Role of Chemotherapy Role of Chemotherapy For Endometrial Carcinoma For Endometrial Carcinoma

Role of Chemotherapy Role of Chemotherapy For Endometrial Carcinoma For Endometrial Carcinoma

IGCS council, GCIG executive boardIGCS council, GCIG executive board

Sapporo Railway Hospital Sapporo Railway Hospital Vice-directorVice-director

Sapporo JapanSapporo Japan

IGCS council, GCIG executive boardIGCS council, GCIG executive board

Sapporo Railway Hospital Sapporo Railway Hospital Vice-directorVice-director

Sapporo JapanSapporo Japan

Satoru Sagae MD PhDSatoru Sagae MD PhDSatoru Sagae MD PhDSatoru Sagae MD PhD

IGCS 10,2006IGCS 10,2006IGCS 10,2006IGCS 10,2006

Endometrial Cancer - Treatment PlanEndometrial Cancer - Treatment PlanEndometrial Cancer - Treatment PlanEndometrial Cancer - Treatment Plan

Surgical Staging

Low Risk　 IA: G1-2

No treatment

Intermediate Risk　 IA: G3　 IB, IC: G1-3　 IIA, IIB: G1-3

　　 Pelvic RT　　 +/- cuff RT

High Risk/ Recurrent　 IIIA, IIIB, IIIC: G1-3　 IVA, IVB: G1-3

　 Pelvic RT 　 +/- cuff RT　 Aortic RT (+) ALN　 &/or Chemotherapy

< 5%*5-10%*

> 10%*IIIA + cytology

No treatment/Chemo/RT?

?**Recurrence risk

Up-to-date adjuvant therapy Up-to-date adjuvant therapy for endometrial cancerfor endometrial cancer

Up-to-date adjuvant therapy Up-to-date adjuvant therapy for endometrial cancerfor endometrial cancer

Radiation （ PRT ） or Chemotherapy

Radiation （ PRT ） or Chemotherapy

Surgical StagingSurgical Staging

Intermediate-riskIntermediate-risk

Low–riskLow–risk

Early stageEarly stage

Advanced stageAdvanced stage

IA/ IB , G1 / 2 IA/ IB , G1 / 2

Low?　　 IA/ B G3 ，ICHigh?　　 II, LVI (+)　　 IIIa cytol(+)　　 Ser., Clear

Low?　　 IA/ B G3 ，ICHigh?　　 II, LVI (+)　　 IIIa cytol(+)　　 Ser., Clear

III / IVA / BIII / IVA / B

RecurrenceRecurrence

Chemotherapy or Radiation

Chemotherapy or Radiation

Concurrent Chemo-Radiation

Concurrent Chemo-Radiation

High–riskHigh–risk

No treatment

Chemotherapy or Radiation

Chemotherapy or Radiation

→GOG 122

→GOG99→JGOG2033

Radiotherapy versus Observation in Radiotherapy versus Observation in early-stage endometrial cancerearly-stage endometrial cancer

Radiotherapy versus Observation in Radiotherapy versus Observation in early-stage endometrial cancerearly-stage endometrial cancer

NRHNRH PORTECPORTEC GOG 99GOG 99 ＊＊

Number of Patients

Local RecurrenceLocal Recurrence

Distant Metastasis

PFSPFS

OSOS

540 717 448

Obs >RTObs >RT

NS NS 　　 NS

NS NS NS NS 　 　 　 　 NS NS

NS NS NS NS 　 　 　 　 NS NS

Obs >RTObs >RT Obs >RTObs >RT

GOG99; high intermediate riskGOG99; high intermediate risk: : G2/G3, Lymph Vas Inv, Myomet Inv >2/3 G2/G3, Lymph Vas Inv, Myomet Inv >2/3

with 1) over 70 years old + 1 factor, 2) over 50 y.o. + 2 factors, 3) allwith 1) over 70 years old + 1 factor, 2) over 50 y.o. + 2 factors, 3) all 　　 3 factors. 3 factors.

JGOG 2033JGOG 2033JGOG 2033JGOG 2033

- Endometrial ca.

