Cáncer de próstata de alto riesgo: oncología médica. Dr. Miguel A. Climent Fundación Instituto Valenciano de Oncología

Transcription

1 Cáncer de próstata de alto riesgo: oncología médica Dr. Miguel A. Climent Fundación Instituto Valenciano de Oncología

2 Definición de paciente de alto riesgo Papel de la quimioterapia. Neoadyuvante +/- Hormonoterapia Adyuvante +/- Hormonoterapia Concomitante con Radioterapia Estudio Stampede y metanálisis Conclusiones

3 Definición de paciente de alto riesgo Papel de la quimioterapia. Neoadyuvante +/- Hormonoterapia Adyuvante +/- Hormonoterapia Concomitante con Radioterapia Estudio Stampede y metanálisis Conclusiones

4 DEFINICION DE ALTO RIESGO

5 DEFINICION DE ALTO RIESGO Otros factores que pueden ser tenidos en cuenta: Extensión del cáncer en la biopsias Patrón terciario del Gleason Tiempo de doblaje de PSA Velocidad de PSA > 2 ngr/ml/año

6 % Biochemical Relapse DEFINICION DE ALTO RIESGO 30-40%

7 DEFINICION DE ALTO RIESGO Impacto del tipo de definición en la SLR bioquímica Nguyen et al. J. Urol. 2009

8 DEFINICION DE ALTO RIESGO

9 PAPEL DE LA QUIMIOTERAPIA Neoadyuvante +/- Hormonoterapia GETUG 12 En marcha: Dana Farber, CALGB 90202, PEACE 2 Adyuvante +/- Hormonoterapia Concomitante con Radioterapia

10 GETUG 12 trial Stratification - Gleason 8 - PSA>20 - T3 R A N D O M I Z E DE x 4 cycles ADT (3 years) Local Treatment at 3 months - pn+ / pn- ADT (3 years) Local Treatment at 3 months Primary endpoint: Progression-free survival To detect a 12% difference with a power of 80% and an alpha risk of 0.05 (two-sided). n= 400 patients Lancet Oncol 2015 Online May 29

11 GETUG 12 trial

12 GETUG 12 trial

13 PSA response (at 3 months) GETUG 12 H H+C PSA 3 months 0.2 ng/ml: 34% vs 15% p<

14 GETUG 12 trial: Sup. libre de recaída 8 years RFS ADT+TXTR+EM: 62% (55-69) ADT: 50% (44-57) HR 0,71 (0,54-0,94) p=0,017 Lancet Oncol 2015 Online May 29

15 GETUG 12 trial

16 GETUG 12 trial Gleason Score < 8 Gleason Score > 7 Lancet Oncol 2015 Online May 29

17 GETUG 12 trial

18 Neoadjuvant Hormonal and Radiation Therapy with/without Docetaxel in High Risk Prostate Cancer:Dana-Farber Institute study High Risk Prostate Cancer: T1b-2a + PSA> 10 or Gleason >7 T2c-T4 R A N D O M I Z ADT ( 6 months ) + Docetaxel x 3 cycles followed by RT (70 Gy) + Docetaxel (20 mg/m2/wkly) ADT ( 6 months ) + RT (70 Gy) E Start Date: June 2005 Primary end-point: overall survival N= 250/350 patients *ClinicalTrials.gov identifier: NCT

19 Neoadjuvant Docetaxel and Hormonal Therapy vs Prostatectomy alone in High Risk Localized Prostate Cancer: CALGB study High Risk Prostate Cancer: Biochemical PFS < 60% by Kattan nomogram PSA < 100 ng/ml Clinical stage: T1-3a N= 750 p R A N D O M I Z E Prostatectomy Docetaxel ( 6 cycles) + ADT (18-24 weeks) Prostatectomy Primary end-point: 5-year progression-free survival N= 198/750 patients *AD: LH-RH agonist *ClinicalTrials.gov identifier: NCT

20 PEACE 2 trial Stratification - Gleason 8 - PSA>20 - T3 R A N D O M I Z E CABAZITAXEL ADT (3 years) Local Treatment at 3 months - pn+ / pn- ADT (3 years) Local Treatment at 3 months

21 INTRODUCCION DE LA QUIMIOTERAPIA Neoadyuvante +/- Hormonoterapia Adyuvante +/- Hormonoterapia RTOG 9902, RTOG 0521 Otros estudios en marcha Concomitante con Radioterapia

22 RTOG 9902: DISEÑO DEL ESTUDIO

23 RTOG 9902: DISEÑO DEL ESTUDIO

24 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study *ClinicalTrials.gov identifier: NCT

