Dra. Inmaculada Maestu Maiques Servicio de Oncología Médica

Presentación del tema: "Dra. Inmaculada Maestu Maiques Servicio de Oncología Médica"— Transcripción de la presentación:

1 ¿Ha cambiado el tratamiento del cáncer de pulmón avanzado en el anciano?
Dra. Inmaculada Maestu Maiques Servicio de Oncología Médica Hospital Universitario Dr. Peset

2 Cambios producidos Población: ancianos en mejores condiciones
Tratamiento: mejores opciones locales y sistémicas Oncólogos: cambio progresivo de ACTITUD Situación social: cada vez más solos

3 No ha cambiado Actitud de algunos profesionales La presión asistencial
La visión monocular de los ensayos clínicos

4 La tecnología a nuestros pies

5 CASO 1 CASO 2 Varón 80 años Diverticulosis
FA paroxística/ Marcapasos DDD por BAV completo DMII Fumador activo 50 a/p Trabajó en contacto con amianto ACO, metformina, bisoprolol Carcinoma Epidermoide Estadio cT4N3M1A (6.2017) Dorsalgia EVA 7/10, Astenia PS 2/asimetría torácica/ Hipoperfusión MMII Varón 83 años HTA Asma Exfumador desde hace 30 años de 15 a/p Trabajó de administrativo Broncodilatadores Adenocarcinoma pulmonar (5.2017) PS 0 Antecedentes Personales Medicación Diagnóstico Exploración

6 Asco 1997: …..sin rastro Hitos: ELVIS (1999), MILES (2003), Frasci…

7 ASCO, 2003 ¿Recomienda?

8 Retrospective trials of cisplatinum-based chemotherapy comparing treatment outcomes between younger and elderly NSCLC patients STUDY No. Pts TREATMENT ORR TTP P value OS P value (%) (mo) (mo) Kelly et al.2001 <70 years old CDDP/VNB or Carbo/PCL NR >70 years old Langer et al. 2002 <70 years old CDDP/PCL (135 mg/m2 or >70 years old mg/m2) vs VP/CDDP Langer et al. 2003 <70 years old CCDP/PCL vs CDDP/GMB >70 years old vs CDDP/TXT vs Carbo/PCL Belani and Fossella 2005 <65 years old CDDP/TXT vs Carbo/TXT 11 vs NS >65 years old vs CDDP/VNB vs NS 10.1 vs NS Goto et al. 2006 <70 years old CDDP/CPT vs Carbo/PCL d NR %d >70 years old 105 vs CDDP/GMB vs CDDP/VNB d %d 32d %d 50d %d (1-year survival) aIn favor of the elderly patients. bFor PCL. cFor Carbo/PCL. dData reported for patients ‡70 years old. ORR, overall response rate; TTP, time to tumor progression; OS, overall survival; NR, not reported; NS, nonsignificant; CDDP, cisplatin; PCL, paclitaxel; VP, etoposide; GMB, gemcitabine; TXT, docetaxel; Carbo, carboplatin; VNB, vinorelbine; CPT, irinotecan. Annals of Oncology review Volume 21 | No. 4 | April 2010 doi: /annonc/mdp360 | 699 Downloaded from annonc.oxfordjournals.org at ESMO access on September 27, 2011

9 Retrospective trials of carboplatin-based chemotherapy comparing treatment outcomes between younger and elderly NSCLC patients STUDY No. Pts TREATMENT ORR TTP P value OS P value (%) (mo) (mo) Hensing et al. 2003 <70 years old Carbo/PCL for 4 cycles vs NS until progression >70 years old Sederholm et al <70 years old Carbo/CMB vs GMB NR a NR >70 years old Lilenbaum et al. 2005 <70 years old PCL vs Carbo/PCL 15b; 28c b; 9.0c NS >70 years old b; 36c b; 8.0c NS Ansari et al. 2007 <70 years old Carbo/GMB vs PCL/GMB NS NS vs Carbo/PCL >70 years old

10 Gemcitabine-based Doublets Versus Single-agent Therapy for Elderly Patients With Advanced Nonsmall Cell Lung Cancer A Literature-based Meta-analysis. Antonio Russo, Sergio Rizzo, Fabio Fulfaro, Vincenzo Adamo, Daniele Santini Bruno Vincenzi, Nicola Gebbia, and Ignazio Carreca. Cancer 2009;115:1924–31.