-Hysterectomy + BSO ( complete resection )

- Myometrial inv. ≧ 1 / 2

Ran

do

mize

Regimen I

Regimen II

PelvicRadiation Therapy

CPA 333 mg / m2

Doxorubicin 40 mg / m2

CDDP 50 mg / m2

q 3 - 4 weeks, x 3 <

Phase III ( Phase III ( CAPCAP vs vs PRTPRT ) )

＊ 1994 to 2000 for 7 years 1994 to 2000 for 7 years 103 member institutions103 member institutions ＊ Evaluable n=385

Sagae et al. ASCO 2005 abstr # 5002

JGOG 2033Patient Characteristics

JGOG 2033Patient Characteristics

RT (%) CAP (%)

Median ageMedian age 59 (37-85) 59 (32-75)

StageStage

ICIC 63.7 58.3

II AII A 5.2. 4.2

II BII B 5.2 13.0

III AIII A 14.5 11.5

III BIII B 0 0.5

III CIII C 11.4 12.5

Grade 1Grade 1 55.4 55.2

Grade 2Grade 2 27.5 33.3

Grade 3Grade 3 17.1 10.4Sagae et al. ASCO 2005 abstr # 5002

SUBGROUP ANALYSIS SUBGROUP ANALYSIS WITH NEW CRITERIA FOR INTERMEDIATE RISKWITH NEW CRITERIA FOR INTERMEDIATE RISK

SUBGROUP ANALYSIS SUBGROUP ANALYSIS WITH NEW CRITERIA FOR INTERMEDIATE RISKWITH NEW CRITERIA FOR INTERMEDIATE RISK

　 Low intermediate risk (LIR)

　　 stage IC patients under 70 years of age 　　 and with G1/2 endometrioid adenocarcinoma

　 High intermediate risk (HIR)

　　 (1) stage IC patients over age 70 years 　 or having G3 endometrioid adenocarcinoma

　　 (2) stage II or IIIA (positive cytology) patients with 　　　　　 deeper than 50% myometrial invasion in the corpu

s. Sagae et al. ASCO 2005 abstr # 5002

SITES OF INITIAL RECURRENCESITES OF INITIAL RECURRENCE

Site* PRT (n=186) CAP (n=188)

No. of recurrent cases 28(15.1%) 31(16.5%)

Pelvis 10 5

Vagina only 1 7

Peritoneal Cavity 2 2

Liver 3 1

Lung 11 14

PAN LN 2 9

others 7 3

*Include multiple recurrences Sagae et al. ASCO 2005 abstr # 5002

JGOG 2033 CONCLUSIONSJGOG 2033 CONCLUSIONS

1. Both pelvic radiation therapy and chemotherapy were equally effective with 85% of 5 year survival

in all 374 pts with stage Ic (75%) through stage II, IIIc (25%).

2. In subgroup analysis, among 184 pts with low interm

ediate risk, the survival of both treatments was over 90% without any statistical significance.

3. However, among 119 pts with high intermediate risk, CAP arm significantly 15% improved PFS and OS when compared with PRT. 　

Sagae et al. ASCO 2005 abstr # 5002

GOG 122GOG 122GOG 122GOG 122

- Endometrial ca.

- Surgical stage III / IV

- Hysterectomy + BSO

- PAN ( - )

- PAN ( + ) with negative scalene node and negative chest CT

Ran

do

mize

Regimen I

Regimen II

Whole AbdomenRadiation Therapy

Doxorubicin 60 mg / m2

CDDP 50 mg / m2

q 4 weeks

Phase III ( Phase III ( AP AP vs vs WAI WAI ))

Randall ME, et al. J Clin Oncol 24:36,2006Randall ME, et al. J Clin Oncol 24:36,2006

Randall ME, et al. J Clin Oncol 24:36,2006Randall ME, et al. J Clin Oncol 24:36,2006

GOG #122GOG #122

• Adjuvant chemotherapy appears to benefit all substages and histologic subtypes of stage III disease (not analyzed by grade)

• Hazard ratio for death with chemotherapy for all stage III disease combined is 0.68

• 5 year PFS for stage III disease is 50%-60%

• 5 year OS for stage III disease is 55%-65%

• 35% of recurrences on chemotherapy arm were initially limited to the pelvis

Randall ME, et al. J Clin Oncol 24:36,2006Randall ME, et al. J Clin Oncol 24:36,2006

Effects of Single agentEffects of Single agentEffects of Single agentEffects of Single agentAgent

Doxorubicin ( ADM )Doxorubicin ( ADM )EpirubicinPirarubicin

CyclophosphamideIfosphamide

Response rate (%)

CisplatinCarboplatin

VincristineVinblastine

Etoposide (oral )Medroxyprogesterone acetateTamoxifen

372610

18 8

20241415

142510

Effects ofEffects of ADMADM - - base therapybase therapyEffects ofEffects of ADMADM - - base therapybase therapy

Regimen Mean response rate ( range )

ADM ADM + CPA+ CPACPA 500 mg/m2 + ADM 60 mg/m2

ADM ADM ++ CDDPCDDPCDDP 50-60 mg/m2 + ADM 50-60 mg/m2

ADMADM + CPA + + CPA + CDDPCDDPCDDP 50-60 mg/m2 + ADM 40-50 mg/m2

+ CPA 400-600 mg/m2

39% ( 31 - 46% )39% ( 31 - 46% )

