Primaire behandeling van het endometrium carcinoma: Rol van lymfadenectomie, radiotherapie en chemotherapie Ignace Vergote PUS Gent 16/11/2006

Treatment paradigm shift Endometrioid Endometrial Cancer Role of Radiotherapy and Lymphadenectomy Treatment paradigm shift Minimize overtreatment Identify pts not requiring LND and/or RT Minimize undertreatment Identify pts benefiting from LND and/or RT

Endometrial carcinoma Role of lymphadenectomy

ENDOMETRIAL CARCINOMA: Lymph nodes (1) Spread preferentially to the pelvic lymph nodes (Morrow, 1991). Highest incidence in obturator nodes (Benedetti, 1998) More than 50 % of the nodes < 1 cm (Girardi, 1993, Benedetti, 1998). Other occult pelvic disease not found at lymphadenectomy, such as in lymphatic channels in the parametrium or in parametrial lymph nodes, occurs infrequently and is an unlikely source of recurrence (Berman, 2004)

ENDOMETRIAL CARCINOMA: Lymph nodes (2) Lymph node status is the most powerful prognostic factor of pelvic relapse (Morrow 1991, Mariani 2002). Many studies showed that isolated pelvic recurrences are rare in patients who undergo FULL lymphadenectomy ONLY (i.e. not treated with external radiotherapy or with brachytherapy) (Mohan 1998, Larson 1998, Berclaz 1999, Fanning 2001, Straughan 2002, Mariani 2002, Rittenberg 2003, Vergote 2006). 3

ENDOMETRIAL CARCINOMA Pelvic lymph node metastases G1 G2 G3 Endometrium 0% 3% 0% Inner 1/3 3% 5% 9% Middle 1/3 0% 9% 4% Outer 1/3 11% 19% 34% Creasman , 1987 (n = 621) 1

Site of recurrence in endometrial cancer Mayo Clinic Series: n = 915 treated primarily with surgery 190 relapses (21%) Mariani A et al, Gynecol Oncol 2004, 120-6

Retrospective analysis of lymphadenectomy in apparent early stage endometrial cancer (all HT) DUKE University (n =509) Cragun, JCO, 2005 Inclusion criteria: clinical stage I/IIa with pelvic (+paraaortic) ln without grossly positive pelvic nodes or extrauterine disease at laparotomy. Patients with poorly differentiated tumors having more than 11 ln nodes removed had improved PFS (but not OS).

ENDOMETRIAL CARCINOMA: Lymphadenectomy BUT NCI study (Trimble, 1998) - n=9185 Stage I : Lymph node sampling did not appear to convey survival advantage. Lymphadenectomy combined with radiotherapy results in a increased risk of complications (Lewandowski, 1990; Larson, 1992, Keys 2004, Creutzberg 2004).

ENDOMETRIAL CARCINOMA Para aortic lymph node metastases G1 G2 G3 Endometrium 0% 3% 0% Inner 1/3 1% 4% 4% Middle 1/3 5% 0% 0% Outer 1/3 6% 14% 23% Creasman , 1987 (n = 621) 2

ENDOMETRIAL CARCINOMA STAGE I AND II Para-aortic lymphadenectomy n=895 47/48 with aortic node metastases had : a. Grossly positive pelvic lymph nodes b. Grossly possitive adnexal metastases c. Serosal infiltration Morrow (GOG), 1991

Para-aortic lymph node metastases in endometrial cancer Approximately 27% - 40% of patients with proven para-aortic lymph node metastases are longterm survivors after pelvic and para-aortic RT Potish et al. Obstet Gynaecol 1985 Morrow et al. Gynaecol Oncol 1991 Corn et al. Int J Radiation Oncol Biol Phys 1992 Rose et al. Int J Radiation Oncol Biol Phys 1992 Mariani et al. Gynaecol Oncol 2000 Cragun et al JCO 2005 Mariani 2005: Adequate para-aortic lymphadenectomy AND para-aortic radiotherapy results in improved survival.

