Carcinoma dell’endometrio

La strategia terapeutica adiuvante:

ruolo della chemioterapia

Annamaria Ferrero

AO Ordine Mauriziano Torino

Carcinoma dell’endometrio

• The most common gynecologic malignancy in the western world

• The prognosis is generally good because the

majority of patients are diagnosed in an early stage

• Stage for stage, however, the survival is about the same as for ovarian cancer

(da Hogberg, IGCS 2008)

Carcinoma dell’endometrio

Macroscopic Radical Surgery

Micrometastatic disease

No micrometastatic

disease Cure

Disease progression in the

absence of

effective adjuvant treatment

(da Hogberg, IGCS 2008)

Thomas Hogberg, Bangkok 2008

Fattori prognostici classici

•Età

•Grading

•Tipo istologico

•Infiltrazione miometriale (MI)

•Invasione spazi linfovasculari (LVSI)

•Invasione stroma cervicale (CSI)

•Stato linfonodale

•Estensione extrauterina

LVSI an independent prognosi factor in endometrial cancer.

- Briet et al., Gynecol Oncol, 2005 - Gadducci et al., Anticancer Res. 2009

Sopravvivenza a 5 anni – Classificazione FIGO

Stage

I G1 G2 G3

Ia 93 91 80

Ib 92 93 82

Ic 91 86 75

FIGO 1988 FIGO 2009

Stage I IA

Stage

II G1 G2 G3

IIa 90 84 68

IIb 81 77 65

IB

Ia + Ib

IIa

Classi di rischio

Old FIGO-staging (1988)

Gr1 Gr2 Gr3

IA IB IC IIA IIB

IIA 6%

New FIGO staging (2009)

Gr1 Gr2 Gr3

IA IB IIB

Thomas Hogberg, Bangkok 2008

(da Hogberg, IGCS 2008)

Radioterapia

Interpretation: Adjuvant external beam radiotherapy cannot

be recommended as part of routine treatment for women with

intermediate-risk or high-risk early-stage endometrial cancer

with the aim of improving survival. The absolute benefit of

external beam radiotherapy in preventing isolated local

recurrence is small and is not without toxicity.

Chemioterapia

Conclusions: Patients with stage IB/IC, grade 3 endometrioid adenocarcinoma have a significant risk for extra-pelvic recurrence. Most patients will not be salvaged and will succumb to their disease, suggesting that current loco-

regional adjuvant treatment strategies are not optimal and evaluation of more systemic therapies is warranted.

Trattamento

Low risk Surgery only

Surgery only or surgery + VBT (PORTEC2)

Intermediate risk

Surgery + RT (Traditional treatment)

Surgery + CT? (Maggi et al., JGOG-2033) Surgery + RT + CT?

(NSGO-EC-9501/EORTC 99551) High risk

IIB Radical hysterectomy? + high risk treatment

(da Hogberg, IGCS 2008)

Thomas Hogberg, Bangkok 2008

Carcinoma dell’endometrio

Pelvic RT±VBT±CT?

Pelvic RT±VBT?

Pelvic+para-aortic RT±VBT?

CT? Pelvic+para-aortic RT±VBT±CT?

More toxic treatments

”As every student of this disease has observed, many of the patients are suited only to the mini-mum procedure, because of age, obesity, or frailty from complicating medical

problems”

Morrow CP et al. 1991

(da Hogberg, IGCS 2008)

Thomas Hogberg, Bangkok 2008

Temi

• Chemioterapia nel carcinoma dell’endometrio

• Ruolo adiuvante

• Integrazione con la radioterapia

• Istotipi speciali

• Nuovi agenti

• Studi in corso

Chemioterapia

nel carcinoma dell’endometrio

¾Endometrial cancer was considered a relatively chemoresistant disease.

¾Chemotherapy was reserved for patients who progressed on progestational therapy or for those who had no other curative option.

¾As a result:

ƒ chemotherapy was considered only for a small population of patients

ƒ drugs were typically evaluated in patients who carried the poorest prognosis.

(da McMeekin, Annals of Oncology, 2009)

Dagli studi clinici alla pratica clinica

¾ One must be careful in generalizing results from clinical trials to all patients with endometrial cancer.

