Radiotherapy in high risk
early endometrial cancer
Wui-Jin Koh, MD
Department of Radiation Oncology
University of Washington, Seattle, WA
Endometrial cancer case
 64
yo, diet-controlled DM, BMI=35
 PMB  EMB = Gr2 endometriod adenocarcinoma
 CXR neg, CBC/BMP WNL, pt deemed surgical
candidate
 Vaginal hysterectomy + BSO
 Path
– 3 cm tumor, LVSI+, 75% myoinvasion
– Cul-de-sac washings negative
Case from 3/07 Int Gynecologic Cancer Society tumor board, submitted by Dr Karl Podratz
www.igcs.org
Endometrial cancer case
(64 yo, Gr 2, LVSI+, 75% invasion)
 Would
you consider the patient cancer to be
– Low risk?
– Intermediate risk?
– High risk?
Endometrial cancer case
(64 yo, Gr 2, LVSI+, 75% invasion)
 What
further therapy would you recommend?
– Observation
– Vaginal brachytherapy
– External radiation +/- brachytherapy
– Chemotherapy
– Chemotherapy and radiation
– Surgical staging including retroperitoneal LND
www.igcs.org
Endometrial cancer case
(64 yo, Gr 2, LVSI+, 75% invasion)
 Systematic
pelvic and PALN dissection to
renal vessels
 No intraabdominal disease noted
 Path: 34 pelvic and 16 PALN harvested
– All lymph nodes histologically negative
– Repeat peritoneal cytology negative
www.igcs.org
Endometrial cancer case
(64 yo, Gr 2, LVSI+, 75% invasion, 50/50 LN-)
Would
you now consider the patient cancer to be
–Low risk?
–Intermediate risk?
–High risk?
Endometrial cancer case
(64 yo, Gr 2, LVSI+, 75% invasion, 50/50 LN-)
 What
further therapy would you recommend?
– Observation
– Vaginal brachytherapy
– External radiation +/- brachytherapy
– Chemotherapy
– Chemotherapy and radiation
www.igcs.org
Radiotherapy in high-risk early
endometrial cancer
 Complex,
controversial and confusing
 “At
least Professor Vergote (IGCS president)
did not ask you to talk on radiotherapy in
early stage ovarian cancer”
– Ted Trimble, IGCS president-elect
Radiotherapy in high-risk early
endometrial cancer - definitions
 Adjuvant
RT following primary surgery
– RT alone has curative potential in medically
inoperable patients
 Early
= Uterine confined (stage I/II)
 Adenocarcinoma,
endometriod histology
– Uterine papillary serous carcinoma as a distinct
entity
Proposed definition of ‘risk’ in EC
 High
risk - extrauterine disease
– (ie – not early stage)
– Implies that treatment is needed
 Low
risk - Stage IA all grades, IBG1, IBG2, IIA?
 Intermediate
risk
– IBG3
– All stage IC’s
– Cervical stromal involvement
Endometrial cancer – general observations
 Role
of adjuvant RT in early disease
– Historically overused
– Current decreased trend is a good thing!
– No randomized trial (n=3) has shown overall
survival benefit
 improvement
 Role
in pelvic control, ?PFI
of chemotherapy increasing in extrauterine
disease, but unproven in early disease
Adjuvant RT for Uterine-confined EC
Issues
– Prognostic factors and definitions of risk
– Extent of surgical staging
– Patterns of failure after surgery
– Toxicity of adjuvant therapy
Intrauterine pathologic prognostic factors
 Grade
 DMI
 LVSI
 Cervical
 Cell
stromal invasion
type - papillary serous / clear cell
 Lower
uterine segment involvement?
 Tumor
bulk
 Biomolecular
markers (PTEN, Her2/neu, p53…)
Does surgical extent alter risk in EC?
 Therapeutic
benefit?
– Kilgore (Gynecol Oncol 1995); ASTEC 2006
 Alters
individual assessment and classification
of risk
– 1988 FIGO surgicopathologic staging
– Risk assessment of clinical vs pathologic uterineconfined EC (Zaino, Cancer 1996)
– The harder you look for it, the greater the sensitivity
Surgical-Pathological staging considerations
 Without
LNS, prognosis primarily based on
grade and depth of myometrial invasion (DMI)
 Grade
& DMI predicts for LN+
 Patients
with LN+ now upstaged to IIIC
– Stage migration
– 92.7% 5-yr survival for pathological Stage I cancer
with no adverse risk features other than grade and
myoinvasion (Morrow, Gynecol Oncol 1991)
Endometrial cancer case
(64 yo, Gr 2, LVSI+, 75% invasion, 3/3 LN-)
Would
you now consider the patient cancer to be
–Low risk?
–Intermediate risk?
–High risk?
–High intermediate risk?
Role of RT in non-surgically staged EC
historical analysis
 Aalders,
Obstet Gynecol, 1980
– 540 St I pts, all received ICBT, 6000 rads
– Randomized to no vs 4000 rads pelvic RT
– No difference in overall survival or overall relapse
– Pelvic RT decreased pelvic failure, but altered
pattern of failure
– ? benefit in patients with grade 3 and > 50% DMI
Efficacy of RT in non-surgically staged EC
historical analysis
 Kucera,
Gynecol Oncol 1990
– Selective addition of pelvic RT to patients with
high risk intrauterine features ‘equalized’
outcome to good prognostic group.
 Carey,
Gynecol Oncol 1995
– Selective use of pelvic RT in high risk patients
achieved good overall outcome.
Role of RT in non-formally staged EC?
Contemporary analysis
 PORTEC (Creutzberg Lancet 2000, Sholten IJROBP 2005)
– 714 patients, ICG1, IBG2, ICG2, IBG3
– ICG3 specifically NOT included
– Randomized to NAT vs 46 Gy pelvic RT
– No brachytherapy
– RT decreases LRF, but has no impact on survival
RT
not indicated in IBG2, < 60 yo
– RT increases morbidity
Role of RT in non-formally staged EC?
 PORTEC (Scholten IJROBP 2005)
– Centralized path review – 134 cases ‘excluded’ based on
stage IB Gr1 ‘downstaging’ – did not affect outcome
– 10 yr LR failure rate: S – 14%, S+RT – 5% (p < 0.001)