11 Pretreatment Quality of Life and Functional Status Assessment Significantly Predict Survival of Elderly Patients With Advanced Non–Small-Cell Lung Cancer Receiving Chemotherapy: A Prognostic Analysis of the Multicenter Italian Lung Cancer in the Elderly Study Paolo Maione, Francesco Perrone, Ciro Gallo, et al. JCO, 2005 Better values of baseline QoL (P ) and IADL (P .04) were significantly associated with better prognosis, whereas ADL (P .44) and Charlson score (P .66) had no prognostic value. Performance status 2 (P .006) and a higher number of metastatic sites (P .02) also predicted shorter overall survival

12 2005, SIOG ¿Recomienda? A geriatric assessment (GA) should be
implemented for older patients with cancer. Extermann M, Aapro M, Bernabei R, et al. Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG).Crit Rev Oncol Hematol 2005; 55:

13 STUDY NVALT-3 R Can baseline CGA predicts toxicity?
Wymenga et al, ASCO 2007: A 7537 Carboplatin (AUC 5)/Gemcitabina x 4 cicles Carboplatin(AUC 5)/Taxol x 4 ciclos R CGA 7 X MGA 6X MGA Can baseline CGA predicts toxicity? Toxicity end point CGA prediction All grade III-IV toxicities no Toxicity related SAE’s no Grade II neurological toxicity no Grade II neuropsychiatric toxicity yes The ability to finish all cycles yes

14 CGA vs toxicity endpoints
STUDY NVALT-3 cont. CGA vs toxicity endpoints Finishing all courses was predicted by ADL (p=0.001) IADL (p=0.001) Physical function (QLQ-C30) (p=0.003) Grade 2+ neuropsychiatric toxicities was predicted by GFI (p=0.006) GDS (p=0.006) Emotionalfunctioning (QLQ-C30) (p=0.008) Role functioning (QLQ-C30) (p=0.001)

15 El valor de la comorbilidad
ELVIS? SICOG (Frasci et al.): 20% Charlson score > 2 (75% comorbilidad) Dato Finalización precoz (< 3 ciclos) MST (semanas) Total G+V V Total G+V V Zubrod PS /91(31%) /44(23%) /47(43%) 2 17/29(59%) /16(50%) /13(70%) Charlson score /98(30%) /48(21%) /50(42%) > /22(82 %) /12(66%) /10(80%) Multivariate Cox analysis of survival: PS and Charlson score only parameters Significantly predicting survival.

16 Assessment of functional status, symptoms and comorbidity in advanced non small cell lung cancer (ANSCLC) elderly patients treated with gemcitabine & vinorelbine. Maestu I, Muñoz J,Gómez-Aldaraví L, Esquerdo G, Yubero A, Torregrosa MD, Romero R Clinical and Transational Oncology, 2007 Performance status, ADL, IADL and weight loss were significantly related to survival in multivariate analysis FIRST-LINE TREATMENT WITH VINORELBINE (VRL) PLUS GEMCITABINE (GEM) FOR ELDERLY PATIENTS WITH ADVANCED NON-SMALL-CELL LUNG CANCER (NSCLC): MOLECULAR CORRELATES. IASLC, Seoul 2007 I. MAESTU1, D. ISLA2, M.- PEDRAZA3, J. MUÑOZ4, J. ORAMAS5, R. GARCÍA-GÓMEZ6, S. DEL BARCO7, B. CANTOS8, M. TARON9, R. ROSELL9 N HR CI95% AGE <= 75 23 3,578 [1,515-8,452] > 75 27 SEX male 40 3,014 [1,078-8,43] female 10 PS 0-1 42 0,332 [0,122-0,902] 2 8 ADL < 6 11 3,54 [1,341-9,343 "= 6" 39

17 ASCO, 2009 ¿Recomienda?

18 ASCO ¿Recomienda?

19 EORTC y SIOG ¿Recomiendan?
Ann Oncol Apr;21(4): EORTC Elderly Task Force and Lung Cancer Group and International Society for Geriatric Oncology (SIOG) experts' opinion for the treatment of non-small-cell lung cancer in an elderly population. Pallis AG1, Gridelli C, van Meerbeeck JP, Greillier L, Wedding U, Lacombe D, Welch J, Belani CP, Aapro M. Third-generation single-agent treatment is considered the standard of care for patients with advanced/metastatic disease. Platinum-based combination chemotherapy needs to be evaluated in prospective trials. Prospective elderly-specific trials are needed Non-small-cell lung cancer (NSCLC) represents a common health issue in the elderly population. Nevertheless, the paucity of large, well-conducted prospective trials makes it difficult to provide evidence-based clinical recommendations for these patients. The present paper reviews the currently available evidence regarding treatment of all stages of NSCLC in elderly patients. Surgery remains the standard for early-stage disease, though pneumonectomy is associated with higher incidence of postoperative mortality in elderly patients. Given the lack of demonstrated benefit for the use of adjuvant radiotherapy, it is also not recommended in elderly patients. Elderly patients seem to derive the same benefit from adjuvant chemotherapy as younger patients do, with no significant increase in toxicity. For locally advanced NSCLC, concurrent chemoradiotherapy may be offered to selected elderly patients as there is a higher risk for toxicity reported in the elderly population. Third-generation single-agent treatment is considered the standard of care for patients with advanced/metastatic disease. Platinum-based combination chemotherapy needs to be evaluated in prospective trials. Unfortunately, with the exception of advanced/metastatic NSCLC, prospective elderly-specific NSCLC trials are lacking and the majority of recommendations made are based on retrospective data, which might suffer from selection bias. Prospective elderly-specific trials are needed

