no significant benefit associatedwith completion oophorectomy in the younger woman. TheGynecologic Oncology Group (GOG) has studied the role oflymph node involvement, and the article by Major et al. [12]from the early 1990s is still quoted as it showed the incidenceof pelvic lymph node metastasis in LMS was under 5 %,whereas for carcinosarcomas and endometrial stromal sarco-mas it may be of the order of 15-20 %. A number of other,more recent reviews have also confirmed the relatively lowincidence of lymph node metastasis, as a result of which it isgenerally recognised that pelvic lymphadenectomy has littleto offer in these patients unless the nodes are obviouslyclinically involved [13–17]. These tumours tend to spreadvia haematogenous routes directly to the lungs, bones andliver. As already alluded to, it is necessary to refer thesepatients to the local tumour board or multidisciplinary teamso that their cases can be registered and discussed and appro-priate further management identified.

For the patient with no evidence of disseminated disease,there is presently still no level 1 evidence to support theroutine use of adjuvant chemotherapy, hormonal therapy orradiotherapy. These tumours are not often recognised preop-eratively, and it is only after hysterectomy that a diagnosis ismade. Completion staging imaging should be done with atleast CT of the chest, abdomen and pelvis. There is someevidence that PET–CT may be of value [10, 18]. It is alsoimportant to get expert pathology review and discussion at thetumour board. The distinction between low-grade and high-grade tumours may not always be clear-cut, and an expertgynaecological pathologist will improve the chances of gettingthe correct histological grading. The management of smoothmuscle tumours of unknown malignant potential is, by defini-tion, uncertain, but it is generally believed that they should befollowed up for a number of years by specialist teams so thatlate relapse can be dealt with appropriately [19].

The immediate issues for discussion include further stagingwith imaging, and whether there is any place for furthersurgery, i.e. completion bilateral salpingo-oophorectomy andlymphadenectomy, and then the final part of the discussion

will be to review whether there is any role for adjuvanttreatment.

Adjuvant Treatment

What adjuvant treatments are available? Currently theseinclude external beam radiotherapy, vaginal brachytherapy,chemotherapy, hormonal therapy and new targeted agents.So what and where is the evidence to support any of these?The number of randomised clinical trials has been small,and historically many have combined the different subtypesof uterine sarcoma, making it difficult to determine the realvalues of any treatment in the adjuvant setting. The evidenceavailable comes from a small number of randomised clinicaltrials, a Cochrane analysis and experience from singlecentres. All of these are discussed herein. Until now, therehas been no level 1 evidence to support the use of anyadjuvant therapies. Reichardt [20] recently produced excellentupdated summarised guidelines.

Chemotherapy

The issue of adjuvant treatment is starting to change as a coupleof recent articles have suggested that there may be some benefitfrom the use of adjuvant chemotherapy. Two earlier collabora-tive reviews failed to demonstrate any survival advantage forchemotherapy in LMS [21, 22], and another article from theItalian cooperative group, in 2001, again failed to show anysurvival benefit [23]. This is being addressed further by aninternational collaborative trial looking at the role of adjuvantchemotherapy, and this will be discussed shortly. Historically,the first trials to look at adjuvant chemotherapy came from theGOG [24, 25], but many of the historical articles are difficult toassess as they concerned non-randomised trials, contained amixture of all three types of uterine sarcomas and did not reportresults in the manner used today [24–29]. Omura was the firstto show that adjuvant doxorubicin could reduce the risk ofrelapse but without any impact on survival, and this was thepattern over the next 20 years until newer schedules wereintroduced. The drugs that have been assessed mainly focusaround the anthracyclines, ifosfamide and dacarbazine, al-though more recently gemcitabine, docetaxel and trabectedinhave been evaluated [21–30]. This is in contrast to carcinosar-comas, where anthracyclines, taxanes and platinum-baseddrugs are more effective.

