Radiation Therapy in Early Stage Endometrial Cancer: Update and ...

Radiation Therapy in
Early Stage Endometrial Cancer:
Update and Perspectives
Arno J. Mundt MD
Professor and Chair
Department of Radiation Oncology
University of California San Diego

Radiation Therapy in Uterine Cancer
• Long history
• 1st report published in 1909
• Heyman (1935) reported a 58.2% 5-yr survival in
early stage pts with the “Stockholm Method”
(radium packing)
• Demonstrated curative potential of RT
Heyman and Colleagues
Radiumhemmet
(1930s)

Historical Perspective
• Soon became commonplace, particularly
pre-op
• By the 1980s, preoperative RT use declined
• Today, RT is almost exclusively delivered
post-operatively in pts with adverse
pathologic features
• Pelvic RT and/or vaginal brachytherapy (VB)
• Enthusiasm has waned for other previously
popular approaches, e.g. whole abdominal
RT (WART) and intra-peritoneal 32 P

When discussing preoperative RT, one needs to
resurrect the old FIGO staging system…
FIGO 1971
Clinical Staging System
Stage I Corpus only
IA Uterine cavity ≤ 8 cm
IB Uterine cavity > 8 cm
Stage II Corpus and cervix
Stage III Extra-uterine disease
(pelvis only)
Stage IV Extra-pelvic disease
Rectal or bladder
involvement
FIGO =International Federation of Gynecology and Obstetrics

Preoperative RT
Arguments Offered For
Cytoreduction prior to surgery
↓Spread of viable cells at surgery
Better treatment tolerance
Irradiation of well-oxygenated tumors
Arguments Offered Against
Over-treatment of low risk patients
Loss of pathologic prognostic information*
*most compelling argument (but overcome by operating
within 2-3 days)

Preoperative RT
Excellent pelvic control and survival in clinical stage
I patients
Pelvic 5-yr
Year Control Survival
Salazar 1978 93% 82%
Chung 1981 94% 88%
Bedwinek 1984 90.8% 71%
Weigensberg 1984 85.6% 70-80%*
Baram 1985 NS 72.4%
Delmore 1987 97.2% 84-91%
Grigsby 1991 95.7% 84%
NS=not stated
*5-yr DFS

Preoperative RT
Serious complications are rare, particularly when
brachytherapy is used alone
Grigsby (1991)
Retrospective review of 685 clinical stage I patients
treated with preoperative RT
Significant
Treatment n GI toxicity
ICB→S 538 0.9%
ICB + pelvic RT→S 82 2.4%
ICB→S→pelvic RT 65 9.2%
ICB=intracavitary brachytherapy, S=surgery

Preoperative RT
Greatest benefit in stage I g3 tumors
Sause et al. (1990)
Retrospective comparison of preop ICB versus surgery alone
Grade 3/deep MI pts → postop pelvic RT
5-year DFS
All patients Grade 3
ICB→S 94% 76%
S 91% 53%
Some institutions still recommend preoperative RT in
clinical stage I g3 pts

Preoperative RT
Stronger rationale exists
in clinical stage II pts,
particularly those with
gross cervical
involvement
Analogous to bulky
stage IB cervix pts

Preoperative RT
• 5-yr survivals in clinical stage II pts range
from 70-80%
Year 5-yr Survival
Bruckman 1978 80%
Surwitt 1979 70%
Kinsella 1980 75% (83% 5-yr DFS)
Grigsby 1985 78%
• Best outcomes in low grade tumors and
those with microscopic cervical involvement
• Limited data in clinical stage III tumors

Preoperative RT
What is the preferred preoperative RT approach?
To answer this question, Wiegensberg (1984)
performed a randomized trial
Clinical Stage I
Patients
Regimen 1
ICB → Hysterectomy
Regimen 2
Pelvic RT → Hysterectomy

Preoperative RT
• Preoperative ICB pts had
• Lower rate of residual disease
• Fewer pelvic failures
• Improved disease-free survival
• Fewer complications
Residual Pelvic
Disease Failure 5-yr DFS
ICB→S 50.9% 3.6% 80%
Pelvic RT→S 70% 12.6% 70%
p = .02

