NEW ASPECTS OF ADJUVANT THERAPY IN ENDOMETRIAL CANCER (update of our current treatment policy) Zvi Bernstein M.D. ONCOLOGY DIVISION Rambam Health Care Campus Lin Oncology Staff Meeting, 1 08.01.2009
May 23, 2015
NEW ASPECTS OF ADJUVANT THERAPY IN ENDOMETRIAL CANCER
(update of our current treatment policy)Zvi Bernstein M.D.
ONCOLOGY DIVISIONRambam Health Care Campus
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EC FIGO STAGE
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2007: CLINICAL CANCER ADVANCES2007: CLINICAL CANCER ADVANCES
• 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.
Lin Oncology Staff Meeting, 308.01.2009
ASCO 2007 Comprehensive Conclusion:
“COMBINING EBRT WITH SURGERY
IS NOT EFFECTIVE AND WILL LIKELY END ANY DEBATE ABOUT CONTINUED
USE EBRT FOR PATIENTS WITH ENDOMETRIAL CANCER”
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Introduction (1)
• EC usually diagnosed at early stage (up to 80% diagnosed as stage I, 13% with stage II)
• 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%.
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Introduction (2)
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.
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Introduction (3)
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
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SURGICAL STAGING
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“Probably the most controversial aspect of this is the component of lymphadenectomy,”
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Lymphadenectomy (ACOG & ASGO,NCCN)
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“Complete dissection should be the gold standard!”
“90% of involved nodes are only microscopically positive and the extent of dissection influences survival. ”
08.01.2009
Lymphadenectomy (FIGO)
• Pelvic LN sampling.
• Para-aortic LN sampling indications:
-suspicious para-aortic or common iliac LN-grossly positive adnexa
-grossly positive pelvic LN
-full thickness myometrial invasion
-high grade tumors
-clear cell, serous papillary, carcinosracoma histologic subtype
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“MORE SURGERY – LESS RADIOTHERAPY!”
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2000: TRENDY SLOGAN
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Number of Nodes Removed Over Time
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Abu-Rustum et al. Gyn Oncol 103:714-718, 2006
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Lymphedema Risk vs. Number of Nodes Removed
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Abu-Rustum et al. Gyn Oncol 103:714-718, 2006
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NCCN GUIDELINES
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Completely Surgically Staged Patient ?Completely Surgically Staged Patient ?
“AT LEAST 8 LN
(4 FROM THE EACH
SIDE OF THE PELVIS)”Perry W. Grigsby, M.D.Mallinckrodt Institute of Radiology
Washington University
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Do Numbers Count?
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467 patients
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509 patients
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Lymph Nodes Assessment
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Risk Factors for RecurrenceGOG#33 (1987)
Prospective surgical-pathological study (1180 patients)
Uterine Factors• Grade• Depth of MMI• LVS invasion• Cervical extension• Histologic type• Tumor location
Extrauterine Factors• Pelvic / PA nodes mts.• Adnexal mts.• +-ve peritoneal cytology (?)• Extension through serosa• Peritoneal implants
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Morrow, Gyn Oncol 40:55-65,1991
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FIGO Degrees of Risk within Stage I ECGOG#33 (1987)
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GOG # 99 (2004)
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GOG # 99 (2004)
• Complete surgical staging including pelvic and para-aortic node sampling
• Surgical stage IB, IC, IIA (occult) and IIB (occult)
• All histologic types except serous papillary and clear cell
• Randomized to pelvic RT vs. no further therapy
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GOG # 99 (Patients)
• 392 evaluable patients
• 58.5% IB, 32.1% IC, only 9.4% stage II(occult)
• 82.3% inner and middle third invasion, only
17.6% outer third invasion
• 81.6% grade 1 and 2, only 18.4% grade 3
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GOG # 99 (Results) Recurrence Pattern Surgery Surgery+EBRT
Vagina, by randomization 13/172 (7.6%) 2/179 (1.1%)
Vagina, by treatment 15/172 (8.7%) 1/179 (0.6%)
received
Total pelvic failure, by 20/172 (12%) 3/179 (1.7%)
randomization
Total pelvic failure, by 22/172 (13%) 1/179 (0.6%)
treatment received
Surgery Surgery +EBRT
Alive (4 years) 86% 92%
Dead of disease 15/202 (7.4%) 8/190 (4.2%)
Intercurrent deaths 18/202 (8.9%) 14/190 (7.4%)
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PROBLEMS WITH GOG # 99
• The number of events was smaller than expected and approximately 50% of deaths were due to intercurrent disease and the study was insufficiently powered to demonstrate a statistically significant survival difference.
