¿Qué aporta la quimioterapia en el cáncer de endometrio? Ana Santaballa Bertrán, MD, PhD Agradecimientos

¿Qué aporta la quimioterapia en el CE ¿Qué aporta la quimioterapia en el CE? (Tratamiento de la enfermedad avanzada)

¿Qué aporta la quimioterapia en el CE ¿Qué aporta la quimioterapia en el CE? (Tratamiento de la enfermedad avanzada)

¿Qué aporta la quimioterapia en el CE ¿Qué aporta la quimioterapia en el CE? (Tratamiento de la enfermedad avanzada) ¿Puede aportar algo más la quimioterapia al tratamiento del CE? (Tratamiento adyuvante)

ENFERMEDAD AVANZADA ¿qué aporta la quimioterapia? Análisis de la evidencia 2016

¿Cuáles son los fármacos más activos en monoterapia? Tasa de respuestas (%) Adriamicina 20-35% Epirrubicina 25% Cisplatino 20-40% Carboplatino 30% Paclitaxel 36% Docetaxel 33% DLP 10% Antraciclinas, taxanos y platinos. Tasa de respuestas: 20-35%

¿ Monoterapia o combinación? Tasa de respuestas SG A vs AC 1 22 vs 30 6.7 vs 7.3 (P=0.48) A vs AP2 25 vs 42 9.2 vs 9 (NA) A vs AP 3 17 vs 43 7 vs 9 (p=0.65) Response rates improved from 17%–25% with single-agent doxorubicin to 33%–43% in the combination therapy arms, but there was no benefit in overall survival [ MAYOR INCIDENCIA DE MIELOTOXICIDAD Y EMESiS GRADO 3-4 CON LA COMBINACIÓN Thigpen JT, et al. J Clin Oncol. 1994;12(7):1408-1414. Thigpen JT, et al. J Clin Oncol. 2004;22(19):3902-3908. van Wijk FH,et al. Ann Oncol 2003;14:441–448.

¿ Cual es la mejor combinación? Esquema Tasa de respuestas SLP (meses) SG (meses) Adriamicina/cisplatino (AP) Adriamicina-paclitaxel (AT)1 40 43 7.2 6 12.6 13.6 Adriamicina/cisplatino (AP) carboplatino-paclitaxel (CP)2 27 35 6.7 7.7 _ Fleming GF, et al. Ann Oncol. 2004;15(8):1173- 1178. Weber B, et al. Proc Am Soc Clin Oncol. 2003;22(Supplement): Abstract 1819.

¿Cuál es la mejor combinación? GOG 177 ESTADIOS III-IV o RECAÍDAS No tratamiento previo Adriamicina 60 mg/m2 CDDP 50 mg/m2 GCSF Adriamicina 45 mg/m2 Paclitaxel 160 mg/m2 273 pacientes Fleming GF, et al. J Clin Oncol. 2004;22(11):2159-2166.

Fleming GF, et al. J Clin Oncol. 2004;22(11):2159-2166. GOG 177 TR SLP SG AP 34% 5 meses 12.3 meses TAP 57% 8 meses 15.3 meses Mayor neurotoxicidad grado 3 con el triplete (12% v s 1%) Fleming GF, et al. J Clin Oncol. 2004;22(11):2159-2166.

GOG 209 Adriamicina 45 mg/m2,CDDP 50 mg/m2, D1 ESTADIOS III-IV o RECAÍDAS No tratamiento previo Enfermedad medible RE/RP Adriamicina 45 mg/m2,CDDP 50 mg/m2, D1 Paclitaxel 160 mg/m2, D2 c/3 semanas GCSF Paclitaxel 175 mg/m2, CBDCA AUC 6 , D1 Diseño de no inferioridad 1300 pacientes Miller D, et al. Gyn Oncol. 2012;125(3): Abstract LBA1

Nuevo standard primera línea: CARBOPLATINO-PACLITAXEL GOG 209 Tasa de respuestas (%) SLP (meses) SG (meses) TC 51 13 37 TAP 40 HR:1.01 Menor incidencia de toxicidad mayor o igual a grado 2 con TC: neuropatía (19 vs 26%), trombocitopenia (12 vs 23%), emesis (4 vs 7%), diarrea (2 vs 6%) y alteraciones metabólicas (8 vs 14%) Nuevo standard primera línea: CARBOPLATINO-PACLITAXEL Miller D, et al. Gyn Oncol. 2012;125(3): Abstract LBA1