Preoperative RT
Technique
• ICB, pelvic RT or both
• Preferred approach in stage I disease is
ICB alone
• Pelvic RT added in patients found to have
deep MI and/or grade 3 disease
• In stage II pts, preoperative pelvic RT and
ICB used

Heyman-Simon
Capsules
Preoperative RT Technique
• Traditionally low-dose-rate
(LDR) techniques
• Fletcher-Suit combined with
Heyman-Simon capsules
• 3500-6500 mg-hr (vaginal apex
60-70 Gy)
• If combined with pelvic RT,
2500 mg-hr intrauterine
• Some prescribe to Point A
(à la cervical cancer)
• No recommendations for HDR
brachytherapy

Is there a Future for
Preoperative RT?
Very limited at best
At most centers today,
only in clinical stage II pts
with gross cervical
involvement

Is preoperative superior to postoperative RT?
To answer this question, the Gynecologic Oncology
Group (GOG) launched GOG 16
Clinical Stage 1
Grade 1-3
Regimen 1
Preoperative RT
Regimen 2
Postoperative RT
However, it closed due to poor accrual
Interest now turned to “tailored” postoperative RT

Postoperative RT

FIGO 1988
Surgical Staging System
Early Stage Disease
Stage I Corpus only
IA Limited to the endometrium
IB ≤1/2 myometrial invasion
IC >1/2 myometrial invasion
Stage II Corpus and cervix
IIA Endocervical glands only
IIB Cervical stromal invasion

All Patients
Receive Adjuvant RT
Even low grade
minimally invasive
tumors
Postoperative RT
Early Stage Disease
Very Contentious Issue
No Patients
Receive Adjuvant RT
Even high grade
Deeply invasive
tumors
Center A Center B

Postoperative RT
Early Stage Disease
Controversy Exists Even When Given
Pelvic RT
Alone
Pelvic RT
+
VB
VB
Alone
Center A Center B Center C

Postoperative RT
Rationale
• Early stage pts with adverse pathologic
features are at risk for extra-uterine disease
• Most commonly cited pathologic factors:
– Myometrial invasion (MI)
– Tumor grade
– Cervical involvement
• Importance demonstrated in GOG 33

Surgical-pathologic study of 621 stage I pts
Grade
MI
GOG 33
+ Lymph Nodes
Pelvic Paraortic
1 3% 2%
2 9% 5%
3 18% p

More useful to combine grade and MI
+Pelvic Nodes
Invasion G1 G2 G3
None 0% 3% 0%
Inner 3% 5% 9%
Middle 0% 9% 4%
Deep 11% 19% 34%
+Paraortic Nodes
Invasion G1 G2 G3
None 0% 3% 0%
Inner 1% 4% 4%
Middle 5% 0% 0%
Deep 6% 14% 23%
Creasman WT et al. Cancer 1987;60:2035

Cervical involvement and CSI are also correlated with
positive nodes
+ Lymph Nodes
Pelvic Paraortic
Site
Fundus 8% 4%
Isthmus-Cervix 16% p=.01 14% p=.0001
Capillary Space
Involvement
Negative 7% 4%
Positive 27% p=.0001 19% p=.0001
Creasman WT et al. Cancer 1987;60:2035

Rationale also provided by the correlation between
adverse pathologic factors and vaginal failure
Price (1965)
41 clinical stage I pts undergoing surgery alone
Vaginal Recurrence
All patients 14%
Grade 1 4.4%
2 5.7%
3 13.6%
MI None 3.7%
1/2 15.1%
Unfortunately, grade and MI not combined in the analysis
Price et al. Am J Obstet Gynecol 1965;91:1060

Other Factors
• Other factors cited as risk factors for pelvic
and/or vaginal failure:
– Tumor Size
Schink (1991)
– Lower Uterine Segment (LUS)
Mayr (1995)
• LUS is a common indication for adjuvant RT
even without other high risk factors
Schink et al. Cancer 1991;78:63
Mayr et al. Radiology 1995;196:323

