Management of Endometrial Cancer

in 2008

Marcus E. Randall, MD, FACRChair and Professor

Markey Foundation Endowed ChairDepartment of Radiation Medicine

University of Kentucky Medical Center

Endometrial Carcinoma

•Classification of Disease Categories– Locoregional disease

• Low-risk disease: stage IA grades 1-2

• Intermediate-risk disease: all other stage I, stage II

• High-risk disease: stage III and IVA

– Disseminated disease: stage IVB or recurrent

EARLY STAGE ENDOMETRIAL CANCER:

INTERMEDIATE RISK

DOES EVERYONE NEED RT?

GOG # 99

• Complete surgical staging including pelvic and para-aortic node sampling

• Surgical stage IB, IC, IIA (occult) and IIB (occult) (Low and Intermediate Risk)

• All histologic types except serous papillary and clear cell

• Randomized to pelvic RT vs. no further therapy

GOG # 99

• 392 evaluable patients

• 58.5% IB, 32.1% IC, only 9.4% stage II(occult)

• 82.3% inner and middle third invasion, only 17.6% outer third invasion

• 81.6% grade 1 and 2, only 18.4%

• grade 3

GOG # 99

Recurrence Pattern Surgery Surgery+EBRT

Vagina, by randomization 13/172 (7.6%) 2/179 (1.1%)

Vagina, by treatment 15/172 (8.7%) 1/179 (0.6%)

received

Total pelvic failure, by 20/172 (12%) 3/179 (1.7%)

randomization

Total pelvic failure, by 22/172 (13%) 1/179 (0.6%)

treatment received

GOG # 99

Surgery Surgery +EBRT

Alive (4 years) 86% 92%

Dead of disease 15/202 (7.4%) 8/190 (4.2%)

Intercurrent deaths 18/202 (8.9%) 14/190 (7.4%)

Conclusion: The use of adjuvant RT, in women with intermediate risk endometrial cancer, decreases the risk of recurrences but has an inappreciable effect on overall survival

PROBLEMS WITH GOG # 99

• The number of events was smaller than expected and approximately 50% of deaths were due to intercurrent disease. Therefore, the study was insufficiently powered to demonstrate a statistically significant survival difference.

• The patient population was largely composed of low risk patients.

GOG # 99• Recognized during study that patient

population being accrued was mostly low risk. Therefore, “low intermediate” and “high intermediate” risk groups were defined based on GOG #33 data base.

“HIGH INTERMEDIATE RISK”

• Moderately-poorly differentiated tumor and

• Presence of LVSI and

• Outer 1/3 myometrial invasion

Age >50 with any 2 risk factors above

Age >70 with any 1 risk factor

Others considered “low intermediate risk.”

GOG #99: CONCLUSION

• Adjunctive 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.

Keys et al. Gynecol Oncol 2004; 92:744-751.

Trial design for ASTEC/EN.5

Surgery

High risk pathology and no macroscopic disease

RANDOMIZE

No external beam RT External beam RT

Primary endpoint: Overall survival

Secondary endpoint: Recurrence-free survival

905 cases

453 cases 452 cases

2% EBRT, 51% Brachytherapy 98% EBRT, 52% Brachytherapy

EN.5: 　 July 1996-ASTEC: 　 July 1998-

Analyzed by ITT principle

71% ATH BSO29% ATH BSO PLN

HR=1.01, 95%CI=0.71-1.42. P=0.98 5y-OS: EBRT 84%, no EBRT 84%

HR=0.53, 95%CI=0.29-0.97. P=0.038 5y-RFS: EBRT 4%, no EBRT 7%

Outcomes of ASTEC/EN.5Overall survival

Isolated vaginal or pelvic initial recurrence

JGOG2033 ：

Randomized phase III trial of pelvic RT versus cisplatin-based chemotherapy in

patients with 　 intermediate risk endometrial carcinoma

S. Sagae, N. Susumu, Y. Udagawa, K. Niwa, R. Kudo, S. Nozawa, for the Japan Gynecologic Oncology Group

(ASCO 2005)

Trial design for JGOG 2033

Surgery

>1/2 myometrial invasion, no residual tumorFIGO stage IB, IC, IIA, IIB, IIIA, IIIB, IIIC

RANDOMIZE

Pelvic Radiation Therapy (PRT)

Chemotherapy (CAP)

Primary endpoint: Overall SurvivalSecondary endpoints: PFS, incidence of toxicity

475 cases

238 cases237 cases

Enrollment: Jan 1994 - Dec 2000

Analyzed on ITT principle

ATH BSO+ PLN (95.3%)

PRT:45-50Gy, PAN (5.7%), Brachytherapy (3.1%)

