Uterine Sarcomas :Where do we stand? Dr.Beena.K.Radiation OncologistAIMS,Cochin

Uterine sarcomas are large fleshy tumours .*

Contents New WHO ClassificationManagement options in each sub group and role of RT.Target Volumes of RT.

IntroductionUterine sarcomas are uncommon : 3% of all uterine neoplasm.

Heterogeneous group with varying behavior.

Insufficient data to make standard recommendations.

Rarity of disease makes adequately powered randomized trials impractical.

Classification :RECENT WHO 2014

ESS LOW GRADEEndometrial stromal origin :resembles proliferative phase Low grade ,

ESS HIGH GRADEPreviously was part of undifferentiated endometrial ca .(WHO 2003 )Now redefined in the present WHO as high grade ESSUniform round cells ,with occasional low grade areas.ER,PR _ve,CD10 Ve,Cyclin D1 +VeYWHAE - FAM22 fusion +ve .(10:17 translocation)Hormone treatment is not effective .Prognosis better than undifferentiated sarcoma.

AdenosarcomaOnly mesenchymal component is malignant.Usually low grade ,ER ,PR positive.

LMS40-60% uterine sarcoma : Most common.Smooth muscle origin Associated with tamoxifen therapy Desmin,+ve, ER,PR +ve ~ 30%Stage 1 and II 5 yr survival:40-70%Overall 5 yr survival: 15-25 %

UNDIFFERENTIATED UTERINE SARCOMANo differentiation, pleomorphic. classified as Undifferentiated Endometrial Sarcoma WHO 2003. (UES).High grade ESS is now removed from this group (WHO 2014 )Prognosis : bad Die within 2 yrs of diagnosis. PFS:7-10 mths,OS: 11-23 mths

CARCINOSARCOMAPreviously known as MMT :Both components are malignant high grade endometrial carcinoma with sarcomatous metaplasia.

Behavior is similar to high grade endometrial papillary, clear cell carcinoma.(peritoneal, nodal mets)

Staging and treatment is similar to high grade endometrial carcinoma with Sx, chemo and pelvic RT .

Evaluation: Diagnosis mostly post op.Slide review by an experienced pathologist for typing.

Pre op diagnosis : very rarely either from imaging or from FC. CT /MRI scan abdomen ,pelvis ,CT chest. If there is a highly vascular solid ,solitary tumor on USS ,

CT :heterogeneous enhancement, Hyper intense on MRI both T1,T2.

Role of surgeryEn bloc removal of tumor with hysterectomy. prophylactic lymphadenectomy is not recommended except in carcinosarcoma.Lymph nodal spread : 7-15% in uterine confined ESS and in LMS its rare. Lymphadenectomy is done in patients with suspicious nodes or gross extra uterine spread.R0 resection is associated with better PFS.

Surgery : conservative Ovarian preservation : in ESS and LMS :in younger age group (chance of ovarian spread : 3%[Shah et al])Most retrospective series : no difference in recurrence rate whether ovaries preserved or notMorcellation : Contraindicated :~50% increased risk of recurrence and adversely affects survival.If morcellation has been done re-surgery is indicated :In re-surgery ~29% upstaging.Coservative surgeries like myomectomy :High recurrence rate

ESS /LMS/Adenosarcoma FIGO 2009 staging

CARCINO SARCOMA STAGING

RADIOTHERAPYRoutine adjuvant ,historically.

Adjuvant : EBRT to sterilize the microscopic disease in pelvic nodes and tumor bed .Palliative RT to pelvis or sites of distant mets/ recurrence.Medically inoperable.

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DRR LAT & AP Fields#333D PLAN

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Bowel sparing

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PHASE III STUDY ON ADJ RTEUROPEAN JOURNAL OF CANCER 44 (2008) 808818

EORTC PHASE IIIObservation vs adj pelvic RT (51Gy/28 Fr):224 pts. , 112 in each arm99 pts :LMS, 92 pts :CS,30 pts :ESSMajority of patients were stage I:197 pts. LR, DFS, OS, Distant mets.

DFSP:0.352

OSP:0.92FAILED TO PROVE SURVIVAL ADVANTAGE.

LOCOREGIONAL RECURRENCEP=0.0013

CS/LMS LOCAL RECURRENCE

Largest Retrospective Review 3650 patients :US National Oncology database.

LRFFS SARCOMA/ESS

LRFFS CS /LMS

Published in 2011

Trials in Uterine sarcoma with RT

CARCINO SARCOMA : Randomized Trials

studystageyrsRT detailsNMFUOSLRecDistmetReed et al EORTCNO RT

RT1-II

N=911988-200150.4 Gy/28 Fr45

Vs.