Postoperative RT in Clinical Stage I Endometrial Cancer:
Corpus, Cervical and Lower Uterine Segment Involvement-
Patterns of Failure
Mayr N et al. Radiology 1995;196:323
But….
Only 4 patients with +LUS were treated with surgery alone
2/4 (50%) recurred
And deep MI defined as >2/3 invasion
Many or all four may have been stage IC

41 pathologic stage I pts
All +LUS but negative cervical involvement
Pelvic/Vaginal Recurrence
-RT +RT
Low Risk 0/25 0/2
(≤1/2 MI, g1-2)
High Risk 3/6 1/8
(> ½ MI, g3)
LUS involvement does not appear to be an independent risk factor for
recurrence
Phelan et al. Gynecol Oncol 2001:83:513

What evidence
supports the use of
adjuvant RT
in stage I-II disease?

Numerous studies focused on postoperative RT
in pathologic stage I-II pts
Important differences exist
• Patients vary
Some include only low risk tumors, others focus on
high risk ones
• Surgical approaches vary
Some include full surgical staging (pelvic and pelvic
lymph node assessment) others do not
• RT approaches vary
Some treat pts with pelvic RT, others focus on VB
alone or pelvic RT + VB

Postoperative RT
Stage I-II Disease
• Despite such differences, pelvic/vaginal
control rates >95% in most reports
• Survival rates are also excellent
– Stage I 82-98%
– Stage II 68-93%

Selected Pathologic Stage I-II
Postoperative RT Studies
Recurrence 5-yr
Author Stage RT Vagina Pelvis SV
Alektiar IBg1-2 VB - 4% 94%
Alektiar IB-IIB VB 2% 4% 93%
Anderson IB-IC VB 0.9% 1.9% 84%
Boz IAg3-IC P 4% 88%
Calvin IIA-B P+/-VB,VB 2% 4% 85.2%
Carey IBg3-II P+/-VB 3.9% 81%
Chadha IBg3-IC VB 0% 81%
Feltmate II P+/-VB,VB 3.7% 3.7% 93%
Greven IA-IIB P+/-VB,VB 3.7% 0.7% 86%
Nori I-II VB+/-P 2% 96.6%
Rush IB-IC P 0% 0% 92%
Weiss IC P 0% 1.6% 86%*
Burke T, Muggia F, Mundt AJ. Uterine Cancer.
In: Devita, Hellman, Rosenberg (eds). Principles and Practice of Oncology (2005)

Retrospective studies suggest a benefit to RT in pts
with adverse pathologic factors
Pelvic Recurrence
+RT -RT
Carey (1995)
Hi risk pts
(deep MI, g3, +cervix)
3.9%* 14.3%
Pitson (2002)
Stage II 5.6% 22.2%
*includes non-irradiated patients
Carey et al. Gynecol Oncol 1995;57:138
Pitson et al. Int J Radiat Oncol Biol Phys 2002;53:862

Retrospective review of 927 stage I-II patients
Vaginal Recurrence
+RT -RT
Low risk stage I 0% 3.2%
(g1-2, 1/3 MI)
Stage II 0% 12.8%
Elliott et al. Int J Gyne Cancer 1994:4:84

608 stage IA-IIA patients
22% pts with high risk features received adjuvant RT
Multivariate analysis: adjuvant RT associated with ↑DFS and ↑Survival
controlling for age, grade, stage, and surgical staging
p-value HR 95% CI
DFS 0.001 0.43 0.25-0.74
OS 0.004 0.41 0.22-0.75
Macdonald et al. Gynecol Oncol 2006;103:661

Postoperative RT
Pathologic Stage I-II Disease
“Four” prospective randomized clinical trials
(RCT) have been performed evaluating
postoperative RT in early stage patients
Norwegian Trial
PORTEC
GOG-99
ASTEC/NCIC

Clinical Stage I
N=540
TAH-BSO without
lymph node sampling
No assessment of
peritoneal cytology
Norwegian Trial
Aalders (1980)
Vaginal
Brachytherapy
60 Gy (LDR)
@ vaginal
surface
Aalders et al. Obstet Gynecol 1980;56:419
Regimen 1
Pelvic RT
40 Gy
(midline block after
20 Gy)
Regimen 2
No further
therapy