58% ( 33 - 81% )58% ( 33 - 81% )

46% ( 26 - 56% )46% ( 26 - 56% )

Chemotherapy for Endometrial cancerChemotherapy for Endometrial cancerChemotherapy for Endometrial cancerChemotherapy for Endometrial cancer

ADM

AP

GOG 107GOG 107CA

RR.PFSRR.PFSNSNS

EORTCEORTC5587255872

GOG 48GOG 48

Standard regimen = ADM + CDDPStandard regimen = ADM + CDDP

ATNSNS

GOG 163GOG 163

ADMADM + CDDP + CDDP vsvs ADMADM + TXL+ TXL + CDDP + CDDPADMADM + CDDP + CDDP vsvs ADMADM + TXL+ TXL + CDDP + CDDP

- Endometrial ca.

- Stage III / IV or Recurrent disease

- Measurable disease

- No prior cytotoxic chemotherapy

Ran

do

mize

Regimen I

Regimen II

Doxorubicin 60 mg / m2

CDDP 50 mg / m2

G-CSF

Doxorubicin 45 mg / m2

CDDP 50 mg / m2

Paclitaxel 160 mg / m2

G-CSF

GOG 177GOG 177Phase III studyPhase III study

q3 weeksx 7

q3 weeksx 7

Results of GOG 177Results of GOG 177Results of GOG 177Results of GOG 177

Regimen CR (%) OR (%) Alive without PD (%)

6.8 33.3 8.3

21.6 * 56.7 * 23.9 *

AAPP

TTAAPP

Treatment may have contributed to the death of 5 patients onthe TAP regimen. Treatment and disease may have contributed to the death of 5 patients on the TAP regimen. * p < 0.05

Chemotherapy for Endometrial cancerChemotherapy for Endometrial cancerChemotherapy for Endometrial cancerChemotherapy for Endometrial cancer

ADM

AP

GOG 107GOG 107CA

EORTCEORTC5587255872

GOG 48GOG 48

AT

GOG 163GOG 163

TTAAPPGOG 177GOG 177 Toxic !Toxic !

GOG 209GOG 209GOG 209GOG 209

- Endometrial ca.

- Surgical stage III / IV or Recurrent

- Measurable disease

- ER, PR status

Ran

do

mize

Regimen IRegimen I

Regimen IIRegimen II

Doxorubicin 45 mg / m2

CDDP 50 mg / m2

day 1Paclitaxel 160 mg / mPaclitaxel 160 mg / m22

day 2G-CSF

Paclitaxel 175 mg / mPaclitaxel 175 mg / m22 CBDCA AUC = 6 day 1

TTAAP P vs vs TTCCPhase III study Phase III study

Ongoing with GOG Japan (JGOG)

Japanese Phase II studiesJapanese Phase II studiesJapanese Phase II studiesJapanese Phase II studies

- Advance, Recurrent- Advance, Recurrent Endometrial cancer Endometrial cancer

- 23 Pts.- 23 Pts.

- Advance, Recurrent- Advance, Recurrent Endometrial cancer Endometrial cancer

- 32 Pts.- 32 Pts.

Paclitaxel ( Taxol )Paclitaxel ( Taxol ) 210 mg / m210 mg / m22

q 3 weeksq 3 weeks

Docetaxel ( Taxotere )Docetaxel ( Taxotere ) 70 mg / m70 mg / m22

q 4 weeksq 4 weeks

RR = 30.4 %RR = 30.4 %

RR = 31.3 %RR = 31.3 %

- Prior CT or RT- Prior CT or RT

- Prior CT or RT- Prior CT or RT

Hirai et al. Gynecol Oncol 94;471,2004Hirai et al. Gynecol Oncol 94;471,2004

Katsumata et al. Br J Cancer 93;999,2005Katsumata et al. Br J Cancer 93;999,2005

Option of Taxanes / PlatinumOption of Taxanes / PlatinumOption of Taxanes / PlatinumOption of Taxanes / Platinum

Docetaxel Docetaxel

Paclitaxel Paclitaxel

CBDCACBDCA

CDDPCDDP

Taxanes Taxanes Platinum Platinum

SCOTROC, SGCTC, OV-10, GOG 111, SCOTROC, SGCTC, OV-10, GOG 111, AGO, GOG 158, JGOG 3016, AGO, GOG 158, JGOG 3016, JGOG P II study 2041, JGOG P III study 2043 JGOG P II study 2041, JGOG P III study 2043

