The role of surgery and treatment trends in uterine sarcoma

The role of surgery and treatment trends in uterine sarcomaL.Benoit a,*,L.Arnould b,N.Cheynel a,S.Goui c,F.Collin b,J.Fraisse c, J.Cuisenier ca Service de chirurgie digestive,thoracique et cance´rologique,Hoˆpital du Bocage,CHU,Dijon,Franceb Service d’anatomie pathologique,Centre G-F Leclerc,Dijon,Francec Service de chirurgie,Centre G-F Leclerc,Dijon,FranceAccepted for publication6January2005Available online16February2005KEYWORDS Uterine sarcoma; Surgery; Metastases; Pelvic recurrences Abstract Aims.To report a series of uterine sarcomas treated in one institution. Methods.We report72cases of uterine sarcomas treated in a single institution, comparing the periods1966–1989and1990–2001.The parameters studied were histological type,tumour stage and treatment.The control of pelvic,local and/or metastatic disease were also studied.Results.The histological types consisted in34leiomyosarcomas,25mixte mullerian tumours,12endometrial stromal sarcoma and one angiosarcoma.The median age at diagnosis was60.5years.The presenting symptoms were genital bleeding,pelvic or abdominal pain.The proportion,of stage I was lower in1966–1989 than in1990–2002.During the1966–1989period,surgery was systematically used. The percentage of second-line surgery(post-radiotherapy or-chemotherapy)rose from2.2%in1966–1989to19.2%in1990–2002.Radiotherapy was administered in 55.5%of cases.There was no difference between the two periods.Chemotherapy was administered in37.5%of cases with also no difference between the two periods.The overall2-year survival was54.6%and the5-year survival36.1%.The median survival was32.3months(3days–25years).The overall5-year survival by stage was47.5%for stage I,60.6%for stage II and15.0%for stages III and IV.The median duration of pelvic disease control was19.2months.The5-year pelvic disease control by FIGO stage was66.6%for stage I,62.5%for stage II and18%for the more advanced stages. Conclusion.Surgery remains the reference treatment.Local and regional disease control,as adjuvant therapies do not seem to decrease the risk of metastatic spread or increase survival.q2005Elsevier Ltd.All rights reserved.IntroductionUterine sarcomas represent small percentage of alluterine malignancies and about1%of all femalegenital tract neoplasms.1The tumours derive fromEJSO(2005)31,434–442 0748-7983/$-see front matter q2005Elsevier Ltd.All rights reserved.doi:10.1016/j.ejso.2005.01.010*Corresponding author.Address:1,rue Pr.Marion,BP77980,21079Dijon Cedex,France.Tel.:C380737500;fax:C380671915.E-mail address:laurent.benoit@chu-dijon.fr(L.Benoit).mesenchymatous elements constituting the uterine corpus:endometrial stroma and smooth muscle. Other types of tumour such as angiosarcomas, rhabdomyosarcomas and malignantfibrous histio-cytomas are more rare and not specific to the uterine site.Uterine sarcomas may also be associ-ated with mixed epithelial and mesenchymatous tumours,which have a similar prognosis and biological behavior.For all those types of sarcomas, two prognostic categories may be distinguished. Thefirst category consists in high-grade malignant tumours:leiomyosarcomas(LMS),undifferentiated endometrial sarcomas,previously referred to as high-grade endometrial stromal sarcomas(ESS), and carcinosarcomas(CS),covering all mixte Mullerian tumours(MMT)in the WHO classification.1 The sarcomas whose site is not specifically the uterus are included in thefirst group.The second group consists in low-grade tumours:low-grade endometrial stromal sarcomas and adenosarcomas.The rarity and histological differences in those tumours underlie the difficulty in determining treatment protocols.Neither chemotherapy nor radiotherapy has shown efficacy.Surgery is the only consensus treatment but even the value of oophor-ectomy or lymphadenectomy is controversial while the survival benefit of secondary excision has rarely been evaluated.This retrospective study of72 cases evaluates the position and change in thera-peutic practices for the management of uterine sarcomas over a37-year period.Patients and methodsCasesThe authors collated82patients