Transcript IGCS

Role of Chemotherapy
For Endometrial Carcinoma
IGCS council, GCIG executive board
Sapporo Railway Hospital
Vice-director
Sapporo Japan
Satoru Sagae MD PhD
IGCS 10,2006
Endometrial Cancer - Treatment Plan
Surgical Staging
Low Risk
IA: G1-2
No treatment
< 5%*
Intermediate Risk
IA: G3
IB, IC: G1-3
IIA, IIB: G1-3
Pelvic RT
+/- cuff RT
5-10%*
IIIA + cytology
High Risk/ Recurrent
IIIA, IIIB, IIIC: G1-3
IVA, IVB: G1-3
Pelvic RT
+/- cuff RT
Aortic RT (+) ALN
&/or Chemotherapy
> 10%*
*Recurrence risk
No treatment/Chemo/RT?
?*
Up-to-date adjuvant therapy
for endometrial cancer
Low–risk
Early stage
Intermediate
-risk
Surgical
Staging
Advanced stage
Recurrence
High–risk
IA/ IB , G1 / 2
No treatment
Low?
IA/ B G3，IC
High?
II, LVI (+)
IIIa cytol(+)
Ser., Clear
Radiation （PRT ）
or Chemotherapy
III / IVA / B
→GOG99
→JGOG2033
Chemotherapy
or Radiation
→GOG 122
Chemotherapy
or Radiation
Concurrent
Chemo-Radiation
Radiotherapy versus Observation in
early-stage endometrial cancer
PORTEC
GOG 99＊
540
717
448
Obs >RT
Obs >RT
Obs >RT
NRH
Number of Patients
Local Recurrence
Distant Metastasis
PFS
OS
NS
NS
NS
NS
NS
NS
NS
NS
NS
GOG99; high intermediate risk: 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) all 3 factors.
JGOG 2033
Phase III ( CAP vs PRT )
Regimen I
-Hysterectomy + BSO
( complete resection )
- Myometrial inv. ≧ 1 / 2
＊ 1994 to 2000 for 7 years
103 member institutions
＊Evaluable n=385
Randomize
- Endometrial ca.
Pelvic
Radiation Therapy
Regimen II
CPA
333 mg / m2
Doxorubicin 40 mg / m2
CDDP
50 mg / m2
q 3 - 4 weeks, x 3 <
Sagae et al. ASCO 2005 abstr # 5002
JGOG 2033
Patient Characteristics
Median age
Stage
IC
II A
II B
III A
RT (%)
59 (37-85)
CAP (%)
59 (32-75)
63.7
5.2.
5.2
14.5
58.3
4.2
13.0
11.5
III B
III C
Grade 1
0
11.4
55.4
0.5
12.5
55.2
Grade 2
Grade 3
27.5
17.1
33.3
10.4
Sagae et al. ASCO 2005 abstr # 5002
SUBGROUP ANALYSIS
WITH 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 corpus.
Sagae et al. ASCO 2005 abstr # 5002
SITES OF INITIAL RECURRENCE
Site*
No. of recurrent cases
Pelvis
Vagina only
Peritoneal Cavity
Liver
Lung
PAN LN
others
*Include multiple recurrences
PRT (n=186)
CAP (n=188)
28(15.1%)
31(16.5%)
10
1
2
3
11
2
7
5
7
2
1
14
9
3
Sagae et al. ASCO 2005 abstr # 5002
JGOG 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
intermediate 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 122
Phase III ( AP vs WAI )
Regimen I
- Endometrial ca.
- Hysterectomy + BSO
- PAN ( - )
- PAN ( + )
with negative scalene
node and
negative chest CT
Randomize
- Surgical stage III / IV
Whole Abdomen
Radiation Therapy
Regimen II
Doxorubicin 60 mg / m2
CDDP
50 mg / m2
q 4 weeks
Randall ME, et al. J Clin Oncol 24:36,2006
Randall ME, et al. J Clin Oncol 24:36,2006
GOG #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 24:36,2006
Effects of Single agent
Agent
Response rate (%)
Doxorubicin ( ADM )
Epirubicin
Pirarubicin
Cisplatin
Carboplatin
Cyclophosphamide
Ifosphamide
Vincristine
Vinblastine
Etoposide (oral )
Medroxyprogesterone acetate
Tamoxifen
37
26
10
20
24
14
15
18
8
14
25
10
Effects of ADM - base therapy
Regimen
Mean response rate ( range )
ADM + CPA
CPA 500
mg/m2
+ ADM 60
39% ( 31 - 46% )
mg/m2
ADM + CDDP
CDDP 50-60 mg/m2 + ADM 50-60 mg/m2
ADM + CPA + CDDP
mg/m2
CDDP 50-60
+ ADM 40-50
+ CPA 400-600 mg/m2
mg/m2
58% ( 33 - 81% )
46% ( 26 - 56% )
Chemotherapy for Endometrial cancer
GOG 48
GOG 107
EORTC
55872
ADM
RR.PFS
NS
CA
AP
NS
AT
GOG 163
Standard regimen = ADM + CDDP
ADM + CDDP vs ADM + TXL + CDDP
GOG 177
Phase III study
- Stage III / IV or
Recurrent disease
- Measurable disease
- No prior cytotoxic
chemotherapy
Randomize
- Endometrial ca.
