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12 Quimioterapia, 1ª - 2ª línea y mantenimiento. Cáncer de Pulmón
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12 Quimioterapia, 1ª - 2ª línea y mantenimiento. Cáncer de Pulmón

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Autor/a Dra. Margarita Majem …

Autor/a Dra. Margarita Majem
V Jornada de Revisión del Congreso Mundial de Cáncer de Pulmón.
ARCO MEDITERRANEO. Valencia 8-Nov-2013

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  • 1. TRATAMIENTOS SISTÉMICOS EN CPNM AVANZADO: Quimioterapia Margarita Majem 8 de noviembre de 2013
  • 2. PRIMERA LÍNEA. CUESTIONES PENDIENTES 1. 2. 3. 4. 5. ¿Podemos demorar el inicio de la QT de 1º línea? ¿Podemos hacer QT personalizada? ¿Podemos optimizar el tratamiento de los pacientes ancianos? ¿Podemos mejorar los resultados de la QT de 1º línea con nuevos tratamientos? ¿Algún esquema es más eficaz de los que disponemos?
  • 3. ¿Podemos demorar el inicio de la QT de 1º línea?
  • 4. ¿Podemos esperar a iniciar un tratamiento de 1º línea en CPNM? - A “watch and wait” approach (WW) is commonly used in clinical practice: - Asymptomatic patients with clinical features of indolent behavior - palliation of symptoms is achievable with radiotherapy. - Whether this approach would have any effect on survival outcomes has not previously been evaluated
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  • 7. Conclusions: Comentarios: •25% of patients initial WW strategy. -La mayoría de los pacientes precisan QT inmediata, WW strategy es la excepción. •50% of patients in WW strategy never received CT -El único beneficio de la WW strategy es retrasar la QT • Patients in WW strategy who received CT similar OS than upfront CT. -Podemos perder pacientes candidatos a recibir QT  peor supervivencia • patients in WW strategy that did not received CT inferior OS
  • 8. ¿Podemos hacer QT personalizada?
  • 9. O15-02: The Spanish Lung Cancer Group (SLCG) BRCA1RAP80 Expression Customization (BREC) randomized phase III trial of customized chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients with wildtype epidermal growth factor receptor (EGFR) (NCT00617656/GECP-BREC) Rafael Rosell1, Teresa Moran1, manuel A. Cobo Dols2, Manuel Domine3, Maria Sanchez-Ronco4, Isabel Bover5, Mariano Provencio6, Bartomeu Massuti7, Alain Vergnenegre8, Guillermo Lopez-Vivanco9, Gilles Robinet10, Amelia Insa11, Margarita Majem12, Ramon De Las Peñas13, Maria Angeles Sala14, Dolores Isla15, Nathalie Baize16, Javier Garde17, Imane Chaib1, Carlos Camps18 IASLC, 15th World Conference on Lung Cancer October 27-30 , 2013 Sydney, Australia
  • 10. Background • Two ERCC1-directed randomized trials (Cobo et al. JCO 2007; Bepler et al. JCO 2013) – no survival benefit for ERCC1-directed treatment over non-selected chemotherapy. • SLCG phase II customized chemotherapy trial (Rosell et al. PLoS ONE 2009) – BRCA1 and RAP80 expression had a combinatory effect on outcome in NSCLC patients.
