Tumori non epiteliali dell’utero

Tumori non epiteliali dell’utero

Angiolo Gadducci

(Pisa)

Torino, 26 febbraio 2010

I tumori del corpo dell’utero: strategie terapeutiche in evoluzione

Uterine Sarcoma: Survival by stage

Stage patients 5-year Survival Histology

I 113 53%

LMS II-IV 50 8%

I 23 55%

ESS

II-IV 42 12%

I 82 50%

CS II-IV 100 12%

From Salazar and Dunne, 1980

Prognostic relevance of histology in uterine sarcoma

Salazar

Not

Wheelock

Not

George

Not

Kahanpaa

Not

Covens

Not

Echt

Not

Malmstrom

Not

Olah

Yes

Wolfson

Not

CTF

Yes

Authors Prognostic relevance

Variables predictive of survival by Cox proportional hazard model (423 pts)

RR (95% CI) p value

Stage (I, II, III, IV) 4.89 (4.08-5.87) <0.0001

Grade ^(G₁^,G₂^{, G}₃⁾ 3.02 (2.48-3.67) <0.0001

Age (continous) 1.81 (1.59-2.06) <0.0001

Histology ^{(CS, LMS)} 1.45 (1.25-1.68) 0.03

From Olah, 1992

Variables predictive of survival by Cox proportional hazard model (249 pts)

Variable Wald χχχχ² Risk Ratio 95% Confidence p value Limits

Stage

I reference

II 1.58242 1.680 0.749-3.768 0.2084

III 16.04944 2.586 1.625-4.117 0.0001

IV 38.90724 4.613 2.853-7.457 0.0001 Mitotic count (mitoses per 10 HPF)

<10 reference

10-20 3.07388 1.887 0.928-3.837 0.0796

>20 12.69189 3.346 1.722-6.502 0.0004

Histologic type

LMS reference

LG-ESS 4.27787 0.257 0.071-0.931 0.0386

HG-ESS 0.04206 0.951 0.586-1.543 0.8375 CS 8.59031 0.509 0.324-0.799 0.0034

Gadducci for CTF ²⁰⁰⁰

Characteristics of CS

Dominant role of the epithelial component

Relatively high incidence of lymph node involvement

Sensitivity to CDDP-based CT

Better clinical outcome compared with LMS

 Hysterectomy and bilateral salpingo-oophorectomy is the gold standard for tumors limited to the uterine corpus

 Ovaries could be preserved in young patients with LMS

Surgery in uterine sarcoma

Surgery pts recurrence rate

TAH + BSO 26 76.9%

TAH + MSO 8 62.5%

TAH + BSO 21 33%

TAH + MSO 21 24%

10-y DFS

TAH + BSO 25* 57%

TAH + MSO 25* 58%

*matched by stage, grade and age

Stage I-II LMS

recurrence by ovarian surgery

from Berchuck, 1990

from CTF, 1996

from Giuntoli, 2003

Comprehensive surgical staging (peritoneal cytology and biopsies, omentectomy, pelvic and para-aortic lymph node dissection) and, when

appropriate, tumor debulking is warranted in CS

 In others histologic subtypes, lymphadenectomy should be performed only in pts with enlarged nodes discovered at the time of the surgical procedure

Surgery in uterine sarcoma

Adjuvant RT in uterine sarcomas

Authors Decrease in local failure Improvement in survival Salazar ¹⁹⁸⁰ yes not

George ¹⁹⁸⁶ yes not Kahanpaa ¹⁹⁸⁶ yes not Nielsen ¹⁹⁸⁹ yes not Echt ¹⁹⁹⁰ yes not Ali 1993 yes not Tinkler ¹⁹⁹³ not not Manchul* 1994 yes yes

CTF 1996 yes not

Chi 1997 yes not Gerszten* 1998 yes yes Ferrer 1999 yes yes Yamada* 2000 yes not Demiaud-Alexandre 2001 yes not Soumarova 2002 yes yes Weitmann** 2002 yes not

Giuntoli 2003 yes not

*CS;**ESS

Recurrent disease in pts with stage I-II uterine sarcomas

Histology Patients Recurrence Median time Sites of recurrence to recurrence P D P+D LMS 90 35 (39%) 18 mos 5 23 7

(14%) (66%) (20%)

LG-ESS 20 5 (25%) 36 mos 5 0 0 HG-ESS 20 11 (55%) 5 mos 3 4 4

(27%) (36%) (36%)

