1. Role of Chemotherapy For Endometrial Carcinoma
IGCS council, GCIG executive board
Sapporo Railway Hospital
Vice-director
Sapporo Japan
I am going to talk about the role of chemotherapy for endometrial cancer, especially about the current progress of high risk and intermediate ( low and high ) risk endometrial cancer patients.
Satoru Sagae MD PhD
IGCS 10,2006

2. No treatment/Chemo/RT?
Endometrial 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%*
As you know, NCCN guidelines show various kinds of treatment modalities according to postoperative stages. For example, as you can see, by the risk of recurrence, low risk is stage Ia tumor grade 1-2, intermediate risk is including with Ia G3, IB,IC, and Stage II. And high risk is stage III,IV, in each risk group, radiation therapy was a main modality for the last decades, but currently chemotherapy for the patients with high risk group is also considerable as therapeutic selective after an important GOG122 results, as you know.
IIIA + cytology
> 10%*
No treatment/Chemo/RT?
*Recurrence risk ?*

3. Up-to-date adjuvant therapy for endometrial cancer
IA/ IB , G1 / 2
No treatment
Low–risk
Low?
　　IA/ B G3，IC
High?
　　II, LVI (+)
　　IIIa cytol(+)
　　Ser., Clear
Early stage
Radiation （PRT ） or Chemotherapy
Intermediate
-risk
Surgical Staging
→GOG99
→JGOG2033
Chemotherapy
or Radiation
Advanced stage
High–risk
III / IVA / B
At present under some current clinical trials, intermediate risk patients are dividing into low or high, which GOG99 and our trial JGOG 2033 trials. For example, our criteria is low intermediate risk are including Ic, G1-2, younger 70 years old and high intermediate risk including Ic with G3 or older than 70 years old patients and stage II, IIIa cytology +, rare serous or clear cell histology. GOG99 has similar criteria, which trials showed high intermediate risk patients will be useful with adjuvant radiation or chemotherapy for survivial.
High risk patients should be treated with chemotherapy with or withour radiation therapy, further concurrent chemoradiation,
We performed randomized control study for the patients with intermediate and high risk endometrial cancer, which awas named as JGOG 2033.
GOG122 was targeted with high risk advanced stage endometrial cancer.
Today I am talking about our JGOG 2033 study at first, and then move to GOG122. following after these trials, I am talking about current advances of chemotherapy for endometrial cancer, such as GOG177. And also ongoing studies, such as GOG209, Japanese trials will ve discussed and focus of best regimen will be presented including some molecular targeting therapies
→GOG 122
Chemotherapy
or Radiation
Recurrence
Concurrent Chemo-Radiation

4. Radiotherapy versus Observation in early-stage endometrial cancer
NRH
PORTEC
GOG 99＊
Number of Patients
540
717
448
Local Recurrence
Obs >RT
Obs >RT
Obs >RT
Distant Metastasis
NS NS 　　 NS
PFS
For early-stage endometrial cancers. as you know, we have three large RCT series about adjuvant radiotherapy.
Conclusively, these three studies showed the loco-regional recurrence rate was significantly lower in the pelvic irradiation group versus no adjuvant therapy or brachytherapy groups.
However, none of the studies recognized a significant survival benefit.
In low risk or intermediate low risk endometrial cancer patients, no benefit on survival is seen with adjuvant radiation in GOG99. But in intermediate high risk patients, radiation was useful in GOG99.
Intermediate high risk diagnosed as 1) 2) 3).
NS NS 　 　 NS OS
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.

5. JGOG 2033 Randomize Phase III ( CAP vs PRT ) Regimen I Pelvic
Radiation Therapy
Randomize
- Endometrial ca.
Hysterectomy + BSO
( complete resection )
- Myometrial inv. ≧ 1 / 2
Regimen II
CPA mg / m2
Doxorubicin 40 mg / m2
CDDP mg / m2
We performed randomized control study for the patients with intermediate and high risk endometrial cancer, named as JGOG 2033.
JGOG2033 was a Straightforward Randomization between two arms, Pelvic radiotherapy (PRT) and Cyclophosphamide, Doxorubicin and Cisplatin (CAP) Chemotherapy. Like GOG122. GOG122 was targeted for stage III/IV endometrial cancer patients
Eligibility criteria were endometrial cancer patients with deeper than 50% myometrial invasion, with no residual tumor after TAH&BSO, pelvic or para-aortic lympadenectomy.
Patient accrual for of this study occurred from 1994 to 2000 for 7 years from at 103 member institutions of the JGOG.
Pelvic radiation therapy was including with average 50Gy dose, and CAP regimen included CPA 333mg/m2, Doxo 40mg/m2, and CDDP 50mg/m2, every 3-4 weeks, more than 3 courses (average 3 course)
＊ 1994 to 2000 for 7 years
103 member institutions
＊Evaluable n=385
q weeks, x 3 <
Sagae et al. ASCO 2005 abstr # 5002

