Uterine Sarcomas :Where do we stand?

Dr.Beena.K.

Radiation Oncologist

AIMS,Cochin

Contents

New WHO Classification

Management options in each sub group and role of RT.

Target Volumes of RT.

Introduction Uterine 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 GRADE

Endometrial stromal origin :resembles proliferative phase

Low grade , <1% of uterine malignancy : (JAZF1rearrangement(7 ,17 translocation)

Mostly indolent ,younger age group IHC :ER,PR,positive,CD10 +ve, hormones effective. 5yr DFS : Stage I and II :90%, stage III,IV:50%. Recurrence is common even in stage I

ESS HIGH GRADE Previously was part of undifferentiated endometrial ca .(WHO

2003 ) Now redefined in the present WHO as high grade ESS Uniform round cells ,with occasional low grade areas. ER,PR _ve,CD10 –Ve,Cyclin D1 +Ve YWHAE - FAM22 fusion +ve .(10:17 translocation) Hormone treatment is not effective . Prognosis better than undifferentiated sarcoma.

Adenosarcoma

Only mesenchymal component is malignant. Usually low grade ,ER ,PR positive. <6 % of uterine sarcomas Staging and treatment similar to ESS low grade 5 yr. survival :70%

LMS

40-60% 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 SARCOMA No 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

CARCINOSARCOMA

Previously 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 surgery

En 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 not Morcellation : 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

RADIOTHERAPY

Routine 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.

DRR LAT & AP Fields#333D PLAN

Bowel sparing

PHASE III STUDY ON ADJ RT

EUROPEAN JOURNAL OF CANCER 44 (2008) 808–818

EORTC PHASE III

Observation vs adj pelvic RT (51Gy/28 Fr):224 pts. , 112 in each arm

99 pts :LMS, 92 pts :CS, 30 pts :ESS Majority of patients were stage I:197 pts. LR, DFS, OS, Distant mets.

DFS

P:0.352

OS

P:0.92

FAILED TO PROVE SURVIVAL ADVANTAGE.

LOCOREGIONAL RECURRENCE

P=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

study stage yrs RT details

N MFU OS LRec Distmet

Reed et al EORTCNO RT

RT

1-II

N=91

1988-2001

50.4 Gy/28 Fr

45

Vs.

46

NG NG 47%

24%

29%

35%

Wolfson et al NO RT(chemo)

RT

I-IVN=206

1993-2005

WA:30Gy,pelvis:49.8

101Vs.105

5.3 yrs. 45%

35%

24%

17%

53%

56%

study Arms

Stage yrs. N RT MFUyrs.

Loco Reg.

Distantmets.

OS

Sampath et al

No RT

RT

I - IV 1980-2005

638

490

EBRT +/- Brachy

5 20%Vs.

10%

NA

Smith SEER

No Vs. RT

I - IV 1973-2003

1571

890

varying

3.9 33%

42%

Gerszten et al

No

RT

I-III 1977-92

31

29

45-50G

2.7 yrs.

55%

3%

53%

83%At 3yrs

CARCINOSARCOMA -Non randomized Evidence for OS

CARCINO SARCOMA

5 YR SURVIVAL

Role of RT ESS

Post op Adjuvant. No level I evidence :retrospective data better LC

Medically inoperable.

Palliative :stage IV, or recurrence

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

RADIATION IN LMS

STAGE 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 .

CARCINOSARCOMA

Managed 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.

Chemotherapy The 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 LMS No 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 :Chemo High 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.

Carcinosarcoma

Retrospective 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 ESS

Progestins 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 2015

Carcinosarcoma ,Clear cell ,papillary

RECURRENCE/METS Locoregional 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 POINTS Benefit 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.

FUTURE Multi 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.