CS 66 27 (41%) 8 mos 10 11 6

(37%) (41%) (22%)

196 78 (40%) 23 38 17

(29%) (49%) (28%) Gadducci for CTF, 1997

Totally resected stage I/II high-grade uterine sarcoma

Adjuvant pelvic

RT Observation

RANDOM

versus

Phase III randomised study to evaluate the role of adjuvant pelvic RT in uterine sarcomas stages I and II: An EORTC-CGCG study

from Reed 2008

DFS by treatment OS by treatment

Log-rank: p=0.3524

Log-rank: p=0.9231

Phase III randomised study to evaluate the role of adjuvant pelvic RT in uterine sarcomas stages I and II: An EORTC-CGCG study

from Reed 2008

Any local recurrence 11 (24%) 21 (47%) 10 (20%) 12 (24%) Any distant metastases 16 (35%) 13 (29%) 27 (54%) 16 (33%)

RT (n = 46)

control (n = 45)

RT (n = 50)

control (n = 49)

CS (n. 91) ^{LMS (n.99)}

Phase III randomised study to evaluate the role of adjuvant pelvic RT in uterine sarcomas stages I and II: An EORTC-CGCG study

from Reed 2008

Sites of recurrence

DOX and IFO in uterine sarcomas:

Data from GOG trials

DOX 60 mg/m^{2 pts RR (%)}

LMS* 28 25.0

CS* 41 9.8

IFO (+ MESNA) 1.5 g/m² daily x 5

CS** 28 32.2

LMS** 35 17.2

ESS** 21 33.3

(*from Omura 1983; **from Sutton 1989,1992 and 1996)

Phase I study of high-dose IFO + DOX in

advanced sarcomas. Swiss Group Clinical Research

DOX 60-90 mg/m² (divided in 2-3 days) + IFO 10-12 g/m²

(continous infusion over 5 days) + G-CSF

Enrolled patients : 33 (11 with gynecologic sarcoma) Evaluable patients: 31

From Leyvraz, 1998

CR 13%

PR 42%

3-year survival 25%

DOX 90 mg/m² + IFO 10 g/m² + G-CSF is manageable and should be tested in phase II trials

New drugs tested in advanced or recurrent uterine LMS

Drugs dose and schedule pts RR

Doxil ^{50 mg/m2} every 4 weeks 32* 5 (16%) Sutton 2005

Gemcitabine ^{1000 mg/m2 d 1,8, 15} 42** 9 (20.5%)

every 4 weeks Look 2004

Gemcitabine ^{900 mg/m2 d 1,8}

+ docetaxel ^{100 mg/m2} d 8 every 3 weeks 42* 15 (36%)

Hensley 2008

Gemcitabine ^{900 mg/m2 d 1,8}

+ docetaxel ^{100 mg/m2} d 8 every 3 weeks 48** 13 (27%)

Hensley 2008

*chemonaive pts; **prechemotreated pts

Phase II study of adjuvant gemcitabine + docetaxel for completely resected stage I-IV high grade uterine LMS

Study population: 25 pts with completely resected stage I-IV LMS

Adjuvant CT: Gemcitabine 900 mg/m² d 1, 8 + Docetaxel 75 mg/m² d 8 (+ GCSF or pegfilgrastim) every 3 weeks x 4 cycles 23 evaluable pts

G3 toxicities: neutropenia, 8.7%; febrile neutropenia, 8.7%; anemia 8.7%; thrombocytopenia, 4.3%; diarrhea, 4.3%;

hyperglycemia, 8.7%; pulmonary 8.7%

With median follow-up of 49 months

Among all pts: 2-year PFS: 45%, median OS not yet reached.

Among the 18 pts in stage I-II: 2-y PFS: 59%, median OS not yet reached Gemcitabine/docetaxel yielded 2-y PFS superior to historical rates

Hensley ²⁰⁰⁹

Combination regimens with CDDP+DOX+ IFO in advanced CS

Seltzer 1980 6 5 (83) 3 (50)

Moore 1986 15 9 (60) 6 (40)

Grosh 1986 9 3 (33) 0

Wheelock 1986 3 1 (33) 1 (33)

Jansen 1987 6 5 (83) 2 (33)

Melviya 1988 11 8 (72) 6 (54)

Andersen 1989 6 6 (100) 4 (76)

Peters 1989 8 5 (62) 5 (62)

Plaxe 1990 5 2 (40) 1 (20)