Norwegian Trial
Pelvic RT decreased vaginal/pelvic failures in pts with
high risk features (deep MI, grade 3) tumors
Vaginal/Pelvic Recurrence
-Pelvic RT +Pelvic RT
Grade 1-2 tumors
≤1/2 MI 4.0% 2.3%
>1/2 MI 9.8% 9.4%
Grade 3 tumors
≤1/2 MI 5.6% 2.1%
>1/2 MI 19.6% 4.5%
Aalders et al. Obstet Gynecol 1980;56:419

Norwegian Trial
No overall benefit in survival with pelvic RT
5-yr Survival
Pelvic RT 89%
No Pelvic RT 91%
Only in pts with deeply invasive g3 tumors
Deaths from Cancer
Pelvic RT 18.2%
No Pelvic RT 27.5%
Low risk pts had a higher rate of distant
metastases leading to more cancer deaths!
Aalders et al. Obstet Gynecol 1980;56:419

. PORTEC Trial
Post Operative Radiation Therapy in
Endometrial Carcinoma
Creutzberg (2000)
Select Stage I
grade 1 >1/2 MI
grade 2 any MI
grade 3

PORTEC Trial
Irradiated pts had a superior pelvic control
5-yr Pelvic Recurrence
Pelvic RT 4%
No Pelvic RT 14%
p < .001
No benefit in overall survival
Even after controlling for age, grade and MI
5-yr Survival
Pelvic RT 81%
No Pelvic RT 85%
Creutzberg et al. Lancet 2000;355:1404

Locoregional Recurrence
Creutzberg et al. Lancet 2000;355:1404
14%
4%

Stage IB-II (occult)
N=392
TAH-BSO with
selective bilateral
pelvic and para-aortic
lymphadenectomy
Assessment of
peritoneal cytology
GOG 99 Trial
Keys et al. Gynecol Oncol 2004;92:744
Regimen 1
Pelvic RT
50.4 Gy/ 1.8 Gy fractions
No vaginal brachytherapy
Regimen 2
No further
therapy

GOG 99 Trial
Irradiated pts had a superior pelvic control
2-year Locoregional
Recurrence
Pelvic RT 3%
No Pelvic RT 12%
p < .01
RT pts had a non-significant improved
survival
4-year Survival
Pelvic RT 92%
No Pelvic RT 86% p = .55

Survival
Keys et al. Gynecol Oncol 2004;92:744
Surgery +RT
Surgery

Post-hoc analysis
High Intermediate Risk (HIR) patients
Age ≥ 70 with 1 of the following risk factors
(grade 2-3, LVI, outer 1/3 MI)
Age ≥ 50 with 2 factors
Any age with all 3 factors
Only 1/3 of treated patients
A non-significant ↑survival favoring RT
Insufficient statistical power
4-year Survival
Pelvic RT 88%
No Pelvic RT 74% p = NS

Stage IA-IIA
Intermediate/High Risk
IA-IBg3, IC-IIA
N= 905
TAH-BSO
Assessment of
peritoneal cytology and
nodes not required
If done, +cyto and +node
patients included (1/3 of
enrollment)
ASTEC/NCIC
Regimen 1
Pelvic RT
40-46 Gy/ 1.8-2 Gy fractions
VB optional (54%)
Regimen 2
“Observation”
VB optional (52%)
ASTEC/NCIC Committee
Lancet 2009;373-46

Results
• No benefit to pelvic
RT in terms of overall
and cause-specific
survival
• Significant reduction
in local relapse as 1 st
failure site 6.1% vs
3.2%
• Increase in lifethreatening
acute
(

What do these
trials teach us?

