1. Radiotherapy in high risk early endometrial cancer
Wui-Jin Koh, MD
Department of Radiation Oncology
University of Washington, Seattle, WA

2. 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

3. Endometrial cancer case (64 yo, Gr 2, LVSI+, 75% invasion)
Would you consider the patient cancer to be
Low risk?
Intermediate risk?
High risk?

4. 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

5. 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

6. 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?

7. 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

8. 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

9. 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

10. 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

11. 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 in pelvic control, ?PFI
Role of chemotherapy increasing in extrauterine disease, but unproven in early disease

12. 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

13. Intrauterine pathologic prognostic factors
Grade
DMI
LVSI
Cervical stromal invasion
Cell type - papillary serous / clear cell
Lower uterine segment involvement?
Tumor bulk
Biomolecular markers (PTEN, Her2/neu, p53…)

14. 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 uterine-confined EC (Zaino, Cancer 1996)
The harder you look for it, the greater the sensitivity

15. 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)

16. 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?

17. 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

18. 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.

19. 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

20. 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 < )
Grade 1: S- 4%, S+RT – 17%
Grade 3-4: S+RT – 3%

21. 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

22. 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”

23. Role of RT in surgically staged EC? GOG 99 (Keys, Gynecol Oncol 2004)
Overall survival: HR 0.86 (90% CI , p=0.56), median f/u 69 m

24. 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.”

25. Role of RT in surgically staged EC? GOG 99 (Keys, Gynecol Oncol 2004)
S (n=202)
88% 18 13 1
S+RT (n=190)
97% (p=0.007) 3* 2* 8
2-yr recur-free
Confined pelvic/
vaginal failure
Isolated vaginal
Failure
GI comp ≥ Gr 3
* 2 of these patients refused radiotherapy

26. 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?

27. 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 0.5 cm
5 yr DFS 87%, 5 yr OS 93%
No vaginal/pelvic failure, 3 failed in upper abd
No significant late morbidity

28. 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

29. 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

30. Cost of therapy IVBT less costly than external beam RT
Patient convenience
Ancillary costs
Time to recovery
Time away from employment

31. IVBT as adjuvant for uterine-confined EC
Vaginal failures occur in % (with identifiable risk factors)
Despite surgery!
IVBT addresses primary site of preventable failure
Especially in surgically staged patients
PORTEC 2 – ext RT vs IVBT

32. 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 (!?)

33. Role of external RT in EC?
Documented extrauterine disease
High 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

34. Contemporary imaging tools in RT planning
CT with digital subtraction RA
IMA AB
CIB
Circ
iliac

35. Contemporary RT imaging/planning tools
CT reconstruction
PET
Rose, 1997
Mundt, U Chicago

36. RT isodose distribution
4-field pelvic ‘box’
IMRT
PTV
100%
70%
PTV
100%
70%
Courtesy: Arno Mundt, MD

37. Dose-volume histogram analysis
Conv
IMRT
Courtesy: Arno Mundt, MD

38. Incompletely staged EC
70+% of endometrial cancer cases in the US are NOT operated on by Gyn Oncologists
Radiologic Imaging
Consider surgical staging
If you agree that you would not give pelvic RT if no LN involvement is found

40. 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)

41. 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 rate for RT s/p TAH ~ 5%
0.65 x LN+% > 5% ---> LN+% > 8% to justify PRT?

42. 1999 NCCN guidelines for surgically staged EC - adjuvant RT
Grade 1 2 3
St IA IB IC
IIA
IIB
Obs / ICBT /
PRT +/- ICBT
Obs
Obs
Obs / ICBT /
PRT +/- ICBT
ICBT /
PRT +/- ICBT
Obs
Obs / ICBT /
PRT +/- ICBT
PRT +/- ICBT
PRT +/- ICBT
Obs / ICBT*
ICBT*
PRT + ICBT
PRT + ICBT
PRT + ICBT
PRT + ICBT
* if DMI ≤ 50%

43. 2001 NCCN guidelines for surgically staged early EC - adjuvant RT
Grade 1 2 3
St IA IB IC
IIA
IIB
Obs / ICBT /
PRT +/- ICBT
Obs
Obs
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
PRT +/- ICBT
Obs / ICBT*
Obs / ICBT*
PRT + ICBT
PRT + ICBT
PRT + ICBT
PRT + ICBT
* if DMI ≤ 50%

44. 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

45. 2006 NCCN guidelines for surgically staged early EC - adjuvant RT
Grade 1 2 3
St IA IB IC
IIA
IIB
Obs / ICBT /
PRT +/- ICBT
Obs
Obs
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT
Obs / ICBT /
PRT +/- ICBT
Obs / ICBT /
PRT +/- ICBT
ICBT /
PRT +/- ICBT
Obs / ICBT
PRT +/- ICBT
Obs / ICBT
PRT +/- ICBT
ICBT/
PRT +/- ICBT
PRT + ICBT
PRT + ICBT
PRT + ICBT

46. 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 -
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

47. Adjuvant ext pelvic RT for EC - circa 1984
Grade 1 2 3
St IA IB IC
IIA
IIB
University of Washington, Seattle

48. Adjuvant ext pelvic RT for EC - circa 1990 surgically staged
Grade 1 2 3
St IA IB IC
IIA
IIB
University of Washington, Seattle

49. 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

50. Adjuvant RT for EC - 2007 Surgically staged
Grade 1 2 3
St IA IB IC
IIA
IIB
ICBT
ICBT?
ICBT
ICBT
ICBT
ICBT
ICBT
University of Washington, Seattle

51. 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

52. 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%

53. 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

54. 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