9 ensayos, QT menos intensa vs más intensa SLP 6  7 meses, HR 0.82, CI 0.77-0.96 OS 9  10.5 meses, HR 0.86, CI 0.77-0.96 Mayores efectos adversos (st, GI)

SEGUNDA LÍNEA: The need for better options

Quimioterapia.Segunda línea ¿INTERVALO LIBRE DE PLATINO? TASA DE RESPUESTAS: ILP < 6 meses: 25% ILP > 24 meses: 65% A multicenter, retrospective cohort study evaluated the applicability of the concept of “platinum sensitivity” to endometrial cancer. As the length of platinum- free interval (generally the time since adjuvant chemotherapy) increased, PFS and OS with subsequent platinum-based therapy increased Nagao S, et al.Gynecol Oncol 2013; 131:567–573.

QUIMIOTERAPIA SEGUNDA LÍNEA TRAS PLATINO Paclitaxel has performed the best, with response rates consistently greater than 20%, although these data predate the use of paclitaxel as a part of first-line treatment [53–56]. Other agents tested but demonstrating limited response rates include oxaliplatin, topotecan, liposo- mal doxorubicin, etoposide, cyclophosphamide, pemetrexed, gemcitabine, and ifosfamide Bestvina et al. TheOncologist 2016;21:1–10

Evolución de la incidencia y mortalidad por cáncer de endometrio SUPERVIVENCIA ENF.AVANZADA O RECAIDA: 7-15 MESES For advanced or recurrent disease, survival has remained unchanged over the last 25 years (median survival: 7-15 months), highlighting the need for better therapies

QUIMIOTERAPIA + TERAPIA DIRIGIDA

Aghajanian C, et al.J Clin Oncol 2015;abstr 5500 GOG 86P RAMA CONTROL: CARBOPLATINO-PACLITAXEL (GOG 209) SLP SG (meses) CARBOPLATINO-PACLITAXEL- TEMSIROLIMUS HR: 1.22 (92% 0.9- 1.5) 25 CARBOPLATINO-PACLITAXEL-BEVACIZUMAB HR:0.85 (92% 0.6-1.02) 34 CARBOPLATINO-IXABEPILONA-BEVACIZUMAB HR: 0.87 ( 92% 0.6-1.07 ) 25.2 SG rama control: 22.7 Aghajanian C, et al.J Clin Oncol 2015;abstr 5500

Lorusso D, et al. J Clin Oncol. 2015;33(suppl): Abstract 5502. Randomized Phase II Trial of Carboplatin- Paclitaxel (CP) Compared to Carboplatin- Paclitaxel-Bevacizumab (CP-B) in Advanced (stage III-IV) or Recurrent Endometrial Cancer: The MITO END-2 Trial the Multicenter Italian Trials in Ovarian Cancer (MITO) END-2 trial, was also presented at ASCO 2015. This trial enrolled women with one or fewer prior chemo- therapy regimens and compared carboplatin/paclitaxel with carboplatin/paclitaxel/bevacizumab. The addition of bevacizumab increased the overall response rate from 54% to 72.7%, with an improvement in PFS from 8.7 months to 13.0 months [52]. Lorusso D, et al. J Clin Oncol. 2015;33(suppl): Abstract 5502.

Lorusso D, et al. J Clin Oncol. 2015;33(suppl): Abstract 5502. Randomized Phase II Trial of Carboplatin- Paclitaxel (CP) Compared to Carboplatin- Paclitaxel-Bevacizumab (CP-B) in Advanced (stage III-IV) or Recurrent Endometrial Cancer: The MITO END-2 Trial Lorusso D, et al. J Clin Oncol. 2015;33(suppl): Abstract 5502.

Análisis de la evidencia 2016 TRATAMIENTO ADYUVANTE ¿qué aporta y qué puede aportar la quimioterapia? Análisis de la evidencia 2016

Tratamiento adyuvante ¿Quién necesita tratamiento? FACTORES PRONÓSTICO

Categorías de riesgo Grado 1 Grado 2 Grado 3 IA (no invasión miometrio) BAJO RIESGO (riesgo recaída local < 5%) IA (invasión miometrio <50%) IB II III ALTO RIESGO (supervivencia 5 años 67-33%) RIESGO INTERMEDIO Riesgo de recaída a los 5 años: 20-25%

Quimioterapia adyuvante RT ± QT basada en platino OS: HR 0,68, 95% CI 0.51-1.02 PFS: HR 0.63, 95% CI 0.44-0.89 Riesgo de muerte a los 5 años puede ser reducido con QT RR = 0.74 (0.51-1.06) Cochrane Database Syst Rev. 2011