¾ Trial eligibility typically requires normal end organ

function and higher PS, and enrolled patients are frequently younger than the general population of endometrial cancer patients.

¾ Endometrial cancer patients often carry significant

medical comorbidities such as hypertension, cardiac disease, and diabetes making it more difficult to administer more

toxic combination regimens. Clinical trials do not report the frequency of these conditions routinely.

(da McMeekin, Annals of Oncology, 2009)

Single Agent Response Rates in Patients With No Prior Chemotherapy

(da Fleming et al, JCO 2007)

Selected Phase II Trials of Combination Chemotherapy in Patients With No Prior Chemotherapy

(da Fleming et al, JCO 2007)

Metastatic Endometrial Carcinoma:

Randomized Trials

(da Ray et Fleming, Ann Onc 2009)

GOG - 177

.

AP: doxorubicin 60 mg/m2 and cisplatin 50 mg/m2

TAP: doxorubicin 45 mg/m2 and cisplatin 50 mg/m2 (day 1), followed by paclitaxel 160 mg/m2 (day 2) with filgrastim support

Conclusions: TAP significantly improves RR, PFS, and OS compared with AP.

GOG - 184

*Both arms received G-CSF.

**Paclitaxel was administrated on day 2.

Chemioterapia

Conclusions: More intense combination chemotherapy significantly improves the disease-free survival and the data indicate a modest improvement in OS.

The addition of anthracyclines (e.g. doxorubicin) or the taxanes (Taxol) to cisplatin increases the response rate.

More intensive regimens are associated with the gain in survival.

However, grade 3 and 4 myelosuppression and gastrointestinal toxicity are also increased.

Temi

• Chemioterapia nel carcinoma dell’endometrio

• Ruolo adiuvante

• Integrazione con la radioterapia

• Istotipi speciali

• Nuovi agenti

• Studi in corso

Studi sul trattamento adiuvante del carcinoma dell’endometrio: CT vs RT

(da Zagouri et al, Obstetrics and Gynecology International 2010)

GOG - 122

Postoperative whole abdominal radiotherapy versus combination doxorubicin-cisplatin chemotherapy in advanced endometrial

carcinoma. *30-Gy in fractions with a 15-Gy boost.

Chemotherapy significantly improved overall and progression-free survival compared with WAR

JGOG - 2033

JGOG - 2033

(da Susumu et al, Gynecol Oncol 2008)

High–intermediate risk (HIR) was defined as (1) stage IC patients over age 70 years or having G3 endometrioid adenocarcinoma or (2) stage II or IIIA (positive cytology) patients with deeper than 50% myometrial invasion in the corpus.

JGOG - 2033

(da Susumu et al, Gynecol Oncol 2008)

Temi

• Chemioterapia nel carcinoma dell’endometrio

• Ruolo adiuvante

• Integrazione con la radioterapia

• Istotipi speciali

• Nuovi agenti

• Studi in corso

RTOG - 9708

.

¾ Phase II study to assess the feasibility.

¾ Radiation to the pelvis along with cisplatin (50 mg/m2) on days 1 and 28.

Vaginal brachytherapy after the external beam radiation.

Four courses of cisplatin (50 mg/m2) and paclitaxel (175 mg/m2) at 4-week intervals following completion of radiotherapy.

¾ Local–regional control is excellent following combined modality treatment in all patients suggesting additive effects of chemotherapy and radiation.

Studi sul trattamento adiuvante del carcinoma dell’endometrio: CT + RT

(da Zagouri et al, Obstetrics and Gynecology International 2010)

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. Hogberg

, P. Rosenberg

, G. Kristensen

, CF de Oliviera

, R dePont Christensen

B Sorbe

, H Andersson

, T Salmi

, C

Lundgren

K Boman

, A Clarke

, NS Reed

.

1Nordic Society of Gynecologic Oncology, Odense, Denmark,

2Europ Org for Research and Treatment of Cancer, Brussels, Belgium

NSGO EORTC

NSGO EC-9501/EORTC-55991

(da Hogberg, IGCS 2008)

NSGO EC-9501/EORTC-55991

Radical surgery TAH+BSO (+PLA)

RT+CT RT

CT+RT

OR

Randomization

≥ 44 Gy XRT ±

optional VBT (39%)

(VBT 44%) May 1996 to January 2007

n=196

n=382

n=186

• Surgical stage I, II,

IIIA (positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only) with high risk for micro-metastatic disease

CT:　intially AP.