• Recognized during study that patient population being accrued was mostly low risk. Therefore, “low intermediate” and “high intermediate” risk groups were defined based on GOG #33 data base.
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RISK GROUPS (1)GOG # 99 (2004)
Low risk:
• Grade 1–2 histology, with invasion through less than 50% of the myometrium.
• Grade 3 without myometrial invasion.
• Disease confined to the uterine fundus.
• No lymphovascular involvement.
• No evidence of metastases.
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RISK GROUPS (2) GOG # 99 (2004)
High-intermediate
• Moderately-poorly differentiated tumor
• Presence of LVSI
• More than 50% myometrial invasion
• Age >50 with any 2 risk factors above
• Age >70 with any 1 risk factor
• No evidence of metastases
Others considered “Low intermediate risk.”Lin Oncology Staff Meeting, 2908.01.2009
GOG # 99 (2004)
Risk of recurrence at 2 year:- High intermediate risk ( 132 pts. ) - 27%- Low intermediate risk ( 260 pts. ) - 6%
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GOG #33 (1987)
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RISK GROUPS (3)
GOG # 99 (?)High risk:
• Serosal involvement ( any Grade )
• Positive Peritoneal Cytology (IC Gr. 3)
• Adnexal , pelvic or P/A metastases (any Grade and MMI)
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GOG #99: CONCLUSION
• Adjunctive RT in early stage intermediate risk endometrial carcinoma decreases the risk of recurrence, but should be limited to patients whose risk factors fit a “high intermediate” risk definition.
Keys et al. Gynecol Oncol 2004; 92:744-751.
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Three important phase III randomized trials in 2007-2008
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Trial design for ASTEC/EN.5
Surgery
High risk pathology and no macroscopic disease
RANDOMIZE
No external beam RT External beam RT
Primary endpoint: Overall survival
Secondary endpoint: Recurrence-free survival
905 cases
453 cases 452 cases
2% EBRT, 51% Brachytherapy 98% EBRT, 52% Brachytherapy
EN.5: July 1996-ASTEC: July 1998-
71% TAH BSO29% TAH BSO PLN
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83% - Endometrioid17% - SPC29% - any LND
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Outcomes of ASTEC/EN.5
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Outcomes of ASTEC/EN.5
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ASTEC/EN.5 CONCLUSION
• 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.
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ASTEC/EN.5 CONCLUSION (2)
• EBRT alone is not indicated in the treatment of women with early-stage 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.
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NSGO EORTC
A randomized phase-III study on adjuvant treatment with radiation (RT) ± chemotherapy
(CT) in early stage high-risk endometrial cancer (NSGO-EC-9501/EORTC 55991)
On behalf of NSGO and EORTC
T. Hogberg1, P. Rosenberg1, G. Kristensen1, CF de Oliviera2, R de Pont Christensen1 B Sorbe1, C Lundgren1, H Andersson1, T Salmi1, NS Reed2.
1Nordic Society of Gynecologic Oncology, Odense, Denmark, 2Europ Org for Research and Treatment of Cancer, Brussels, Belgium.
08.01.2009
NSGO EC-9501/EORTC-55991
Radical surgery TAH+BSO (+PLA)Radical surgery TAH+BSO (+PLA)
RT+CTRT+CT
RT
CT+RTCT+RTOR
Randomization
Primary endpoint Progression-free survival (PFS)
Primary endpoint Progression-free survival (PFS)
Surgical stage I, II, IIIA ( positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only)
Endometrioid Type – 61%Serous, clear cell, or anaplastic carcinomas (39%) were eligible regardless of other risk factors
44 Gy XRT ± optional brachytherapy (BT:39%)
44 Gy XRT ± optional brachytherapy (BT:39%)
CT : intially AP Later AP, TP, TAP, TEP
196 cases
186 cases
382 cases
May 1996 to January 2007
(BT:44%)(BT:44%)
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NSGO EC-9501/EORTC-55991 2008 Updated Results (1)
• 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%).
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NSGO EC-9501/EORTC-55991 2008 Updated Results (2)
• Cancer-specific overall survival improved in radiation/ chemotherapy group (10% at 5 y. from 78 % to 88 %).
• Combined modality improved progression-free but also cancer specific overall survival
• No difference of overall survival by randomization between combined modality and radiation alone
• RT+CT was better than RT alone.