73% of LRF’s were isolated vaginal
– Risk factors – age ≥ 60, Gr 3, ≥ 50% myoinvasion
If at least 2 of 3 risk factors present
 10 yr LRF rate: S- 23.1%, S+RT – 4.6%

– Late toxicity - 5 yr actuarial rates (Creutzberg, IJROBP 2001)
All grades: S – 4%, S+RT – 26% (p < 0.0001)
 Grade 1: S- 4%, S+RT – 17%
 Grade 3-4: S+RT – 3%

Role of RT in non-formally staged EC?
“In view of the significant locoregional control benefit, radiotherapy remains indicated
in Stage I endometrial carcinoma patients with high-risk features for locoregional relapse.”
PORTEC – Scholton, IJROBP 2005
Role of RT in surgically staged EC?
Contemporary analysis
 GOG
99 (Roberts, SGO 1998 abst)
– 392 pathologic stage IB/IC/occult II patients, all grades
– Randomized to NAT vs 50 Gy pelvic RT
– No brachytherapy
– Significant decrease in pelvic failures
– “Use of adjunctive RT in women with intermediate risk
EC decreases the risk of recurrences but has an
inappreciable effect on overall survival”
Role of RT in surgically staged EC?
GOG 99 (Keys, Gynecol Oncol 2004)
Overall survival: HR 0.86 (90% CI 0.57-1.29, p=0.56), median f/u 69 m
Benefit of RT in HIR subset of GOG 99?
(Keys, Gynecol Oncol 2004)
 “High
Intermediate
Risk”
– Gr 2 or 3, LVSI, outer
third myometrial
invasion
– Age > 50 and 2 of
above
– Age > 70 and 1 of
above
“Adjuvant RT in early stage intermediate risk endometrial carcinoma decreases the
risk of recurrence, but should be limited to patients whose risk factors fit a
high intermediate risk definition.”
Role of RT in surgically staged EC?
GOG 99 (Keys, Gynecol Oncol 2004)
2-yr recur-free
S (n=202)
88%
S+RT (n=190)
97% (p=0.007)
Confined pelvic/
vaginal failure
18
3*
Isolated vaginal
Failure
13
2*
GI comp ≥ Gr 3
1
8
* 2 of these patients refused radiotherapy
Patterns of failure in early endometrial cancer
undergoing surgery only– implications for treatment
 The
majority of pelvic failures in both PORTEC and
GOG 99 were isolated vaginal
 Are
non-radiated isolated vaginal failures curable?
– PORTEC – 5 yr survival 65%
– GOG 99 – 5/13 DOD on preliminary evaluation
 Predictors
of vaginal relapse
– Gr 3 histology, LVSI+ (Mariani, Gyn Oncol 2005)
 Can
adjuvant vaginal brachytherapy address potential
vaginal failures, and improve the therapeutic index?
IVBT as adjuvant for uterine-confined EC
- intermediate risk
 Chadha
et al, Gynecol Oncol 1999
– 38 pathologic stage I EC, full surgical staging
– IB/G3 - 12, IC/G1 - 14, IC/G2 - 9, IC/G3 - 3
– IVBT 7 Gy x 3 @ 0.5 cm
– 5 yr DFS 87%, 5 yr OS 93%
– No vaginal/pelvic failure, 3 failed in upper abd
– No significant late morbidity
IVBT as adjuvant for uterine-confined EC
- intermediate risk
 Ng
et al, Gynecol Oncol 2000
– 77 pathologic stage I EC, full surgical staging
– IBG3 - 17, ICG1 - 10, ICG2 - 33, ICG3 - 17
– IVBT 60 Gy LDReq to upper 2 cm mucosa
– 5 yr DFS = 82%, 5 yr OS = 94%
– 11 recurrences