20 La combinación es más eficaz
Lancet 2011; 378: 1079–88 La combinación es más eficaz pero más tóxica

21 Basic & Clinical Pharmacology & Toxicology
The Calvert–Crokcoft–Gault formula was employed to calculate a dose of carboplatin with a target AUC of 5 mg⁄ min. ⁄mL in patients under 70 years and 4 mg⁄ min. ⁄mL in patients aged 70 or older. The carboplatin systemic exposure measured by the AUC (mg ⁄ min. ⁄mL) was 5.36 (5.02; 5.69) for the older group

22 The guideline for chemotherapy for stage IV NSCLC strongly support treatment based on functional status and comorbidity Estado Funcional ¿ECOG o EVALUACIÓN GERIÁTRICA?

23

24

25 ESOGIA Diferencia en toxicidad grado 3-4 en conjunto
(especial trombocitopenia)

26 Clinical Lung Cancer,Vol. 17, No. 5, 341-9ª2016
A total of 23 publications from 18 studies were included. The present review has demonstrated that a geriatric assessment can detect multiple health issues not reflected in the Eastern Cooperative Oncology Group performance status. Impairments in geriatric domains have predictive value for mortality and appear to be associated with treatment completion. It would be useful to develop and validate an individualized treatment algorithm that includes these geriatric domains.

27 ASCO 2015 ¿ Recomendación? CLINICAL QUESTION A8
What is the best chemotherapy for treatment of the elderly with stage IV NSCLC? Decisions on the selection of chemotherapy should not be made or altered based on age alone Elderly patients should be treated on the basis of functional status and stage as per previous guidelines. Because both PS 2 and elderly populations are heterogeneous, and diminished PS can be a consequence of cancer-related symptoms or MCC, chemotherapy decisions in these subgroups must be individualized, with patient and caregiver input, to optimize outcomes fully with regard to efficacy and treatment-related toxicities.

28 CASO 1 CASO 2 Mediastinoscopia Videotoracoscopia IABVD/IAIVD
Pfeiffer 9/10 GDS Yesavage 2/15 Buen apoyo familiar IMC 26,23 P.Peso 8% en un mes Albúmina 3,8 g/dl CONUT: normal Minitoracotomía para biopsia quirúrgica IABVD/IAIVD Pfeiffer 10/10 GDS Yesavage 0/15 Buen apoyo familiar IMC 27,43 No pérdida de peso Albúmina 4,1 gr/dl CONUT: normal ESFERA Funcional Cognitivo Emocional Social Nutricional

29 ¿ Por qué diagnosticar? N Engl J Med 2009;361:958-67

30 CASO 1 CASO 2 Varón 80 años Diverticulosis
FA paroxística/ Marcapasos DDD por BAV completo DMII Fumador activo 50 a/p Trabajó en contacto con amianto ACO, metformina, bisoprolol Carcinoma Epidermoide Estadio cT4N3M1A (6.2017) Dorsalgia EVA 7/10, Astenia PS 2/asimetría torácica/ Hipoperfusión MMII Varón 83 años HTA Asma Exfumador desde hace 30 años de 15 a/p Trabajó de administrativo Broncodilatadores Adenocarcinoma pulmonar EGFR, ALK y ROS1 nativos (5.2017) PS 0 Antecedentes Personales Medicación Diagnóstico Exploración

31 Inhibidores de primera generación: Gefitinib y Erlotinib
1. Inhibidores de Tirosin-quinasas de EGFR (EGFR-TKIs) Inhibidores de primera generación: Gefitinib y Erlotinib Los EGFR TKIs reducen de forma significativa la progresión de enfermedad en pacientes con CPCNPA y mutación EGFR, representando una opción válida de tratamiento en este grupo de edad. Meta-análisis sobre el efecto de los EGFR TKIs en población anciana con tumores portadores de mutación EGFR. La estratificación por subgrupos de edad mostró que los EGFR TKIs fueron más efectivos en prolongar la SLP en pacientes ancianos HR 0.39 (p = 0.008) frente a los pacientes más jóvenes (HR, 0.48; p = 0.04) Roviello G, Zanotti L, Cappelletti MR, Gobbi A, Dester M, Paganini G, et al. Are EGFR tyrosine kinase inhibitors effective in elderly patients with EGFR-mutated non-small cell lung cancer? Clin Exp Med. 2017;Apr 8