The initial GOG studies, which included both LMS andcarcinosarcomas, focused on either doxorubicin or doxorubicinwith ifosfamide, and although they did show that there was atendency to reduce the risk of recurrence, there was no survivalbenefit [24, 25]. Several articles reported experience from dif-ferent centres over the next 15 years [21–30]. Ameta-analysis in

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1997 reviewed adjuvant chemotherapy in all types of soft tissuesarcomas which contained a significant proportion of uterinetumours, but again there was no evidence to support the role ofadjuvant chemotherapy [21]. The overview of Bramwell [22] in2001 came to similar conclusion. In the early years of thiscentury, a further study from Italy evaluated epirubicin andifosfamide in soft tissue sarcomas, which again included uterineLMS, but they again failed to show a survival benefit for LMS,although overall there was a hint again of benefit, but this failedto achieve statistical significance [23]. Until recently the litera-ture has not really shown any supportive evidence for theroutine use of adjuvant chemotherapy. Several recent articleshave addressed this topic which remains debatable [31–33].

The drugs selected for adjuvant chemotherapy have usuallyestablished themselves at first in advanced disease stages. Arecent meta-analysis and systematic review [34••, 35] haslooked at chemotherapy for inoperable or locally advanceddisease. This will be discussed in more detail shortly, butdoxorubicin, ifosfamide, docetaxel and gemcitabine are thekey active drugs. However, it is therefore probably fair to saythat at the time of writing there remains no proven evidencefor the use of adjuvant chemotherapy outside the clinical trialsetting. It is therefore necessary to discuss these issues now.There appears to be an increased rate of response to docetaxeland gemcitabine. This follows on from a series of studiesinitiated by Hensley et al. [36] which have inspired newapproaches in this group of tumours.

This combination is now being investigated by the GOG277 study, which is a collaboration between the GOG andother international partners. So what is the background to this?The SARC 0005 prospective phase II randomised trial ofadjuvant gemcitabine and docetaxel followed by doxorubicinfor high-grade uterus-limited LMS was reported by Hensleyet al. [37•]. This showed that although 12 of 46 patientsshowed recurrence, it was concluded that 78 % of the womenwith disease confined to the uterus treated with adjuvantchemotherapy remained progression-free at 2 years. Thiswas better than other historical controls, which had shownbetween 50 and 70 % chance of relapse. A study such as thisuses small numbers of patients and there may be a degree ofselection in terms of the patients included in the study, andthus it is essential that this is taken further in a largerandomised trial. On the basis of the promising results identi-fied in the SARC 0005 study, Hensley et al. presented anoutline protocol to the GOG, and this has now been adopted.There was much debate about whether the control arm shouldinvolve an aromatase inhibitor such as letrozole or no treat-ment, and the final decision after much lively debate was tohave a no-treatment comparator arm. Pautier et al. [38] report-ed the French cooperative SARCGYN study, which comparedchemotherapy and radiotherapy with radiotherapy alone. Itclosed prematurely owing to poor recruitment, but againshows indications of delay in progression-free survival with

cisplatin, doxorubicin and ifosfamide, even if overall survivalbenefit could not be shown.

Radiotherapy

There are no randomised clinical trials that show any survivaladvantages of postoperative external beam radiotherapy. Inspite of this, it is sometimes still given to so-called high-riskpatients. The historical data [39–48] from the 1960s to the1980s suggested a benefit to patients from adjuvant externalbeam radiotherapy, but the only randomised clinical trial is theEuropean Organisation for Research and Treatment of Cancer(EORTC) 55874 study; this included 103 uterine LMS [49].Uterine LMS unlike carcinosarcomas tend to spread by thehaematogenous route, so local relapse is less of an issue andpatients develop distant metastatic spread. The Mayo Clinicseries showed no benefit, although a series of over 200patients from California suggested a survival benefit, butwas a non-randomised series [50].

As the only randomised trial to include LMS, the EORTC55874 trial compared adjuvant radiotherapy versus observa-tion in uterine sarcomas. It included 103 LMS; there was asmall but non-significant reduction in local failure (22 vs 26)and no survival advantage. Substantially more patientsdeveloped distant failure in the adjuvant radiotherapy arm(27 vs. 16). This author’s policy is to advise that adjuvantradiotherapy should be withheld in women with uterineLMS where there has been complete macroscopic removal oftumour, and there remains no firm evidence to give treatmentwhich has not been shown to be of benefit. New and effectiveadjuvant treatments are desperately required. Molecular pro-filing may be the next approach to allow strategies to bedeveloped to personalise care.