25 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study *ClinicalTrials.gov identifier: NCT

26 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study *ClinicalTrials.gov identifier: NCT

27 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study *ClinicalTrials.gov identifier: NCT

28 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study Slide 7 Presented By Howard Sandler at 2015 ASCO Annual Meeting

29 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study Slide 11 Presented By Howard Sandler at 2015 ASCO Annual Meeting

30 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study Slide 14 Presented By Howard Sandler at 2015 ASCO Annual Meeting

31 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study Slide 12 Presented By Howard Sandler at 2015 ASCO Annual Meeting

32 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study Slide 13 Presented By Howard Sandler at 2015 ASCO Annual Meeting

33 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study Slide 15 Presented By Howard Sandler at 2015 ASCO Annual Meeting

34 Hormonal and Radiation Therapy followed by Docetaxel: RTOG 0521 study Slide 20 Presented By Howard Sandler at 2015 ASCO Annual Meeting

35 PROGRESSION RANDOMIZATION 2 ND PROGRESSION Adjuvant treatment - TAX-3501* (Eisenberger) RP Deferred arm Immediate arm Observation ADT 18 months ADT 18 months + Docetaxel q3w x 6 ADT 18 months ADT 18 months + Docetaxel q3w x 6 Primary end-point: progression-free survival N=228/1689 patients at high risk of progression (<60% 5 year FFD as Kattan nomogram) *ClinicalTrials.gov identifier: NCT

36 Adjuvant treatment - TAX-3501* (Eisenberger)

37 SWOG 9921: Hormonal Therapy vs Hormonal Therapy plus Chemotherapy after Prostatectomy High Risk Localized Prostate Cancer after Radical Prostatectomy (n=1360 p) R A N D O M I Z E Hormonal Therapy ( 2 years) Hormonal Therapy (2 years) plus + mitoxantrone/prednisone (6 cycles) Primary Endpoint: Overall Survival Status: Closed. Initiated 10/99; Closed 12/2007

38 Veteran Affairs CSP 553 study: Adjuvant Chemotherapy in High Risk Localized Prostate Cancer High Risk Localized Prostate Cancer after Prostatectomy (pt3b or T4, pt3a+gleason > 7, PSA > 20 ng/ml or risk of PSA progression > 50% ) Post-RP: PSA < 0.1 (n= 228 / 636 p) R A N D O M I Z E Primary Endpoint: Progression-free survival Study start: June 2006 Docetaxel (75 mg/m2 every 3 weeks) + prednisone ( 6 cycles) Observation

39 Ad Pro SPCG 12 Study start R A D P R O S T E C T O M Y High Risk patients R A N D O M I S A T I O N Docetaxel 75 mg/m 2 i.v. q 3 w x 6 Surveillance until endpoint is reached Estimated number of patients; 396 End point PSA>0,5 ng/ml In 2 samples one week apart Hormone and RT aloud when end point is reached

40 Adjuvant treatment ADRAD* (Scandinavian Prostate Cancer Group) Neo-adj ADT + RT In high risk localized PC N = 198/378 R A N D O M I Z E Docetaxel q3w x 6 cycles + ADT (9 months) ADT alone (9 months) Primary end-point: progression-free survival P R O G R E S S I O N *ClinicalTrials.gov identifier:nct

41 INTRODUCCION DE LA QUIMIOTERAPIA Neoadyuvante +/- Hormonoterapia Adyuvante +/- Hormonoterapia Concomitante con Radioterapia

42 SOGUG / URONCOR Adenocarcinoma de próstata T3N0M0 (Gleason 8,9,10) T4N0M0 TxN1M0 PSA >20 ng/ml RT + HT + QT Dosis 73.8 Gy (1.8 Gy) Hormonas 3 años LHRH Docetaxel 20 mg/m 2 s -1 a +8 RADIOTERAPIA + HT Dosis 73.8 Gy (1.8 Gy) Hormonas 3 años LHRH Enfermos 134 casos

43 CHEMORADIOTHERAPY IN LOCALLY ADVANCED PROSTATE CANCER Weekly Docetaxel in escalating dose with RT (3D-CRT; DT: 70 2Gy/1 8Gy fr) was tested in a phase I trial MTD: 20mg/m2 Kumar et al. Phase I trial of weekly docetaxel with concurrent three-dimensional conformal radiation therapy in the treatment of unfavourable localized adenocacinoma of the prostate. JCO;22(10):

