Carcinoma endometriale: la terapia adiuvante Quale e Quando Vincenzo Scotto di Palumbo Ospedale Santo Spirito in Sassia Roma

La stadiazione FIGO 1988

Grading e sopravvivenza

Invasione miometriale e sopravvivenza

Il problema linfonodale

Fattori di prognosi e sopravvivenza

Terapia adiuvante ormonoterapia radioterapia chemioterapia combinazioni

Ormonoterapia Cochrane Gynecological Cancer Group: “Progestagens for endometrial cancer” Metanalysis of 6 clinical trials (4351 patients) Only 3 trials with Stage I patients In 3 trials also patients with advanced disease Martin-Hirsch P L, Jarvis G, Kitchener H, Lilford R. Progestagens for endometrial cancer (Cochrane Review). The Cochrane Library, Issue 1, 2008

Cochrane review: adjuvant progestagens

Radioterapia adjuvante Fasci esterni Brachiterapia Combinazione delle due modalità

Locoregional recurrence All stage I patients: External beam radiotherapy vs No external beam radiotherapy Distant recurrence All stage I patients: External beam radiotherapy vs No external beam radiotherapy Adjuvant radiotherapy for stage I endometrial cancer; systematic review and meta-analysis (Cochrane Review). In: Annals of Oncology 22, 1596-1604, 2007

Endometrial cancer related deaths Subgroup analysis of patients at least 1 high risk factor, Ic or grade 3 Endometrial cancer related deaths Subgroup analysis of patients at least 2 high risk factor, Ic or grade 3 Adjuvant radiotherapy for stage I endometrial cancer; systematic review and meta-analysis (Cochrane Review). In: Annals of Oncology 22, 1596-1604, 2007

Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: results of the randomized MRC ASTEC and NCIC CTC EN.5 trials Inclusion criteria Stage 1A grade 3 Stage 1B grade 3 Stage 1C grade 1-3 Serous or clear-cell cancers EN.5 started July 1996; ASTEC July 1998 905 patients randomized J Orton. ASCO 2007

Results Overall Survival Recurrence-free Survival Isolated Vaginal or Pelvic Initial Recurrence J Orton. ASCO 2007

Metanalisi su overall survival 0.2 % difference in 5-year OS (87.8% in EBRT and 88% in no EBRT) 95% CI of difference = -2.0% to 3.0% J Orton. ASCO 2007

Maggi R, BJC 95: 266-271, 2006

Caratteristiche dello studio Inclusions criteria Stage IC grade 3 Stage IIA-IIB grade 3 with myometrial invasion > 50% Stage III Maggi R, BJC 95: 266-271, 2006

Sopravvivenza libera da malattia Maggi R, BJC 95: 266-271, 2006

Sopravvivenza totale Maggi R, BJC 95: 266-271, 2006

Stage III or IV “low volume” - Any histology Residual tumour less than  2 cm after surgery 424 pts Whole abdominal radiotherapy (WAI) 30 Gy in 20 daily fractions Boost to the pelvis or to an extended field encompassing pelvic and para-aortic lymph nodes Chemotherapy Doxorubicin 60 mg/m2 Cisplatin 50 mg/m2 Every 3 weeks, for 8 cycles (only Cisplatin was to be infused during the 8°cycle) Randall ME, J Clin Oncol 24: 36-44, 2006

Sopravvivenza libera da malattia HR 0.71 (95%CI 0.55-0.91, p<0.01) Randall ME, J Clin Oncol 24: 36-44, 2006

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

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

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) Inclusion criteria Stage IC, II or III cancer plus grade 3 histology Serous or clear-cell cancers Aneuploid tumors plus grade 3 histology Aneuploid tumors plus stage IC, II or III cancer Thomas Hogberg, ASCO. 2007

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) RANDOMIZATION Thomas Hogberg, ASCO. 2007

Sopravivenza libera da malattia HR 0.62 (CI 0.40-0.97) p=0.03; estimated difference in 5-yr PFS 7% from 72% to 79%

Sopravivenza totale HR 0.65 (CI 0.40-1.06) p=0.08; estimated difference in 5-yr OS 8% from 74% to 82%

Considerazioni degli autori HR 0.35 (CI 0.16-0.77) p=0.009; estimated difference in 5-yr PFS 14% from 73% to 87%

Conclusions Despite that 27% of patients randomized to CT+RT received no, or only party of the prescribed CT, CT+RT was better than RT alone as adjuvant therapy for patients with early endometrial cancer at high risk for micrometastases

GOG 184 Register R Endometrial carcinoma A N Surgical stage III D Regimen I* Doxorubicin** 45mg/mq Cisplatin 50mg/mq G-CSF*** 5mcg/kg 2-11 R A N D O M I Z E Endometrial carcinoma Surgical stage III Hysterectomy and BSO <2 cm Residual disease Optimal Lymph Node Sampling Pelvic +/- Para-Aortic Irradiation Intravaginal Brachytherapy Regimen II* Doxorubicin** 45mg/mq day 1 Cisplatin 50mg/mq day 1 Paclitaxel 160mg/mq day 2 G-CSF*** 5mcg/kg 3-12 *q weeks 3 x 6 courses **Maximum total doxorubicin dose is 270 mg/mq for both regimen

Serie OSS 2005 - 2007 Laparotomia Laparoscopia Età media 75 64 BMI medio 23.7 19.3 Stadio: Ia 6 1 Ib 7 3 Ic IIa IIb 2 IIIa 4 IIIc IVb Istotipo: Adenocarcinomi 29 Sieropapilliferi Adenosquamosi N. medio di linfonodi 20.1 13.4 Tempo operatorio medio (min) 102 205 Perdita ematica media (cc) 105 82

OSS policy st I Ia G1, G2 osservazione Ia G3 RT pelvica se presenti RF Ib G1, G2 osservazione Ib G3 RT pelvica se presenti RF Ic G1 osservazione Ic G2, G3 RT pelvica + CT istotipi speciali RF età>60a, LVI, dimensioni del T, coinvolgimento della parte bassa del corpo

OSS policy st II, III IIa G1 osservazione IIb G2, G3 RT pelvica IIIa G1, G2 osservazione se solo cit + IIIa G3 RT pelvica + CT IIIb CT + RT IIIc CT + RT pelvi ev LA