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Endometrial Carcinoma: Role of Lymphadenectomy, Radiotherapy, and Chemotherapy

This article discusses the role of lymphadenectomy, radiotherapy, and chemotherapy in the primary treatment of endometrial carcinoma. It covers the importance of lymph node status as a prognostic factor and the potential benefits and risks of different treatment approaches. The goal is to optimize treatment outcomes and minimize both overtreatment and undertreatment. The text is in English.

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Endometrial Carcinoma: Role of Lymphadenectomy, Radiotherapy, and Chemotherapy

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

  2. Endometrioid Endometrial CancerRole 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

  3. Endometrial carcinoma Role of lymphadenectomy

  4. 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)

  5. 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).

  6. ENDOMETRIAL CARCINOMAPelvic 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)

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

  8. 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).

  9. ENDOMETRIAL CARCINOMA: LymphadenectomyBUT • 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).

  10. ENDOMETRIAL CARCINOMAPara 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)

  11. ENDOMETRIAL CARCINOMA STAGE I AND IIPara-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

  12. Para-aortic lymph node metastases inendometrial 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.

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

  14. Leuven seriesInt J Gyn Cancer 2006, 16: 1885-1893

  15. 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.

  16. LAVH for endometrial cancer: safetyLeuven series AJOG 2006, in press Multiviariate analyse for DFS: only histological type significant

  17. Safety issues in the laparoscopic approach: pos cytology? Intrauterine manipulator

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

  19. LAVH for endometrial cancer: safetyObermair et al., Gynecol Oncol 2004;92:789-93 No port site M+, similar patterns of recurrence

  20. GOG LAP 2 randomized study laparoscopy versus laparotomy (SGO 2006) • N = 2616 • 23% of those randomized to laparoscopy required laparotomy. • Laparoscopy: shorter hospital stay and longer operative time. • No survival or relapse data yet .

  21. 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 no2. Macroscopic extraut disease macroscopic extraut disease Treat according to local standard practice

  22. 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

  23. ASTEC Trial Design: Surgery(n = 1408) Kitchener et al, ESGO 2005 Trial was designed to look at an increase in 5-year overall survival of10% from 80% to 90% with a significance level of 5% and a power of 90%

  24. ASTEC Trial: Surgery Kitchener et al ESGO 2005

  25. ASTEC Surgery Kitchener et al ESGO 2005

  26. ASTEC Surgery Kitchener et al ESGO 2005

  27. 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.

  28. Lymphadenectomy in Endometrial carcinomaKitchener 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

  29. Endometrial carcinoma Role of adjuvant brachytherapy in low risk patients

  30. ENDOMETRIAL CANCER STAGE I AND IIAdjuvant 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

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

  32. 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.

  33. Endometrial carcinoma Role of adjuvant external radiotherapy

  34. ENDOMETRIAL CARCINOMAAdjuvant 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

  35. PORTEC studyStage 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

  36. Overall survival by treatment arm

  37. 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.

  38. ENDOMETRIAL CARCINOMAGOG 99Adjuvant 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

  39. GOG 99 Overall survival

  40. 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

  41. 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 EQUALLYINVALID SUBGROUP ANALYSIS

  42. Endometrial carcinoma Emerging role of chemotherapy in the adjuvant setting

  43. JGOG 99Adjuvant 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

  44. Italian study (Maggi et al Br J Cancer 2006, 95:265) n = 345 Stage Ic G3, IIG3 (> 50 % infiltration) and III 45 - 50 Gy pelvis CAP (50/45/600mg/m² q 4 wks) OS and DFS similar (more distant relapses in RT arm, more local relapses in chemo arm)

  45. 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.

  46. 55% 42% Overall Survival HR 0.68 (95%0.52-0.89, p<0.01) Randall ME, J Clin Oncol 24: 36-44, 2006

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

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

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