Endometrial Cancer

William Small Jr., MD

Professor of Radiation Oncology
The Robert H. Lurie Comprehensive Cancer
Center of Northwestern University

Learning Objectives:
Discuss the role of radiation therapy in early stage
and advanced stage endometrial cancer.
Review controversies in Radiation Techniques.
Explain the role of surgery and surgical staging in the
management of endometrial cancer.
Review the role of chemotherapy in the
management of early and advanced stage
endometrial cancer.

When utilizing IMRT in the post-operative

treatment of endometrial cancer the MOST
important aspect of treatment is?

1. Daily image guidance.

2. Asking the patient to have a full bladder on a
daily basis.
3. Assuring that bone and bowel are excluded
from the CTV.
4. Carful attention to an ITV.

Who will win the Super Bowl this Year ?

1. The Chicago Bears.

2. The NFL team from Chicago.
3. I dont care as long as the Packers are not in
the Super Bowl.

Endometrial Cancer
Estimated New Cancer Cases and Deaths by Sex, 2012
Men

Women

Incidence

Deaths

Incidence

Deaths

All

848,170

301,820

All

790,740

275,370

Prostate

241,740

28,170

Breast

226,870

39,510

Lung

116,470

87,750

Lung

109,690

75,590

Colon/Rectum

73,420

26,470

Colon/Rectum

70,040

25,220

Bladder

55,600

10,510

Uterine

47,130

8,010

American Cancer Society, Surveillance Research, 2012

The reports of my death have

been greatly exaggerated.
-Mark Twain

There are three kinds of lies: Lies,

Damned Lies, and Statistics.
-Benjamin Disraeli
-Mark Twain

FIGO 1988

Surgical staging System

Early stage disease
Stage I
IA
Limited to the endometrium
IB
< half of the endometrium
IC
> half of the endometrium
Stage II Corpus and cervix
IIA
Endocervical glands only
IIB
Endocervical stromal invasion

FIGO 1988

Surgical staging System

Late stage disease
Stage III
IIIA
Tumor Involves the serosa and/or adenexa
(direct extension or metastasis) and/or cancer
cells in ascites or peritoneal washings
IIIB Vaginal Involvement
III C Metastasis to Pelvic or Para-aortic Lymph Nodes
Stage IV
IVA
Tumor Involves the bladder or bowel mucosa
IVB Distant Metastasis

FIGO 2009

Surgical staging System

Early stage disease
Stage I
IA
No or < half of the endometrium
IB
= or > half of the endometrium
Stage II Corpus and cervix
Endocervical stromal invasion

Int J Obs Gyn, May 2009,

FIGO 2009

Surgical staging System

Late stage disease
Stage III
IIIA
Tumor Involves the serosa and/or adenexa
(direct extension or metastasis)
IIIB Vaginal and/or parametrial Involvement
III C1 Metastasis to Pelvic Lymph Nodes
IIIC2 Metastasis to Para-aortic +/- pelvic Lymph Nodes
Stage IV
IVA Tumor Involves the bladder or bowel mucosa
IVB Distant Metastasis and/or inguinal metastasis

Post Operative Radiotherapy

Early Stage Disease
Very contentious Disease
All Patients
Receive Adjuvant RT
Even Low Grade
Minimally Invasive
Tumors

No Patients
Receive adjuvant RT
Even High Grade
Deeply Invasive
Tumors

Center A

Center B

In intermediate risk endometrial cancer, the risk of

recurrence with and without pelvic RT is approximately?

1.
2.
3.
4.

3% vs. 12 %.
3% vs. 20%
1% vs. 5%
10% vs. 30%.

Postoperative RT Rationale
Early stage patient with adverse pathologic features
are at risk for extra uterine disease and recurrence
Most commonly cited pathologic factors
-Myometrial Invasion (MI)
-Tumor Grade
-Cervical involvement
- Age
- LVSI
Importance demonstrated in GOG33

GOG 33
Surgical Pathologic study of 621 stage I pts
Positive
Pelvic LNs

Positive
PA LNs

Grade
1

3%

2%

9%

5%

18%

None

1%

1%

Superficial

5%

3%

Middle

6%

1%

Deep

25%

P<0.0001

11%

P<0.0001

MI

P<0.0001

17%

P<0.0001

More useful to combine grade &

MI
Positive Pelvic LNs

Positive PA LNs

Invasion

G1

G2

G3

Invasion

G1

G2

G3

None

0%

3%

0%

None

0%

3%

0%

Inner

3%

5%

9%

Inner

1%

4%

4%

Middle

0%

9%

4%

Middle

5%

0%

0%

Creasman WT et al, Cancer 1987;60:2035

Deep

11%

19%

34%

Deep

6%

14%

23%

Cervical involvement and also CSI are

correlated with Positive LNs
Positive
Pelvic LNs

Positive
PA LNs

Site
Fundus

8%

Isthmus cervix

16%

Negative

7%

Positive

27%

4%
P = 0.01

14%

P= 0.0001

Capillary Space
involvement
4%
P=0.0001

19%

P= 0.0001

Rationale also provided by the correlation

between adverse pathologic factors and vaginal
failure
Price 1965
41 clinical stage I patients undergoing surgery alone
Vaginal Recurrence
All Patients

14%

Grade
1

4.4

5.7

13.6

None

3.7

< half

4.7

> half

15.1

MI

Unfortunately Grade and Myometrial invasion not combined in the analysis

Price et al. Am J Obstet Gynecol 1965; 91:1060

What evidence supports the use of

Adjuvant Radiation Therapy is
Stage I & II Endometrial
Carcinoma ?

Retrospective studies also suggest benefit

of Adjuvant RT in patients with adverse
pathologic factors
Pelvic
Recurrence
with RT

Pelvic
Recurrence
without RT

Carey 1995
High Risk pts
Deep MI, G3,
+Cx, Adenos.

