Radiotherapy in high riskearly endometrial cancer

Wui-Jin Koh, MDDepartment of Radiation OncologyUniversity 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 Podratzwww.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 in pelvic control, ?PFI

Role of chemotherapy increasing in extrauterine disease, but unproven in early disease

Issues– Prognostic factors and definitions of risk

– Extent of surgical staging

– Patterns of failure after surgery

– Toxicity of adjuvant therapy

Adjuvant RT for Uterine-confined EC

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…)

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

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)

Surgical-Pathological staging considerations

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?

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

Role of RT in non-surgically staged EChistorical 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.

Efficacy of RT in non-surgically staged EChistorical 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?Contemporary analysis

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 indicatedin Stage I endometrial carcinoma patients with high-risk features for locoregional relapse.”PORTEC – Scholton, IJROBP 2005

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?Contemporary analysis

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 therisk 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)

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

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?

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

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

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 (!?)

IVBT as adjuvant for uterine-confined EC

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

Contemporary imaging tools in RT planning

ABIMA

CIB

RA

Circiliac

CT with digital subtraction

Contemporary RT imaging/planning tools

Rose, 1997

Mundt, U Chicago

PETCT reconstruction

RT isodose distribution

PTV 100%

70%

Courtesy: Arno Mundt, MD

PTV100%

70%

4-field pelvic ‘box’ IMRT

Small Bowel

0

20

40

60

80

100

0 20 40 60 80 100 120

Percent Dose

Conv

IMRT

Dose-volume histogram analysis

Courtesy: Arno Mundt, MD

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

Table 1. Incidence of pelvic lymph node involvement as a function oftumor grade and myometrial invasion in clinical stage I endometrial cancer –

results of a prospective surgicopathologic study (Creasman et al, 1987)

Grade

Depth of InvasionG1 G2 G3

Endometrium only 0/44 (0%) 1/31 (3%) 0/11 (0%)

Inner 1/3 3/96 (3%) 7/131 (5%) 5/54 (9%)

Middle 1/3 0/22 (0%) 6/69 (9%) 1/24 (4%)

Deep 1/3 2/18 (11%) 11/57 (19%) 22/64 (34%)

Fig. 1. Estimation of pelvic lymph node involvement based on intrauterine tumor grade and depth of myometrial invasion.

y = 2.9773x - 0.8485R 2 = 0.7257

0

5

10

15

20

25

30

35

40

0 1 2 3 4 5 6 7 8 9 10

Risk-product (grade x numerator fractional depth of myometrial 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)

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?

Incompletely staged EC - Adjuvant RT?

1999 NCCN guidelines for surgically staged EC - adjuvant RT

Grade 1 2 3

St IA

IB

IC

IIA

IIB

Obs Obs

Obs Obs / ICBT /PRT +/- ICBT

Obs / ICBT /PRT +/- ICBT

Obs / ICBT /PRT +/- ICBT

Obs / ICBT* ICBT*

PRT + ICBT

PRT +/- ICBT

PRT + ICBT

PRT +/- ICBT

ICBT / PRT +/- ICBT

* if DMI ≤ 50%

PRT + ICBTPRT + ICBT

www.nccn.org

2001 NCCN guidelines for surgically staged early EC - adjuvant RT

Grade 1 2 3

St IA

IB

IC

IIA

IIB

Obs Obs

Obs / ICBT Obs / ICBT /PRT +/- ICBT

Obs / ICBT /PRT +/- ICBT

Obs / ICBT /PRT +/- ICBT

Obs / ICBT* Obs / ICBT*

PRT + ICBT

PRT +/- ICBT

PRT + ICBT

Obs / ICBT / PRT +/- ICBT

Obs / ICBT / PRT +/- ICBT

* if DMI ≤ 50%

PRT + ICBTPRT + 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 2 3

St IA

IB

IC

IIA

IIB

Obs Obs

Obs / ICBT Obs / ICBT /PRT +/- ICBT

Obs / ICBT /PRT +/- ICBT

Obs / ICBT /PRT +/- ICBT

Obs / ICBTPRT +/- ICBT

Obs / ICBTPRT +/- ICBT

PRT + ICBT

ICBT/PRT +/- ICBT

Obs / ICBT / PRT +/- ICBT

Obs / ICBT / PRT +/- ICBT

PRT + ICBTPRT + 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 2 3

St IA

IB

IC

IIA

IIB

University of Washington, Seattle

Adjuvant ext pelvic RT for EC - circa 1990surgically staged

Grade 1 2 3

St IA

IB

IC

IIA

IIB

University of Washington, Seattle

Adjuvant RT for EC - Y2KSurgically 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 - 2007Surgically staged

Grade 1 2 3

St IA

IB

IC

IIA

IIB

ICBT?

ICBT ICBT

ICBT

ICBT

ICBT

ICBT

University of Washington, Seattle

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