46NGNG47%

24%29%

35%Wolfson et al NO RT(chemo)

RTI-IVN=2061993-2005WA:30Gy,pelvis:49.8101Vs.1055.3 yrs.45%

35%24%

17%53%

56%

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CARCINOSARCOMA -Non randomized Evidence for OS

studyArmsStageyrs.NRTMFUyrs.Loco Reg.Distantmets.OSSampath et alNo RT

RTI - IV1980-2005638

490EBRT +/- Brachy520%Vs.

10%NASmith SEERNo Vs. RT I - IV1973-20031571

890varying3.933%

42%Gerszten et alNo

RT

I-III1977-9231

2945-50G2.7 yrs.55%

3%53%

83%At 3yrs

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CARCINO SARCOMA

5 YR SURVIVAL

Role of RT ESSPost op Adjuvant. No level I evidence :retrospective data better LCMedically inoperable.Palliative :stage IV, or recurrence

NCCN Category 2B and ESMO guidelines suggest Adj RT in Stage II-IVA.

RADIATION IN LMSSTAGE I-IVA :Improves LRC: Survival (No level I evidence ).No improvement in survival probably because of the high and early metastatic potential. Other indications :medically inoperable Palliative /recurrent cases :to reduce bleeding ,pain .

CARCINOSARCOMAManaged similar to endometrial high grade carcinoma Multi institutional retrospective reviews favour Chemo and RT ,with sandwitch regimen being slightly better.

With chemotherapy taxol+ carbo 6 cycles and adjuvant RT. Level I data for adjuvant RT.

Chemo EBRT vs. Chemo brachy has to be addressed in future trials.

ChemotherapyThe role of chemotherapy as an adjuvant is at best controversial.

None of the published literature have shown any statistically significant benefit as regards DFS or OS in adjuvant setting, except the SARC GYN study,

Most of the trials are underpwered.

Chemotherapy in LMSNo randomized trial has shown a significant survival advantage.SARC GYN study DFS improved with adjuvant chemo+RT compared to RT alone.Hensley et al reported a 2 yr PFS of 59% in stage I-IV 78% in stage I,II patients.( with Gem-doce followed by doxo )GOG 277 ongoing adjuvant chemo study (Gem +Doce x4 -Doxo x 4)

LMS -Chemo

In recurrent /metastatic setting : PFS improvement with single agent/combination chemo .Agents being tried are Ifosfamide,platinum,gemcitabine ,doxorubicin Second line agents :Trabactedin with or without chemo /Pazopanib/bevacizumab /mTOR inhibitors.

HGUS :ChemoHigh chance of local and systemic failure.In SARC GYN phase III : adjuvant pelvic RT vs Chemo (doxo,ifos,cis)-RT (9 cases were HGUS.)3yr DFS 41% vs 55%(p=0.048)Data suggests the use of chemo followed by RT in high grade uterine sarcomas . Standard recommendation not possible.Participation in multicentre clinical trials is recommended.

CarcinosarcomaRetrospective reports favour sequential chemotherapy and RT in adjuvant setting (Menczer et al ,Wong et al)

Managed similar to high grade endometrial cancer .

Hormones Low grade ESSProgestins are preferred Aromatase inhibitors also show promise, in ESS.(ORR of 67%)

Duration :Adjuvant setting 2yrs to 5 yrs and in recurrent/metastatic setting until progression.Chemotherapy is of limited use in low grade ESS.

ESS LOW GRADE NCCN 2015

Undifferentiated Sarcoma/LMSNCCN2015

CARCINOSARCOMA NCCN 2015Carcinosarcoma ,Clear cell ,papillary

RECURRENCE/METSLocoregional Rec :Resection : if feasible especially in ESS .Metastatectomy :for oligo mets :developing after good DFS, if R0 feasible.Palliative chemo ,agents tried are Doxorubicin ,Gemcitabine ,taxanes ,Ifosfamide Targeted agents as second line like Pazopanib ,bevacizumab ,mTOR and multikinase inhibitors with or without chemo.Best approach is participation in multicentre trials.

PRACTICE POINTSBenefit of adjuvant RT is limited to improved LRC.

LRC with Radiation is not translated in to survival .

Ongoing area of research is effective chemo regimens /targeted agents to control metastasis and to improve survival.

FUTUREMulti institutional studies IRC :International Rare Cancer Initiative :

Exploring the role of CTRT vs. Adjuvant chemo /targeted treatments in each subgroup is warranted.

Comparison of EBRT vs. brachytherapy with newer effective systemic treatment in each subgroup.

Uterine sarcomas are large fleshy tumours .**

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