Endometrioid Endometrial Carcinoma Stage I – Univ Hospitals Leuven Algorythm 1995 -2005

Leuven series Int J Gyn Cancer 2006, 16: 1885-1893 Low risk N=85 High risk, N- N=57 High risk, N+, RT N=10 Site of recurrence Vaginal 5 (5.8%) 3 (5.2%) 1 (10%) Pelvis 1 (1.7%) Distant 2 (2.3%) 5 (8.8%) 2 (20%) Total 7 (8.1%) 9 (15.7%) 3 (30%) Overall survival 93% 88% 80%

Endometrial carcinoma (clinical stage I) Univ Hospitals Leuven series All patients with only vaginal relapse (n=9) were cured locally with salvage radiotherapy. The pelvic relapse rate in the high risk group with negative nodes was very low as only one patient recurred in the pelvis only.

LAVH for endometrial cancer: safety Leuven series AJOG 2006, in press LAVH (n = 69) TAH (n = 100) P value Age 63 66 NS BMI 26 29 < 0.0001 Grade 3 (%) 16% 19% Stage Ia 36% 0.01 Operative time 172 132 Lymphadenectomy 40% 57% 0.03 Nr nodes 15 21 0.05 DFS 91% 84% OS 93% 86% Multiviariate analyse for DFS: only histological type significant

Safety issues in the laparoscopic approach: pos cytology? LAVH TAH Sonoda et al., 2001Gynecol Oncol 14/131 (10.3%) 7/246 (2.8%) Vergote et al., 2002 Gynecol Oncol 1/58 (1.7%) 4/98 (4.1%) Intrauterine manipulator

Indication for LAVH Leuven series BMI < 34 (“ < 90 kg”) Uterine size < 10 cm Satisfactory descensus LAVH (+/- laparoscopic lymphadenectomy) succesful in 2/3 patients

LAVH for endometrial cancer: safety Obermair et al LAVH for endometrial cancer: safety Obermair et al., Gynecol Oncol 2004;92:789-93 TLH (n = 226) TAH (n = 284) P value Age 62 65 0.008 Weight 83 74 <0.0001 Grade 3 (%) 12 29 Endometrioid (%) 95 Serous (%) 2 10 >50% myo inv (%) 15 30 Nr nodes 9 17 Node pos (%) 3 21 No port site M+, similar patterns of recurrence

GOG LAP 2 randomized study laparoscopy versus laparotomy (SGO 2006) 23% of those randomized to laparoscopy required laparotomy. Laparoscopy: shorter hospital stay and longer operative time. No survival or relapse data yet .

ASTEC Trial Design: Surgery (n = 1408) Kitchener et al, ESGO 2005 Endometrial cancer, thought pre-operatively to be confined to the corpus Fit for Lymphadenectomy or External Beam Radiotherapy RANDOMISE TAH/BSO TAH/BSO + LN 1. Low risk pathology 3. High risk pathology and no 2. Macroscopic extraut disease macroscopic extraut disease Treat according to local standard practice

ASTEC Trial Design: Radiotherapy ( n = 905) Surgery according to local standard practice Surgery on trial High risk pathology and no macroscopic extraut disease RANDOMISE No external beam RT External beam RT

ASTEC Trial Design: Surgery (n = 1408) Kitchener et al, ESGO 2005 Trial was designed to look at an increase in 5-year overall survival of 10% from 80% to 90% with a significance level of 5% and a power of 90%

ASTEC Trial: Surgery Kitchener et al ESGO 2005 TAH/BSO (n = 704) + LN (n = 704) Total Age Median (range) 63 (36-89) 63 (34-93) Technique used: Laparotomy Laparoscopic 94% 6% FIGO stage (excluding LN pos pat) IA IB IC IIA IIB III/IV 13% 48% 21% 5% 8% 42% 27% 4% 45% 24%