3.9%

14.3%

Pitson 2002
Stage II (55%
IIA)

5.6%

22.2%

Carey et al, Gynecol Oncol 1995; 57:138

Piston et al, Int J Radiation Oncol Bio Phys 2002; 53:862

Retrospective studies also suggest

benefit of Adjuvant RT in patients with
adverse pathologic factors
In a retrospective review of 927 patients
Stage I&II pts
Vaginal Recurrence
with RT either Vault
or Total Vagina

Vaginal Recurrence
without RT

Stage I Low Risk

G 1 2, <1/3 MI

1%

3.2%

Stage I High Risk

G3 &/Or >1/3 MI

1.3%

11.7%

Stage II

5.2 %

12.8%

Elliot at al., Int J Gyne cancer 1994; 4 : 84

Post operative RT Stage I & II Disease

Five prospective randomized trials have been
conducted to evaluate post operative
radiotherapy in early stage disease

Norwegian Trial
PORTEC 1
GOG 99
ASTEC/EN 5
PORTEC 2

Norwegian Trial
Clinical Stage I
540 Patients
TAH + BSO
without LN
Sampling
No assessment of
peritoneal cytology

Vaginal
Brachytherapy
LDR 60 Gy @vaginal
surface
Arm 1

Arm 2

Pelvic RT 40 Gy
Midline block
after 20 Gy

No further
therapy

Aalders et al, Obstet Gynecol 1980; 56(4);419

Norwegian Trial
Pelvic RT reduces vaginal / pelvic failures in patients with
high risk features (deep MI & G3 Tumors)

Vaginal/Pelvic recurrence

Grade 1 < MI
2 Tumors > MI

No RT
4%
9.8%

With RT
2.3%
9.4%

Grade 3
Tumors

5.6%
19.6%

2.1%
4.5 %

< MI
> MI

Aalders et al, Obstet Gynecol 1980; 56(4);419

Norwegian Trial
No Overall survival benefit with Radiotherapy
5 Years Survival Rate
Pelvic RT
89%
No Pelvic RT
91%
Only in Patients with deeply invasive Grade 3
Tumors
Death from Cancer
Pelvic RT
18.2%
No Pelvic RT
27.5%
Aalders et al, Obstet Gynecol 1980; 56(4);419

LVSI

LVSI was evaluated in the last 151

patients on trial.
Vessel invasion seen in 19.9 % of
the patients.
Local recurrence 21 % in the no
Pelvic RT group versus none in the
Pelvic RT group.

Aadlers Trial: Conclusions

Grade 3> 50 % invasion pelvic RT.
All patients with LVSI receive pelvic RT
All other patients with invasion receive
VBT.

PORTEC Trial
Post Operative Radiation Therapy in
Endometrial Carcinoma
Selected Clinical Stage I
Grade 1 > MI
Grade 2 any MI
Grade 3 < MI
715 Patients
TAH + BSO without LN
Sampling
All histologies

Regimen 1
Pelvic radiotheraoy
46 Gy / 23 Fractions
No Vaginal Brachytherapy

Regimen 2
No further Treatment

HIR Definition Recent

Publication

Age > 60
Grade 3
Invasion >50%
HIR defined as: 2 of those 3 factors present
(except for grade 3 with deep invasion = high
risk, eligible for PORTEC3)

Fig. 3

Source: International Journal of Radiation Oncology * Biology * Physics (DOI:10.1016/j.ijrobp.2011.04.013 )

Copyright Elsevier Inc. Terms and Conditions

PORTEC 10-year outcome with PA review

Locoregional recurrence (actuarial rates)
All pts

5-yr

10-yr

RT
No RT

3%
13%

5%
14%

<0.001

Exclusion of IB grade 1 (n=134):

RT
No RT

4%
15%

5%
17%

<0.001

Creutzberg, Lancet 2000; Scholten, IJROBP 2005

PORTEC 15-year outcome

( Median f/u: 13.3 Years)

Locoregional recurrence (actuarial rates)

5.8 % in the Radiotherapy Arm
15.5 % in the NAT Arm

Nout et al; JCO, 2011

Site of Loco-regional Recurrences

74% of the locoregional recurrences were

isolated vaginal recurrences.

Nout et al; JCO, 2011

GOG 99 Trial
Stage IB - II (Occult)
Regimen 1
Pap/Serous-Clear
Pelvic radiotheraoy
Cell Excluded
50.4 Gy / 1.8 Gy/ Fraction
392 Patients
No Vaginal Brachytherapy
TAH + BSO with
Regimen 2
selective Bilateral
Pelvic & Para- aortic
No further Treatment
lymphadenectomy
Keys et al. Gynecol Oncol 2004; 92;744
Assessment of
peritoneal cytology

Overall Results
Median follow-up of surviving patients 68 months.
The 24-month cumulative incidence of recurrence
(CIR) rate was 3% in the RT group and 12 % in the
no additional therapy group.
13 of the 18 loco-regional recurrences in the NAT
arm were in the vaginal vault (72%)

Overall Results
CIR at 24 months of isolated local (vagina or pelvic)
1.6% versus 7.4%
48 month Kaplan-Meier estimates for survival
86% in the NAT group, 92 % in RT group (p=0.55).
The GI, GU, Cutaneous and Hematological side
effects were significantly higher in the RT group.

HIR group (GOG-99)

Prognostic factors:
advanced age
high grade (2 or 3)
outer 33% myometrial invasion
lymph-vascular space invasion (LVI)
HIR (high intermediate risk):

at least 70 yr with any other risk factor

at least 50 yr with any 2 other risk factor

any age with all 3 other factors

Keys, Gynecol Oncol 2004

GOG-99: recurrence

HIR, NAT: 27%

HIE, RT: 13%

Relative hazard RT: 0.42 (58% hazard reduction)

HIR: 33% of patients, 67% of recurrences
Keys, Gynecol Oncol 2004

GOG 99: Survival

LIR: 92 - 94%
HIR, RT: 88%
HIR, no RT: 74%

Relative hazard for RT: 0.86 (ns); HIR: 0.73

Keys, Gynecol Oncol 2004

MRC ASTEC Radiotherapy and

NCIC EN.5 Trial
Adjuvant external beam radiotherapy (EBRT) in the
treatment of endometrial cancer: results of the randomized
MRC ASTEC and NCIC CTG EN.5 trials
ASTEC ISRCTN 16571884
EN.5 clinicaltrials.gov NCT 00002807
Presented by
Jane Orton
On behalf of all ASTEC and EN.5 Collaborators

Trial Design
Surgery

High risk pathology and no macroscopic disease

RANDOMIZE

No external beam RT

External beam RT

Inclusion Criteria ASTEC and EN.5

FIGO
Stage

Grade 1

Grade 2

Grade 3

Papillary
Serous/cle
ar cell

IA

1 (<1%)

1 (<1%)

8 (1%)

15 (2%)

IB

1 (<1%)

5 (1%)

99 (11%)

48 (5%)

IC

213 (24%)

337
(37%)

100
(11%)

27 (3%)

IIA

9 (1%)

19 (2%)

6 (1%)

3 (<1%)

IIB

2 (<1%)

1 (<1%)

Eligibility Criteria
Brachytherapy allowed if
centre policy
stated before randomisation
used in both arms
Positive para-aortic nodes an exclusion
Positive pelvic lymph nodes
Eligible for ASTEC
Ineligible for EN.5

Brachytherapy

In the ASTEC trial HDR: Two

fractions of 4 Gy at 0.5 cm from the
vaginal mucosa over 3-7 days or
LDR: 15 Gy upper third of the
vagina.
In the EN-5: Given in accordance
with local practice.