6. JGOG 2033 Patient Characteristics
RT (%)
CAP (%)
Median age
59 (37-85)
59 (32-75)
Stage IC
63.7
58.3
II A
5.2.
4.2
II B
5.2
13.0
III A
14.5
11.5
III B
0.5
III C
11.4
12.5
Grade 1
55.4
55.2
Grade 2
27.5
33.3
Grade 3
17.1
10.4
The study groups were well balanced for patient characteristics including age, postmenopausal status, co-morbidity, type of hysterectomy, postoperative stage.
Median age was 59 years old in each arm. The distribution of postoperative stages was approximately 61% of IC, 14% of II, 13% of IIIA and 12% of IIIC. 75% in stage I/II, 25% in stage III.
tumor grade,55% of G1, 30% of G2, and 15% of G3.
None of other characteristics were significantly different between groups by univariate analysis.
Pelvic lymphadenectomy was performed in 96% of the patients, and paraaortic lymphadenectomy was performed in 29% of the patients..
Sagae et al. ASCO 2005 abstr # 5002

7. This slide shows the progression-free survival of all patients by randomized treatment group.
As you can see, Data for the two groups nearly overlap without any difference.
PFS rate at 5 years was 84.0% in the PRT group and 82.1% in the CAP group.
Sagae et al. ASCO 2005 abstr # 5002

8. This slide shows that the OS rates in both groups were also similar, with no statistical difference.
The OS rate at 5 years was 85.9% in the PRT group and 87.1% in the CAP group.
Therefore, we think both treatment modalities are equally effective for relatively earlier stage endometrial cancer patients.
Sagae et al. ASCO 2005 abstr # 5002

9. 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.
Furthermore, we performed subgroup analysis, this is statistically under lower power
A new criteria of low-intermediate risk and high-intermediate risk is as you can see, low is Ic with younger than 70 years old or G1/G2, or as high intermediate risk , we defined (1) stage IC patients over age 70 years or having G3 endometrioid adenocarcinoma Or (2) stage II or IIIA with positive cytology patients with deeper than 50% myometrial invasion in the corpus.
Sagae et al. ASCO 2005 abstr # 5002

10. In this slide, we show progression free survival of 4 subgroups, Low-intermediate risk group with PRT, or CAP, High-intermediate risk group with PRT, or CAP.
Among 184 Low IR patients, PFS rates at 5 years in the PRT and CAP groups were 94.3% and 88.6% respectively, with no statistically significant difference.
However, Among 119 HIR patients, the CAP group had significantly higher PFS rate (83.6%) than PRT group(66.2%) with P value
Sagae et al. ASCO 2005 abstr # 5002

11. Next, in this slide, we show overall survival of 4 subgroups,
As you see, among 183 LIR patients, OS rates at 5 years in the PRT and CAP groups were 95.0% and 91.7% respectively, with no statistically significant difference. In log-rank test, p value was
On the other hand,
among 119 HIR patients, the CAP group had significantly higher PFS rate (89.7%) than PRT group(73.6%) with P value
Sagae et al. ASCO 2005 abstr # 5002

12. MULTIVARIATE ANALYSIS
Factor
PFS
Risk Ratio
P-value OS
Treatment (CAP vs PRT)
1.10
0.71
0.69
0.23
Age (>60 vs <60)
Co-morbidity
2.13
1.76
<0.01
0.03
3.53
2.25
0.01
Tumor grade(G2/3 vs G1)
1.58
1.66
Cervical involvement
2.14 -
Peritonenal cytology
2.07
Pelvic LN mets
4.50
The multivariate analysis showed that
age and tumor grade (G2/3) were the most important poor prognostic factors for both PFS and OS in this trial.