ASTEC Surgery Kitchener et al ESGO 2005 TAH/BSO (n = 704) + LN (n = 704) Total Differentiation or Grade Well or Grade 1 Moderate or Grade 2 Poor or Grade 3 34% 48% 18% 46% 20% 47% 19% Lymphovascular Permeation 21% 23% 22% Number nodes 1-4 5-9 10-14 >14 10% 25% 41% Nodal Involvement 9%

ASTEC Surgery Kitchener et al ESGO 2005 TAH/BSO (n = 704) + LN (n = 704) Total Alive Dead 89% 11% 88% 12% HR 1.05 (NS) Cause of death: Disease related Treatment related Disease & treatment related Other (not disease or treatment related) 71% 3% - 26% 59% 10% (8) 2% 28%

ASTEC Surgery Kitchener et al ESGO 2005 No evidence for effect of lymphadenectomy on OS or PFS in subgroups defined by Age Histological type Grade Myometrial invasion Performance Status Number of nodes removed.

Lymphadenectomy in Endometrial carcinoma Kitchener et al ESGO 2005 The ASTEC study is not large enough to detect a survival difference of 2-3% (isolated lymphatic recurrences). Lymphadenectomy can be used to better select patients for adjuvant radiotherapy

Endometrial carcinoma Role of adjuvant brachytherapy in low risk patients

ENDOMETRIAL CANCER STAGE I AND II Adjuvant vaginal vault irradiation VAGINAL RELAPSES Surgery only Surgery + Vaginal Irradiation 2 - 15 % 0.5 - 3 % BUT IN PROSPECTIVE STUDIES THE SIDE EFFECTS (especially severe sexual dysfunction due to vaginal atrophy and adhesions) ARE AS HIGH AS 50%. Leibel 1980, Berek 1988, Sorbe 1989, Vergote 1991 and many others

Endometrium G1/2 Stage Ia-b: Vag recur - No RT

Radiotherapy of vaginal relapse in patients not treated primarily with adjuvant radiotherapy Mandall 1985: 95% (n =20) (vagina). Curran 1988: 100% (n = 15) (vagina). Ackerman 1996: 79% (n = 32), vagina: Poulsen 1997: 88% (n = 17) (vagina, FU 61 months, low risk). Roberts 1998: 61% (n = 16). Nag 2002: 77% 8y-disease specific survival (vagina, n = 13). Creutzberg 2003: 65% 5y OS in vaginal relapses (n=35, intermediate risk) Jingran 2003: 86% 5-y local control in vaginal relapses (n=52) Hogberg 2004: 83% survival 39 months after relapse (n =12) Huh 2005: 75% 5-y survival after vaginal relapse (65 mnths med f-up) (n = 62) Leuven 2006: 100% local control in 9 vaginal relapses treated at relpase with RT CURE RATE IS HIGH IN RELAPSES CONFINED TO THE VAGINA, especially in low risk disease. 8

Endometrial carcinoma Role of adjuvant external radiotherapy

ENDOMETRIAL CARCINOMA Adjuvant radiotherapy: RANDOMIZED TRIALS The Norwegian Radium Hospital series n = 540 Stage I HT + BSO + Vag brachy With or without 40 Gy to the pelvis NO DIFFERENCE IN SURVIVAL (89 vs 91 % at 5 years) LESS PELVIC RELAPSES (5.4 VS 9.9%) Aalders 1980 5

PORTEC study Stage I endometrial carcinoma Grade 1 ; myometrial invasion ³ 1/2 Grade 2 Grade III; myometrial invasion < ½ TAH-BSO without lymphadenectomy postoperative radiotherapy R no further treatment

Overall survival by treatment arm

PORTEC study Creutzberg 2003: 8-year actuarial survival is 77% in the control group and 71% in the radiotherapy group (NS) Still it is concluded: For patients with intermediate risk (IbG3, IcG1-2, IIoccultG1-2, age > 60) radiotherapy is indicated (PORTEC 2 randomizes external versus brachytherapy) For high-risk patients external radiotherapy is indicated.