Trial Profile
905 Randomized

453
No EBRT

452
EBRT

98% No EBRT
2% received EBRT

92% received EBRT

8% No EBRT

51% Brachytherapy

52% Brachytherapy

453 assessed
for primary outcome
measure

452 assessed
for primary outcome
measure

Patient Characteristics
Baseline characteristics balanced between treatment groups
median age 65 years
98 % performance status 0-1
83% endometrioid histology
25% lymphovascular space invasion
4% positive peritoneal cytology
Surgery received
71% TAH/BSO
29% TAH/BSO plus lymphadenectomy
4% of patients (with nodes harvested) had positive pelvic
nodes

Radiotherapy Details
EBRT
N=452

2
45
25
34

Percentage (%)
40
60

24 (5%)

80

Distribution of EBRT dose used

Median:
Total Dose (Gy)
Fractions
Duration in days

416 (92%)
10 (3%)

20

EBRT +/brachytherapy
Brachytherapy
alone
None
Missing

Treatment
compliance
(% of patients who
received total dose
of 40-46 Gy in 20-25
fractions)

82%

10

15

20

25

30 35 40 45
Total dose (Grays)

50

55

60

65

70

Acute and Late Toxicity

Acute toxicity (post surgery and

radiotherapy)
Worst score
Mild
Moderate
Severe/Life threatening

Late Toxicity
Severe/Life threatening

No EBRT
N=453

EBRT
N=452

121 (27%)

258 (57%)

77 (17%)
38 (8%)
3 (<1%)

143 (32%)
100 (22%)
14 (3%)

3%

8%

Isolated Vaginal or Pelvic Initial

Recurrence (ASCO Presentation)
1.0

Events
28
14

No EBRT
EBRT

0.9

Totals
453
452

0.8

Cumulative incidence

0.7

3% difference in 5 year cumulative incidence rate

(4% in EBRT to 7% in no EBRT)

0.6

HR=0.53, 95% CI=0.29-0.97, p=0.038

0.5
0.4

Only includes 42/123 total recurrences

0.3
0.2
0.1
0.0
0
PATIENTS at Risk
No EBRT
EBRT

81
78

35
32

Years from randomisation

453
452

425
420

366
376

282
281

211
212

142
142

Isolated Vaginal or Pelvic Initial

Recurrence
5-year cumulative incidence 6.1 % versus
3.2 % (p=0.02)

Overall Survival: by centre

brachytherapy policy (ASCO
Presentation)
[no. events/no. entered]
EBRT
No EBRT

O-E Variance

Hazard Ratio (Fixed)

Brachytherapy
Yes

23/196

29/190

-3.99

12.98

0.74 (0.43-1.27) p=0.268

No

30/181

25/184

3.96

13.69

1.34 (0.79-2.27) p=0.284

0
0.5
EBRT Better
Interaction Test: chi-square=2.37, df=1, p=0.123

2
5
No EBRT Better

Recurrence-Free Survival: by
centre brachytherapy policy
(ASCO Presentation)

Meta-analysis: overall survival

Study

EBRT
n/N

No EBRT
n/N

Peto OR (IPD)
95% CI

PORTEC
GOG
ASTEC + EN5

57/354
30/190
65/452

48/360
36/202
66/453

714
392
905

1.22 [0.83, 1.79]

0.86 [0.57, 1.29]
1.00 [0.71, 1.41]

Total (95% CI)

152/996

150/1015

2011

1.02 [0.82, 1.27]

Peto OR (IPD)
95% CI

Test for heterogeneity: Chi = 1.51, df = 2 (P = 0.47), I = 0%

Test for overall effect: Z = 0.20 (P = 0.84)
0.1

0.2

0.5

Favours EBRT

10

Favours No EBRTl

0.2% difference in 5-year OS (87.8% in EBRT and 88% in no EBRT)

95% CI of difference = -2.0% to 3.0%

What is the most common outcome after a vaginal

cuff relapse when no previous radiotherapy has
been delivered?

1. Patients are salvaged without complications

2. Patients are salvaged with complications
3. No patients are salvage

The Myth that Isolated Vaginal

Recurrences are Easily Salvageable
Accompanying editorial to GOG 99 by Michael
Berman noted: Yet vaginal recurrences usually are
treated successfully with radiotherapy in patient not
previously treated with adjunctive radiation
The data from GOG 99 noted that 12 of 13 patients
in the NAT arm were treated with salvage
radiotherapy crude observations noted 5 of these
thirteen died of endometrial cancer.

Immediate versus delayed RT

Salvage rate may not be as high as those
commonly quoted.
> 70% results are typically quoted.
Most studies do not support this even in isolated
vaginal recurrences.
Survival typically range around 40 50 %.
Poorer outcomes in non-vaginal pelvic recurrences.