Quimioterapia adyuvante Comparing the addition of chemotherapy vs no treatment after surgery and radiotherapy Autor N Criterios inclusión Tratamiento Kuoppala 156 IC-IIIA RT vs RT + CEP GOG-34 181 I-IV RT vs RT + Dox. MaNGO-ILIADE3 157 I-III RT vs CA + RT NSGO & EORTC 383 RT vs RT + QT plt. Cochrane Database Syst Rev. 2011

RT (%) RT-QT (%) TOTAL NSGO/EORTC MaNGO-ILIADE III N 191 187 76 80 534 Edad 64 (44-79) 64 (38-83) 59 (42-78) 58 (39-77) 62 (8-83) FIGO IA IB IC II III NA 27 (14%) 47 (25%) 98 (51%) 12 (6,2%) 3 (1,52%) 4 (2,1%) 17 (9,1%) 62 (33%) 92 (49%) 12(6,4%) 2 (1,1%) 22 (29%) 51 (67%) 3 (4%) 30 (37,3%) 50 (63,3%) 44 (8,2%) 109 (20%) 190 (36%) 76 (14,4%) 106 (19,7%) 9 (1,7%) Grado 1 2 3 19 (10%) 36 (19%) 92 (48%) 44 (23%) 15 (8%) 31 (17%) 108 (58%) 33 (18%) 36 (47%) 34 (45%) 3 (3,9%) 7 (8,8%) 46 (58%) 27 (34%) 149 (28%) 261 (49%) 80 (15%) Histología Endometrioide Seroso-C.Claras 112 (59%) 76 (40%) 116 (62%) 64 (34%) 72 (95%) 77 (96%) 2 (2.6%) 377 (71%) 142 (26%) The role of adjuvant combined treatment with PRT and CT in endometrial cancer has been studied in patients with intermediate and high risk (51-52). The trial of the EORTC 5591 with included stage I-IIIC patients, compared PRT +/- BT plus cisplatin based chemotherapy vs PRT +/- BT. The pooled analysis of NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III trials demonstrate that combined treatment (four cycles of platinum-based chemotherapy given either before or after RT) improve disease free survival and show a trend towards improved OS. survival in stage III patients optimally debulked. The limitation of these studies are that 25%-40% of the patient population were stage III or incompletely surgically staged.The type of CT used and the number of cycles are another concerns that precludes generalization of these results. Kuoppala T1, Mäenpää J, Tomas E et al .Surgically staged high-risk endometrial cancer: randomized study of adjuvant radiotherapy alone vs. sequential chemo-radiotherapy Gynecol Oncol 2008; 110(2):190-5.   Hogberg T1, Signorelli M, de Oliveira CF, et al. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.Eur J Cancer. 2010 ;46(13):2422-31. Hogberg. Eur J Cancer 2010

NSGO & EORTC + MaNGO-ILIADE III Disease progression: RT: 70/267 (26%) Local 4% vs distancia 19% RT-QT: 43/267 (16%) Local 2% vs distancia 13% A statistically significant improvement in PFS for combined chemoradiotherapy was seen in the NSGO/EORTC trial and in pooled results of the two trials. Although there was no significant improvement in OS in either individual or pooled results, combination therapy did show an improvement in cancer-specific survival in the NSGO/EORTC trial as well as in the pooled analysis (HR, 0.55; 95% confidence interval [CI], 0.35–0.88; p 5 .01) [17]. Although most of these trials used four to six cycles of doxorubicin/platinum-based regimens, carboplatin plus pac- litaxel is the most commonly used adjuvant therapy based on results in more advanced disease [20]. When chemoradio- therapy is administered, radiation is variably used before chemotherapy, after chemotherapy, or in a “sandwich” fashion, with three cycles of chemotherapy given before radiotherapy and three cycles given after radiotherapy. Hogberg. Eur J Cancer 2010

Cáncer de endometrio Supervivencia global a 5 años Seroso (%) Cls claras (%) Endometrioide (%) Estadio I 74 88 95 Estadio II 56 67 86 Estadio III 33 48 Estadio IV 18 37 Kosary. SEER Program, NCI, 2007.