44 Características de los pacientes PATIENT CHARACTERISTICS Arm A (n=64) Arm B (n=66) Overall population (n= 130) Age (years), median (IQR) 68.0 ( ) 67.5 ( ) 68.0 ( ) ECOG PS as per Karnosfky scale, n (%)* a (90.7) 46 (86.8) 95 (88.8) 1 5 (9.3) 7 (13.2) 12 (11.2) Stage at diagnosis, n (%)* b Tx, T1, T2 9 (14.1) 13 (20.6) 22 (17.3) T3, T4 55 (85.9) 50 (79.4) 105 (82.7) pn+, n (%)* b 15 (23.4) 9 (14.3) 24 (18.9) Gleason score, n (%)* b (well-differentiated) 2 (3.1) 2 (3.2) 4 (3.2) 7 (moderately differentiated) 14 (21.9) 12 (19.1) 26 (20.5) 8-10 (poor differentiated) 48 (75.0) 49 (77.8) 97 (76.4) Baseline PSA, n (%) c 20 ng/ml 15 (23.4) 20 (30.3) 35 (26.9) <20 ng/ml 48 (75.0) 42 (63.6) 90 (69.2)

45 Número de ciclos y retrasos/reducciones Arm B (n=66) Arm B (n=66) No.docetaxel cycles median (IQR) 9 (8.9, 9.9) No. cycles/patient, n (%) 8 cycles 51 (77,3) 9 cycles 50 (75.7) 10 cycles 19 (28.8) Docetaxel dose delay, n (%)* 21 (31.8) Hematological toxicity 1 (1.5) Non-hematological toxicity 13 (19.7) Other causes (Holiday or logistic reasons) 15 (22.7) Docetaxel reduction, n (%) * 4 ( 6.1) Non-hematological toxicity 1 Other causes (weight change) 4

46 Efectos secundarios Patients reporting at least one, n (%) Arm A (N=64) Arm B (N=60) Overall Safety Population (N= 124) P value* AE 59 (92.2) 59 (98.3) 118 (95.16) >0.05 Related AE 54 (84.4) 58 (96.7) 112 (90.3) <0.05 Grade 3 related AE 2 (3.1) 21 (35.0) 23 (18.6) < Serious related AE - 1 (1.7) 1 (0.8) >0.05

47 % Patients Most common treatment-related grade 2 Adverse Events reported 65 Arm A Arm B 56,7 12,5 8,3 31,3 3,1 23,3 13,3 15 9,4 11,7 10 3,1 1,6 17,2 26,6 23,3 6,3 21,

48 % Patients Grade 3-4 Adverse Events 23,3 Arm A Arm B 8,3 1,7 1,7 3,3 1,6 1,7 1,7 1,7 1,7 1,6

49 Definición de paciente de alto riesgo Papel de la quimioterapia. Neoadyuvante +/- Hormonoterapia Adyuvante +/- Hormonoterapia Concomitante con Radioterapia Estudio Stampede y metanálisis Conclusiones

50 Slide 1 Presented By Nicholas James at 2015 ASCO Annual Meeting

51 Inclusion criteria Presented By Nicholas James at 2015 ASCO Annual Meeting

52 STAMPEDE Outcome measures Presented By Nicholas James at 2015 ASCO Annual Meeting

53

54 STAMPEDE Patient characteristics Presented By Nicholas James at 2015 ASCO Annual Meeting

55 STAMPEDE Docetaxel: Failure-free survival Presented By Nicholas James at 2015 ASCO Annual Meeting

56 STAMPEDE Docetaxel: Survival Presented By Nicholas James at 2015 ASCO Annual Meeting

57 STAMPEDE Treatment effect by metastatic status: FFS Presented By Nicholas James at 2015 ASCO Annual Meeting

58 STAMPEDE

59 STAMPEDE

60 Conclusions Presented By Nicholas James at 2015 ASCO Annual Meeting

61 METANÁLISIS

62 METANÁLISIS

63 METANÁLISIS

64 METANÁLISIS

65 Conclusiones La administración quimioterapia adyuvante en enfermedad de alto riesgo prolonga la supervivencia libre de recaída: GETUG, RTOG, STAMPEDE, metanálisis. Una mejoría de la supervivencia global se evidencia en el ensayo RTOG 0521 Los resultados de otros estudios están pendientes de ser conocidos. Es necesario mayor seguimiento de los ensayos. De la misma manera que se ha observado en la enfermedad metastásica hormonosensible, es probable que la QT aporte beneficio en supervivencia en los pacientes con enfermedad de alto riesgo.