• The next question is if RT+CT better than CT alone
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PORTEC – 2 (2008)
Vaginal brachytherapy versus external beam pelvic radiotherapy for high-intermediate risk
endometrial cancer: Results of the randomized PORTEC-2 trial
R. A. Nout, H. Putter, I. M. Joergenliemk-Schulz, J. J. Jobsen, L. C. Lutgens, E. M. van der Steen-Banasik, J. W. Mens, A. Slot, V. T. Smit and C. L. Creutzberg
Leiden University Medical Center, Leiden, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands; Medisch Spectrum Twente, Enschede, Netherlands; MAASTricht Radiation Oncology Clinic, Maastricht, Netherlands; Radiotherapy Institute Arnhem, Arnhem, Netherlands; Daniel den Hoed Cancer Center, Rotterdam, Netherlands
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PORTEC – 2 Design
TAH / BSO no LNDEligibility:
High intermediate risk group-age>60+ IC G1-2 or IB G3
-stage IIaN=427 pts
EBRTN=214
BrachytherapyN=213
Primary endpoint: rate of vaginal relapseSecondary endpoints: OS, QOL
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PORTEC – 2 Trial Results
EBRT
Vaginal relapse: 1.9%
Locoreg. relapse: 2.5%
Distant relapse: 5.7%
Pelvic relapse: 0.6%
No deaths: 20 pts
DFS: 89%
OS: 90%
BT P
0.9% (p = 0.97)
4% (p = 0.15)
6.3% (p = 0.37)
3.5% (p = 0.03)
20 pts
89%
90%
Median F/U 36 months
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PORTEC – 2 Toxicity Results
EBRT
QOL Diarrhea ~30%
Impairment in: ~30%
daily activities
Decreased social: ~20%
functioning
G1-2 GI toxicity: 54%
G1-2 GU toxicity: 27%
Skin toxicity: 20%
BT PBT P
~10% (p = 0.001)
~13% (p = 0.03)
~10% (p=0.001)
13% (p = 0.001)
22% (p=0.1)
2% (p = 0.001) 48Lin Oncology Staff Meeting, 08.01.2009
PORTEC – 2 Conclusions
• VBT as effective as EBRT for intermediate high risk EC.
• Despite the slightly but significantly increased pelvic failure rate in the VBT arm.
• OS and RFS were similar.• QOL significantly better with brachytherapy• VBT should be the treatment of choice for
patients with high-intermediate risk EC.• Remaining question: treat at recurrence or treat
upfront?
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GOG # 99 vs PORTEC-2
GOG # 99
(2004)
EBRT in early stage intermediate risk endometrial carcinoma decreases the risk of recurrence, but should be limited to patients whose risk factors fit a “high intermediate” risk definition.
PORTEC-2
(2008)
Brachytherapy should be the treatment of choice for patients with high-intermediate risk endometrial carcinoma.
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JGOG 2033
Randomized phase III trial of pelvic RT versus cisplatin-based chemotherapy in patients with
intermediate risk endometrial carcinoma
S. Sagae, N. Susumu, Y. Udagawa, K. Niwa, R. Kudo, S. Nozawa, for the Japan Gynecologic Oncology Group
Gynecologic Oncology 108 (2008) 226–233
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Trial design for JGOG 2033
Surgery
>1/2 myometrial invasion, no residual tumorFIGO stage IC, IIA, IIB, IIIA, IIIB, IIIC
RANDOMIZE
Pelvic Radiation Therapy (PRT)
Chemotherapy (CAP)
Primary endpoint: Overall SurvivalSecondary endpoints: PFS, toxicity
475 pts.
238 pts. 237 pts.
Enrollment: Jan 1994 - Dec 2000
TAH BSO+ PLN (95.3%)
PRT:45-50Gy, PART (5.7%), Brachytherapy (3.1%)
Cyclophosphamide 333 mg/m2Doxorubicin 40 mg/m2Cisplatin 50 mg/m2Every 4 weeks for 3 or more courses
193 pts.192 pts.
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Comparison PRT CAP
Completed Tx 98.9% 97.3%
Median No. of courses - 3 ( 3-7 )
Median duration of Tx 5.1 wks 11.4 wks
Stopped Tx due to toxicity 1.6% 4.8%
TREATMENT
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Adverse Effects
Toxicity PRT (n=193) CAP (n=192)
Grade 0-2 190 (98.4%) 181(95.3%)
3-4 3 ( 1.6%) 9 (4.7%)
Tx-related death 0 (0%) 0 (0%)
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JGOG 2033 RESULTS
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JGOG 2033 Conclusion
Adjuvant chemotherapy may be a useful alternative to radiotherapy for intermediate-risk endometrial cancer.