  • 11. Screening Period PostIntervention Period Intervention Period 10 days 6 Cycles of Chemotherapy every 21 days BRCA1 mRNA RAP80 mRNA D1: Cisplatin 75mg/m2 D1: Docetaxel 75mg/m2 Control arm Follow-up Randomization 1:1 Experimental arm high Experimental Group 1 low RAP80 int low BRCA1 D1: Cisplatin 75mg/m2 D1+D8: Gemcitabine: 1250mg/m2 high int Experimental Group 2 low RAP80 high Experimental Group 3 February 2008 int BRCA1 D1: Cisplatin 75mg/m2 D1: Docetaxel 75mg/m2 high int RAP80 BRCA1 D1: Docetaxel 75mg/m2 15.10.2012 March 2013
  • 12. 1116 patients screened 734 did not enroll* 382 patients randomized (intention-to-treat population) 190 Control Arm (doc/cis) 40 no available data at cut-off 5 inclusion error 3 did not receive study treatment 192 Experimental Arm 81 Experimental Group 1 (gem/cis) 62 Experimental Group 2 (doc/cis) 49 Experimental Group 3 (doc) 47 no available data at cut-off 3 inclusion error 5 did not receive study treatment 279 patients in the per-protocol population 142 Control Arm (doc/cis) 16 not evaluable for response** 137 Experimental Arm 45 Experimental Group 1 (gem/cis 49 Experimental Group 2 (doc/cis) 43 Experimental Group 3 (doc) 142 evaluable for PFS & OS 126 evaluable for response 91 assessed for change in target lesion 35 without assessment of change in target lesion*** 137 evaluable for PFS & OS 18 not evaluable for response** 119 evaluable for response 87 assessed for change in target lesion 32 without assessment of change in target lesion*** PFS=progression-free survival . OS=overall survival . * Insufficient tumor sample for mRNA expression analysis, patient decision, investigator criteria. ** No response assessment, off-study. *** Non-measurable disease at baseline or at time of response assessment
  • 13. Progression-free survival by treatment arm Median PFS: Control arm 5.5 months (95% CI, 5.08 to 5.91) Experimental arm 4.4 months (95% CI, 3.27 to 5.48) 4·4 Patients at risk 5·5
  • 14. Progression-free survival in control arm and the three experimental groups Control Arm (n=142): 5.5 months (95% CI, 5.08 to 5.91) Experimental Group 1 (n=45): 5.4 months (95% CI, 5.08 to 5.77) Experimental Group 2 (n=49): 5.5 months (95% CI, 3.83 to 7.16) Experimental Group 3 (n=43): 2.5 months (95% CI, 1.16 to 3.84) Control 5·5 2·5 5·4 Patients at risk 5·5 Exp. Group 3 Exp. Group 1 Exp. Group 2
  • 15. Overall survival in control arm and the three experimental groups Control Arm (n=142): 12.66 months (95% CI, 10.07 to 15.26) Experimental Group 1 (n=45): 7.7 months (95% CI, 3.85 to 11.55) Experimental Group 2 (n=49): 11.3 months (95% CI, 7.66 to 14.84) Experimental Group 3 (n=43): 7.3 (95% CI, 5.36 to 9.11) Exp. Group 2 7·2 7·7 12·7 Exp. Group 3 Control Exp. Group 1 11·3 Patients at risk 20
  • 16. Multivariate analysis of overall survival in PS 0 and PS 1 patients ECOG PS 0 Hazard Ratio (95% C. I) ECOG PS 1 P Hazard Ratio (95% C. I) P Treatment arm Control Experimental 1.0 (Ref) 1.0 (Ref) 0.74 (0.37-1.47) 0.39 2.02 (1.37-2.98) <0.001 Low 1.25 (0.53-2.92) 0.61 1.26 (0.70-2.25) 0.45 Intermediate 1.58 (0.67-3.76) 0.30 1.36 (0.80-2.29) 0.26 RAP80 expression High 1.0 (Ref) 1.0 (Ref) Low 1.0 (Ref) 1.0 (Ref) BRCA1 expression Intermediate 1.25 (0.49-3.15) 0.64 1.01 (0.60-1.71) 0.98 High 2.22 (0.82-6.02) 0.12 1.38 (0.80-2.38) 0.24 Histology Squamous cell carcinoma Non-squamous cell carcinoma 1.0 (Ref) 1.02 (0.43-2.45) 1.0 (Ref) 0.96 1.33 (0.87-2.03) 0.20 Gender Female Male 1.0 (Ref) 2.34 (0.88-6.24) 1.0 (Ref) 0.09 0.87 (0.51-1.49) 0.61 Smoking status Never/former smoker Current smoker 1.0 (Ref) 2.69 (1.04-6.94) 1.0 (Ref) 0.04 1.42 (0.93-2.16) 0.11 Second-line treatment Yes No Age 1 1 0.96 (0.44-2.10) 0.91 2.52 (1.66-3.83) <0.001 1.02 (0.98-1.06) 0.32 0.97 (0.95-0.99) 0.02
  • 17. Conclusions • Prespecified interim analysis showed a detrimental effect in the experimental arm. Trial prematurely closed • Significant interaction between PS and treatment arm. Favorable effect for the experimental arm among patients with PS 0 • We are now examining alternative biomarkers that could elucidate DNA repair mechanisms. Comentarios: -BRCA1, RAP80 no soc factores predictores  RAP80 factor de confusión??. -Nuevos biomarcadores para QT personalizada
  • 18. ¿Podemos optimizar el tratamiento de los pacientes ancianos?