with a diagnosis of uterine sarcoma in their healthcare facility.Of these,four were excluded as they were sub-sequently found to have sarcomas of non-uterine origin.In addition,six cases in which the patho-logical diagnosis of sarcoma was not confirmed on histological review were excluded(n Z6).A total of 72cases were thus included in the study.The data were obtained from the patients’records.The tumours were staged at the time of diagnosis using the modified International Federation of Gynaecology and Obstetrics(FIGO),staging system on the basis of the surgical data or,in the event of deferred surgery,on the basis of the clinical,biopsy and imaging data,and the histological diagnosis was based on the WHO classification.1Resection was considered curative when no gross lesion persisted at the end of the surgical procedure(R0).The duration of survival was the primary end-point.This was determined as the time from the date of diagnosis to the date of death or last follow-up.The cut-off for the survival,study was Decem-ber31,2002.The current status of the survivors was determined for all women.The time to recurrence was taken to be the interval between thefirst surgical procedure and management or discovery, by clinical examination or imaging,of the recur-rence.In the event of metastases in the month following diagnosis,the tumour was restaged FIGO IV.Patients dying‘of other causes’,but in whom disease progression was radiologically suspected were considered to have died of cancer.Case records were retrospectively reviewed with regard to patient characteristics,presenting symptoms, pre-operative diagnosis,tumour stage and charac-teristics,site of relapse,salvage therapy,and survival.Investigation was conducted for changes in the diagnostic conditions or therapeutic prac-tices by comparing the periods,1966–1989and 1990–2001.These two periods were chosen because in1990there was a modification in the head of surgical department.For the two periods,the parameters studied were histological type,tumour stage and therapy.The control of pelvic,local and/or metastatic disease was also studied. StatisticsStatistical analysis was performed included Kaplan–Meier life table analyses for determination of the effect of clinical and pathologic variables on recurrence and survival.Log-rank test,was used. Those variables found to be significant by univariate analysis were examined by multivariate analysis using the Cox proportional hazards model.For all statistical tests,two-tail P values!0.05were considered statistically significant.ResultsPatientsPatients characteristics are summarized in Table1. The median age at the time of diagnosis was60.5 years(range:33–91years).The histological diag-nosis,was based on specimens obtained by surgery, endometrial curettage,20and cervicovaginal smear.1Of the patients,34had LMS,25had a MMT,12a ESS and one had a angiosarcoma.The frequency of the different histological diagnoses was not different between the two periods analysed (Table2).None of the patients had personal orUterine sarcoma435familial history of sarcoma.Two patients had a history of breast carcinoma that was invasive and treated by mastectomy and radiotherapy in one case,and an in situ tumour treated by conservative surgery in the other case.The two patients presented with breast carcinoma 7and 1year,respectively,before the discovery of the sarcoma.One patient had undergone uterine myomectomy 18years before.All the patients except one were symptomatic.The most common presenting symptoms were genital bleeding,pelvic or abdomi-nal pain,poor general condition.2Haemorrhagic shock and a dyspnea were the presenting symptoms in one case each.A tumour mass was present in nine cases.The mass was pelvic (5),abdominopelvic (3),or located in the left iliac fossa (1).Inguinal lymphadenopathies resulted in diagnosis in onecase,as did vaginal nodules in one case,1and cervical polyps in three other cases.The FIGO staging distribution was:37,stage 1,8stage II,and 27stage III and IV.There was a trend to observe less FIGO stage I in 1966–1989than in 1990–2002period (p Z 0.06)(Table 