Lesson 1
Adjuvant RT is associated with a
significant and profound improvement in
loco-regional control in early stage
endometrial cancer, particularly
in women with high risk features

Lesson 2
Adjuvant Pelvic RT is associated with
increased toxicity, primarily related to
the GI tract

Severe GI toxicity highest in GOG 99
Suggesting an increased risk in surgically
staged patients
Severe GI Sequelae
PORTEC 3% (5-year, actuarial)
GOG-99 8% (2-year, crude)
In GOG-99, 2 RT pts died from intestinal
injury and 6 developed grade 3-4 SBO
(compared to 1 non-RT pt)

Intensity Modulated RT
• Intensity modulated RT (IMRT) may decrease
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

Clinical Outcome Studies
Adjuvant IMRT in Endometrial Cancer
Pelvic Chronic
n FU DFS Control Toxicity
Knab 31 24 m 84% 100% No ≥ G2
Beriwal 47 20 m 84% 100% 3.3%
3 yr ≥ G2
Knab et al. Int J RadiatOncolBiolPhys 2004;60:303
Beriwal et al. Int J RadiatOncolBiolPhys 2006;102:195

What do the
randomized
trials not teach
us?

Un-Answered Question 1
Does adjuvant RT Increase
survival in early stage endometrial
cancer patients?

Is Survival Increased?
• None of the trials found a significant
benefit in survival with RT
• However, none were well-suited to
answering this question

Limitation #1
Follow-up times are limited
Longer follow-up of patients who
recur may be
necessary to assess impact on
survival

Limitation #2
Only two trials contained
surgery alone (control) arms
All women in the
Norwegian Trial received
adjuvant VB
Half the patients in ASTEC/NCIC
received VB

Limitation #3
GOG 99 included many low risk patients
(58% IB, 82% g1-2)
PORTEC excluded high risk pts
(Stage IC g3-II)
GOG 99 included patients least likely to benefit
and PORTEC excluded those most likely to
benefit

Meta-analysis of adjuvant RT in stage I endometrial cancer
4 randomized trials (3 published, 1 unpublished)
1770 patients
Significant improvement in locoregional control
Kong et al.
Ann Oncol 2007

No improvement in survival seen in overall group
Borderline survival advantage favoring RT
Patients with 2 high risk factors (Grade 3, > ½ MI)
Kong et al. Ann Oncol 2007

Review of SEER data
4010 stage IC g3-4 and stage II (all grades)
2306 pts (Surgery → external beam +/- VB)
1704 pts (Surgery alone)
Significant benefits in OS and CSS
In stage IC g3-4, stage II g2, stage g3-4
Lee et al. JAMA 2006;295:389

Is Survival Increased?
• Far from an academic question
• Lack of a perceived survival benefit led
some to withhold adjuvant RT, even in
women with multiple high risk features
• Despite multiple randomized trials
demonstrating a profound locoregional
control benefit

Immediate versus Delayed RT
• Salvage rates 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
• Survivals typically range around 40-50%
• Poorer outcomes in non-vaginal pelvic
recurrences

Salvage RT Series
Locally Recurrent Endometrial Cancer
Local 5-yr
Author n Control 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 (’03) 35 77% 65%

Overall Survival is Poor
Particularly in high grade tumor recurrences
Lin et al.
Int J Radiat Oncol Biol Phys
2005;63:500

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

Recommendation
• Adjuvant RT should not be withheld in stage
I-II patients due to a lack of a perceived
survival benefit
• A more judicious approach is to properly
select patients with high risk features
• If withheld, follow closely to detect
recurrences quickly, hopefully when small
and isolated to the vagina

Un-Answered Question 2
What is the optimal adjuvant RT approach
in early stage patients?

Optimal Approach
• Much is made of the fact that many of the
pelvic recurrences in the GOG 99 surgery
arm were in the vaginal vault
• Prompted some investigators to
recommend VB as the sole adjuvant
therapy in early stage surgically staged
patients

Optimal Approach
• However, while most pelvic failures were in the
vagina, 28% were non-central (sidewall)
• Concerning since GOG 99 patients were
“surgically staged”
• Most likely will be higher in patients with
incomplete surgical staging
• Sidewall recurrences, even when small, are
rarely salvaged
• Necessary doses associated with considerable
toxicity risk even when IMRT is used