Later AP, TcP, TAP, TEcP.

Primary endpoint:

Progression-free survival (PFS)

• Patients with serous, clear cell, or anaplastic carcinomas were eligible regardless of other risk factors

Thomas Hogberg, NSGO – 4

(da Hogberg, IGCS 2008)

NSGO EC-9501/EORTC-55991

Progression-free survival

0.000.250.500.751.00

0 1 2 3 4 5

analysis time

random = 1 random = 2

CT not completedRT (n=196) RT + CT (n=186)CT completed

HR 0.53 (CI 0.33-0.87) p=0.01; estimated difference in 5-yr PFS 9% from 74% to 83%

(da Hogberg, IGCS 2008)

NSGO EC-9501/EORTC-55991/ILIADE

Progression-free survival

0.000.250.500.751.00

0 1 2 3 4 5

analysis time

XRT XRT+CT

PFS depending on randomization POOLED DATA

HR 0.54 (CI 0.37-0.79) p=0.001 estimated difference in 5-yr PFS 12% from 70% to 82%

Thomas Hogberg, NSGO - 9

(da Hogberg, IGCS 2008)

NSGO EC-9501/EORTC-55991

Overall survival depending on randomization

0.000.250.500.751.00

0 1 2 3 4 5

analysis time

random = 1 random = 2

CT not completedRT (n=196) RT + CT (n=186)CT completed

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

Thomas Hogberg, NSGO - 11

(da Hogberg, IGCS 2008)

NSGO EC-9501/EORTC-55991/ILIADE

Overall survival depending on randomization

0.000.250.500.751.00

0 1 2 3 4 5

analysis time

XRT XRT+CT

OS depending on randomization POOLED DATA

HR 0.68 (CI 0.46-1.0) p=0.047; estimated difference in 5-yr OS 7% from 74% to 81%

Thomas Hogberg, NSGO - 12

(da Hogberg, IGCS 2008)

Finnish study

Radical surgery

TAH+BSO+PLA (80%)

B: RT+CT A: RT

CT1-XRT 28 Gy-CT2- XRT 28Gy-CT3

Randomization

•Surgical stage IA-B Gr3 (n=28), IC- IIIA Gr1-3 (n=128)

2x28 Gy (split course) XRT April 1992 to April 1996

n=72

n=156

n=84

• Patients with clear cell carcinoma

(n=3) were eligible ^{CT :}　Cyclophosphamide 500, epirubicine 60, cisplatin 50 mg/m²

Primary endpoint:

Overall survival (OS)

Thomas Hogberg, NSGO – 24

(da Kuoppala et al. Gynecol Oncol 2008)

Finnish study

Thomas Hogberg, NSGO – 25

(da Kuoppala et al. Gynecol Oncol 2008)

Recurrence rate:

-22.6% in Group B -18.0% in Group A

(p=0.496)

Toxicity:

Chemotherapy was

associated with a low rate of acute toxicity,

but appeared to increase the risk of bowel

complications

.

Temi

• Chemioterapia nel carcinoma dell’endometrio

• Ruolo adiuvante

• Integrazione con la radioterapia

• Istotipi speciali

• Nuovi agenti

• Studi in corso

Cellule chiare

Conclusions: CC tumors require comprehensive surgical staging.

Platinum based adjuvant chemotherapy in a doublet or triplet format in

combination with paclitaxel and/or doxorubicin should be considered as part of treatment of these women.

Careful long term surveillance following treatment is indicated given the higher rate of recurrence compared to endometrioid endometrial cancer.

Sieroso papillifero

Conclusions: Women diagnosed with UPSC should undergo comprehensive surgical staging and an attempt at optimal cytoreduction.

Platinum/taxane-based adjuvant chemotherapy should be considered in the treatment of both early- and advanced-stage patients.

Careful long-term surveillance is indicated as many of these women will recur.

Prospective clinical trials of women with UPSC are necessary in order to

delineate the optimal therapy for women with newly diagnosed and recurrent disease.