Salvage RT Series
Locally Recurrent Endometrial Cancer
Author

Number

Local Control

5 Years Survival

Kuten (1989)

51

35%

18%

Jereczek(2000)

73

48%

25%

Curran (1988)

47

48%

31%

Jhingran (2003)

91

75%

43%

Hoekstra (1993)

26

84%

44%

Sears (1994)

45

54%

44%

Hart (1998)

26

65%

53%

Wylie (2000)

58

65%

53%

Lin (2005)

50

74%

53%

Creutzberg
(2003)

35

77%

66%

Salvage treatment with high-dose-rate

brachytherapy for isolated vaginal
endometrial cancer recurrence

And the risk of toxicity should NOT be ignored

22 isolated vaginal recurrences
18 EBRT + HDR, 4 HDR alone
Median follow-up 32 month
18% grade 3-4 GI toxicity
50% grade 3 vaginal sequelae
Petignat et al. Gynecol Oncol 2006; 101:445

Population Based
Data

SEER analysis: efficacy of RT

SEER program (NCI), 10% US population
21.249 patients, 1988-2001
19% of patients had RT (82% EBRT)
43% had surgical node sampling
Lee et al, JAMA 295, 389-97, 2006

Multivariate Analysis
Table 2. Cox regression analysis with relative survival endpoint
Covariates
Stage 1A, Grade I
Stage 1B, Grade I
Stage 1C, Grade I
Stage 1A, Grade II
Stage 1B, Grade II
Stage 1C, Grade II
Stage 1A, Grade III/IV
Stage 1B, Grade III/IV
Stage 1C, Grade III/IV
Race/ethnicity=Black
Pathologic Node Negative at TAH-BSO
Age at Diagnosis (per decade, base age 65)
Radiation + Stage 1A, Grade I
Radiation + Stage 1B, Grade I
Radiation + Stage 1C, Grade I
Radiation + Stage 1A, Grade II
Radiation + Stage 1B, Grade II
Radiation + Stage 1C, Grade II
Radiation + Stage 1A, Grade III/IV
Radiation + Stage 1B, Grade III/IV
Radiation + Stage 1C, Grade III/IV

HR (95% CI)
1.000
1.13 (0.97-1.31)
2.06 (1.63-2.61)
1.38 (1.14-1.67)
1.47 (1.27-1.72)
2.04 (1.64-2.54)
2.47 (1.97-3.11)
2.64 (2.21-3.16)
5.09 (4.09-6.32)
0.54 (0.46-0.63)
0.90 (0.83-0.98)
1.79 (1.73-1.86)
0.85 (0.40-1.80)
0.91 (0.64-1.29)
0.45 (0.32-0.64)
1.37 (0.82-2.28)
1.00 (0.81-1.24)
0.96 (0.76-1.21)
1.02 (0.66-1.57)
0.98 (0.80-1.19)
0.74 (0.58-0.93)

*Baseline reference group= no radiation, stage 1A, grade 1 cohort.

p value
reference
.13
<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
.67
.59
<.001
.23
.97
.75
.93
.82
.009

What is the best RT

It is clear that radiotherapy is indicated in high risk
early stage endometrial cancer.
Can VBT replace external beam for the majority of
these patients?

An American
Brachytherapy Society
Survey Regarding the
Practice Patterns of PostOperative Irradiation for
Endometrial Cancer
William Small Jr., M.D.
Beth Erickson, M.D.
Francis Kwakwa, M.A.

Has there been an increasing trend

for referrals for vaginal
brachytherapy?
YES

54.2

NO

31.8

NO
OPINOIN

12.8

PORTEC - 2 trial (2002-2006)

Stage I-IIA endometrial carcinoma
age > 60 and IC grade 1-2, or IB grade 3
stage 2A (except grade 3 > 1/2)
surgery: TAH-BSO
Groningen
Waddenzee
Friesland

Noord
Holland

pelvic radiotherapy

Flevoland

Zuid Holland

vaginal brachytherapy

Drenthe

Ijsselmeer

Overijssel

Gelderland

Utrecht

Noord Brabant

Zeeland

Limburg

PORTEC-2
Randomized Between:
Pelvic Radiotherapy 46 Gy in 23 fractions
VS
Vaginal Brachytherapy 21 Gy HDR or 30 Gy LDR

PORTEC-2 Author Conclusions

Despite the slightly but significantly increased
pelvic failure rate in the VBT arm, DM, RFS and OS
were similar. As patient reported quality of life after
VBT wasbetter, VBT should be the treatment of
choice for patients with high-intermediate risk
endometrial cancer

PORTEC-4
HIR endometrial carcinoma
Vaginal brachytherapy vs no further
treatment
21 Gy in 3 fractions vs 15 Gy in 3 fractions

R
1

VBT 3 x 7 Gy at 5 mm

VBT 3 x 5 Gy at 5 mm
No further treatment
Close FU; EBRT/VBT for vaginal
relapse

How should you treat so called

intermediate risk patients?
The data on unselected patients consistently
shows a reduction in vaginal recurrences.
I believe the best technique is to look at
all the risk factors before deciding on an
individual patient.

Departments of Radiation Oncology, Preventive Medicine, and Obstetrics and

Gynecology, Division of Gynecologic Oncology, Robert H. Lurie Comprehensive Cancer
Center, Northwestern University Feinberg School of Medicine, Chicago, IL.

Int J Radiol Oncol Biol Phys,. Volume 84, Number 2 (2012) 415-419.

Patient and tumor characteristics (n = 252)

Characteristic
Patients (n)
Follow-up (mo)
Median
Range
Age (y)
Median
Range
Type of surgery
TAH/BSO without
LN biopsy
TAH/BSO with
LN biopsy
Pelvic LNs removed
Median
Range
Para-aortic LNs
removed (n)
Median
Range

VBT
169

NAT

83
<0001

104
1-330

61
0-328
.71

61
29-89

60
33-85

28 (16.6)

18 (21.7)

.39

141 (83.4)

66 (79.5)

.49
.03

10
0-36

8
0-32
.002

3
0-19

2
0-12

Patient and tumor characteristics (n = 252)

Characteristic
Tumor histologic grade
1
2
3

Depth of invasion (cm)

Median
Range
Lymphatic or vascular
space invasion
Interval from surgery
to RT (d)
Median
Range

VBT

NAT

p
.01

96
(56.8)
64
(37.9)
9
(5.3)

63
(75.9)
17
(20.5)
3
(3.6)
.0006

0.30
0.072.40

0.22
0.020.90

19/153
(12.4)

4/72
(5.6)

41
8.257

NA

.16

Patient outcomes data

Variable
Disease status (all patients)
Alive without disease
Dead of another cause
Alive with disease
Dead of disease
Recurrence
Interval from surgery
to recurrence (mo)
Median
Range
Recurrence location*
Vagina
Pelvis
Para-aortic
Upper abdomen
Lung
Status after recurrence
Alive without disease
Died of another cause
Alive with disease
Died of disease

VBT
(n = 169)

NAT
(n = 83)

p
.07

145 (85.8)
18 (10.7)
1 (0.6)
5 (3.0)
8 (4.7)

40
9-102

78 (94.0)
2 (2.4)
1 (1.2)
2 (2.4)
6 (7.2)

19
2-49

1
4
1
3
3

3
2
0
1
0

3 (37.5)
1 (12.5)
1 (12.5)
3 (37.5)

3 (50)
0 (0)
1 (16.7)
2 (33.3)

Abbreviations: NAT no adjuvant therapy; VBT = vaginal brachytherapy

Data in parentheses are percentages
*Several patients had multiple sites of recurrence

NS
NS

Vaginal
Brachytherapy
Techniques

When delivering Vaginal Brachytherapy in a patient

with endometroid histology what is your typical
target?