Baker 1991 11 4 (36) 3 (27)

CTF 1997 17 11 (65) 6 (35)

Van Rijswijk 2003 32* 18 (56) 11 (34)

*Gynecological CS 129 77 (59) 48 (37)

authors pts RR (%) CR (%)

GOG randomized trial

Optimally debulked stage I,II III, or IV CS

Whole abdominal RT

IFO + CDDP

1.5 g/m² d 1-4 20 mg/m² d 1-4 x 3 cycles

RANDOM

versus

Randomised GOG trial in pts with stage I-IV MMT after optimal surgical debulking

WAI IFO + CDDP

1.5 g/m² d 1-4 20 mg/m² d 1-4 x 3 cycles

versus

206 pts with RD< 1 cm and no extra-abdominal disease

pts 5-y recurrence rate HR for CT (95% CI)

CT 101 52% 0.789 (0.530-1.176)

WAI 105 58%

Wolfson, 2007

Randomised GOG trial in pts with stage I-IV MMT after optimal surgical debulking

WAI IFO + CDDP

1.5 g/m² d 1-4 20 mg/m² d 1-4 x 3 cycles

versus

206 pts with RD< 1 cm and no extra-abdominal disease pts 5-y death rate HR for CT (95% CI)

CT 101 55% 0.712 (0.484-1.048)

WAI 105 65%

Wolfson, 2007

Phase III study of IFO + TAX in advanced uterine CS: a GOG study

Study population: 179 pts with stage III-IV, persistent or recurrent uterine CS

CT RR PFS OS sensory

months neuropathy

IFO 2 g/m² d 1-3 29% 2 8.4 9%

IFO 1.6 g/m² d 1-3 45% 5.8 13.5 30%

+ TAX 135 mg/m² d 1

P value 0.017 0.03 0.03 <0.0001

Homesley

,

Phase III study of IFO + TAX in advanced uterine CS: a GOG study

IFO + TAX

HR for progression 0.71 95% CI, 0.51-0.97, p= 0.03 HR for death 0.69 95% CI, 0.49-0.97, p= 0.03

Homesley

,

pts RR

TAX (175 mg/m²) + CBDCA AUC 6 5 80%

Toyoshima 2004

TAX /Docetaxel + CBDCA/CDDP 38 63%

Leiser 2007

Phase II trials in advanced/recurrent CS

TAX (175 mg/m²) + CBDCA AUC 6 55 55%

Powell 2009

The GOG is currently conducting a randomised phase III trial (GOG 209), comparing DOX + TAX + CDDP vs TAX + CBDCA in endometrial cancer.

 Similarly, a randomized trial evaluating the efficacy and toxicity of CBDCA+ TAX vs CDDP + IFO in advanced or recurrent uterine CS is warranted

Chemotherapy in advanced/recurrent CS

 Anecdotal response of LG-ESS to Gn-RH analogues (Scribner ¹⁹⁹⁸; Mesia ^2000; Burke ²⁰⁰⁴) and to letrozole (Maluf ^2001, Pink ^2006, Brechot ²⁰⁰⁷)

 High recurrence rate of LG-ESS pts placed on ERT following TAH + BSO (Schwartz ^2002, Lo ^2005, Pink ²⁰⁰⁶)

LG-ESS: Hormonal sensitive tumors

 High incidence of recurrence of LG-ESS when the ovaries are left in place in premenopausal women

 ER and PR expression in LG-ESS

 Advanced LG-ESS will regress with progestin: several small series in literature

LG-ESS: Hormonal sensitive tumors

Little evidence in the literature supporting the use of adjuvant CT in any gynaecological sarcomas except CS

Uterine sarcomas have a high tendency to distant recurrences, and recent data on adjuvant CT in STSs are promising

Uterine sarcoma pts should be treated within randomised trials (difficult to be conducted because of their rarity)

As for the drugs to be used, IFO + DOX obtained similar RR in advanced gynaecological sarcomas and in STSs of other sites

Gemcitabine + taxotere: good results in LMS

CDDP-based CT is effective in CS

Conclusions

Classificazione FIGO 2008: LMS

Stadio I: tumore limitato all’utero Ia: < 5 cm

Ib: > 5 cm

Stadio II: il tumore si estende oltre la pelvi IIa: c’è interessamento degli annessi

IIb: estensione ai tessuti pelvici extrauterini Stadio III: il tumore invade i tessuti addominali

IIIa: interessa una sola sede IIIb: coinvolgimento di più sedi

IIIc: linfonodi pelvici e/o paraortici positivi

Stadio IVa: invasione della mucosa vescicale o rettale IV b: metastasi a distanza

Leiomiosarcoma (LMS): indicazioni terapeutiche

A) L’isterectomia totale (ITA) è il trattamento standard nel I stadio . In età perimenopausale/menopausale è raccomandata anche l’annessiectomia bilaterale (SOB)

C) Interventi conservativi (miomectomia) solo in centri con expertise, in donne giovani nullipare desiderose di prole, se il tumore ha dimensioni < 5 cm (stadio IA).