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ADVANCED ENDOMETRIAL CARCINOMA
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422 PTS. 202 – WAI, 194 - PA
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Whole abdominal irradiation vs. doxorubicin/cisplatin (60/50) regimen for stage
III/IV endometrial cancer (GOG #122)
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Clinical data WAI CT
No. of patients 202 194
No. of patients alive 38% 51%
Treatment-related death 4 8
Deaths from cancer 100 78
60-Month PFS
(corrected for stage)
38% 60%
60-Month survival
(corrected for stage)
42% 55%
08.01.2009
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Conclusions
Patients with surgical stage III or IV Endometrial Carcinoma treated with AP experienced a statistically significant improvement in survival when compared with patients who received WAI, but also experienced more frequent and more severe acute toxicity.
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An overview about the performed CT phase-III trials of GOG in endometrial cancer
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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 therapy08.01.2009
P R O J E C TRAMBAM HEALTH CARE CAMPUS
Oncology Division
Endometrial Cancer Adjuvant Treatment Policy
(Updated: November, 2008)Z. Bernstein, A. Amit, E. Gez, S. Billan, R. Abdah-Bortnyak,
L. Lowenstein, A. Kuten
Based on the Guidelines of the Mallinckrodt Institute of Radiology
Washington University
(by Perry W. Grigsby, M.D.)
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Surgically staged patientsat least 8 LN evaluated
(4 from each side of the Pelvis)
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STAGE I
Stage Post-Operative Therapy
IA, IB, IC
Grades I and II
No further therapy
Chemotherapy if ≥ 2/3 Myometrial Invasion
IA, IB, IC
with Grade III or LVSI
Vaginal cuff brachytherapy
HDR 700 cGy at ½ cm X 3
Or
HDR 350 cGy at ½ cm X 6
And
Chemotherapy if ≥ 2/3 Myometrial Invasion
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STAGE II
Stage Post-Operative Therapy
IIA, IIB
Vaginal cuff brachytherapy
HDR 400 cGy at ½ cm X 6
Chemotherapy if ≥ 2/3 Myometrial Invasion
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STAGE IIIStage Post-Operative Therapy
IIIA, IIIB
Vaginal cuff brachytherapy
HDR 350 cGy at ½ cm X 6
Chemotherapy if ≥ 2/3 Myometrial Invasion
IIIC
Pelvis only unless Para-Aortic Nodes Positive
IMRT plus vaginal cuff brachytherapy
5,120 CTV Final
And
HDR 200 cGy at ½ cm X 6
(250 cGy for LVSI, 300 cGy for +/close margins)
+ Chemotherapy
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Groin irradiation is added if the disease involves the distal 1/3 of the vagina.Pelvic IMRT may be given with negative lymph nodes if the patient’s tumor has features of deep myometrial invasion, high grade, or extensive LVSI.
08.01.2009
SIGNIFICANT PELVIC RECURRENCE IN HIGH-RISK EC AFTER CT ALONE
Staged according to the 1988 FIGO criteria (GOG #33)
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• 143 high-risk endometrial cancer patients received adjuvant chemotherapy alone.• All patients underwent primary surgery consisting of total abdominal hysterectomy and bilateral salpingo-oophor-ectomy. •All patients received 4–6 cycles of chemotherapy as the sole adjuvant therapy, consisting primarily of cisplatin and doxorubicin.• Most patients had Stage III–IV disease (83.7%) or unfavorable histology tumors (74.4%).
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RESULTS (1)
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Median follow-up was 27 months (range, 2–96 months).
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RESULTS (2)
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Conclusions:
PVR is common in high-risk pathologic Stage I–IV endometrial cancer patients after adjuvant chemotherapy alone. These results support the continued use of locoregional RT in patients undergoing adjuvant chemotherapy
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Incompletely surgically staged patients
Stage Post-Operative Therapy
IA, IB G1, 2 No further therapy
I; G3 (Any myometrial invasion)
IC (Any Grade)
II, III (Any Grade)
IMRT plus vaginal cuff brachytherapy
5,120 CTV Final
And
HDR 200 cGy at ½ cm X 6 HDR
(250 for LVSI, 300 cGy X 6 for +/close margins)
+ Chemotherapy
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Groin irradiation is added if the disease involves the distal 1/3 of the vagina.08.01.2009
THANK YOU !
7308.01.2009 Lin Oncology Staff Meeting,