1.
2.
3.
4.
5.

Upper 2 cm of the vaginal.

Upper 3 cm of the vaginal
Upper one third of the vagina.
Upper one half of the vagina.
The entire vagina.

When delivering Vaginal Brachytherapy in a patient

with endometroid histology what is your typical
dose?

1. 6 Gy times 5 to the vaginal mucosa.

2. 4 Gy times 6 to the vaginal mucosa.
3. 7 Gy times 3 to 0.5 cm from the vaginal
mucosa.
4. 5.5 Gy times 4 to 0.5 cm from the vaginal
mucosa.
5. Other.

American Brachytherapy Society consensus

guidelines for adjuvant vaginal cuff
brachytherapy after hysterectomy.
William Small, Jr., M.D.,1*, Sushil Beriwal, M.D., 2 D. Jeffrey Demanes,
M.D.,3 Kathryn E. Dusenbery, M.D., 4 Patricia Eifel, M.D.,5 Beth Erickson,
M.D., 6 Ellen Jones, M.D., 7 Jason J. Rownd, M.D.,8 Jennifer F. De Los Santos,
M.D., 9Akila N. Viswanathan, M.D.,10 and David Gaffney, M.D.11

Brachytherapy 11(2012) 58-47.

Pay particular attention to healing especially

on the current proliferation of robotic
surgery.
Choose the applicator that is correct for the
clinical situation.
Cylinders most common which range in size
from 2 4 cm.

Placement of a radio-opaque seed or clip(s)

at the vaginal apex should be considered.
Place the largest cylinder that fits
comfortably.
Minimize movement from placement,
planning and treatment.

7 Gy X 3 to 0.5 cm is the most commonly

prescribed fractionation scheme.
Many sites use different fractionation
schemes.
I use 5.5 Gy X 4 to 0.5 cm.

Diameter Size
(cm)

Vaginal Surface

@ 5 mm

100%

60%

100%

68%

100%

71%

Intensity Modulated Radiation Therapy

IMRT may decreases the risk of severe sequelae
Dosimetric studies demonstrate significant sparing
of small bowel, bladder and rectum
Preliminary outcome studies have noted low toxicity
rates and excellent Pelvic Control.

Atlas Update In Progress

Utilize patterns of recurrence data from
RTOG 0418.
Better define obturator nodal region.
Eliminate all reference to boney landmarks.
Give recommendations regarding rectal
distention.
Included recommendations for common iliacs
and para-aortic CTV.

Dosimetric Studies
IMRT versus conventional Pelvic RT
Small Bowel

Bladder

Rectum

Decreases the volume receiving the prescription dose by

Roeske

50%

23%

23%

Heron

51%

31%

66%

Chen

70%

NS

NS

Ahamad

40 63%

NS

NS

Wong

95%

NS

NS

Clinical outcome studies

Adjuvant IMRT in Endometrial Cancer
Number Follow
up

DFS Pelvic Chronic

Control Toxicity

Knab

31

24m

84% 100%

Beriwal

47

20m

100%

No Grade 2
2.1% at 3
years
Grade 2

Knab et al, Int J Radiat Oncol Biol Phys 2004 ; 60:303

Beriwal et al, Int J Radiat Oncol Biol Phys 2006 ; 66:S41

Efficacy and safety of IMRT after

surgery in patients with endometrial
cancer: RTOG 0418 phase II study
Anuja Jhingran, Kathryn Winter, Lorraine
Portelance, Brigitte Miller, Mohammad Salehpour,
Rakesh Gaur, Louis Souhami, William Small, and
David Gaffney
Supported by RTOG U10 CA21661, CCOP U10 CA37422, and ATC U24 CA 81647 NCI grants.
89

RTOG 0418
Objectives:
Primary to determine the transportability
of pelvic IMRT for patients with endometrial
carcinoma to a multi-institutional setting.
Secondary
To assess adverse events related to this
regimen.
To test the hypothesis that there is a reduction
in short-term bowel injury with this regimen
compared to standard treatments.
To estimate the rates of local-regional control,
distant metastasis, disease-free and overall
survival.

90

RTOG 0418 Endometrial Arm

Protocol
Chemotherapy was not allowed in the endometrial arm.
Guidelines for contouring were detailed in protocol as well as
a web-base atlas.
Dose/volume constraints for targets and normal tissue were
outlined.
Patients were simulated with a both empty and full bladder
scan and a vaginal ITV was contoured encompassing
contours from both scans. Pts. were treated on full bladder
scan.
Dose to nodal PTV and vaginal PTV (ITV with margin) was
50.4 Gy in 28 fractions.
Vaginal brachytherapy was allowed at the discretion of the
physician.
91

RTOG 0418 Endometrial Arm

Protocol
Central quality assurance was performed the first
case from each institution was reviewed by one of
the two PIs prior to treatment and the second case
could be reviewed at the discretion of the PIs.
Adverse events (AEs) were assessed using the
CTCAE v. 3.0.
Primary endpoint - if <5 of 42 treatments delivered
50.4 Gy to the nodal PTV and to vaginal PTV, then
the protocol is considered reproducible.

92

RTOG 0418 Endometrial Arm

GI Toxicity (n=40)

Overall

Grade 0/1

Grade 2+

29

73

11

28

Adverse
Event

# days
from start

Grade

Enteritis

38

Diarrhea

37

Diarrhea

41

Enteritis

41

Enteritis

40

Enteritis

55

Stricture

139

Diarrhea

35

Enteritis

35

Proctitis

35

Diarrhea

24

Diarrhea

41

Diarrhea

35

Diarrhea

51

Diarrhea

23

RTOG 0418
Purpose Secondary Endpoints
To estimate the rates:
Local-regional recurrence
Distant recurrence
Disease-free survival
Overall survival
Assess adverse events

94

RTOG 0418 Endometrial Arm

Study period March 2006 June 2007

58 patients enrolled, 43 eligible patients
Median age 57 (min-max: 36-73)
Median FU 3.5 years (min-max: 1.0-4.4)
OS and DFS rates estimated using the KaplanMeier method.
Local-regional and distant recurrence rates
estimated with the cumulative incidence method.

