Transcript 投影片 1

New Aspects of Adjuvant Therapy in
Endometrial Cancer:
Current Standards and Future
Directions
Jalid Sehouli, Dominique Koensgen,
Gulten Oskay-Ozcelik, Alexander Mustea
Department of Obstetrics and Gynecology,
Charite University Hospital, Campus Virchow-Clinic,
Berlin, Germany
Critical Reviews in Oncology/Hematology, February 2008
1. Introduction
2. Adjuvant therapy in early stage
(stages I/II)
3. Stages III/IV and recurrent
endometrial cancer
4. Future directions
5. Open questions
6. Conclusion
Introduction (I)
• The most common gynecological pelvic malignancy in
western countries, accounting for 6% of all cancer in
women.
• Usually diagnosed at early stage because of
symptomatic abnormal vaginal bleeding.
• Up to 80% diagnosed as stage I, 13% with stage II, and
5-year OS as high as 88% in stage I disease.
• Subgroups of patients with early stages have
significantly decreased 5-OS rates, based on various
prognostic factors, such as IC and grade 3 only a 5-OS
of 66%.
Prognostic factors of endometrial cancer
•
•
•
•
•
•
Histological type
Histological grade
Lymph- and blood vessel invasion
Depth of myometrial invasion
Lymph node status
Tumor diameter (<2cm vs. >=2cm)
Introduction (II)
• Endometrial cancer is often divided into 2 subtypes.
• Type I etiologically related to unopposed estrogens and
occurs mostly in hyperplasic endometrium and better
prognosis.
• Type II occurs mostly in atrophic endometrium with 3
atypical histological subtypes such as clear cell, papillary
serous cancer (UPSC), and poor differentiated, and
associated with high virulence, advanced stage at
diagnosis and poor prognosis.
• Surgery is the primary treatment of both localized and
advanced disease, the adequate surgical staging and
pathological review are the prerequisites for any
discussion about individual need for an adjuvant therapy.
Adjuvant therapy in early stage (stages I/II)
• RT is typically administered to patients with poor
prognostic features, in order to reduce the incidence of
recurrent pelvic disease
• Major Clinical Cancer Advances in 2007--- 6 major
clinical cancer advances and a further 18 that are
considered "notable“, in independent annual review.
• In Gynecologic Oncology: Only 1 finding was considered
as "notable" advance – External-beam radiation does not improve
outcomes in endometrial cancer.
Zosia Chustecka, J Clin Oncol. December, 2007.
Two important phase III
randomized trials in 2007
A randomized phase III study on adjuvant treatment with radiation
/- chemotherapy in early-stage high-risk endometrial cancer
(NSGO-EC-9501/EORTC 55991).
Hogberg T, Rosenberg P, Kristensen G, et al.
Adjuvant external beam radiotherapy in the treatment of
endometrial cancer: results of the randomized MRC ASTEC and
NCIC CTG EN.5 trial.
Orton J, Blake P.
Results: NSGO-EC-9501/EORTC 55991
•
•
•
•
•
•
•
Median follow-up: 4.3 years
Statistically significant improvement in progression-free survival
(hazard ratio 0.62; P = .03) in favor of the combined modality.
Absolute difference in 5-year progression-free survival:
– 7% (79% vs. 72%).
Cancer-specific overall survival at 5 years:
– Improved in radiation/chemotherapy group (5% at 5 years).
Combined modality improved progression-free but also cancer
specific overall survival
No difference of overall survival by randomization between
combined modality and radiation alone
Support for a role for adjuvant chemotherapy
Hogberg T, et al. NSGO-EC-9501/EORTC 55991. ASCO 2007. Abstract 5503
Results: MRC ASTEC and NCIC CTG EN.5 trial
•
•
•
•
•
Overall morbidity (which included documented postsurgical
complications) was greater in the radiation therapy study arm (60%
vs 26%).
No differences in recurrence-free, disease-specific, or overall
survival (hazard ratio 1.01; P = 0.98)
Although it was not a primary end point of the study (not randomized
to receive or not, vault brachytherapy)
– Decreased the risk of isolated recurrence in the vagina
(hazard ratio: 0.53; P = .038).
– This reduction in local recurrence did not influence survival.
EBRT alone is not indicated in the treatment of women with earlystage endometrial cancer at intermediate risk of relapse
Further refinement of which subgroups of women might benefit from
treatment would require an individual patient data meta-analysis.
Orton J, et al, MRC ASTEC and NCIC CTG EN.5. ASCO 2007; Abstract 5504
Stage III/IV and recurrent
endometrial cancer (I)
• Clinicians recognize that patients with primary advanced
and recurrent disease are in fact different patient
populations, because of their heterogeneities in symptoms,
tumor burden, tumor biology and prior treatment (e.g.
radiation, chemotherapy).
