Clique para editar o título mestre

Are there benefits from chemotherapy to early endometrial cancer?

Ursula Matulonis, M.D.Associate Professor of Medicine, Harvard Medical SchoolDirector/Program Leader, Medical Gynecologic Oncology

Dana-Farber Cancer InstituteBoston MA

Email: Umatulonis@partners.org

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.

Type I vs. Type II endometrial cancer

Type I: Endometrioid--Unopposed estrogen (hyperplasia)

-- Low to moderate grade, minimal myometrial invasion

-- Good prognosis

Type II: Serous--Lack of unopposed

estrogen (atrophy)-- High grade, often with

metastases--Poorer prognosis (more

rare but causes a disproportionate number of deaths)

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

Observe or brachy

Adverse risk factors present

obs or brachy Obs or brachy +/- pelvic RT

Obs or brachy +/- pelvic RT

Stage IB (≥ 50% myometrial invasion)

Adverse risk factors not present

obs or brachy Observe or brachy

Obs or brachy +/- pelvic RT

Adverse factors present

Obs or brachy +/- pelvic RT

Obs or brachy +/- pelvic RT

Obs or pelvic RT and/or brachy +/- chemotherapy (cat 2B for chemotherapy)

Adverse risk features: age, +LVI, tumor size, lower uterine

(cervical/gland involvement)www.nccn.org

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

Chemotherapy +/-RT or involved field RT +/- chemotherapy or pelvic RT +/- brachy

Chemotherapy +/-RT or

involved field RT +/- chemotherapy or pelvic RT +/- brachy

NCCN guidelines for stage II and IIIAIIIA: Tumor invades the serosa of the uterus and/or adnexae

www.nccn.org

Is +Peritoneal cytology an independent risk factor? In the absence of adverse pathological features (high grade tumors, deep invasion, serous orclear cell path or extrauterine disease spread), + cytology is not generally treated.

Is intraluminal fallopian tube spread considered stage III?

Surgically staged Stage IIIB or higher

Stage Treatment

Stage IIIB Chemotherapy +/- RT

Stage IIIC1 (+ pelvic nodes)

Chemotherapy +/- RT

Stage IIIC2 (+para-aortic nodes)

Chemotherapy +/- RT

Stage IVA, IVB (no gross residual cancer)

Chemotherapy +/- RT

www.nccn.org

Addition of chemotherapy to RT versus RT alone

Results of 2 pooled studies:NSGO-EC-9501/EORTC-55991

(Nordic study) and MaNGO ILIADE-III

540 patients enrolled; 534 evaluable.

Eur J of Cancer 46:2422, 2010

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

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

Endometrial cancer: GOG 122 for advanced III/IV cancer

Phase III study: GOG 122

Doxorubicin 60 mg/m2Cisplatin 50 mg/m2

every 3 weeks x 8 cycles

WART (AP/PA)30 Gy x 20 = 150 Gy15 Gy boost to pelvic +/- PA

Primary endpoint: PFSSecondary endpoint: OSMedian F/u: 60 months- 73% were stage III

Maximum Doxorubicin total dose = 420 mg/m2

Randall et al, JCO 2006

Progression-free survival improved with chemotherapy: GOG 122

J Clin Oncol; 24:36-44 2006

HR 0.71 (95% CI, 0.55 to 0.91; P = .007)

Survival better with chemotherapy:GOG 122

J Clin Oncol; 24:36-44 2006

HR 0.68 (0.52-0.89; p<0.01)

Survival by treatment and stage

Randall, M. E. et al. J Clin Oncol; 24:36-44 2006

Ongoing studies of adjuvant therapy for endometrial cancer

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 adenocarcinomaStage II endometrioid adenocarcinomaStage I and II type 2 histology (clear cell, serous, squamous cell carcinoma, or undifferentiated carcinoma)

Randomized to:1) observation2) 6 cycles of carboplatin and paclitaxel.

NCT01244789

GOG 249: Phase III

Endometrial cancer1) stage I with high-intermediaterisks with +/- cytology2) stage II (any histology), +/- risk factors3) stage I/II serous or clear cellcancers with neg cytologyn= 562

Pelvic RT optional vaginal cuff boost

Vaginal cuff brachy +3 cycles of paclitaxel 175 mg/m2 +carboplatin AUC 6

High-intermediate risks:age ≥ 70 yrs with one risk factorage ≥ 50 yrs with 2 risk factorsage ≥ 18 yrs with 3 risk factors

Risk factors:grade 2 or 3 tumor+LVI outer ½ myometrial invasion

NCT00807768

NCT00411138

Clique para editar o título mestre

GOG 258

Endometrial cancerstage I-IV

Paclitaxel 175 mg/m2Carboplatin AUC 6q21 days x 6 cycles

Volume directed RT +cisplatin 50 mg/m2 days 1, 28followed by:Paclitaxel 175 mg/m2Carboplatin AUC 5q21 days x 4 cyclesOpened: 6/29/09

Phase IIIN=804

GOG 258

NCT00942357

Incorporation of bevacizumab into early stage endometrial cancer treatment

No extrauterinedisease outsideof the pelvis

NCT01005329

Conclusions

• When does our group use adjuvant chemotherapy for endometrial cancer and What type of chemotherapy?

1) Use IV carboplatin and paclitaxel2) Sequential therapy3) Clinical situations: Stage III or higher regardless of histology, Type II tumors (serous, clear cell) (any stage)Uterine carcinosarcomasAs part of a clinical trial

Follow the NCCN guidelines