13. SITES OF INITIAL RECURRENCE
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
Liver 3
Lung 11 14
PAN LN 9
others
Here, we show data about sites of initial recurrence.
Number of recurrence was almost the same, with 15.1% in PRT arm, and 16.5% in CAP arm.
In both arms, the percentage of intrapelvic and extrapelvic recurrence was similar, as 30% in the pelvis and vagina, and 70% of extra-pelvic sites, such as Peritoneal cavity, Liver , Lung, PAN LN, and other sites.
*Include multiple recurrences
Sagae et al. ASCO 2005 abstr # 5002

14. JGOG 2033 CONCLUSIONS
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%).
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. 　
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%).
In subgroup analysis, among 184 pts with low intermediate risk, the survival of both treatments was over 90% without any statistical significance. However, among 119 pts with high intermediate risk, CAP arm significantly 15% improved PFS and OS when compared with PRT.
We believe the demonstration of a true advantage of chemotherapy requires a large-scale randomized controlled trial with stratification for risk factors including age and tumor grade prior to randomization.
Sagae et al. ASCO 2005 abstr # 5002

15. GOG 122 Randomize Phase III ( AP vs WAI ) Regimen I Whole Abdomen
- Endometrial ca.
- Surgical stage III / IV
- Hysterectomy + BSO
- PAN ( - )
- PAN ( + )
with negative scalene
node and
negative chest CT
Whole Abdomen
Radiation Therapy
Randomize
Regimen II
Just take a look at GOG122. For advanced stage endometrial cancer, Randall reported the results of a GOG randomized Phase III trial of whole abdominal irradiation and platinum-doxorubicin (AP) chemotherapy.
Doxorubicin 60 mg / m2
CDDP mg / m2
q 4 weeks
Randall ME, et al. J Clin Oncol 24:36,2006

16. Randall ME, et al. J Clin Oncol 24:36,2006
In each stage III and IV endometrial cancer, AP chemotherapy was superior to whole-abdominal irradiation as a therapeutic modality. This is overall survival by stage.
Randall ME, et al. J Clin Oncol 24:36,2006

17. 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
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 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.
However, whole abdominal irradiation is not standard at present. AP chemotherapy was too toxic. Further trials with appropriate treatment plan of radiation, sequential or concurrent etc will be required in the nearest future.
Randall ME, et al. J Clin Oncol 24:36,2006

18. Effects of Single agent
Response rate (%)
Doxorubicin ( ADM )
Epirubicin
Pirarubicin 37 26 10
Cisplatin
Carboplatin 20 24
Cyclophosphamide
Ifosphamide 14 15 18 8
Vincristine
Vinblastine
Historically various trials of chemotherapy for advanced or recurrent endometrial cancer showed that doxorubicin and platinum are the most effective drugs as a single agent.
Etoposide (oral ) 14
Medroxyprogesterone acetate
Tamoxifen 25 10

19. Effects of ADM - base therapy
Regimen
Mean response rate ( range )
ADM + CPA
39% ( % )
CPA 500 mg/m2 + ADM 60 mg/m2
ADM + CDDP
58% ( % )
CDDP mg/m2 + ADM mg/m2
In the combination trials, the most active regimen is ADM plus CDDP with 58% response rate. We believe
ADM + CPA + CDDP
46% ( % )
CDDP mg/m2 + ADM mg/m2
+ CPA mg/m2

20. Chemotherapy for Endometrial cancer
GOG 48
GOG 107
RR.PFS NS
ADM CA
EORTC
55872 NS AP AT
In the United States and Europe, Adriamycin alone was equally effective with additional cyclophosphamide under GOG48.
Under GOG107 and EORTC study, AP arm was superior with Adriamycin alone.
Furthermore, AP arm didn’t show any advantage in comparison with Adriamycin plus paclitaxel in GOG163.
Therefore, standard regimen was ADM plus CDDP in the last decade.
GOG 163
Standard regimen = ADM + CDDP