95

RTOG 0418 Endometrial Arm

Tumor Stage and Grade
IB, G2-3
IIIC

IIB

IC, G1-3

IIA

96

RTOG 0418 Endometrial Arm

Outcomes
Endpoint

Number
of
Failures

Overall Survival

Disease-Free
Survival
Local-Regional
Failure
Para-aortic
nodes
Distant
(excluding paraaortic nodes)

5
3
2
3

Estimated 2-Year
Rate
(95% CI)
95.2%
(82.3, 98.8)
90.6%
(76.8, 96.4)
7.0%
(0, 14.8)
4.8%
(0, 11.3)
7.1%
(0, 14.9)

Estimated 3-Year
Rate
(95% CI)
92.4%
(78.0, 97.5)
90.6%
(76.8, 96.4)
7.0%
(0, 14.8)
4.8%
(0, 11.3)
7.1%
(0, 14.9)

97

RTOG 0418 Endometrial Arm

Cause of Death
Cause of Death

n (%)

Treated Cancer
Intracranial hemorrhage

2 (50%)
1 (25%)

Unknown
Total

1 (25%)
4 (100%)

98

RTOG 0418 Endometrial

Arm
Conclusions
IMRT in the post-operative setting is feasible across multiple
institutions using a detailed protocol and centralized Q/A and
may be used in phase III protocols.
G2 and higher small bowel toxicity was reduced from 40% in
traditional XRT to 28% with IMRT (p = 0.13) not powered to
detect a 12% decrease.
Contouring of OARs were all within minor deviations except
for small bowel which needs a better definition.
Contouring of nodal and vaginal tissue had some major
deviations and will need continued monitoring with good Q/A
in a protocol setting.

RTOG 0418 Endometrial Arm

RTOG 0418 Endometrial

Arm

RTOG 0418 Endometrial

Arm

RTOG 0418 Endometrial

Arm

RTOG 0418 Endometrial

Arm

CASE STUDY
The patient was treated with pelvic IMRT on
RTOG 0418 with concurrent weekly cisplatin.
An ITV was accomplished to determine the
CTV.
The consensus contouring guidelines were
utilized to draw the CTV.

Full and Empty Bladder

Full and Empty Bladder

Full and Empty Bladder

The Practice of Post Operative Pelvic IMRT

in Gynecological Malignancies
1) The CTV needs to be as accurate as possible.
2) Internal target motion MUST be accounted for simple daily cone beam CTs are inadequate
because the nodal volumes will follow boney
landmarks whereas the vaginal volumes are
influenced by bladder and rectal filling.
3) Therefore a ITV is critical unless daily bladder and
rectal volume is regulated.

Should IMRT be A
Standard Therapy
In the Postoperative
Treatment of
Endometrial Cancer

A RANDOMIZED PHASE III STUDY OF

STANDARD VS. IMRT PELVIC RADIATION FOR
POST-OPERATIVE TREATMENT OF
ENDOMETRIAL AND CERVICAL CANCER
(TIME-C)
CO-PIS
ANN KLOPP MD, PHD
ANAMARIA YEUNG MD
PRO AND QOL CO-CHAIR
LARI WENZEL, PH.D.
KAREN GIL, PH.D.
COST ANALYSIS CO-CHAIR
ANDRE KONSKI, MD, MBA, MA, FACR
STATISTICIAN
STEPHANIE SHOOK

TIME-C: Objectives
Primary Objective:
oTo determine if acute gastrointestinal toxicity is reduced with IMRT
using patient reported measure of toxicity
Secondary Objective:
oTo determine if acute grade 2 gastrointestinal toxicity (CTCAE v. 3.0) is
reduced with IMRT compared to conventional WPRT.
oTo determine if acute grade 3+ hematologic toxicity (CTCAE v. 3.0) is
reduced with IMRT compared to conventional WPRT.
oTo determine if acute urinary toxicity is reduced with IMRT using a
patient reported measure of toxicity.
oTo assess the impact of pelvic IMRT on quality of life using patient
reported outcomes.

Schema

Eligibility
Women with
endometrial or
cervical cancer
P postrequiring
operative pelvic
radiation or
chemoradiation

Stratification
factors
XRT dose
45 Gy
50.4 Gy
Chemotherapy
P
No Chemotherapy
5 cycles of weekly
cisplatin at 40mg/m2
Disease Site
Endometrial
Cervix

R
A
N
D
O
P
M
I
Z
E

IMRT pelvic radiation

P
treatment

4-field pelvic radiation

P
treatment

Post-Treatment
Complications

PORTEC 1 : Long Term QOL

SF-36 Scores
EBRT

NAT

Remain close to the toilet

related to urinary control

26

10

Urinary Incontinence

30

16

Limitations of daily activity

related to bowel
symptoms

26

15

Nout et al; JCO, 2011

PORTEC 1: EBRT Technique

52% Four Field (5-year comp rate 21%)
18 % Three Field (5-year comp rate 36%)
30 % AP/PA (5-year comp rate 30%)
5 Yr actuarial rate of toxicity 26 % vs. 4 %
Grade 3 or 4: 3 % vs 0 % - 67 % of complications
Grade 1, Grade 2: 7 % vs 1%.
P=0.06 for technique and complication rate.
Creutzberg, In J Rad Oncol Biol Phys, 2001

Vaginal Length after

Vaginal Brachytherapy for
Endometrial Cancer
William Small Jr., MD
Professor
The Robert H. Lurie
Comprehensive Cancer Center of
Northwestern University

Vaginal Length after Intracavitary

Radiotherapy

Looked at 90 patients with intracavitary RT after

treatment for cervical or endometrial CA (48).
Measurements were taken at 6 and 12 months
and then yearly.
The vaginal dilator compliance rate was 68 % of
using 1 o more times per week.