With adequate surgical staging, outcomes are
excellent with VB alone
Recurrences
n Vagina Pelvis
Solhjem 100 0% 0%
Horowitz 164 1% 0.6%
Chadha 38 0% 0%
Fanning 22 0% 0%
Hong 44 2.3% 0%
Solhjem et al. Int J Radiat Oncol Biol Phys 2005;62:1379
Horowitz et al. Obstet Gynecol 2002;99:235
Chadha et al. Gynec Oncol 1999;75:103
Fanning et al. Obstet Gynecol 1996:87:1041
Hong et al. Am J Clin Oncol 1997;29:254

VB versus Pelvic RT
Surgically Staged Patients
Unanswered Questions
• Does surgical staging obviate the need for
and benefit of pelvic RT in high risk
patients?
• When is surgical staging adequate?
• Do the number of nodes matter?
– 5? 10? 15? Or more?
• Do where they are taken from matter?

A Phase III trial is needed comparing VB and
pelvic RT in surgically staged patients
Stage I-II patients
TAH-BSO with
bilateral pelvic and
para-aortic
lymphadenectomy
Assessment of
peritoneal cytology
Regimen 1
Pelvic RT
Regimen 2
Vaginal brachytherapy

• Don’t expect such a trial from the GOG
•An equivalency trial would require thousands
of patients
• GOG 99 took 8 yrs to enroll

So what to do with the
individual patient?

Likelihood of
Cure/Toxicity
With RT
Decision to irradiate (or not)
rests on a careful assessment of the
benefits and risks of treating
(and of not treating)
Likelihood of
Salvage/Toxicity
Without RT
If delivered, select approach with the highest
efficacy and lowest toxicity

Stage I Patients
Limited*/No Lymph Node Surgery
Grade 1 Grade 2 Grade 3
IA -- 1 -- 1 VB 2
IB -- 1 VB 2,3 VB 2,3
IC Pelvic 4,5 Pelvic 4,5 Pelvic 4,5
*

Pelvic RT and VB traditionally combined in pathologic
stage I-II pts, notably stage IC
Pelvic RT Pelvic+VB
ICg1 24.9% 39.5%
ICg2 29.9% 48.4%
ICg3 27.4% 61.3%
Small et al.
Int J Radiat Oncol Biol Phys
2005;63:1502
But published data do not support the combined
approach

256 stage I with deep MI on 7 studies
Local Recurrence
n Pelvic Pelvic+VB
Eifel 15 -- 0%
Sause 26 -- 0%
Konski 29 -- 1.6%
Torissi 40 4.3% --
Piver 32 0% --
Rush 53 0% --
Weiss 61 0% --
Mean 256 1.04% 0.97%
1999;92:599

Complications also increased with combined approach
Randall M et al.
Intracavitary Cuff Boost after External Beam Irradiation
In Early Endometrial Carcinoma
Int J Radiat Oncol Biol Phys 1990;10:49
Rectal Bleeding/
Proctitis
EBRT 3.8%
EBRT+VB 18.6% p = .01
Lack of benefit and increased risk of toxicity
strongly argue against the combined approach in high risk
stage I disease

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 -- -- VB 1
IB -- VB 1 VB 1
IC VB 2 VB 2 VB 2
*>10 nodes, multiple sites (arbitrary cutoff)
1 low risk of pelvic recurrence
2 consider pelvic RT if not “extensive” lymph node surgery

What about
Stage II patients?

In stage II patients, base decisions on the extent of
cervical involvement, myometrial invasion and
surgical staging
Stage II Patients
Limited*/No Lymph Node Surgery
Grade 1 Grade 2 Grade 3
IIA
≤½ MI VB1 VB1 VB1 >½ MI Pelvic Pelvic Pelvic
+/-VB +/-VB +/-VB
IIB Pelvic+VB Pelvic+VB Pelvic+VB
*

VB may not be necessary in stage IIA pts undergoing
pelvic RT
Calvin DB, Connell PP, Rotmensch J, Mundt AJ
Surgery and Postoperative RT in Stage II Endometrial Cancer
AJCO 1999;22:338
44 pathologic Stage II patients
32 (73%) Stage IIA disease
18/32 stage IIA pts treated with pelvic RT alone
None failed in the pelvis
Median follow-up 40 months

