Carcinoma endometriale:Carcinoma endometriale:

la la terapia adiuvanteterapia adiuvante

Quale e QuandoQuale e Quando

Carcinoma endometriale:Carcinoma endometriale:

la la terapia adiuvanteterapia adiuvante

Quale e QuandoQuale e Quando

Vincenzo Scotto di PalumboVincenzo Scotto di Palumbo

Ospedale Santo Spirito in SassiaOspedale Santo Spirito in Sassia

RomaRoma

La stadiazione FIGO 1988La stadiazione FIGO 1988

Grading e sopravvivenzaGrading e sopravvivenza

Invasione miometriale e sopravvivenzaInvasione miometriale e sopravvivenza

Il problema linfonodaleIl problema linfonodale

Fattori di prognosi e sopravvivenzaFattori di prognosi e sopravvivenza

Terapia adiuvanteTerapia adiuvante

ormonoterapia

radioterapia

chemioterapia

combinazioni

OrmonoterapiaOrmonoterapia

Martin-Hirsch P L, Jarvis G, Kitchener H, Lilford R. Progestagens for endometrial cancer (Cochrane Review). The Cochrane Library, Issue 1, 2008

•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

Cochrane review: adjuvant progestagens

Cochrane review: adjuvant progestagens

Radioterapia adjuvanteRadioterapia adjuvante

Fasci esterni

Brachiterapia

Combinazione delle due modalità

Locoregional recurrenceLocoregional recurrenceAll stage I patients: External beam radiotherapy vs No external beam radiotherapy

Distant recurrenceDistant recurrenceAll 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 deathsEndometrial cancer related deathsSubgroup analysis of patients at least Subgroup analysis of patients at least 1 high risk factor1 high risk factor, Ic or grade 3, Ic or grade 3

Endometrial cancer related deathsEndometrial cancer related deathsSubgroup analysis of patients at least Subgroup analysis of patients at least 2 high risk factor2 high risk factor, Ic or grade 3, 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

Inclusion criteria

• Stage 1A grade 3• Stage 1B grade 3• Stage 1C grade 1-3• Serous or clear-cell cancers

Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: results of the randomized MRC ASTEC and NCIC CTC EN.5 trials

EN.5 started July 1996; ASTEC July 1998905 patients randomizedJ Orton. ASCO 2007

Overall Survival Recurrence-free Survival

Isolated Vaginal or Pelvic Initial Recurrence

J Orton. ASCO 2007

ResultsResults

Metanalisi su overall survivalMetanalisi 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, 2006Maggi R, BJC 95: 266-271, 2006

Inclusions criteria

• Stage IC grade 3 • Stage IIA-IIB grade 3 with myometrial invasion > 50%• Stage III

Caratteristiche dello studioCaratteristiche dello studio

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

Sopravvivenza libera da malattiaSopravvivenza libera da malattia

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

Sopravvivenza totaleSopravvivenza totale

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

Stage III or IV “low volume” - Any histologyResidual tumour less than 2 cm after

surgery424 pts

Stage III or IV “low volume” - Any histologyResidual tumour less than 2 cm after

surgery424 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 malattiaSopravvivenza libera da malattia

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

HR 0.71 (95%CI 0.55-0.91, p<0.01)

Sopravvivenza totaleSopravvivenza totale

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

HR 0.68 (95%0.52-0.89, p<0.01)

55%

42%

ConclusionsConclusions

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

A randomized phase III study on adjuvant treatment A randomized phase III study on adjuvant treatment with radiation (RT) +/- chemotherapy (CT)with radiation (RT) +/- chemotherapy (CT)in early stage high-risk endometrial cancer in early stage high-risk endometrial cancer

(NSGO-EC-9501/EORTC 55991)(NSGO-EC-9501/EORTC 55991)

NSGO EORTC

Thomas Hogberg, ASCO. 2007

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

A randomized phase III study on adjuvant treatment A randomized phase III study on adjuvant treatment with radiation (RT) +/- chemotherapy (CT)with radiation (RT) +/- chemotherapy (CT)in early stage high-risk endometrial cancer in early stage high-risk endometrial cancer

(NSGO-EC-9501/EORTC 55991)(NSGO-EC-9501/EORTC 55991)

NSGO EORTC

RANDOMIZATION

Thomas Hogberg, ASCO. 2007

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

Sopravivenza libera da malattiaSopravivenza libera da malattia

Sopravivenza totaleSopravivenza 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 autoriConsiderazioni degli autori

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

ConclusionsConclusions

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 184GOG 184

Endometrial carcinoma

• Surgical stage III

• Hysterectomy and BSO

• <2 cm Residual disease

• Optimal Lymph Node Sampling

Endometrial carcinoma

• Surgical stage III

• Hysterectomy and BSO

• <2 cm Residual disease

• Optimal Lymph Node Sampling

Pelvic+/-

Para-AorticIrradiation

+/-Intravaginal

Brachytherapy

Pelvic+/-

Para-AorticIrradiation

+/-Intravaginal

Brachytherapy

RANDOMIZED

RANDOMIZED

Regimen I*

Doxorubicin**45mg/mqCisplatin50mg/mqG-CSF***

5mcg/kg 2-11

Regimen I*

Doxorubicin**45mg/mqCisplatin50mg/mqG-CSF***

5mcg/kg 2-11

Regimen II*

Doxorubicin**45mg/mq day 1

Cisplatin50mg/mq day 1

Paclitaxel160mg/mq day 2

G-CSF***5mcg/kg 3-12

Regimen II*

Doxorubicin**45mg/mq day 1

Cisplatin50mg/mq day 1

Paclitaxel160mg/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

Register

Laparotomia Laparoscopia

Età media 75 64

BMI medio 23.7 19.3

Stadio: Ia 6 1

Ib 7 3

Ic 7 1

IIa 1 0

IIb 2 1

IIIa 4 1

IIIc 1 1

IVb 1 0

Istotipo: Adenocarcinomi 29 7

Sieropapilliferi 1 1

Adenosquamosi 1 0

N. medio di linfonodi 20.1 13.4

Tempo operatorio medio (min) 102 205

Perdita ematica media (cc) 105 82

Serie OSS 2005 - 2007

OSS policy st I OSS policy st I

• Ia G1, G2 osservazione• Ia G3RT 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, IIIOSS 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