3 distant, 1 pelvis

7 vagina (5 lower 2/3)
– No significant late complications
IVBT as adjuvant for uterine-confined EC
- intermediate risk
 Ng
et al, Gynecol Oncol 2001
– 15 pathologic stage II(occ) EC, surgically staged
– IIA - 5, IIB - 10 (G1 - 5, Gr 2 - 8, Gr 3 - 2)
– IVBT 60 Gy LDReq to upper 2 cm mucosa
– Median f/u = 36 months
– No recurrences
– No significant complications
Cost of therapy
 IVBT
less costly than external beam RT
 Patient
convenience
 Ancillary
costs
– Time to recovery
– Time away from employment
IVBT as adjuvant for uterine-confined EC
 Vaginal
failures occur in 8 - 15% (with
identifiable risk factors)
– Despite surgery!
 IVBT
addresses primary site of preventable
failure
– Especially in surgically staged patients
 PORTEC
2 – ext RT vs IVBT
IVBT as adjuvant for uterine-confined EC
 Effective
in preventing vaginal relapse
– When applied appropriately
– Prevention is better than salvage
 Well-tolerated
 If
disease volume at risk is beyond the
‘reach’ of IVBT, local-regional therapy alone
may be insufficient (!?)
Role of external RT in EC?
 Documented
 High
extrauterine disease
risk of extrauterine disease
– Incompletely staged cases with
significant intrauterine risk factors
– ‘greatest-risk’ subset of early EC,
independent of surgical staging
IC
Gr3, IIB
Contemporary imaging tools in RT planning
CT with digital subtraction
RA
AB
IMA
CIB
Circ
iliac
Contemporary RT imaging/planning tools
PET
CT reconstruction
Rose, 1997
Mundt, U Chicago
RT isodose distribution
4-field pelvic ‘box’
PTV
IMRT
100%
PTV
70%
Courtesy: Arno Mundt, MD
100%
70%
Dose-volume histogram analysis
Conv
IMRT
Courtesy: Arno Mundt, MD
Incompletely staged EC
 70+%
of endometrial cancer cases in the US are
NOT operated on by Gyn Oncologists
 Radiologic
 Consider
Imaging
surgical staging
– If you agree that you would not give pelvic RT if no
LN involvement is found
Table 1. Inciden ce of pelvic lymph node involve ment as a function of
tumor grade and myometrial invasion in clini cal stage I endome trial cancer –
results of a prospective su rgicopathologic s tudy (Creasman et al, 1987)
Grade
G1
G2
G3
Endo metrium only
0/44 (0%)
1/31 (3%)
0/11 (0%)
Inner 1/3
3/96 (3%)
7/131 (5%)
5/54 (9%)
Middl e 1/3
0/22 (0%)
6/69 (9%)
1/24 (4%)
Deep 1/3
2/18 (11%)
11/57 (19%)
22/64 (34%)
Depth of Invasion
Numerator fractional depth of invasion is defined as follows:
Endometrium only = 0; inner 1/3 = 1; 1/3 to 2/3 = 2; greater than 2/3 = 3.
Tumor grade expressed as 1, 2, or 3.
Koh et al, 2001 (based on data from Creasman et al, 1987)
Incompletely staged EC - Adjuvant RT?
 Likelihood
of LN+
– LN+% = 3 x Grade X DMI (in fractional thirds)
– analysis from Creasman, Cancer 1987
 Cure
for pathologic stage III EC with PRT ~ 65%
– Greven, Cancer 1993
 Complication
 0.65
rate for RT s/p TAH ~ 5%
x LN+% > 5% ---> LN+% > 8% to justify PRT?
1999 NCCN guidelines for surgically staged EC adjuvant RT
Grade 1
St IA
Obs
IB
Obs
IC
Obs / ICBT /
PRT +/- ICBT
IIA
Obs / ICBT*
IIB
PRT + ICBT
* if DMI ≤ 50%
2
Obs
3
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
ICBT /
PRT +/- ICBT
PRT +/- ICBT
PRT +/- ICBT
ICBT*
PRT + ICBT
PRT + ICBT
PRT + ICBT
www.nccn.org
2001 NCCN guidelines for surgically staged early EC
- adjuvant RT
Grade 1
St IA
Obs
2
Obs
3
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
IB
Obs / ICBT
IC
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
IIA
Obs / ICBT*
Obs / ICBT*
PRT + ICBT
IIB
PRT + ICBT
PRT + ICBT
PRT + ICBT
* if DMI ≤ 50%
PRT +/- ICBT
www.nccn.org
2006 NCCN guidelines for surgically staged EC adjuvant RT
A
3-dimensional table!!
– Incorporates traditional grade and depth of
invasion
– Adds consideration of patient age, LVSI,
tumor size
2006 NCCN guidelines for surgically staged early EC
- adjuvant RT
Grade 1
St IA
Obs
2
Obs
3
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
IB
Obs / ICBT
IC
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
IIA
Obs / ICBT
PRT +/- ICBT
Obs / ICBT
PRT +/- ICBT
ICBT/
PRT +/- ICBT
IIB
PRT + ICBT
PRT + ICBT
PRT + ICBT
ICBT /
PRT +/- ICBT
www.nccn.org
Adjuvant RT for early endometrial cancer
– metaanalysis and systematic reviews

