oncology

1. Uterine Sarcomas :Where do we stand?
Dr.Beena.K.
Radiation Oncologist
AIMS,Cochin

2. Contents
 New WHO Classification
 Management options in each sub group and role of RT.
 Target Volumes of RT.

3. 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.

4. Classification :RECENT WHO 2014

5. 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

6. 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.

7. 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%

8. 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 %

9. 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

10. 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 .

11. 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.

12. 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.

13. 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

14. ESS /LMS/Adenosarcoma FIGO 2009
staging

15. CARCINO SARCOMA STAGING

16. 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.

19. DRR LAT & AP Fields#33
3D PLAN

20. Bowel sparing

22. PHASE III STUDY ON ADJ RT
EUROPEAN JOURNAL OF CANCER 44 (2008) 808–818

23. 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.

24. DFS
P:0.352

25. OS
P:0.92
FAILED TO PROVE SURVIVAL ADVANTAGE.

26. LOCOREGIONAL RECURRENCE
P=0.0013

27. CS/LMS LOCAL RECURRENCE

28. Largest Retrospective Review
3650 patients :US National
Oncology database.

29. LRFFS SARCOMA/ESS

30. LRFFS CS /LMS

31. Published in 2011

32. Trials in Uterine sarcoma with RT

33. CARCINO SARCOMA : Randomized Trials
study stage yrs RT
details
N MFU OS LRec Dist
met
Reed et
al
EORTC
NO 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-IV
N=206
1993-
2005
WA:30G
y,pelvis:
49.8
101
Vs.
105
5.3 yrs. 45%
35%
24%
17%
53%
56%

34. study Arm
s
Stage yrs. N RT MFU
yrs.
Loco
Reg.
Distant
mets.
OS
Sampath
et al
No
RT
RT
I - IV 1980-
2005
638
490
EBRT
+/-
Brach
y
5 20%
Vs.
10%
NA
Smith
SEER
No
Vs.
RT
I - IV 1973-
2003
1571
890
varyin
g
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

35. CARCINO SARCOMA

36. 5 YR SURVIVAL

38. 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.

39. 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 .

40. 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

41. 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.

42. 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)

43. 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.

44. 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.

45. Carcinosarcoma
 Retrospective reports favour sequential chemotherapy
and RT in adjuvant setting (Menczer et al ,Wong et al)
 Managed similar to high grade endometrial cancer .

46. 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.

47. ESS LOW GRADE NCCN 2015

48. Undifferentiated Sarcoma/LMS
NCCN2015

49. CARCINOSARCOMA –NCCN 2015
Carcinosarcoma
,Clear cell
,papillary

50. 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.

51. 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.

52. 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.