As in stage I patients, one should favor VB alone
in surgically staged stage II patients
Stage II Patients
Surgically Staged Patients*
Grade 1 Grade 2 Grade 3
IIA
≤½ MI VB 1 VB 1 VB 1
>½ MI VB 2 VB 2 VB 2
IIB Pelvic+VB 3 Pelvic+VB 3 Pelvic+VB 3
*>15 nodes, multiple sites (arbitrary cutoff)
1 low risk of nodal involvement
2 favor pelvic RT if not extensive nodal surgery
3 only do VB alone reluctantly if extensive nodal surgery (note:
pre-sacral lymph nodes are not routinely assessed!)

Imperial Beach
What about
Chemotherapy?

A strong rationale exists for chemotherapy in high risk
early stage patients
Creutzberg C et al. JCO 2004;22:1234

Previously, there was a push for replacing RT with
chemotherapy
GOG 156
Stage IB-IIB
TAH-BSO
Selective Pelvic
& PA nodal
dissection
Regimen 1
Pelvic RT
Regimen 2
Adriamycin
Cisplatin
However, it closed due to lack of accrual

The Europeans have completed such a trial
Stage ICg3
Stage IIg3
>50% MI
Stage III
2006;95:266
Regimen 1
Pelvic RT (45-50 Gy)
Regimen 2
CDDP, Adriamycin, Cytoxan
5 cycles

2006;95:266
• Median follow-up 95.5 months
• No difference in 5-year DFS or OS
• RT reduced local recurrence, chemotherapy
reduced distant failure

Chemotherapy alone does not control local disease
Pelvic failure-free survival
with (1) and without (0) cervical
involvement
43 high-risk patients
Adjuvant chemotherapy alone
17 (40%) failed in the pelvis
3-year actuarial pelvic failure 46.5%
Factors predictive of pelvic relapse:
+cervix, stage I-II disease
Int J Radiat Oncol Biol Phys
2001;50:1145

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

Clinical Stage I-II
TAH BSO
Surgical Staging
1 or more risk factors
>1/2 MI
Pelvic/PA nodes
Cervical involvement
Adnexal involvement
Morrow et al.
Gynecol Oncol 1990;36:166
GOG 34
Morrow (1990)
Pelvic
+/-
Paraortic
Irradiation
No
Vaginal
Brachy
Regimen 1
Doxorubicin
60 mg/m 2
N= 92
Regimen 2
No further therapy
N=89

GOG 34
Chemotherapy did not improve outcome
3-yr Extra-Pelvic
Survival 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
But maybe adriamycin alone is not enough

To test a more aggressive regimen, the RTOG
launched RTOG 9708
2006;103:155
Stage I-III
TAH-BSO
+/- Nodal Surgery
Grade 2-3 >1/2 MI
+Cervical Stroma
Extra-uterine (pelvic only)
disease
+washings
Pelvic RT
45 Gy
+VB
CDDP
50 mg/m 2
Days 1,28
Maintenance
Chemo
CDDP
50 mg/m 2
+
Paclitaxel
175 mg/m 2

RTOG 9708
• Unsurprisingly, acute toxicities were
significant (predominantly hematologic)
– 29% grade 3-4 (concomitant phase)
– 83% grade 3-4 (chemotherapy phase)
• High rate of chronic toxicity also seen
– 41% grade 2, 16% grade 3, 5% grade 4

Loco-regional control was high (>95%),
Extra-pelvic recurrences were common
(4-yr distant metastases 19%)
2-yr DFS 83%
Based on these results, a randomized trial was initiated
(RTOG 9905)
Unfortunately, closed due to poor accrual

Combined Modality Trials
• Several new combined modality trials are
underway or in the planning stages
• PORTEC-3 comparing pelvic RT versus
pelvic RT + chemotherapy in high risk pts
• New GOG trial (concept only) compares
pelvic RT versus VB + chemotherapy in
surgically staged patients

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