Cochrane Review
(Kong et al, Ann Oncol 2007)
– Pelvic RT leads to a 72% RR reduction in locoregional relapses
– Trend towards benefit in survival for patients with multiple risk factors (eg Gr3
and stage IC)
– Inherent risk of added toxicity

Ontario program in evidence-based care – Gyn Cancer Disease
Site Group practice guidelines March 2006 (Lukka et al www.cancercare.on.ca/pdf/pebc4-10f.pdf)
– Regardless of surgical staging, external adjuvant RT
 Is recommended for ICG3
 Is NOT recommended for IA/IB G1G2
 Is a reasonable option for IC G1G2, IA/IB G3
Adjuvant ext pelvic RT for EC - circa 1984
Grade 1
St IA
IB
IC
IIA
IIB
University of Washington, Seattle
2
3
Adjuvant ext pelvic RT for EC - circa 1990
surgically staged
Grade 1
St IA
IB
IC
IIA
IIB
University of Washington, Seattle
2
3
Adjuvant RT for EC - Y2K
Surgically staged
Grade 1
2
3
St IA
IB
IC
IIA
IIB
ICBT
ICBT?
ICBT
ICBT
ICBT
ICBT
University of Washington, Seattle
Adjuvant RT for EC - 2007
Surgically staged
Grade 1
2
3
St IA
IB
ICBT
IC
ICBT?
ICBT
IIA
ICBT
ICBT
IIB
ICBT
University of Washington, Seattle
ICBT
Uterine confined EC - who is at risk for
extrapelvic relapse?
 In
GOG 99 – HIR (Keys, Gynecol Oncol 2004)
– > 2/3 DMI, Gr 2 or 3, LVSI+
– Age > 50 & 2 of the above
– Age > 70 & 1 of the above
 42%
of failures in S only group were extrapelvic
 77% of failures in S+RT group were extrapelvic
IC Gr3 endometrial adenocarcinoma –
‘PORTEC registry’ (Creutzberg JCO 2004)
 99
pts with ICG3 treated with RT
– Compared to 345 pts on phase III trial who
actually received RT
– 5 yr LRF rate: ICG3 – 14%, PORTEC pts – 3%
– 5 yr DM rate: ICG3 – 31%
Uterine confined endometrial cancer – summary
 Surgical
staging has made a major impact
– Stage migration
– Therapeutic benefit?
– Tailored adjuvant therapy
 Most
patients do not need adjuvant therapy
 For most intermediate risk EC considered for
adjuvant RT, IVBT may be sufficient
 For those at ‘greatest risk’, external RT alone may
be insufficient as sole adjuvant therapy
– ? ChemoRT - RTOG 9708: Greven, Gynecol Oncol 2006
Uterine confined endometrial cancer – summary
 ‘Risk’ exists
on a continuum, but our categorization
of risk is based on discrete, and sometimes arbitrary
measures
 Majority
do not need adjuvant therapy
– Start with a minimalist mindset and evaluate each case
individually
– No “one size fits all”
– Understand personal and historical biases
 Educate
the patient and the care providers
 Assess
level of risk based on careful assessment of
all available surgicopathologic features
– Multidisciplinary interaction and pathology review