  • 19. O15.03: ESOGIA-GFPC 08-02 Elderly Selection on Geriatric Index Assessment Phase III, randomized, multicenter study comparing in elderly patients (≥70 years) with stage IV NSCL a standard strategy of treatment allocation (carboplatin based bi-therapy or monotherapy with docetaxel) based on PS and age with an experimental strategy allocating the same regimen or BSC according to a comprehensive geriatric assessment Presenting author: R. Corre Co-authors: C. Chouaid, L. Greillier, H. Le Caer, C. Audigier-Valette, N. Baize, H. Bérard, L. Falchero, I. Monnet, E. Dansin, A. Vergnenegre, M. Marcq, C. Decroisette, S. Bota, R.Lamy, B.Massuti, C. Dujon, G. Fraboulet, J. Minguet, C. Plassot, H. Lena
  • 20. STUDY DESIGN Non-squamous Squamous ≤ 75 and PS 0-1 NSCLC > 70 y PS 0, 1 or 2 Stage IV No prior chemo Adequate hemato, hepatic, renal functions R A N D O M I Z A T I O N Based on PS and age CarboPemetrexed CarboGemcitabine > 75 and/or PS 2 Docetaxel A Non-squamous CarboPemetrexed Squamous CarboGemcitabine Normal aGA B Based on aGA Abnormal aGA PS: performance status aGS: abbreviated geriatric assessment CGA: comprehensive geriatric assessment BSC: Best supportive care C G A Pre-frailed subjects Docetaxel Frailed subjects BSC Primary endpoint: Treatment failure-free survival (TFFS) documented progression, death of any cause, exit for toxicity considered unacceptable, or withdrawal of consent Planned sample size: 490 patients for an expected hazard ratio of 1.30, a power of 80%, a two-sided overall type 1 error of 5%, assuming 5% of dropout patients.
