Transcript chemotherapy

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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
Email: [email protected]
Risk categories for recurrence
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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
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Creasman WT, et al. AJ Obstet Gynecol 1999;181:31-34.
Type I vs. Type II endometrial cancer
Type II: Serous
--Lack of unopposed
estrogen (atrophy)
-- High grade, often with
-- Low to moderate grade,
metastases
minimal myometrial
--Poorer prognosis (more
invasion
rare but causes a
-- Good prognosis
disproportionate
number of deaths)
Type I: Endometrioid
--Unopposed estrogen
(hyperplasia)
NCCN guidelines for surgically
staged stage I cancer
Stage IA (<50%
myometrial
invasion)
Stage IB (≥
50%
myometrial
invasion)
+/- adverse
factors
Grade 1
Grade 2
Grade 3
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
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
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
Chemotherapy +/-RT or
involved field RT +/chemotherapy
or
pelvic RT +/- brachy
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?
www.nccn.org
Surgically staged
Stage IIIB or higher
Stage
Treatment
Stage IIIB
Chemotherapy +/- RT
Stage IIIC1 (+ pelvic
Chemotherapy +/- RT
nodes)
Stage IIIC2 (+para-aortic Chemotherapy +/- RT
nodes)
Stage IVA, IVB (no gross Chemotherapy +/- RT
residual cancer)
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
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
Primary endpoint: PFS
Secondary endpoint: OS
Median F/u: 60 months
- 73% were stage III
WART (AP/PA)
30 Gy x 20 = 150 Gy
15 Gy boost to
pelvic +/- PA
Maximum Doxorubicin total dose = 420 mg/m2
Randall et al, JCO 2006
Progression-free survival improved with
chemotherapy: GOG 122
HR 0.71 (95% CI, 0.55 to 0.91; P = .007)
J Clin Oncol; 24:36-44 2006
Survival better with chemotherapy:
GOG 122
HR 0.68 (0.52-0.89; p<0.01)
J Clin Oncol; 24:36-44 2006
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 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.
NCT01244789
GOG 249: Phase III
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
High-intermediate risks:
age ≥ 70 yrs with one risk factor
age ≥ 50 yrs with 2 risk factors
age ≥ 18 yrs with 3 risk factors
Pelvic RT
optional vaginal cuff
boost
Vaginal cuff brachy +
3 cycles of
paclitaxel 175 mg/m2 +
carboplatin AUC 6
Risk factors:
grade 2 or 3 tumor
+LVI
outer ½ myometrial invasion
NCT00807768
NCT00411138
Clique paraGOG
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GOG 258
Endometrial cancer
stage I-IV
Opened: 6/29/09
Phase III
N=804
Paclitaxel 175 mg/m2
Carboplatin AUC 6
q21 days x 6 cycles
Volume directed RT +
cisplatin 50 mg/m2 days 1, 28
followed by:
Paclitaxel 175 mg/m2
Carboplatin AUC 5
q21 days x 4 cycles
NCT00942357
Incorporation of bevacizumab into
early stage endometrial cancer treatment
No extrauterine
disease outside
of the pelvis
NCT01005329
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