Quimioterapia adyuvante Carcinoma no endometrioide

Quimioterapia adyuvante Carcinoma no endometrioide NSGO & EORTC + MaNGO-ILIADE III

Quimioterapia adyuvante Ca seroso RR (%) 1 IA (sin inv miom) 9 IA-IB 29 3-y PFS 94%2 Uterine Papillary Serous Carcinoma Consortium3,4 IA-IB II Obs ±RT (%) QT ± RT (%) RR 25-30 11 50 10 5y-PFS 64 82 41 86 OS 60-70 88 NS Ca células claras Canadian high risk endometrial Consortium5 91 pts. Adjuvant ChT NOT significantly associated with OS Havrilesky. Gynecol Oncol 2007. .Liang, Int J Gynecol Cancer 2016. Fader, Gynecol Oncol 2009. Fader, Gynecol Oncol 2008. Bernantdini, Gynecol Oncol 2016.

Quimioterapia adyuvante Carcinoma endometrioide

Estadio III OS PFS Comparing chemotherapy vs radiotherapy, Stage III Cochrane Database Syst Rev 2014

Cáncer de endometrio Grado 1 Grado 2 Grado 3 IA (no invasión miometrio) BAJO RIESGO (riesgo recaída local < 5%) IA (invasión miometrio <50%) IB II III ALTO RIESGO (supervivencia 5 años 67-33%) RIESGO INTERMEDIO Riesgo de recaída a los 5 años: 20-25%

Ensayo GOG 99 High intermediate risk subgroup N=448 pts. Estadio IB, IC, II. RT vs OBS 2-y CIR 12% vs 3% p = 0,007 High intermediate risk subgroup 2-y CIR 26% vs 6% High intermediate risk subgroup ILV, G3, invasión del 1/3 externo del miometrio Cualquier edad con los tres factores de riesgo 50-69 años con dos factores de riesgo ≥ 70 años con un factor de riesgo TB PORTEC 1 he HIR groups was defined according to age and three pathological criteria: histologic grades 2 or 3, presence of lymphovascular invasion and invasion of the outer third of myometrium. The HIR group includes patients older than 70 meeting one of the speci ed pathological criteria, patients between 50-69 years of age dis- playing 2 of the 3 pathological criteria and patients younger than 50 years of age ful lling all three criteria [15]. A bene t from adjuvant EBRT was demonstrated for the HIR group, but not for patients in the low intermediate risk group. CIR: cumulative incidence of recurrence. Keys. Gynecol Oncol 2004

Vaginal BT → Carbo-Paclitaxel x3 GOG 249 High-intermediate & High-risk EC Pelvic EBRT No PFS benefit Vaginal BT → Carbo-Paclitaxel x3 A total of 601 participants had either stage I disease of serous or clear cell histology, stage II disease, or stage I “high intermediate risk,” McMeekin. Gynecol Oncol 2014 Abstract LBA 431

A clinically applicable molecular-based classification for EC

Estudios adyuvancia PORTEC-3 GOG 249 DGCG/EORTC Criterios IB G3 ILV IB seroso o céls claras IC-IIA G3 IIB-IIIC Estadio I HIR Estadio II Estadio I-II seroso o céls claras I G3 I-II seroso o céls claras Brazos RTP (48,6Gy) RTP + Cis -> Cb/Px4 RTP BT + Cb/Px3 BT BT + Cb/Px6

ESMO-ESGO-ESTRO guidelines Recomendaciones ESMO-ESGO-ESTRO guidelines Grupo Definición Recomendación Evidencia Intermedio Estadio I, G1-2, inv miom ≥50%, ILV - Braquiterapia IB Intermedio-alto Estadio I, G3, inv miom <50%, ILV ± Estadio I, G1-2, ILV+, ± inv miom QT (ensayo clínico) IIIC Alto Estadio I, G3, inv miom >50%, ILV ± Estadio II G1-2 G3 o ILV+ No endometrioide IA ILV- ≥IB RT Boost braquiterapia IIIB IIC IVC

A modo de conclusión,… La quimioterapia con carboplatino-paclitaxel es el tratamiento standard en primera línea de enfermedad avanzada No existe una quimioterapia standard en segunda línea. La quimioterapia adyuvante se recomienda en estadios III. El beneficio de la quimioterapia adyuvante en los estadios iniciales de riesgo intermedio alto y alto riesgo está todavía por definir (ensayos prospectivos en marcha). Cuestiones pendientes: esquema de quimioterapia, número de ciclos, concomitante, sandwich o secuencial a la radioterapia e incluso definir si es necesaria la radioterapia en estadios iniciales.

santaballa_ana@gva.es