ENDOMETRIAL CARCINOMA GOG 99 Adjuvant external radiotherapy or surgery alone in completely staged patietns (i.e. with lymphadnectomy) n = 392 Surgical Stage IB,C or occult II endom ca (all grades, negative lymph nodes) HT + BSO + Pelvic & Paraao ln 50 Gy pelvis Observation NO DIFFERENCE IN SURVIVAL, BUT LOWER RECURRENCE RATE AT 2 YEARS 12% vs 2% (P=0.007) Keys, Gyn Oncol 2004 6

GOG 99 Overall survival

GOG 99 Subgroup analysis « High Intermediate Risk Group » G2 or G3 LVSPI Infiltration outer 1/3 Age ≥ 50 y: ≥ 2 factors Age ≥ 70 y: ≥ 1 factor

GOG 99 Subgroup analysis « High Intermediate Risk Group » 4-y OS of 86% in control arm versus 92% in RT arm (NS), Keys et al conclude « that these patients should get radiotherapy ». However, in the low risk group 7 cancer related deaths occurred in the RT arm versus 3 in the observation arm (NS) Should we conclude something out of this? No, this would be an EQUALLY INVALID SUBGROUP ANALYSIS

Endometrial carcinoma Emerging role of chemotherapy in the adjuvant setting

Myometrial infiltration > 1/2 JGOG 99 Adjuvant external radiotherapy or CAP in “intermediate risk” endometrial carcinoma. n = 475 Myometrial infiltration > 1/2 50 Gy pelvis CAP (333/40/50 mg/m² q 4 wks) Sagae, ASCO 2005 6

全解析症例３７３例の解析結果である　OSでは85-87＆と極めて良好である。

Italian study (Maggi et al Br J Cancer 2006, 95:265) Stage Ic G3, IIG3 (> 50 % infiltration) and III 45 - 50 Gy pelvis CAP (50/45/600 mg/m² q 4 wks) OS and DFS similar (more distant relapses in RT arm, more local relapses in chemo arm) 6

Randomized GOG trial of whole-abdominal irradiation versus AP in advanced endometrial carcinoma (Randall JCO 2005) N = 424 randomized to WAI (30 gy)+ Boost to the pelvis versus AP (8 courses P70- 7 times combined with A60) Stage III or IV with a maximum size of residual tumor of 2 cm. 50% non-endometrioid.

Overall Survival 55% 42% HR 0.68 (95%0.52-0.89, p<0.01) Randall ME, J Clin Oncol 24: 36-44, 2006

Overall Survival Randall ME, J Clin Oncol 24: 36-44, 2006

EORTC randomized phase III trial on adjuvant chemotherapy in surgical stage I-IIa serous and clear cell endometrial carcinoma (Amant et al) 6

AGO-Proposal Study Design Carboplatin AUC 6 -Caelyx 40 mg/m² q 4 wks Doxorubicin-platinum (60/50) chemotherapy R Strata: histology (serous/clear cell vs other), stage Inclusion criteria: adjuvant postoperative therapy endometroid cancer FIGO III/IV (all histological types, e.g.clearcell, ser.-pap) +/- radiotherapy (investigator‘s discretion) Translational resarch program will be included AGO-OVAR

Adjuvant therapy of endometrioid Endometrial carcinoma: Conclusions (1) The combination of radiotherapy and lymphadenectomy results in the highest number of complications. There is no proven overall survival benefit of adjuvant radiotherapy nor lymphadenectomy. However, all randomized trials (including ASTEC) are too small to detect a survival difference of about 2,5 -3.5 % i.e. the incidence of isolated lymphatic relapses. Hence, …

Adjuvant therapy of endometrioid Endometrial carcinoma: Conclusions (2) 3. Hence, we will have to continue TAILORING our therapy. The rationale for lymphadenectomy is mainly to better select patients for further adjuvant therapy. 4. Chemotherapy seems more and more to be indicated in as adjuvant high-risk endometrial carcinoma..

Review Endometrial cancer Lancet 2005;366:491-505

Many new drugs, Exciting results expected.