Regimen I
Doxorubicin 60 mg / m2
CDDP
50 mg / m2
q3 weeksx 7
G-CSF
Regimen II
Doxorubicin 45 mg / m2
CDDP
50 mg / m2
Paclitaxel 160 mg / m2
q3 weeksx 7
G-CSF
Results of GOG 177
Regimen
CR (%)
OR (%)
AP
6.8
33.3
TAP
21.6 *
56.7 *
Alive without PD (%)
8.3
23.9 *
Treatment may have contributed to the death of 5 patients on
the TAP regimen. Treatment and disease may have contributed
to the death of 5 patients on the TAP regimen. * p < 0.05
Chemotherapy for Endometrial cancer
GOG 48
GOG 107
EORTC
55872
GOG 177
ADM
CA
AP
AT
Toxic !
TAP
GOG 163
GOG 209
TAP vs TC
Phase III study
- Surgical stage III / IV or
Recurrent
- Measurable disease
- ER, PR status
Randomize
- Endometrial ca.
Ongoing with GOG Japan (JGOG)
Regimen I
Doxorubicin 45 mg / m2
CDDP
50 mg / m2
day 1
Paclitaxel 160 mg / m2
day 2
G-CSF
Regimen II
Paclitaxel 175 mg / m2
CBDCA
AUC = 6
day 1
Japanese Phase II studies
- Advance, Recurrent
Endometrial cancer
- Prior CT or RT
Paclitaxel ( Taxol )
210 mg / m2
q 3 weeks
- 23 Pts.
Hirai et al. Gynecol Oncol 94;471,2004
- Advance, Recurrent
Endometrial cancer
- Prior CT or RT
RR = 30.4 %
Docetaxel ( Taxotere )
70 mg / m2
q 4 weeks
- 32 Pts.
Katsumata et al. Br J Cancer 93;999,2005
RR = 31.3 %
Option of Taxanes / Platinum
Taxanes
Platinum
Docetaxel
CBDCA
Paclitaxel
CDDP
SCOTROC, SGCTC, OV-10, GOG 111,
AGO, GOG 158, JGOG 3016,
JGOG P II study 2041, JGOG P III study 2043
JGOG 2041
Arm 1 : DP
Randomized phase II
Docetaxel 70 mg/m2
CDDP
60 mg/m2
- Measurable disease
- Prior CT, RT
Randomize
- Advance, recurrent
endometrial cancer
Arm 2 : DC
Docetaxel 60 mg/m2
CBDCA AUC = 6
Arm 3 : TC
Total 90 Pts
Closed 2004
Paclitaxel 180 mg/m2
CBDCA AUC = 6
JGOG 2041 monitoring report
(Oct, 2006)
AE(>G3)
DP (n=24)
GI
Neuro
Hb
WBC
Neutro
Platelet
20.8
0
8.3
75.0
83.3
4.2
RR
60.0%
51.7%
DC (n=30)
3.3
0
31.0
89.7
89.7
10.3
48.3%
TC (n=28)
0.0
7.1
28.6
82.1
82.1
25.0
New RCT Phase III JGOG2043
Randomized
comparative phase III
-Primary endpoint
-PFS
-Secondary endpoint
-OS, AE, Tx, LN
- About 600 patients
Doxorubicin 60 mg/m2
CDDP 50 mg/m2
Randomize
- Intermediate risk I/II
- Advanced III/IV
- Adjuvant
- First-line chemo.
Arm 1 : AP
Arm 2 : DP
DOC 70 mg/m2
CDDP 60 mg/m2
Arm 3 : TC
Paclitaxel 180 mg/m2
CBDCA AUC = 6
Future direction of
Adjuvant Chemotherapy
JGOG PIII
2043
GOG163
AP
AP or AT
？?
DP
GOG 177
TC
？?
？?
TAP
GOG 209
Taxane Anthracycline Platinum
Biologic Therapies in Clinical Trials
• PTEN/MMAC-1
• mTOR inhibitors
– 43% endometrial cancers
– RAD001
– Loss of function increases
AKT, increase mTOR
– CCI-779 (NCIC)
(5/16 PR, 31%, Oza)
– mTOR: Iº-70%, Rec-50%
• EGF-R
over expressed in 60-80%
(UPSC)
• EGF-R Targeted therapy
– Gefitinib (GOG 229-C)
– Trastuzumab（GOG 181b)
– Erlotinib, OSI-774 (NCIC)
7% response rate
Conclusions
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 Meeting
NCRI,UK NCI-US GCIG
Manchester, UK November 28-29,2006
 Review of molecular biology
 Role of surgery, radiotherapy, chemotherapy,
endocrine therapy, biologic therapy
 Potential trials in early stage disease
 Potential trials in advanced or recurrent disease
 Potential trials in clear cell and papillary serous
histologies
 Potential translational research