21. ADM + CDDP vs ADM + TXL + CDDP
GOG 177
Phase III study
Regimen I
Doxorubicin 60 mg / m2
CDDP mg / m2
- Endometrial ca.
- Stage III / IV or
Recurrent disease
- Measurable disease
- No prior cytotoxic
chemotherapy
Randomize
q3 weeksx 7
G-CSF
Regimen II
Doxorubicin 45 mg / m2
CDDP mg / m2
Paclitaxel mg / m2
AP was a golden standard for a long time, but GOG conducted a very famous RCT including AP versus AP with Paclitaxel named GOG 177.
Patients eligibilities were advanced or recurrent endometrial cancer patients with measurable disease, and without any prior chmeotherapy. In each regimen, drug dosages are in this slide.
q3 weeksx 7
G-CSF

22. Results of GOG 177 AP 6.8 33.3 8.3 TAP 21.6 * 56.7 * 23.9 * Regimen
CR (%)
OR (%)
Alive without PD (%) AP
TAP
21.6 * * *
This slide shows TAP arm showed statistically significant survival benefits, but with significant higher death of patients on this arm.
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

23. Chemotherapy for Endometrial cancer
GOG 48
GOG 107
ADM CA
EORTC
55872 AP AT
Until now, as you can review the history of development of clinical trials for endometrial cancer, ADM alone was equally effective with cyclophosphamide/Adriamycin. However, Adriamycin /CDDP was superior than adriamyicn alone with two trials.
Adriamycin /CDDP was equally effective with Adriamycin/paclitaxel. In order to get the more effective combination, GOG conducted a triple drug therapy compared with AP arm. The response rate of TAP arm was superior than AP arm, which thought TAP regimen is standard therapy for endometrial cancer at present. However, toxicities are significantly increased for routine clinical practice. Most of US physicians do not use TAP arm, instead of that Carboplatin/paclitaxel are favorably used under the current survey in the United States.
GOG 163
Toxic !
GOG 177
TAP

24. GOG 209 Randomize TAP vs TC Phase III study
Regimen I
Doxorubicin 45 mg / m2
CDDP mg / m2
day 1
Paclitaxel mg / m2
day 2
G-CSF
- Endometrial ca.
- Surgical stage III / IV or
Recurrent
- Measurable disease
- ER, PR status
Randomize
Regimen II
Now GOG is performing new RCT with TAP versus TC for advanced stage endometrial cancer patients. This is also including with our small group of JGOG, named GOG Japan. GOG Japan is doing some of GOG trials, such as GOG 209. This study is very informative for all gynecologists.
Paclitaxel mg / m2
CBDCA AUC = 6
day 1
Ongoing with GOG Japan (JGOG)

25. Japanese Phase II studies
- Advance, Recurrent
Endometrial cancer
Paclitaxel ( Taxol )
210 mg / m2
q 3 weeks
- Prior CT or RT
- 23 Pts.
RR = 30.4 %
Hirai et al. Gynecol Oncol 94;471,2004
- Advance, Recurrent
Endometrial cancer
Docetaxel ( Taxotere )
70 mg / m2
q 4 weeks
On the other hand, in Japan phase II trials of taxanes for endometrial cancer have been accomplished in recent years. In a small size, but both of taxanes were equally effective with 30.4% of paclitaxel and 31.3% of docetaxel.
- Prior CT or RT
- 32 Pts.
RR = 31.3 %
Katsumata et al. Br J Cancer 93;999,2005

26. Option of Taxanes / Platinum
Docetaxel
CBDCA
Paclitaxel
CDDP
Similar to chemotherapeutic options for ovarian cancer, we thought four different ones, such as TP,DP,TC,DC in chemotherapy for endometrial cancer. So currently we have finished phase II trial 2041 and after that we are going to perform phase III study 2043 for intermediate and high risk endometrial cancer patients.
SCOTROC, SGCTC, OV-10, GOG 111,
AGO, GOG 158, JGOG 3016,
JGOG P II study 2041, JGOG P III study 2043

27. JGOG 2041 Randomize Randomized phase II Total 90 Pts Closed 2004
Arm 1 : DP
Randomized phase II
Docetaxel 70 mg/m2
CDDP mg/m2
Randomize
- Advance, recurrent
endometrial cancer
- Measurable disease
- Prior CT, RT
Arm 2 : DC
Docetaxel 60 mg/m2
CBDCA AUC = 6
This trial is JGOG2041, which was closed in 2004 and randomized into three arms, such as DP,DC,TC in each 30 patients. Because of higher neurotoxicity, TP was excluded in this study.
Arm 3 : TC
Total 90 Pts
Closed 2004
Paclitaxel 180 mg/m2
CBDCA AUC = 6