Advanced or Inoperable Disease

There have been two systematic reviews over the past 8 yearsfromCanada in advanced disease [34••, 51]. The managementof relapsed disease has undergone a number of evolutionsover the course of the past 20 years. The early trials from theGOG evaluated doxorubicin or doxorubicin and ifosfamide.Again the historical articles are a little difficult to interpret asthey included all types of uterine sarcomas [52–59], and it hasonly really been in the last 5–10 years that clinical trials haverecognised the importance of distinguishing these tumourtypes [60–68]. Not only is the pattern of spread different,which reflects the biology, but there is also a difference inresponses to chemotherapy agents. Whereas in carcinosar-comas, platinum-based drugs, taxanes and anthracyclines arekey drugs, in LMS the platinum-based drugs and taxanes havebeen shown to be much less active. Historically, the important

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drugs were ifosfamide and doxorubicin, and studies havelooked at single-agent doxorubicin or combined doxorubicinand ifosfamide. Other drugs that have been incorporated inthese trials include high-dose methotrexate and dacarbazine.

Previous articles have focused on the historical data, andtherefore it is probablymore important to confine our attentionto contemporary views. Single-agent doxorubicin hasremained the drug of choice. Ifosfamide tends to be used assecond-line therapy [34••, 35]. So we should focus on futuredirections. A series of articles by Hensley et al. [62, 68], whoevaluated a combination of gemcitabine and docetaxel, haveled to significant changes in the management. The marine-derived trabectedin has also shown interesting activity and isincreasingly being adopted into practice [69–73]. The selectionof Hensley et al. of gemcitabine and docetaxel caused somesurprise because the individual drugs are not particularly activeand yet in their first phase II trial report they indicated that therewas an around 53 % response rate in 34 patients, some ofwhom had been previously treated with doxorubicin.

Fortunately for the benefit of the author of this article, thisyear has seen the publication of a systematic review from thePrincess Margaret Hospital in Toronto [34••] of systemic che-motherapy for inoperable or locally advanced or recurrent ormetastatic uterine LMS. This was accompanied by an editorial[35]. This is a valuable and useful article, although it focusesonly on a relatively small number of studies which were con-sidered suitable for entry into the review. Not surprisingly, theconclusion is that further new studies are required in order toevaluate the situation further. This has confirmed that doxorubi-cin, which has been used for the past 30 years, remains one ofthe most active drugs. Gemcitabine used as a single agent hadroughly equivalent activity, but combinations of gemcitabineand docetaxel seem to offer benefit. The recent GEDDES trialconducted in the UK has looked at doxorubicin versusgemcitabine and docetaxel in all patients with soft tissue sarco-mas, but did include a significant number of patients withtumours of uterine origin. This trial is due to close in 2013,and obviously the results will not be available for a couple ofyears, but it may help to inform practice in the future. Increas-ingly, the use of gemcitabine and docetaxel has been adopted asa standard of care mainly because the results from the phase IItrial showed such superior benefit compared with conventionaltreatments, but it is difficult to not consider this to be animportant treatment option in this group of patients. The ques-tion is whether for first recurrent disease one would recommenddoxorubicin as a single agent or go straight to docetaxel andgemcitabine. One suspects that in Europe it is more likely thatsingle-agent doxorubicin would be given as the first choice, withdocetaxel and gemcitabine being reserved for relapsed disease.This would seem to be a reasonable working arrangement.

New drugs being investigated include the marine-derivedcompound trabectedin [69–73]. This clearly has activity inuterine sarcomas of smooth muscle origin, but has the

drawback that it undoubtedly causes far greater toxicity, in-cluding myelosuppression, and generally requires the use of acentral line for infusions. This may be important in identifyingpatients to be treated primarily with trabectedin. Further eval-uation of this drug will be required over the course of the nextfew years. Several articles have reported the effects oftrabectedin—it is clearly active and will need further evaluationto find its niche role in management of LMS.