Istotipi speciali

Conclusions: In patients with advanced/recurrent endometrial cancer treated with A, P and/or T, response was not associated with histology.

This exploratory analysis does not support exclusion of S tumors in future trials.

Poorer PFS and OS were observed in CC compared to other types, but a lack of benefit from chemotherapy was not shown, and as this histology represents such a small fraction, it does not seem feasible to have separate chemotherapy trials for CC.

Temi

• Chemioterapia nel carcinoma dell’endometrio

• Ruolo adiuvante

• Integrazione con la radioterapia

• Istotipi speciali

• Nuovi agenti

• Studi in corso

Reviews 2010

Types of endometrial cancer according to the Bokhman model and correlations with

clinicopathological and molecular characteristics

(da Zagouri et al, Obstetrics and Gynecology International 2010)

Cellular pathways currently being targeted in the treatment of endometrial cancer

(da Zagouri et al, Obstetrics and Gynecology International 2010)

Phase II GOG studies for advanced or recurrent endometrial cancer

(da Gehering et al, Gynecologic Oncology 2010)

Temi

• Chemioterapia nel carcinoma dell’endometrio

• Ruolo adiuvante

• Integrazione con la radioterapia

• Istotipi speciali

• Nuovi agenti

• Studi in corso

Dopo NSGO EC-9501/EORTC-55991

Next logical question: what does RT add to CT?

CT CT+RT Radical

surgery

(da Hogberg, IGCS 2008)

Thomas Hogberg, NSGO - 22

GOG 194

PORTEC-3

*Patients with cervical involvement undergo vaginal brachytherapy

PORTEC-3

Studio randomizzato di fase III:

radioterapia + chemioterapia concomitante e adiuvante

vs

radioterapia pelvica esclusiva nel carcinoma endometriale ad alto rischio e in stadio avanzato

an Intergroup trial of the Dutch Cooperative Gynecologic Oncology Group and the UK National Cancer Research Institute

PORTEC-3

PORTEC-3

PORTEC-3

¾ Obiettivi primari

ƒ sopravivenza globale

ƒ sopravvivenza libera da recidiva

¾ Obiettivi secondari:

ƒ tossicità

ƒ qualità di vita

ƒ incidenza e sede delle recidive

Stratificazione:

ƒ per gruppo nazionale

ƒ per tipo di chirurgia (LIAB vs LIAB + PLND vs isterectomia vaginale LA)

ƒ stadio (IB vs IC vs II vs III)

ƒ istologia (endometrioide vs IS)

EORTC 55102 – DGCG

A phase III trial of postoperative chemotherapy or no further treatment for patients with stage I-II medium

or high risk endometrial cancer

Mansoor Raza MIRZA

Rigshospitalet, Copenhagen University Hospital Danish Gynecologic Cancer Group (DGCG)

Frederic AMANT

University Hospitals Leuven EORTC GCG

Executive Committee, 03

February 2010

EORTC 55102 – DGCG:

Background

• Patients with medium and high-risk stage I and II endometrial cancer have, despite radical surgery, a rather high risk for progression.

• Adjuvant radiotherapy was the traditional therapy for many decades with improvement of local control, but absolutely no impact on survival.

• Adjuvant chemotherapy is used without high level of

evidence in this population.

EORTC 55102 – DGCG:

Rationale Adjuvant CT

Stage III, IV, Recurrent:

• Adjuvant CT >Adjuvant RT: 5- years survival

(Randall, JCO 2006)

• Different CTs (A, AP, TAP,

Carbo/Pacl) have been investigated in 1st line phase

2 and 3 trials

(EORTC 55872, Ann Oncol 2003 //

Thigpen, JCO 2004 // Fleming, JCO 2004 // Sorbe, IJGC 2007 //

Michener, Cancer Res Clin Oncol 2005)

CT for stage III & IV improves survival => Level 1a

Stage Ic, II:

• CT = RT: 5-years survival (Maggi, Br J Cancer 2006 // Susumu,

Gynecol Oncol 2008)

• NSGO-EC-9501/EORTC 55991 and MANGO studies: Adjuvant CT+RT may improve survival compared to adjuvant RT in early stage medium and high-risk patients

Need to investigate effect of

adjuvant CT on survival for

stage I and II in a randomized

phase 3 study !!!