  • 21. CAUSES OF TREATMENT FAILURE Definition: documented progression, death of any cause, withdrawal for unacceptable toxicity, or withdrawal of consent Arm A n=241 Arm B n=232 p Progression 150 (66.08%) 156 (71.23%) 0,0970 Toxicity 27 (11.89%) 10 (4.57%) 0,0053 Withdrawal of consent 9 (3.96%) 7 (3.2%) Death 30 (13.22%) 30 (13.70%) Investigator’s decision 9 (3.96%) 13 (5.94%) Intercurrent disease 2 (0.88%) 3 (1.37%) missing 14 13
  • 22. TREATMENT FAILURE FREE SURVIVAL (ITT) OVERAL SURVIVAL (ITT) Arm A: median OS 6.5 months (95% CI 4.93; 7.7) Arm A: median TFF 3.2 months (95% CI 2.91;4.13) Arm B: median OS 6.2 months (95% CI 4.9; 7.8) p=0.7784 Arm B: median TFF 3.2 months (95% CI 2.66;4.43) p=0.7149 Arm A Arm B All N=241 C-pem N=62 C-Gem N=21 Doc N=158 All N=232 C-pem N=84 C-Gem N=25 Doc N=73 BSC N=50 mTFF (months) 3.25 4.4 4.53 3.05 3.21 4.9 4.8 2.7 1.3 mOS (months) 6.5 8.9 6.3 5.9 6.2 10.2 8.4 4.9
  • 23. Conclusions • First phase III customized trial evaluating the impact of a GERIATRIC ASSESSMENT on decision making and treatments allocation. • ESOGIA did not show a superiority of its CGA based strategy of treatment allocation in terms of TFFS • In experimental arm: - 21% of frail patients  exclusive BSC management - Significantly less treatment failures for toxicities. • Results of the QoL and survival adjusted on QoL are still pending • Carboplatin-based doublets according to histology are feasible with a good tolerance profile consistent with previous studies in selected elderly patients. Comentarios: - Valoración subjetiva en la decisión de tratamiento en ancianos  infra/sobre tratamiento. - Utilidad de un instrumento objetivo. - Identificar pacientes ancianos con riesgo de toxicidad severa. - Sin diferencias en términos de eficacia
  • 24. ¿Podemos optimizar el tratamiento en pacientes ancianos? FALTA DE CONSENSO: -Elderly? >65,>70, >80? -Enfermedad localizada: papel de la cirugia, sbrt, adyuvancia. - Enfermedad la: tto concomitante,… - Enfermedad avanzada?
  • 25. ¿Podemos optimizar el tratamiento en pacientes ancianos? FALTA DE CONSENSO: -Elderly? >65,>70, >80? -Enfermedad localizada: papel de la cirugia, sbrt, adyuvancia. - Enfermedad la: tto concomitante,… - Enfermedad avanzada?
  • 26. ¿Podemos optimizar el tratamiento en pacientes ancianos? FALTA DE CONSENSO: -Elderly? >65,>70, >80? -Enfermedad localizada: papel de la cirugía, SBRT, adyuvancia. - Enfermedad la: tto concomitante,… - Enfermedad avanzada? - Debemos tratar pacientes > 80?
  • 27. MO24.02 - Treatment decisions for elderly patients with advanced NSCLC in Italian clinical practice: results from the RIGHT-3 project by Italian Association of Medical Oncology. L. Crinó
  • 28. ¿Podemos mejorar los resultados de la QT de 1º línea con nuevos tratamientos?
  • 29. O15-06
  • 30. Comentarios: •Estudio negativo de Iniparib en SCC •INIPARIB no parece aumentar la toxicidad de Carbo-Gem. •Falta seguimiento ¿?
  • 31. ¿Algún esquema es más eficaz de los que disponemos?
  • 32. MO06-06
  • 33. Comentarios: • Los dos esquemas son eficaces en términos de respuesta, SLP y SG. • Se precisa un estudio fase III confirmatorio
  • 34. MO24.06 - Randomized Phase II study of Pemetrexed plus Carboplatin followed by Pemetrexed versus Paclitaxel plus Carboplatin followed by Pemetrexed in Advanced Non-squamous, NSCLC Yoshimasa Shiraishi
  • 35. 70 69
  • 36. 70 69 Comentarios: • Fase II randomizado • Sin diferencias en los resultados de eficacia, tampoco toxicidad • Inducción 3 ciclos ¿?