2).TreatmentTreatment characteristics are summarized in Table 2.Surgical treatmentTwo patients refused surgical treatment,one from the outset and the other after two radiotherapy sessions.During the 1966–1989period,surgery was the initial treatment in 84.7%of cases.The per-centage of second-line surgery (post-radiotherapyTable 1Clinical characteristics of patients presenting with uterine sarcomaAllESS (n )LMS (n )MMT (n )Histology 7212(16.7%)34(47.2%)25(34.7%)Median age60.554.55666Menopausal status Post-menopausal 5052124Pre-menopausal 22a7131Presenting symptoms Genital Yes 5392122No 193133Pain Yes 5272222No 205123Other–Impaired general condition 242Non-pelvic,non-abdominal tumour 231Other 2–ParityNulliparity 10145Parity:1–3243147Parity21a 4106Not determined 17467FIGO stage I 375169II 8135III/IV27a 61511Tumour-related necrosis Yes 31a 21911No12439Not specified296125Myometrial invasion !2/33171311!2/316349nk25b2176a Case of the unique angiosarcoma belonging to the series.bNot known.L.Benoit et al.436or-chemotherapy)rose from2.2%in1966–1989to19.2%in1990–2002.The incision consisted always ina median laparotomy except for one Pfannenstiel incision and four vaginal routes,two with laparo-scopic guidance.Two of the laparotomy procedures were purely exploratory since this stage III tumours were considered inoperable(Table2).Extrafascial hysterectomy was the most frequent procedure. Radical hysterectomy was conducted for one case of stage II LMS.Three subtotal hysterectomies were performed in one case of stage IV LMS and two cases of stage II MMT.Bilateral salpingooophorectomy was systematically performed except infive cases, for technical reasons(vaginal route)or for perito-neal carcinosis.In one case of a LMS,the adnexa were conserved because of the patient’s age(34 years).Among the women initially treated by hyster-ectomy and bilateral salpingooophorectomy,10 underwent immediate complementary intestinal or peritoneal resection(nine LMS and one CS for four intestinal,two rectosigmoid,and four exten-sive peritoneal resections).Palliative pelvectomy was conducted in one case of MMT associated with a high hemorrhagic risk.All of these patients received additional therapy:radiotherapy(3), brachytherapy(1)or chemotherapy.6In this group,the causes of death were pelvic disease progression(3),local(4)or remote recurrence(3).Five patients underwent bilateral(3)or unilat-eral(1)ilio-obturator and paraaortic(1)lymph node dissection for three MMT,one LMS and one ESS of FIGO stage I(3)and II(2),respectively.None of the nodes had been invaded.Radiotherapy and brachytherapy were given in two cases.None of those patients experienced recurrence sub-sequently,but two died of other causes. Adjuvant treatmentPelvic radiotherapy(24–60Gy in20or27sessions) was administered in55.5%of cases(in11%asfirst-line treatment and in44.4%as post-operative second-line treatment).There was no difference between the two periods(54.3vs57.7%;p Z0.24)butfirst-line pre-operative radiotherapy was used three times more frequently during the more recent period(Table2).Chemotherapy was administered in37.5%of cases,most frequently a regimen that contained an association of doxorubicin,cyclophosphamide, DTIC and vincristine.14There was no between-period difference in the proportion of cases administered chemotherapy(37vs38.4%;p Z0.9). Chemotherapy was administered to26.3%of the stage I cases,25%of the stage II cases and57.7% of the stage III and IV cases,most frequently post-operatively.Two cases(FIGO stages II and I)received pre-operative chemotherapy.Chemotherapy wasTable2Distribution of histological types,FIGO stages and treatments,by period1966–1989vs1990–20021996–1989(n)1990–2002(n)p values FIGOI1918II71p Z0.06 III,IV207HistologyESS57LMS2311MMT178p Z0.35 Angiosarcoma1–SurgeryNo surgery20First-line surgery G post-treatment surgery4120Surgery post-first-line RT or chemotherapy15p Z0.35 Exploratory laparotomy11Exploratory laparotomy C secondary surgery00RadiotherapyNo radiotherapy2111p Z0.24 First-line radiotherapy G secondary radiotherapy35Post-operative radiotherapy2210ChemotherapyNo chemotherapy2916First-line chemotherapy