• Despite the good surgical outcome of patients with
advanced endometrial cancer, approximately 50% of these
patients will experience a recurrence of their cancer and will
then later die due this malignant disease.
• These patients may benefit from adjuvant platinum-based
chemotherapy utilized to decrease the risk of cancer
recurrence.
Whole abdominal irradiation vs.
doxorubicin/cisplatin(60/50) regimen for stage III/IV
endometiral cancer (GOG #122)
Clinical data
WAI
CT
No. of patients
202
194
No. of patients alive
38%
51%
4
8
Deaths from cancer
100
78
60-Month PFS
(corrected for stage)
60-Month survival
(corrected for stage)
38%
60%
42%
55%
Treatment-related death
An overview about the performed phase-III
trials of GOG in endometrial cancer
Trial
Regiment
RR (%) PFS (mos)
OS
#107 Dox
Dox/Cis
27
45
3.8
5.7
9.2
9.0
#139 Dox/Cis (AC)
Circadian (AC)
46
49
6.5
5.9
11.2
13.2
#163 Dox/Cis
Pac/Dox+GCSF
40
44
7.2
6.0
12.4
13.6
#177* Dox/Cis (60 45/50)
Pac/Dox/Cis+GCSF
(160/45/50)---TAP
34
57
5.3
8.3
12.1
15.3
*more toxicity with PFS and OAS no superior to the current standard therapy
Stage III/IV and recurrent
endometrial cancer (II)
• Doxorubicin is one of the most active agents in endometrial
cancer and has formed the backbone of modern
combination regimens.
• The combination of CDDP+DOX accepted as the standard
regimen for advanced or relapsed endometrial cancer.
• Pegylated liposomal doxorubicin demonstrated the
feasibility and activity of combination with carboplatin in
advanced endometiral cancer, and well tolerated and offers
promising activity in prospective randomized study.
• GOG #209 had launched a large phase-III trial, compare
carboplatin/paclitaxel to TAP in women with stage III/IV, or
recurrent endometrial cancer.
Future directions (I)
• Despite the availability of conventional factor such as
ER/PR status and tumor histology, there are currently no
validated molecular markers which have been identified
in order to make any treatment decisions.
• A loss of tumor suppressor gene PTEN is seen about
50% of endometrial cancer and PTEN mutations have
been identified in endometrial hyperplasia, which
targeting the rapamycin (mTOR) pathway.
• Three phase-II trials have been opened to explore the
activity of mTOR inhibitors (AP23573, CCI-779, and
RAD001) in recurrent or metastastic endometrial cancer.
Future directions (II)
• Newer targeting agents are being developed with the aim of
achieving a higher specificity towards a specific population of tumor
cells or toward any specific molecule of the cell cycle, such as
epidermal growth factor receptors (EGFR) or vascular endothelial
growth factor.
• Similar to breast cancer, USPC can over express the HER2/neu
protein about 15%, the value of a therapy with trastuzumab
(Herceptin) is unclear.
• EGFR is over expressed in up to 80%, and associated with
advanced stage and poor prognosis, erlotinib (Tarceva) and ZD1839
(gefitinib) are TK inhibitors have been tested as a phase-II trial.
• Currently, the GOG is assessing GW 572016 (lapatinib) in patients
with advanced and recurrent endometrial cancer, and testing the
combination of imatinib (Glivec) and paclitaxel in advanced and
recurrent USPC.
Open questions (I)
• For high-risk endometrial cancer patients:
is a radiochemotherapy superior to
chemotherapy alone?
• For high-risk endometrial cancer in general:
is chemotherapy superior to irradiation?
• What is the role of radiochemotherapy or
systemic chemotherapy in patients who received
systemic lymph node dissection in case of
negative or positive lymph node metastases?
Open questions (II)
• How can we improve the toxicity of systemic
chemotherapy without compromising the efficacy
for patients with advanced stage?
• Is there any place for new targeted agents as
maintenance therapy in advanced endometrial
cancer?
• What is the best adjuvant therapy for UPSC?
Conclusion
• Pivotal randomized phase-III studies have demonstrated
the efficacy of combination chemotherapy for women
with advanced or recurrent endometrial cancer.
However, the long-term results remain unsatisfying.
• Participation in clinical trials is the only way to achieve
any progress in the clinical management of patients with
endometrial cancer, and this may answer many
questions the still exist.
• Besides outcome parameters such as PFS and OAS, it
is the QoL which should be defined as a primary
objective in future clinical trials for patients with
endometrial cancer.
Comments
• The incidence of endometrial cancer has increased
235% from 1995 to 2005 in Taiwan, and it will be most
common and important cancer of gynecological
malignancies in the future.
• The treatment of endometrial cancer has evolved and
changed in the past decades, so our guideline of
treatment must be deliberated and update.
• We should participate in international global clinic trials
or cooperate multi-center hospitals clinical trials on the
opportunity, or design our protocols for management of
endometrial cancer.
Thank you for your attention