Endometrial Carcinoma.Adjuvant Treatment

NEW ASPECTS OF ADJUVANT THERAPY IN ENDOMETRIAL CANCER

(update of our current treatment policy)Zvi Bernstein M.D.

ONCOLOGY DIVISIONRambam Health Care Campus

Lin Oncology Staff Meeting, 108.01.2009

EC FIGO STAGE


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.


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”


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%.


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.


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


SURGICAL STAGING

Lin Oncology Staff Meeting, 8

“Probably the most controversial aspect of this is the component of lymphadenectomy,”

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Lymphadenectomy (ACOG & ASGO,NCCN)


“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


“MORE SURGERY – LESS RADIOTHERAPY!”


2000: TRENDY SLOGAN

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Number of Nodes Removed Over Time


Abu-Rustum et al. Gyn Oncol 103:714-718, 2006

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Lymphedema Risk vs. Number of Nodes Removed


Abu-Rustum et al. Gyn Oncol 103:714-718, 2006

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NCCN GUIDELINES


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


Do Numbers Count?



467 patients

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509 patients

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Lymph Nodes Assessment


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


Morrow, Gyn Oncol 40:55-65,1991

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FIGO Degrees of Risk within Stage I ECGOG#33 (1987)


GOG # 99 (2004)


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


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


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%)


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.


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.


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%


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)


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.


Three important phase III randomized trials in 2007-2008


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

36Lin Oncology Staff Meeting,

83% - Endometrioid17% - SPC29% - any LND

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Outcomes of ASTEC/EN.5


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.


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.



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.

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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%)

42Lin Oncology Staff Meeting, 08.01.2009

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%).


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


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


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


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


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?


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.


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


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.



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%)


JGOG 2033 RESULTS


JGOG 2033 Conclusion

Adjuvant chemotherapy may be a useful alternative to radiotherapy for intermediate-risk endometrial cancer.


ADVANCED ENDOMETRIAL CARCINOMA


422 PTS. 202 – WAI, 194 - PA


Whole abdominal irradiation vs. doxorubicin/cisplatin (60/50) regimen for stage

III/IV endometrial cancer (GOG #122)


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%

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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.


An overview about the performed CT 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 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.)


Surgically staged patientsat least 8 LN evaluated

(4 from each side of the Pelvis)


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


And



STAGE II


IIA, IIB





STAGE IIIStage Post-Operative Therapy

IIIA, IIIB




IIIC

Pelvis only unless Para-Aortic Nodes Positive

IMRT plus vaginal cuff brachytherapy

5,120 CTV Final

And


(250 cGy for LVSI, 300 cGy for +/close margins)

+ Chemotherapy


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.

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SIGNIFICANT PELVIC RECURRENCE IN HIGH-RISK EC AFTER CT ALONE

Staged according to the 1988 FIGO criteria (GOG #33)


• 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)


Median follow-up was 27 months (range, 2–96 months).

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RESULTS (2)


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


Incompletely surgically staged patients


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


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,

Endometrial Carcinoma.Adjuvant Treatment

Education

Transcript of Endometrial Carcinoma.Adjuvant Treatment