Cyclophosphamide 333 mg/m2Doxorubicin 40 mg/m2Cisplatin 50 mg/m2Every 4 weeks for 3 or more courses

193 cases192 cases

(Median follow up: 60.2M)

Entry 　 475

Randomization

Pelvic Radiation Therapy (PRT): 　238

Chemotherapy (CAP): 　 237

Subsequently eligible = 193

7 did not receive PRT

(18 ineligible)27 excluded due to 　

non-endometrioid histology

Subsequently eligible = 192

4 did not receive CAP

(23 ineligible)22 excluded due to

non-endometrioid histology

Flow chart of patients

TreatmentComparison 　　　　　 PRT

CAP Chemo

Completed Tx 　　　　　　　　 98.9% 　 97.3%

Median No. of courses 　　　　　　　　 3 ( 3-7 )

Median duration of Tx 　　　　　　 5.1 wks 　 11.4 wks

Stopped Tx due to toxicity 　　 　 1.6% 4.8%

Adverse Effects

Toxicity PRT (n=193) CAP (n=192)

Grade 0-2 190 (98.4%) 181(95.3%)

3-4 3 ( 1.6%) 9 (4.7%)

(chi-square test for Grade 3-4 frequency, p=0.077)

Tx-related death 0 　 (0%) 0 　 (0%)

JGOG #2033: Treatment Outcomes

Progression-Free Survival of Intermediate Risk

0

20

40

60

80

100

0 1 2 3 4 5

years

Sur

viva

l rat

e (%

)

12

34 HIR,PRT 38 18 56 66.2%

Log-RankTest Alive Failed Total 5ys rate

HIR,CAP 54 10 64 83.8%

LIR,PRT 95 5 100 94.5%

LIR,CAP 80 10 90 87.6%p=0.110

p=0.024

PRT vs CAPHazard Ratio(CI)

2.58(0.86-7.71)

0.44(0.20-0.97)

Overall Survival of Intermediate Risk

0

20

40

60

80

100

0 1 2 3 4 5

years

Sur

viva

l rat

e (%

)

12

34 HIR,PRT 42 14 56 73.6%

Alive Failed Total 5ys rate

HIR,CAP 59 5 64 89.7%

LIR,PRT 95 4 99 95.1% LIR,CAP 83 7 90 90.8%

p=0.281

p=0.006

Log-RankTest

2.54(0.71-9.04)

PRT vs CAPHazard Ratio(CI)

0.24(0.09-0.69)

JGOG #2033: Treatment Outcomes

A randomized phase-III study on adjuvant treatment with radiation (RT) ± chemotherapy (CT) in early stage high-risk endometrial cancer (NSGO-EC-

9501/EORTC 55991)

On behalf of NSGO and EORTC

T. Hogberg1, P. Rosenberg1, G. Kristensen1, CF de Oliviera2, R dePont Christensen1 B Sorbe1, C Lundgren1, H Andersson1,

T Salmi1, NS Reed2. 1Nordic Society of Gynecologic Oncology, Odense, Denmark, 2Europ Org for Research and Treatment of Cancer,

Brussels, Belgium.

NSGO EORTC

NSGO EC-9501/EORTC-55991

Radical surgery　　 ATH+BSO 　(+PLA) RT+CT

RT

CT+RTOR

Randomization

Primary endpoint　　 Progression-free survival

(PFS)

Surgical stage I, II, IIIA ( positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only)

Patients with serous, clear cell, or anaplastic carcinomas were eligible regardless of other risk factors

44 Gy XRT ± optional brachytherapy (BT:39%)

CT : 　 intially AP　　　 Later AP, TP, TAP, TEP

196 cases

186 cases

382 cases

May 1996 to January 2007

(BT:44%)

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5analysis time

random = 1 random = 2

HR 0.65 (CI 0.40-1.06) p=0.08; estimated difference in 5-yr OS 8% from 74 % to 82 %

CT not completed CT completedRT (n=196) RT + CT (n=186)

NSGO EC-9501/EORTC-55991

Overall survival depending on randomization

Thomas Hogberg, NSGO - 18

0.00

0.25

0.50

0.75

1.00

0 1 2 3 4 5analysis time

random = 1 random = 2

HR 0.51 (CI 0.29-0.91) p=0.02; estimated difference in 5-yr CSS 10 % from 78 % to 88 %

CT not completed CT completedRT (n=196) RT + CT (n=186)

NSGO EC-9501/EORTC-55991

Cancer-specific survival depending on randomization

Thomas Hogberg, NSGO - 19

NSGO EC-9501/EORTC-55991

ConclusionDespite that 27 % of the patients randomized to RT+CT received no or only part of the prescribed CT, RT+CT was better than RT alone as adjuvant therapy for patients with early endometrial cancer at high risk for micrometastases.