JGOG 2041JGOG 2041JGOG 2041JGOG 2041

Randomized phase IIRandomized phase II

- Advance, recurrent endometrial cancer

- Measurable disease

- Prior CT, RTR

and

om

ize

Arm 1 : DPArm 1 : DP

Docetaxel 70 mg/mDocetaxel 70 mg/m22

CDDP 60 mg/m2

Arm 2 : DCArm 2 : DC

Arm 3 : TCArm 3 : TC

Docetaxel 60 mg/mDocetaxel 60 mg/m22

CBDCA AUC = 6

Paclitaxel 180 mg/mPaclitaxel 180 mg/m22

CBDCA AUC = 6Total 90 PtsClosed 2004

JGOG 2041 monitoring reportJGOG 2041 monitoring report(Oct, 2006)(Oct, 2006)

JGOG 2041 monitoring reportJGOG 2041 monitoring report(Oct, 2006)(Oct, 2006)

AE(>G3) DP (n=24) DC (n=30) TC (n=28)AE(>G3) DP (n=24) DC (n=30) TC (n=28)

GIGI 20.820.8 3.3 0.0 3.3 0.0 Neuro Neuro 0 0 0 0 7.17.1Hb Hb 8.3 8.3 31.0 28.631.0 28.6WBC 75.0 89.7 82.1 WBC 75.0 89.7 82.1 Neutro 83.3 89.7 82.1Neutro 83.3 89.7 82.1Platelet 4.2 Platelet 4.2 10.3 25.010.3 25.0

RR 　　 51.7% 　　 48.3% 　　 　　　 60.0% 　

95%CI 　　　 　 　 32.5-70.6% 　 　 　 29.5-67.5% 　　　 　 40.6-77.3%

New RCT Phase III JGOG2043New RCT Phase III JGOG2043New RCT Phase III JGOG2043New RCT Phase III JGOG2043

Randomized Randomized comparative phase IIIcomparative phase III

- Intermediate risk I/II- Advanced III/IV- Adjuvant- First-line chemo.

-Primary endpoint-PFS

-Secondary endpoint-OS, AE, Tx, LN

- About 600 patients

Ran

do

mize

Arm 1 : APArm 1 : AP

Doxorubicin 60 mg/m 60 mg/m22

CDDP 50 mg/m2

Arm 2 : DPArm 2 : DP DOC 70 mg/mDOC 70 mg/m22

CDDP 60 mg/mCDDP 60 mg/m22

Arm 3 : TCArm 3 : TC

Paclitaxel 180 mg/mPaclitaxel 180 mg/m22

CBDCA AUC = 6

Future direction of Future direction of Adjuvant ChemotherapyAdjuvant Chemotherapy

Future direction of Future direction of Adjuvant ChemotherapyAdjuvant Chemotherapy

AP

TC

AP or AT

GOG163GOG163

TAP

GOG 209GOG 209

Taxane Taxane AnthracyclineAnthracycline PlatinumPlatinum

JGOG PIIIJGOG PIII20432043

GOG 177GOG 177

DDPP？ ? ？ ?

？ ?

Biologic Therapies in Clinical TrialsBiologic Therapies in Clinical TrialsBiologic Therapies in Clinical TrialsBiologic Therapies in Clinical Trials

• PTEN/MMAC-1PTEN/MMAC-1

– 43% endometrial cancers

– Loss of function increases AKT, increase mTOR

– mTOR: Iº-70%, Rec-50%

• EGF-R EGF-R

　　 over expressed in 60-80% over expressed in 60-80% (UPSC)(UPSC)

• mTOR inhibitorsmTOR inhibitors

– RAD001

– CCI-779 (NCIC)

　　　 (5/16 PR, 31%, Oza)

• EGF-R Targeted therapyEGF-R Targeted therapy– Gefitinib (GOG 229-C)

– Trastuzumab （ GOG 181b)

– Erlotinib, OSI-774 (NCIC)

　　　　　　　　 7% response rate

ConclusionsConclusions

1.Chemotherapy may be an alternative modality with radiation therapy for high intermediate-risk and high-risk endometrial cancer.

2. Optimal chemotherapeutic agents are

AP, TAP, TC and others with current investigations.

3. Biologics as Future directions are including with

Gefitinib, Trastuzumab, Erlotinib, CCI-779 and others.

Endometrial Cancer State of the Science MeetingEndometrial Cancer State of the Science MeetingNCRI,UK NCI-US GCIGNCRI,UK NCI-US GCIG

Manchester, UK Manchester, UK 　　 November 28-29,2006November 28-29,2006

Endometrial Cancer State of the Science MeetingEndometrial Cancer State of the Science MeetingNCRI,UK NCI-US GCIGNCRI,UK NCI-US GCIG

Manchester, UK Manchester, UK 　　 November 28-29,2006November 28-29,2006

Review of molecular biologyRole of surgery, radiotherapy, chemotherapy, e

ndocrine therapy, biologic therapyPotential trials in early stage diseasePotential trials in advanced or recurrent disease Potential trials in clear cell and papillary serous

histologies Potential translational research