Bruner et al, Int J Radiol Bilo Phys, 1993

Objective

Feasibility study to assess changes in vaginal length

from pre- to post- vaginal brachytherapy for endometrial
cancer in women prescribed vaginal dilators.

Methods
Patients randomized to standard vs enhanced education:
Standard:

Enhanced:

Given smooth plastic vaginal dilator

Dilatation began 2-4 wks post
completion of VBT
Written instructions on dilator use
Encouraged to engage in sexual
intercourse with vaginal penetration as
per institution standard
Attention control telephone calls at
weeks 1, 4, 12, and 18

Standard +
intensive, theory
driven education and
counseling

Endpoint Change in Vaginal Length

Metric Vaginal Sound

Modified plastic vaginal dilator

Calibrated in centimeters
15 cms long X 2.85 cms in diameter
Inter-rater reliability tested by GOG during two training sessions
with live models
- 88 MDs and RNs from over 45 institutions attended a 1/2 hr
didactic session followed by a 1- hr clinical practicum
- Measurements taken by instructor and student at each insertion
Inter-rater reliability was high with intraclass correlation coefficients
of 0.88 among instructors and 0.76 among trainees
For purposes of this study each individual physician underwent a
training session with the study PI and a the investigators ability to
reliably measure was confirmed on a patient.
Bruner et al Int J Gynecol Cancer.;16(5):1749-55, 2006

Results
Preliminary findings of the first 23/50 women with VL
data pre and 6 mo post VBT:
PreVBT VL 8.7cm (SD + 1.51)
PostVBT VL 8.8cm (SD + 1.58)
Dilator compliance was variable at 6mos:
22% using the dilator <1 time/week
22% using the dilator 1 time/week
56% using the dilator 2-3 times/week

Conclusions
No difference in VL from before
to 6 mos after VBT for the
treatment of endometrial cancer

Increased dilator use may be

beneficial in preventing loss of
vaginal length post VBT but
requires further study

Second Primaries
Treatment delivered

Observed/Expected

No Radiation

0.92

Brachytherapy Alone

0.97

EBRT Alone

1.1

EBRT and Brachy

1.22

Any Radiation

1.09

Brown et al., Int J Radiol Biol Phys, 2010.

Colon Cancer

Source: International Journal of Radiation Oncology * Biology * Physics 2010; 78:127-135 (DOI:10.1016/j.ijrobp.2009.07.1692 )
Copyright 2010 Elsevier Inc. Terms and Conditions

Vaginal Cancer

Source: International Journal of Radiation Oncology * Biology * Physics 2010; 78:127-135 (DOI:10.1016/j.ijrobp.2009.07.1692 )
Copyright 2010 Elsevier Inc. Terms and Conditions

Cumulative Risk of Bladder Cancer

Bladder Cancer Risk

PORTEC 1
At a median follow-up of 13.3 years 19% of
the patients had a second primary.
22% in the EBRT group,
16% in the no additional treatment group
P=0.10

Creutzberg, Int J Radiol Biol Phys, In Press

Locally Advanced Disease

In general, most reports have used involved
field radiotherapy for patients with Stage III
disease.

Whole Abdominal
Radiotherapy
GOG 122 noted a significant worse outcome in
advanced patients with WAR (38% 5-year survival)
as compared to chemotherapy.
GOG 122 delivered 30 Gy to the whole abdomen
and 15 Gy to the pelvis 25 % of patients with
stage IV.
Our series of WAR patients noted a 86 % 5-year
survival, Smith et al noted a 77 % 3-year survival.

Pelvic Recurrence Advanced

Disease
Author

Stage

Radiotherap
y

Chemotherap Observatio
y
n

Patel et al,
2007

III

13%

33% - 77 %
non Vag
Vault

Mundt et al,
2001

I-IV

39.5 % 53%
non Vag

Small et al,
2000

I-IV

10 %

Randall et al, III-IV

2008

13% (Initial)

18% (Initial)

Hoekstra et
al,
2009

0%

IIIC

EBRT and outcome

Pelvic relapse

Disease-specific survival

Overall survival

Klopp et al Gyn Oncology 2009

SEER DATA
Schmid et al (Gyn Onc, 2009) reviewed the
SEER data base from 1988 2001
5-year disease specific survival (DSS) with
RT 67.9% vs 53.4% without RT (p<0.001).
Single lymph node DSS 74.3 vs. 54.4 %
(p<0.001), 2-5 lymph nodes DSS 59.7 vs.
52.7 % (p=0.089).

SEER DATA

Endometroid 73.7 vs 61.9% (p=0.007)

Clear Cell 77.1 vs. 39.2% (p=0.046)
Papillary Serous 44 vs. 45.5 % (p=0.48)
Sarcoma 44.9 vs 46.3 % (p=0.51)
The data remained significant on multivariate
analysis

My Current General
Treatment Approach

Stage I Patients
Limited*/No Lymph Node Surgery
Given PORTEC/ASTEC Results Becoming Increasingly Similar to
Dissected Patients

Grade I

Grade II

IA (Inv)

VB2,3

VB2,3

VB 3

IB

VB4

VB4

Pelvic +/VBT

IA (No
Inv)

Grade III
VB

*<10 nodes, limited number of sites (arbitrary definition ) Radiographic

Imaging for all but Stage 1A Grade1 and 2
1 Low risk of vaginal recurrence and nodal involvement
2 Consider observation for minimal invasion no high risk features.
3 Consider pelvic RT instead if +LVI and close to MI +/- advanced age
4 Consider pelvic RT instead if +LVI, deep invasion, advanced age

In surgically staged patients, VB alone is

becoming the preferred adjuvant RT
approach
Stage I Patients Surgically Staged*
Grade 1

Grade 2

Grade 3

IA ( No Inv)

--

--

VB

IA (Inv)

-- 1

VB 2

VB 2

IB

VB 3

VB 3

Pelvic +/- VB4

*>10 nodes, multiple sites (arbitrary cut off)

1 Consider VB depending on other high-risk features.
2 Consider observation depending on other high-risk features.
3 Consider Pelvic Radiotherapy if with high-risk features
4 Consider VBT if limited invasion and minimal high-risk features.

Stage II Patients
In general, I deliver pelvic radiotherapy
followed by a VBT boost depends on the
surgery that is accomplished.

Stage III Patients

I generally deliver tumor directed
radiotherapy.