Thomas Hogberg, NSGO - 25

NSGO EORTC

EARLY DISEASE:CONCLUSIONS

1. Patients with low risk disease probably do not need RT. They can be observed and RT used for salvage of local recurrences (must not immediately treat locally recurrent patients with systemic therapy on the theory they are “incurable.”

CONCLUSIONS2. Adjuvant RT (of some sort) plays an

important role in improving local control and possibly survival in most other patients with high intermediate risk endometrial carcinoma.

3. The increasing reliance on up-front surgical therapy and staging, including LN assessment, has raised new questions about the use of and appropriate extent of post-operative RT.

CONCLUSIONS4. Given early data suggesting that

chemotherapy might be effective on an adjuvant basis in high risk early stage disease, the Gynecologic Oncology Group is planning to open a study evaluating chemotherapy with cuff brachytherapy in high risk stage I-II disease.

Phase III trial of pelvic radiation therapy versus vaginal cuff brachytherapy followed by

paclitaxel/carboplatin chemotherapy in patients with high risk, early stage endometrial cancer:

ELIGIBILITY CRITERIA:• Surgically staged high-intermediate risk endometrial

cancer defined by GOG 99 (age >/= 70 with 1 risk factor, or >/= 50 with 2 risk factors)- using risk criteria of: Grade 2-3 tumor, (+) LVSI, outer 1/3 myometrial invasion + any age with all 3 risk criteria

• Stage IIb endometrial cancer of any histology• Stage I-IIb papillary serous or clear cell cancers

Study Chairs: Scott McMeekin, Marc Randall, Carol Aghajanian

LOCALLY ADVANCED ENDOMETRIAL CANCER

Chemotherapy for Measurable Disease Endometrial Carcinoma

•GOG Protocol 177:Parameter Dox/Tax/Cis Dox/Cis

Patients 134 129Response 77 (57%) 44 (34%)Complete Response 29 (22%) 9 (7%)Median PFS 8.3 mo. 5.3 mo.Median OS 15.3 mo. 12.3 mo.Ref: Fleming et al. JCO 22: 2159-2166, 2004.

Whole Abdominal Radiotherapy versus Combination Doxorubicin-Cisplatin

Chemotherapy In Advanced Endometrial Carcinoma: A Randomized Phase III Trial

Of The Gynecologic Oncology Group

Randall ME et al. Journal of Clinical Oncology 24:36-44, 2006.

GOG #122: TREATMENT ARMS

• Whole Abdominal Irradiation (WAI)

• Doxorubicin and Cisplatin (AP Chemo)

• Randomization was balanced within institutions. No other stratification was used.

TREATMENTComparison WAI AP

Chemo Completed Tx 84% 63%Stopped tx due 3% 17%

to toxicityMedian duration 1.3 mos. 5.1 mos.

of treatment Did not receive n=12* n=3*

protocol tx (#)

*Not assessed for adverse effects but included in analysis of treatment outcomes.

ADVERSE TREATMENT EFFECTS

Grade 3- 4 Toxicity WAI (%) AP (%)

White blood count 4 62

Abs. Neutrophil <1 85

Gastrointestinal 13 20

Hepatic 3 1

Cardiac 0 15

Neurologic <1 7

Tx-related deaths n=4 n=8

GOG #122: TREATMENT OUTCOMES

SUMMARY: MANAGEMENT OF STAGE III-IV ENDOMETRIAL

CARCINOMA

1. Make every effort to have patient surgically staged and maximally debulked.

2. Whole abdominal RT alone is probably no longer an acceptable treatment.

MANAGEMENT OF STAGE III-IV ENDOMETRIAL CARCINOMA

3. Combination chemotherapy has a definite place in the management of these patients, Based on GOG #122, this currently represents the treatment of choice, assuming toxicity can be limited or managed.

4. Role of combined chemo-RT is unclear, but early results are promising. Might well be the best treatment.

Chemotherapy for Advanced or Measurable Disease Endometrial

Carcinoma•GOG Protocol 209: Advanced or Recurrent (Measurable) Disease*

Regimen I** Doxorubicin 50 mg/m2 d1Cisplatin 60 mg/m2 d1

Paclitaxel 160 mg/m2/3h d2

Regimen II Paclitaxel 175 mg/m2/3hCarboplatin AUC 6 d1

*Each regimen given every 3 weeks

**Regimen I requires G-CSF.

Proposed GOG Study (GOG 704)

Chemotherapy alone (6 cycles of

Carbo-Taxol) Vs

RT Concurrent with weekly cisplatin followed by 4 cycles of Carbo-Tax

Study Chairs:

Dr. Daniela Matei (Medical Oncology)

Dr. Marc Randall (Radiation Oncology)

Dr. David Mutch (Gynecologic Oncology)

QUESTIONS?