G second11p Z0.06 Post-operative chemotherapy169Uterine sarcoma437thus administered pre-operatively in2.8%of cases, i.e.less than10%of the cases who received chemotherapy.According to FIGO classification,all the FIGO stage I cases underwent surgery(89.2%first line, 10.8%afterfirst-line radiotherapy or chemother-apy).The therapeutic strategy was similar for the stage II cases.Management was similar for the stage III and IV cases,but7.4%were inoperable and only underwent exploratory laparotomy. Recurrences and metastasesForty-two patients had metastases(58.3%).The most frequent metastatic sites were the lung,liver and peritoneum.The latter affected23patients. Elsewhere metastases consisted in single pulmonary metastases in eight cases(11.1%)and in a hepatic metastasis in one case(1.4%).A breast metastasis was inaugural in one case of MMT(Table1).Two patients,one presenting with ESS and the other with LMS,experienced aortic ischemia due to external tumoral compression,and one died during surgery.A patient died of radiation-induced bone sarcoma,12years after ESS diagnosis.There was no between-period difference in the probability of pelvic disease control.The control of FIGO stage II disease was statistically superior to that of stage I and to control of the more advanced disease(Table 4).The same results also applied to disease control (pelvic recurrence and/or metastasis)(Table5).Surgery for remote recurrences was conducted on six patients with controlled local disease.All the patients had undergone prior hysterectomy with bilateral salpingooophorectomy followed by radio-therapy(4),brachytherapy(2),chemotherapy(1), or,in one can,of ESS,hormonotherapy.Surgery consisted in peritoneal(2),intestinal(2)or pul-monary(2)resections,followed by systemic che-motherapy in four cases of LMS.Debulking combined with intraperitoneal chemotherapy with cisplatin and adriamycin was conducted in one case of ESS,while frontal cerebral metastasis was resected in one case of CS.The latter two patients are still in complete remission,with a mean follow-up of36months.SurvivalSurvival according to the study period to the histological subtype and to the stage is summarized in Tables3–5.The overall2-year survival rate was 54.6%(SD Z0.06)and the5-year survival was36.1% (SD Z0.06).There was no difference between the 2periods analysed(1966–1989vs1990–2002)in the 2-or5-year survivals,nor was there any difference according to histological type.The overall rate of pelvic disease control at2years was48.6%(SD Z 0.06).At5years,the correspondingfigure was 39.2%(SD Z0.06)(Table4).The median duration of pelvic disease control was19.2months(SD Z7.21 months).The5-year disease control,according to FIGO stage,was37.6%(SD Z0.09)for stage1,62.5% (SD Z0.17)for stage II and11%(SD Z0.06)for the more advanced stages(Table5).Multivariate analysisOverall,the probability of death was 1.75-fold higher for the group aged R55years than for the group aged!50years and2.13-fold higher for the FIGO stage III/IV group than for the FIGO stage I/II group.The risk of metastasis was2.47-fold higher (b/SD Z2.81;p Z0.006)for the FIGO stage III/IV group than for the FIGO stage I/II group.The1990–2002group had a1.89-fold higher risk of metastasis than the earlier group(b/SD Z1.8;p Z0.009).After adjustment for age,there was no significant difference in pelvic disease control between stages I and II.After adjustment for age,the probability of metastasis was lower(p Z0.07)for stage II than for stage I(OR Z0.30)(but the stage II population was small).Pelvic radiotherapy exerted no detectable effect on the probability of metastasis in stages I and II disease.Myometrial invasion depth had no detectable effect on tumour-related necrosis.The probability of pelvic recurrence was increased was increased3.65-fold(p!10K3)in FIGO stages III/IV vs stages I/II.DiscussionThe results of the current study underline the aggressive nature of uterine sarcomas and the challenges encountered in designing treatment plan.Moskovic et al.2had already compared the survival rates for two observation periods(1970–1980,vs1980–1990)without observing any