What About Lymph Node

Dissection

GOG 33- Creasman

A surgical/pathologic study of 621 patients with clinically stage I

endometrial cancer
Percent of patients with positive pelvic LNs

Invasion

Grade 1

Grade 2

Grade 3

None

Inner

Middle

Deep

11

19

34

Efficacy of systematic pelvic lymphadenectomy in endometrial

cancer (MRC ASTEC trial): a randomised trial

85 Centres, 4 Countries, 1408 women

Hysterectomy and BSO +/- pelvic
lymphadenectomy
In GOG 33
LNs
Intermediate or high risk early stage disease% positive
5-9%
FIGO (1988) IA or IB with high grade pathology
FIGO (1988) IC or IIA

10-34%

Controversial point: To control for post-surgical

treatmentrandomized (independent of lymph
node status) into the ASTEC radiotherapy trial

Lancet 2009; 373: p125-36

ASTEC Tx Randomization
Because women were randomized to adjuvant
radiotherapy without regard to the results of
the pelvic lymph node dissection:
This is a study of the surgical benefit to removing
lymph nodes.
It does not answer the question of whether
detecting occult nodal metastasis in low and
intermediate risk patients better directs adjuvant
tx and thus improves survival.

ASTEC Survival and sites of recurrence

Cause
Of Death

No
LN

LNs
removed

Total

88
13%

103
15%

Disease

65%

63%

Treatment
related

5%

7%

Disease &
Treatment

2%

Not Disease

30%

28%

What About Chemotherapy?

Is it the next step to improving
overall survival?

GOG 122 Schema

GOG 122
Dox/CDDP

WART

p=.01

Adjuvant chemotherapy versus radiotherapy in highrisk endometrial carcinoma: result of a randomised

trial
Stage IC G3
STAGE II G3
>50% MI
Stage III

Regimen 1:
Pelvic RT (45-50 gy)
Regimen 2:
CDDP, Adriamycin, Cytoxan
5 cycles
R Maggi et al, BJC,2006;95:266

Adjuvant chemotherapy versus radiotherapy in highrisk endometrial carcinoma: result of a randomised

trial
Median follow up 95.5 months
No difference in 5 Year DFS or OS
RT

locoregional initial recurrence: 7 %,

Distant: 21 %,
Both:5

Chemotherapy

locoregional initial recurrence: 11%,

Distant: 16 %,
Both:5 %

RT reduced local recurrence, chemotherapy reduced distant

failure

R Maggi et al, BJC,2006;95:266

Chemotherapy
Such results suggest that a more prudent
approach would be to combine
chemotherapy and RT
Published trials, however, have reported
mixed results

GOG 34
Chemotherapy did not improve outcome
3 Years Survival

Extra-Pelvic
Failure

RT Alone

75%

22.5%

RT + Adriamycin

68%

16.3%

P = NS

P = NS

Moreover, 12 (7%) of these surgically staged patients

developed a SBO after pelvic +/- PART
Maybe adriamycin alone is not enough

To test a more aggressive regimen, the RTOG

launched RTOG 9708
Stage I III
TAH BSO
+/- Nodal Surgery
Grade 2-3 > MI
+ cervical stroma
Extra-uterine
(Pelvic only)
disease +
washings

Pelvic RT 45
Gy +VB
CDDP
50 mg/m2
Days 1,28

Four cycles
Chemo
CDDP
50 mg/m2
+
Paclitaxel
175 mg/m2

Kathryn Greven et al., Gynecol Oncol 2006;103:155

Concurrent and adjuvant

chemotherapy
Phase II trial RTOG (46 pts):
stage I-II high risk or stage III (66%)

Concurrent: cisplatin 50 mg/m2 days 1, 28

Adjuvant: 4x cisplatin 50 mg/m2 and paclitaxel 175 mg/m2

4-yr locoregional relapse 4%, distant 19%

4-yr DFS 81%, OS 85% (stage III: 77 and 72%)
No recurrences in stage IC, IIA, IIB
promising data, phase III needed attempted in RTOG
9901 closed for lack of accrual. Only high-risk early
stage in that trial related to competing Phase III GOG
randomized trial for Stage III patients,
Greven et al, Gynecol Oncol 2006

NSGO EC-9501/EORTC-55991
May 1996 to January 2007

Randomization
n=382

RT
44 Gy XRT

n=196

optional VBT (39%)

Radical surgery
TAH+BSO (+PLA)

RT+CT
Surgical stage I, II,
IIIA (positive peritoneal fluid
cytology only), or IIIC (positive
pelvic lymph nodes only) with high
risk for micro-metastatic disease
Patients with serous, clear cell, or anaplastic
carcinomas were eligible regardless of other risk
factors

OR

(VBT 44%)

n=186

CT+RT
CT : intially AP
Later AP, TcP, TAP, TEcP

Primary endpoint
Progression-free survival (PFS)
Thomas Hogberg, Lund Univ Hosp Oct 2009

NSGO EC-9501/EORTC-55991
PFS progression-free survival (PFS)

0.79

0.75

Chemo/RT

0.50

RT alone

0.72

0.25

HR 0.63 (95 % CI 0.41 - 0.98) p = 0.04

0.00

probability of survival

1.00

PFS NSGO-EC-9501/EORTC-5591

123
143

110
119

84
82

years
Number at risk
random = 0 191
random = 1 186

170
175

149
158
random = 0

random = 1

Thomas Hogberg, Lund Univ Hosp Oct 2009

Combined Modality Trials

Several new combined modality trials are underway or in the
planning stages
GOG 249 compares pelvic RT versus VB + chemotherapy in
intermediate risk Stage I and IIa patients
PORTEC-3 comparing pelvic RT versus pelvic RT + chemotherapy
in high risk pts
GOG 258 compares chemotherapy alone versus chemotherapy
plus volume directed RT in advanced stage patients.

When utilizing IMRT in the post-operative

treatment of endometrial cancer the MOST
important aspect of treatment is?

1. Daily image guidance.

2. Asking the patient to have a full bladder on a
daily basis.
3. Assuring that bone and bowel are excluded
from the CTV.
4. Carful attention to an ITV.

Conclusions
RT continues to play an important role in endometrial
cancer
Its optimal role is still evolving
Attention turning to combined modality approaches in
high risk patients following surgery
Novel approaches, notably IMRT and in the future IGRT,
should help improve the quality and delivery of RT in
these women.