28. JGOG 2041 monitoring report (Oct, 2006)
AE(>G3) DP (n=24) DC (n=30) TC (n=28) GI
Neuro Hb
WBC
Neutro
Platelet
RR 　　 % 　　48.3%　　 　　　60.0%　
95%CI　　　 　 　 %　 　 　 %　　　 　 %
Among three arms, adverse effects are different in each of them, which Gastrointestinal symptom is severe in Doce/CDDP. Anemia and thrombocytepenia are more prominent in Doce/Carbo or Taxol/Carbo. Furthermore, response rates at one year period were 51.7%, 60.0% in DP and TC, respectively, but DC was slightly inferior with 48.3% response rate.

29. New RCT Phase III JGOG2043 Randomize Randomized comparative phase III
Arm 1 : AP
Doxorubicin 60 mg/m2
CDDP mg/m2
- Intermediate risk I/II
- Advanced III/IV
- Adjuvant
First-line chemo.
Primary endpoint
PFS
Secondary endpoint
OS, AE, Tx, LN
- About 600 patients
Randomize
Arm 2 : DP
DOC mg/m2
CDDP 60 mg/m2
Following JGOG 2041 study, We are now conducting a new phase III trial for endometrial cancer in Japan.
For intermediate risk stage I/II and stage III/IV endometrial cancer patients, as adjuvant setting, as first line chemotherapy three arms will be randomized including AP, DP,and TC regimens. Doses are as you can see. Primary endpoint is PFS, and secondary endpoints are overall survival, adverse effects, treatment, lymphnode. In each arm, 200 patients will be entried.
Arm 3 : TC
Paclitaxel 180 mg/m2
CBDCA AUC = 6

30. Future direction of Adjuvant Chemotherapy
JGOG PIII
2043
GOG163 AP
AP or AT ？?
GOG 177 DP TC
TAP
As a future direction, Taxanes plus Platinum will be a standard regimen and JGOG2043 will answer the best of ones for endometrial cancer, we hope. ？? ？?
GOG 209
Taxane Anthracycline Platinum

31. Biologic Therapies in Clinical Trials
PTEN/MMAC-1
43% endometrial cancers
Loss of function increases AKT, increase mTOR
mTOR: Iº-70%, Rec-50%
EGF-R
　over expressed in 60-80% (UPSC)
mTOR inhibitors
RAD001
CCI-779 (NCIC)
　　　(5/16 PR, 31%, Oza)
EGF-R Targeted therapy
Gefitinib (GOG 229-C)
Trastuzumab（GOG 181b)
Erlotinib, OSI-774 (NCIC)
　　　　　　　　7% response rate
There are so many Biologic Therapies in Clinical Trials, against molecular target.
Mainly two major streams are existing against PTEN which express 43% of endometrial cancers
Loss of function of PTEN increases AKT, increase mTOR. Primary tumor express 70% recurrent one 50%.Therefore, mTOR inhibitors are very important to treat, such as RAD001, CCI-779 (NCIC) 　(5/16 PR, 31%, Oza).
Another one is against EGF-R , which over expressed in 60-80% (especially UPSC). EGF-R Targeted therapy is also encouraged with Iressa (GOG 229-C), Herceptin（GOG 181b), and Erlotinib, OSI-774 (NCIC) with 7% response rate.

32. 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.
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 Iressa, Herceptin, Erlotinib, CCI-779 and others.

33. Review of molecular biology
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　　　　　　　　　　
Like ovarian cancer, we have another important meeting of endometrial cancer next month.
On November 28 and 29th, endometrial cancer state of the science meeting will be held in Manchester, UK. This meting is sponsored by NCRI,UK, NCI-US, and GCIG.
Contents are review of molecular biology, role of therapeutic modalities, and potential trials in early stage, advanced stage, and clear cell and papillary serous histologies, furthermore potential translational research also.
We are very expecting to attend this meeting.
Thank you for your attention.