signifi-cant difference.Ten years later,with5-year survival rates consistent with previous studies,3–9 we reached the same conclusion.The diagnosis of uterine sarcoma is frequently retrospective,usually following hysterectomy.The early diagnosis of stage I disease in the present post-1990series may be related to enhanced gynaecological follow-up or patient awareness. However,as it has been observed in other series, tumour stage is not the only predictor of outcome. Indeed,in previous published series,3,4,7,10lowL.Benoit et al.438grade ESS displayed always a best clinical outcome than the other sarcomas.In our series,we found a trend for better outcome in low grade ESS but, probably due to the number of the cases,the differences was not significant.Surgical treatmentSurgery is usually the initial stage of disease management.It constitutes the only reference treatment and enables precise staging.Chen et al. and Dinh et al.considered that the probability of extrauterine disease when the tumour is confined to the uterus may be as high as62%.11,12It is, therefore,hardly surprising that recurrence occurs in73%of stage I disease.13More radical initial surgery remains controversial.14Extrafascial hyste-rectomy with bilateral salpingooophorectomy seems an appropriate response to the aggressive-ness of LMS or ESS,but is probably inadequate for MMT.15In the latter setting,pelvic or even paraaortic lymphadenectomy is recommended in the event of lymphadenopathy,with omentectomy, multiple peritoneal biopsies and systematic abdominal lavage.It is accepted that parametrial exeresis is of no value except in the event of cervical involvement.16The role of bilateral sal-pingooophorectomy,including in post-menopausal women,is under debate.Adnexectomy is reported to improve the prognosis of LMS and decrease the frequency of ESS recurrence.17,18Gaducci considers that the survival rate after castration is inferior to that when the adnexa are conserved(33vs17%), even though the hormone-sensitive nature of the tumours argues in favor of bilateral oophorectomy.17 In young women,only in the event of low-gradeTable3Overall survival by study period,histological type and stageTotal Two-year survival(SD)Five-year survival(SD)Median survival(SD)(month)Overall720.5460.36132.25(12.2) Period1966–1989460.540(0.07)0.349(0.07)37.2(15.2) 1990–2002260.543(0.10)0.434(0.11)28.2(8.4)p Z0.75 Histological typeLMS340.523(0.08)0.302(0.08)27.3(19.8) MMT250.577(0.01)0.385(0.1)34.8(12.18) ESS120.585(0.14)0.585(0.14)36.7(20.75) Angiosarcoma10(0.08)0(0.09)0p Z0.18 StageI370.687(0.182)0.475(0.18)52.9(30.7) II80.600(0.091)0.600(0.075)NC(–)III/IV270.393(0.06)0.150(0.06)7.5(2.8)p Z0.013 Table4Probability of pelvic disease control by study period and FIGO stageTotal Two-year survival(SD)Five-year survival(SD)Median survival(SD)(month)Overall720.480(0.06)0.392(0.06)19.2(7.21)Period1966–1989460.477(0.07)0.380(0.07)12.1(13.47)1990–2002260.479(0.10)0.426(0.1)18.9(6.36)p Z0.49StageI370.666(0.08)0.569(0.086)82.5(–)NCII80.625(0.17)0.625(0.17)NC(–)NCIII/IV270.185(0.07)0.111(0.06) 3.21(2.01)p!10K4Uterine sarcoma439stage-I endometrial stromal sarcoma the adnexa should be spared.17Like Morice et al.,the present authors have always preferred the conventional treatment except in one case.18The value of lymph node resection is also highly controversial.In this series,the procedure was conducted five times without detecting any metas-tasis.Goff et al.19has reported lymph node invasion rates for early-stage leimyosarcoma and endo-metrial stromal sarcoma of 47and 0%,respectively,while for the Gynaecologic Oncology Group,the frequency of lymph-node metastases in stage I/II LMS did not exceed 3.5%.10Lymph nodes metastasis are considered more frequent in case of recurrence or peritoneal spread of LMS,but would remain stable for endometrial stromal sarcomas.19There-fore,the low risk of lymph node involvement in leiomyosarcoma is not an argument for systematic lymphadenectomy.Metastatic nodes are reported to be more frequent in the pelvis (37.5%)than in the para-aortic region (14.3%).20Irrespective of histo-logical type,the 3-year survival