B) ITA-SOB è il trattamento standard nel II stadio

B) Nel I-II stadio I-II : può essere proposta CT adiuvante con regimi contenenti DOX + IFO o gemcitabina + taxotere.

Classificazione FIGO 2008: sarcoma stroma endometriale e adenosarcoma

Stadio I: tumore limitato all’utero

Ia: limitato all’endometrio/endocervice (no invasione miometriale)

Ib: invade meno di metà del miometrio Ic: invade più di metà miometrio

Stadio II: il tumore si estende oltre la pelvi IIa: interessamento degli annessi

IIb: estensione ai tessuti pelvici extrauterini Stadio III: il tumore invade i tessuti addominali

IIIa: interessa una sola sede IIIb: coinvolgimento di più sedi

IIIc: linfonodi pelvici e/o paraortici positivi

Stadio IVa: invasione della mucosa vescicale o rettale IV b: metastasi a distanza

Sarcoma dello stroma endometriale (SSE): Indicazioni terapeutiche

A) ITA-SOB è il trattamento standard nel I stadio .

C) Interventi conservativi (miomectomia) solo in centri con expertise, in donne giovani nullipare desiderose di prole adeguatamente informate.

C) Ormonoterapia adiuvante, selezionata in base all’assetto recettoriale, può essere proposta nel I-II stadio

C) RT precauzionale può essere proposta su base individualizzata nel I-II stadio

Sarcoma dello stroma endometriale (SSE): Indicazioni terapeutiche

B) Stadio III con malattia resecabile: è raccomandata chirurgia completa (ITA-SOB, chirurgia citoriduttiva, ed eventualemente linfadenectomia pelvica e lombo-aortica) seguita da ormonoterapia

C) Stadio III con malattia completamente recata: CT con DOX + IFO è proponibile in casi accuratamente selezionati (elevato indice mitotico, RE-, RP-).

RT in casi selezionati in relazione alla presenza di fattori di rischio.

B) Stadio avanzato non resecabile: Ormonoterapia è il trattamento primario.

CT con DOX + IFO riservata a tumori non ormonoresponsivi.

RT va proposta sulla base della sintomatologia.

Sarcoma endometriale indifferenziato: indicazioni terapeutiche

A) ITA-SOB è il trattamento standard nello stadio I- II.

B) CT adiuvante con DOX + IFO e’ generalmente offerta in stadio I-II.

C) RT adiuvante può essere proposta su base individualizzata in stadio I- II.

B) CT è il trattamento standard nella malattia localmente avanzata. RT va tenuta in considerazione sulla base della sintomatologia.

Classificazione FIGO 2008: carcinosarcoma

Stadio Ia: limitato all’endometrio o infiltrazione miometriale < 50%

Ib: infiltrazione miometriale > 50%

Stadio II: invasione dello stroma cervicale^

Stadio IIIa: invasione della sierosa del corpo uterino e/o gli annessi*

IIIb: invasione vaginale o parametriale IIIc₁: linfonodi pelvici positivi

IIIc₂: linfonodi paraortici positivi con o senza linfonodi pelvici positivi

Stadio IVa: invasione della mucosa vescicale e/o rettale

IV b: metastasi a distanza (incluse le metastasi intraddominali e/o ai linfonodi inguinali)

^l’interessamento ghiandolare endocervicale da solo deve essere considerato come stadio I e non come stadio II

*la citologia peritoneale positiva deve essere riportata separatamente ma non modifica lo stadio

Carcinosarcoma (CS): indicazioni terapeutiche

A) ITA-SOB con stadiazione chirurgica è il trattamento standard nel I-II stadio.

B) Nel I-II stadio I-II : può essere proposta CT adiuvante con regimi contenenti CDDP + IFO + DOX o CBDCA + TAX.

C) RT precauzionale può essere proposta su base individualizzata nel I-II stadio