  • 37. QT mantenimiento
  • 38. S124: Efficacy and Safety of Maintenance Pemetrexed in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (NSCLC) after Completing at Least 4 Cycles of Pemetrexed plus Cisplatin Induction Treatment: a Cross-trial Analysis of Two Phase III Trials G. Scagliotti, et al. •Paramount: 4 cycles of induction treatment •Clinical practice /guidelines: 2 additional cycles •¿ 2 more cycles could accomplish the same outcome as the maintenance therapy?. • Two arms of PARAMOUNT •maintenance (N=359) • placebo (N=180), 4 cycles without PD • Homogeneous population from JMDB : •346 patients with nonsquamous NSCLC • ECOG 0 -1 • completed at least 4 cycles of pem+cis without PD. • Patients enrolled in Korea and Taiwan were excluded
  • 39. S124: Efficacy and Safety of Maintenance Pemetrexed in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (NSCLC) after Completing at Least 4 Cycles of Pemetrexed plus Cisplatin Induction Treatment: a Cross-trial Analysis of Two Phase III Trials G. Scagliotti, et al. 7.5 vs 5.6 vs 6.2 m 16.9 vs 14.0 vs 14.2m Conclusions: -The PARAMOUNT placebo arm showed results consistent with the JMDB group. -Pemetrexed maintenance after 4 cycles of CP results in a statistically significant increase in OS and PFS vs 2 additional cycles of CP treatment.
  • 40. S124: Efficacy and Safety of Maintenance Pemetrexed in Patients with Advanced Nonsquamous Non-small Cell Lung Cancer (NSCLC) after Completing at Least 4 Cycles of Pemetrexed plus Cisplatin Induction Treatment: a Cross-trial Analysis of Two Phase III Trials G. Scagliotti, et al. Comentarios:7.5 vs 5.6 vs 6.2 m •Comparación de 2 estudios. Ensayo aleatorizado? •Resultado interesante: 4 ciclos = 6 ciclos 16.9 vs 14.0 vs 14.2m •Pem mantenimiento tras 4 CP mejor eficacia que 6 CP Conclusions: -The PARAMOUNT placebo arm showed results consistent with the JMDB group. -Pemetrexed maintenance after 4 cycles of CP results in a statistically significant increase in OS and PFS vs 2 additional cycles of CP treatment.
  • 41. MO24.07 - nab-Paclitaxel plus carboplatin in patients (pts) with squamous cell (SCC) nonsmall cell lung cancer (NSCLC): analysis of pts treated beyond 4 cycles in a pivotal phase 3 trial (ID 3438)
  • 42. PFS: 6.3 m OS: 12.1 m
  • 43. Comentarios: • análisis exploratorio, no pre-planeado. •Nab-P mejor perfil de toxicidad. • Resultados de eficacia esperanzadores. •Mantenimiento en SCC ? •doblete vs monoterapia: Gem, Nab-P •Ensayo prospectivo Nab-P? PFS: 6.3 m OS: 12.1 m
  • 44. QT segunda línea
  • 45. O15-07
  • 46. 4.8 vs 1.6
  • 47. 4.8 vs 1.6
  • 48. Comentarios: •Pem > Gefitinib en 2º línea CPNM WT •ARMS > secuenciación directa para la determinación de EGFR. •Importancia de un biomarcador en la selección de tto, incluso 2º linea •Cambio en nuestra práctica? • Determinación EGFR • Dudoso  EGFR-TKI
  • 49. Conclusiones: -Ganetespib + Docetaxel mejora SG y SLP vs Docetaxrl en pacientes Dx >6m y LDH elevada -No beneficio en OS en mKRAS.
  • 50. ¿qué podemos incorporar en nuestra práctica? • El único beneficio de la WW strategy es retrasar la QT. Podemos perder pacientes candidatos a recibir QT  peor supervivencia. • Ningún biomarcador para QT personalizada. • Valoración subjetiva en la decisión de tratamiento en ancianos – edad no es un criterio para ecidir el tto por si solo. – ECOG !! – COMORBILIDADES – Instrumento objetivo • • Pemetrexed en primera línea : – CIS-PEM 4 ciclos = 6 ciclos – Pem mantenimiento tras 4 CP > 6 CP Pem > Gefitinib en 2º línea CPNM WT
  • 51. GRACIAS!