for stage I patients having undergone lymphadenectomy was not sig-nificantly different from that in the absence of lymphadenectomy (66vs 52.6%).10For some authors,lymphadenectomy is mainly of prognostic value.21PrognosisDespite complete surgical resection,the recur-rence rate may reach 61%,with local recurrence in over half of those cases.5,11,12Leiomyosarcoma recurs outside the pelvis in almost 80%of cases.17Metastasis most frequently occurs in the first 2years after diagnosis.10The most frequent meta-static sites are the lungs,liver and bone.Cutaneous sites have rarely been reported,but account for 5%in the present series.Surgical treatment of relapseSurgical treatment of an apparently ‘single’metas-tasis is only indicated if the control of the pelvic disease has been achieved.One of our patients,who presented with ESS and underwent surgical resection of a brain metastasis,has thus been in remission for 4years.Levenback et al.reported 43%5-year survival after resection of pulmonary metas-tases,22while,for Anderson et al.,survival did not exceed 26months.23In a study of 41cases of LMS,Leitao et al.reported a 71%survival at 2-years after secondary resection.24The emergence of recur-rence in the 12months following first-line surgery and the quality of the resection were the only two prognostic factors identified by those authors.Excision of the hepatic metastases of LMS is reported to yield 33%5-year survival with a median survival of 40months,i.e.greater than that obtained with chemotherapy alone.25Radiotherapy and chemotherapyThe poor disease control is in itself an indication for adjuvant therapy.In most cases,radiotherapy improves local control but not survival.3,6,7On the basis of the results of a recent clinical trial,there is no difference in terms of overall survival or disease-free survival for sarcomas,but radiotherapy seemsTable 5Probability of disease control by study period,stage and histological typeTotalTwo-year survival (SD)Five-year survival (SD)Median survival (SD)(month)Overall 720.395(0.06)0.320(0.06)13.44(5.8)Period1966–1989460.0409(0.07)0.339(0.07)10.7(9.7)1990–2002260.42(0.10)0.285(0.09)16.3(4.5)p Z 0.95Stage I 370.462(0.097)0.376(0.09)16.8(8.3)II 80.625(0.17)0.625(0.17)NC (–)III/IV270.154(0.07)0.115(0.06) 1.11(0.6)p !10K 4Histological type ESS 120.500(0.14)0.500(0.14)10.7(23.7)LMS 340.374(0.08)0.229(0.07)11.9(8.6)MMT250.355(0.103)0.355(0.103)20.0(5.3)p Z 0.71L.Benoit et al.440to provide a superior local disease control for MMT and no benefit with respect to LMS.26Neodajuvant chemotherapy may be considered in the event of isolated rectosigmoid spread or tumours initially considered inoperable,whilefirst-line hysterectomy with bilateral salpingooophor-ectomy remains thefirst-line treatment even in case of vesical or peritoneal involvement,or even with metastasis.18Systematic chemotherapy for remote metastases is disappointing.27Nordal et al.has shown that the introduction of chemotherapy in the seventies had no impact on patient survival.28The most active drugs are doxorubicin and ifosfamide,with a response rate of30%but no improvement in survival.2,29In advanced LMS,mitomycin,doxor-ubicin and cisplatin seem,however,to be more promising.30The results of the‘SARC-GYNI’clinical trial comparing post-operative adjuvant che-motherapy combined with pelvic external-beam radiotherapy to pelvic radiotherapy alone are expected in2007.ConclusionsUterus sarcomas are rare neoplasm with a poor prognosis.Surgery,is the reference treatment for primary tumour and,when possible,for metas-tases.Adjuvant radiotherapy seems to improve the local control of the disease,but like different chemotherapy regimens,do not improve the survi-val of the patients.The lack of efficacies of these adjuvant therapies may explain why,even with a diagnosis at a earlier stage,the poor prognosis of these tumours are not dramatically changed during the last30years.New drugs,as taxanes,have currently not demonstrated their efficacy,31but deserve further investigation while awaiting other more effective molecules or strategies. 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