Newer Targeted Agents

The introduction of targeted agents and molecular testing holdsgreat promise for the future, but at the time of writing no agenthas established itself. The initial targets of epidermal growthfactor receptor and vascular endothelial growth factor have beenlooked at, but no evidence of activity has been found yet. Small-molecule tyrosine kinase inhibitors have also yet to show anyimpact. Some recent articles have identified the mammaliantarget of rapamycin pathway and the Akt/phosphatidylinositol3-kinase pathway may be relevant, but nothing has been clini-cally proven in practice, but there are several emerging newagents that work through these pathways. Insulin-like growthfactor receptors have shown some initial promise, but a break-through has not been made yet. It must be remembered thatthese drugs are still in relatively early phases of development,having been around for only about a decade, and additionallyuterine LMS are uncommon and not of highest priority regard-ing commercial development. However, we should encouragenew clinical studies in the field [74–79].

Targeted agents have so far not established a definite role forthemselves. Pazopanib was investigated in the PALETE studyand shows potential [79]. Insulin-like growth factor receptor 1compounds are also under review, but more work is needed.

Hormonal Therapies

Hormonal therapy is also important in a small group ofpatients. The author is of the view that routine oestrogen andprogestogen receptor testing should be conducted on the ini-tial specimen at the time of diagnosis. This then providesimportant information for later treatment. There is no provenbenefit from the use of hormonal therapy as an adjuvant in thefirst-line setting, but because these patients often have a longnatural history, it may be many years before there is recur-rence, and the availability of the initial blocks for histologicalanalysis may not be straightforward.

In the recurrent setting, patients with oestrogen receptor/progestogen receptor positive tumoursmay be treated by tamox-ifen, megestrol acetate, combinations of the two or increasinglyaromatase inhibitors, such as letrozole [80]. The rate of responseto these compounds is around 15-30 %, and some of the

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remissions may be very long lasting. I have seen morethan a dozen patients with long-term control. This hasalso been reported by O’Cearbhaill [80] from the Memo-rial Sloan-Kettering Cancer Center. The PARAGON trialis also evaluating the use of aromatase inhibitors ingenital tract neoplasms which are strongly oestrogenreceptor/progestogen receptor, positive and this will help toprovide further information about their value.

Surgery

There remains an important role for surgery in selected patientswhere metastasectomy is considered for patients with isolatedor small numbers of lesions which are relatively slowgrowing, and some patients with chronic relapsing LMSmay be treated with repeated metastasectomy over a numberof years. Biologically these appear to be a rather differentgroup of patients, usually oestrogen receptor and progestogenreceptor positive. Lung lesions as well as isolated liver metas-tases may be suitable for such an approach [81–83].

Radiofrequency ablation is another supplementary optionthat may be considered in more slow growing tumours [84].The issue of secondary debulking surgery for Uterine LMS isunproven, but in individual cases discussed at TumourBoards, it may be reasonable to consider this. Giuntoli et alhave written up their experience [85].

Conclusion

In summary, LMS are relatively uncommon tumours. The pri-marymanagement should be by surgery with hysterectomywithor without bilateral salpingo-oophorectomy. There is no provenbenefit for pelvic lymphadenectomy. At this point in time thereremains no proven benefit for the use of adjuvant chemotherapywith either radiotherapy or chemotherapy or hormonal therapy.Entry of patients into clinical trials is strongly to be recommend-ed to help address whether there is a benefit for adjuvantchemotherapy with gemcitabine and docetaxel. For recurrentdisease, many would argue that single-agent doxorubicin re-mains the treatment of choice and that gemcitabine anddocetaxel should be kept in reserve. Newer agents, includingtrabectedin, remain under evaluation. For the future, the targetedor molecular agents hold great promise. The Memorial Sloan-Kettering Cancer Canter group has tried to develop nomogramsto allow risk groups to be identified to improve future treat-ments, and this is another interesting approach [86•].

Compliance with Ethics Guidelines

Conflict of Interest Nicholas Reed declares that he has no conflict ofinterest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by theauthor.

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