2. Are there benefits from chemotherapy to early endometrial cancer
Are there benefits from chemotherapy to early endometrial cancer? Ursula Matulonis, M.D. Associate Professor of Medicine, Harvard Medical School Director/Program Leader, Medical Gynecologic Oncology Dana-Farber Cancer Institute Boston MA

3. Risk categories for recurrence
Low Risk
no poor prognostic features
Intermediate Risk
deep myometrial invasion
presence of lymphovascular invasion
high grade or rare tumor histology
High Risk
positive nodes
extrauterine disease
Creasman WT, et al. AJ Obstet Gynecol 1999;181:31-34.

4. Type I vs. Type II endometrial cancer
Type II: Serous
--Lack of unopposed estrogen (atrophy)
-- High grade, often with metastases
--Poorer prognosis (more rare but causes a disproportionate number of deaths)
Type I: Endometrioid --Unopposed estrogen (hyperplasia)
-- Low to moderate grade, minimal myometrial invasion -- Good prognosis

5. NCCN guidelines for surgically staged stage I cancer
+/- adverse factors
Grade 1
Grade 2
Grade 3
Stage IA (<50% myometrial invasion)
Adverse risk factors not present
observe
Observe or brachy
Adverse risk factors present
obs or brachy
Obs or brachy +/- pelvic RT
Stage IB (≥ 50% myometrial invasion)
Adverse factors present
Obs or pelvic RT and/or brachy +/- chemotherapy (cat 2B for chemotherapy)
Adverse risk features: age, +LVI, tumor size, lower uterine (cervical/gland involvement)

6. NCCN guidelines for stage II and IIIA IIIA: Tumor invades the serosa of the uterus and/or adnexae
Grade 1
Grade 2
Grade 3
All Stage II
Vag Brachy +/- pelvic RT
Pelvic RT + vaginal brachy
Pelvic RT + vag brachy +/- chemotherapy (category 2B)
Stage IIIA
Chemotherapy +/-RT or involved field RT +/- chemotherapy or pelvic RT +/- brachy
Is +Peritoneal cytology an independent risk factor? In the absence of adverse pathological features (high grade tumors, deep invasion, serous or clear cell path or extrauterine disease spread), + cytology is not generally treated. Is intraluminal fallopian tube spread considered stage III?

7. Surgically staged Stage IIIB or higher
Treatment
Stage IIIB
Chemotherapy +/- RT
Stage IIIC1 (+ pelvic nodes)
Stage IIIC2 (+para-aortic nodes)
Stage IVA, IVB (no gross residual cancer)

8. Addition of chemotherapy to RT versus RT alone
Results of 2 pooled studies: NSGO-EC-9501/EORTC (Nordic study) and MaNGO ILIADE-III
540 patients enrolled; 534 evaluable.
Eur J of Cancer 46:2422, 2010

9. NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III (pooled data)
**Nordic trial showed that addition of CT to RT was associated with a significant 36% reduction in the risk of relapse or death and a sig 49% reduction in the risk of death from endometrial cancer; MaNGO trial showed same direction but not significant.
Eur J of Cancer 46:2422, 2010

10. Problems with these studies
Nordic trial - study closed early because of poor accrual - chemotherapy could be given either before or after RT - RT is lower than standard of care (44Gy) - serous and clear cell cancers were allowed. - no standard chemotherapy regimen prescribed.
MaNGO trial - higher staged cancers included - serous and clear cell excluded
Other problems: pooled data of different stages, histologies, treatments.
Eur J of Cancer 46:2422, 2010

11. Endometrial cancer: GOG 122 for advanced III/IV cancer
Phase III study: GOG 122
Endometrial cancer: GOG 122 for advanced III/IV cancer
Doxorubicin 60 mg/m2 Cisplatin 50 mg/m2 every 3 weeks x 8 cycles
WART (AP/PA) 30 Gy x 20 = 150 Gy 15 Gy boost to pelvic +/- PA
Primary endpoint: PFS Secondary endpoint: OS Median F/u: 60 months - 73% were stage III
Maximum Doxorubicin total dose = 420 mg/m2
Randall et al, JCO 2006

12. Progression-free survival improved with chemotherapy: GOG 122
HR 0.71 (95% CI, 0.55 to 0.91; P = .007)
J Clin Oncol; 24:

13. Survival better with chemotherapy: GOG 122
HR 0.68 ( ; p<0.01)
J Clin Oncol; 24:

14. Survival by treatment and stage
Randall, M. E. et al. J Clin Oncol; 24:

15. Ongoing studies of adjuvant therapy for endometrial cancer

16. Danish study, n=678 (AGO, EORTC, MaNGO, and others)
Stage I and II endometrial cancer treated with surgery. Phase III study, n = 678 Eligibility: Stage I grade 3 endometrioid adenocarcinoma
Stage II endometrioid adenocarcinoma
Stage I and II type 2 histology (clear cell, serous, squamous cell carcinoma, or undifferentiated carcinoma) Randomized to: 1) observation 2) 6 cycles of carboplatin and paclitaxel.
NCT

17. GOG 249: Phase III Pelvic RT optional vaginal cuff boost
Endometrial cancer 1) stage I with high-intermediate risks with +/- cytology 2) stage II (any histology), +/- risk factors 3) stage I/II serous or clear cell cancers with neg cytology n= 562
Vaginal cuff brachy + 3 cycles of paclitaxel 175 mg/m2 + carboplatin AUC 6
High-intermediate risks: age ≥ 70 yrs with one risk factor age ≥ 50 yrs with 2 risk factors age ≥ 18 yrs with 3 risk factors
Risk factors: grade 2 or 3 tumor +LVI outer ½ myometrial invasion
NCT

18. NCT

19. GOG 258
GOG 258
Paclitaxel 175 mg/m2 Carboplatin AUC 6 q21 days x 6 cycles
Endometrial cancer stage I-IV
Volume directed RT + cisplatin 50 mg/m2 days 1, 28 followed by: Paclitaxel 175 mg/m2 Carboplatin AUC 5 q21 days x 4 cycles
Opened: 6/29/09 Phase III
N=804
NCT

20. Incorporation of bevacizumab into early stage endometrial cancer treatment
No extrauterine disease outside of the pelvis
NCT

21. Conclusions
When does our group use adjuvant chemotherapy for endometrial cancer and What type of chemotherapy? 1) Use IV carboplatin and paclitaxel 2) Sequential therapy 3) Clinical situations: Stage III or higher regardless of histology, Type II tumors (serous, clear cell) (any stage) Uterine carcinosarcomas As part of a clinical trial Follow the NCCN guidelines