EORTC 55102 – DGCG: External Beam Radiotherapy / Brachytherapy

EBRT vs Observation (level 1a evidence, Meta-analysis of

PORTEC-1, GOG-99, ASTEC, Lancet 2009)

• no effect on survival

• improves local control

• acute & late complications

Brachytherapy vs EBRT (level 1b evidence,

PORTEC-2 trial, Nout, JCO 2009), 427 pts

• same local control as

EBRT though less toxic

EORTC 55102 – DGCG phase III study

Stratification:

ƒ Histological type: endometrioid vs. non-endometrioid

ƒ Stage of disease

ƒ Para-aortic and pelvic LNE vs. pelvic LNE

®

678 Node-negative patients

1:1

FIGO 2009

(*) Recommended chemotherapy:

Carboplatin AUC 5 IV + Paclitaxel 175mg/m² IV, Q21 days, 6 courses

EORTC 55102 – DGCG

¾ Primary endpoint:

ƒ Overall Survival

¾ Secondary endpoints:

ƒ Tossicità

ƒ Disease Specific Survival

ƒ Progression-Free Survival

ƒ Toxicity (both acute and late)

ƒ Compliance

ƒ Quality of Life (QLQ-C30 + QLQ-EN34*)

ƒ Rate of isolated pelvic relapse

ƒ Rate of isolated distant relapse

ƒ Rate of mix (local and distant)

GOG-0209 endometrio:

Background

• Il regime TAP si è dimostrato il più efficace (GOG-0177) (RC=22%; DFS mediano=9 mesi

• Il regime AP non è mai stato testato ma è

largamente in uso (familiare in oncoginecologia)

• Il regime TC è terapeuticamente equivalente alla tripletta TAP in termini di sopravvivenza?

• TC è superiore a TAP in termini di tossicità?

GOG-0209 endometrio

FIGO III/IV o recidiva

Randomizzazione N=675 x braccio, 7 cicli di

Trial di equivalenza per overall survival: HR<1.20 Doxo 45 mg/m

Cisplatin 50 mg/m

Paclitaxel 160 mg/m

Pegfilgrastim 6mg

Carboplatin AUC 6

Paclitaxel 175 mg/m

Conclusioni

¾ Importanza della chemioterapia nel trattamento

adiuvante del carcinoma endometriale ad alto rischio:

Sola o combinata con la RT?

¾ I regimi polichemioterapici sono più efficaci anche se più tossici:

Qual è il migliore?

¾ Partecipazione a studi clinici

¾ Targeted therapy

Clinically presumed:

FIGO Ia-II any histo type, FIGO Ib G3 endometrioid, FIGO Ia/b histo type II

(*) LNE = Pelvic + para-aortic;

Definitions according to LION or Mayo (No.) FIGO III not Ro and pos. LN or cytology only; FIGO IV

Recurrent FIGO I/II

R

Chemo 1 eg.

Carbo-paclitaxel

Chemo 2 eg.

Carbo- Ixabepilone Bulky LN

LNE

N- N+

No bulky LN

In OP

R Chemo 1 eg.

Carbo-paclitaxel Chemo +.

Radiotherapy

R

Chemo 1 eg.

Carbo-paclitaxel Observation

with extra LN disease

withoutextra LN disease

NEtwork STudy in Endometrial Cancer (NESTEC)

R Mayo trial (Dowdy, Mariano) AGO ECLAT trial (Emons)

R NSGO trial (Hogberg)

R AGO/NOGGO trial (Sehouli) DGCG trial (Mirza)

surgery

LNE* no LNE

N- N+

R

55102 – DGCG part of worldwide

NESTEC trials

Leading groups:

R

NESTEC: EVERY WOMEN WITH ENDOMETRIAL CANCER CAN PARTICIPATE IN A CLINICAL TRIAL

Chemotherapy is better

LNE indicated

(to allocate chemotherapy to node(+) patients)

No need of LNE

(regardless of nodal status, all patients

receive CT)

Population can be spared from adjuvant

CT New standard of care

for this population

Node(-) intermediate & high risk stage I & II patients

YES NO