32 1. Inhibidores de Tirosin-quinasas de EGFR (EGFR-TKIs)
Inhibidores de segunda generación: Afatinib Posición ventajosa dada la polifarmacia de los pacientes de edad dada la no implicación de CYP3A4 en su metabolización. Muchos de los fármacos comunmente empleados, actuan como inhibidores o inductores de CYP450. Schnell D, Buschke S, Fuchs H, Gansser D, Goeldner RG, Uttenreuther-Fischer M, et al. Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment. Cancer Chemother Pharmacol 2014;74(2): Inhibidores de tercera generación: Osimertinib Beneficio observado en todos los subgrupos analizados, incluidos los mayores de 65 años (n = 177; HR 0,34, IC 95% 0,23-0,50). Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–640.

33 2. Inhibidores de Tirosín-quinasas: ALK
Crizotinib Beneficio confirmado en todos los subgrupos, incluyendo aquellos con más de 65 años o PS (ECOG) de 2. En el grupo de mayor edad, la HR se muestra favorable para crizotinib (HR, 0.37, IC 95%, 0,17–0,77). Perfil de toxicidad en la población > 65 años (16% de la población) evaluado de forma retrospectiva. El porcentaje de toxicidad grado II-IV fue mayor en el grupo de más edad (15 frente a 7%), aunque la diferencia no fue estadísticamente significativa Blackhall F, Shaw A, Janne PA, Kim DW, Wilner KD, Schnell P, et al. Crizotinib safety profile in elderly and non-elderly patients with advanced ALK+ non-small cell lung cancer. Proc IASCL abstr P

34 2. Inhibidores de Tirosín-quinasas: ALK
Ceritinib y alectinib En el estudio ALEX ( alectinib vs crizotinib en primera línea de tratamiento), con SLP comol objetivo primario. La ventaja para alectinib fue similar cuando el punto de corte se estableció en 65 años con una HR de 0,48 (IC 95%, 0,34–0,70) para los menores de 65 años y 0,45 (IC 95%, 0,24–0,87) para el grupo de ancianos. Peters S, Camidge R, Shaw AT, Gadgeel S, Ahn JS, Kim DV, et al. Alectinib vs crizotinib in untreated ALK positive Non-Small-Cell Lung Cancer. N Engl J Med 2017; 377:

35 ASCO 2015 ¿ Recomendación? CLINICAL QUESTION B5
What is the optimal second-line treatment for elderly patients with stage IV NSCLC? Recommendation B5 The evidence does not support the selection of a specific secondline chemotherapy drug or combination based on age alone. This recommendation has not changed. As stated in Recommendation A8, age alone is not a contraindication to chemotherapy for NSCLC.

36 CASO 1 CASO 2 NINGÚN INGRESO POR TOXICIDAD Carboplatino AUC 4 +
Vinorelbina oral 60 mg/m2 X 6 ciclos Respuesta Parcial Progresión con implante en pared 5 meses después Radioterapia paliativa PD-L1 < 1% Carboplatino AUC 4 + Pemetrexed 500 mg/m2 X 6 ciclos Respuesta Parcial Episodio de TVP Progresión pulmonar 9 Meses después PD-L1 < 1% Docetaxel 60 mg/m2 Respuesta parcial tras dos ciclos NINGÚN INGRESO POR TOXICIDAD

37 ¿Inmunoterapia? Nivolumab N Engl J Med 2015;373:123-35.

38 … Pembrolizumab…. ¿Corte en 65 años? …los mayores de 75 años…
Herbst, The Lancet, 2016

39 Primera línea de tratamiento
PD-L1 50% Reck M, NEJM 2016

40 ¿ La población es representativa?
ESTUDIO/EDAD MEDIANA LÍMITES n > 65 años (%) n> 75 años (%) Segunda línea CheckMate 017 63 39-85 322 (45%) 29 (11%) CheckMate 057 62 21-85 243 (41%) 43 (7%) KEYNOTE 010 56-69 429 (41%) OAK 64 33-85 397 (47%) Primera línea KEYNOTE 024 64/66 33-90 164(54%) KEYNOTE021 54-70

41 SI HA CAMBIADO An important concern is that current cancer trials generally have age limitations, in addition to strict exclusion criteria per organ system. Thus, the average elderly cancer patient will generally not be allowed to participate. In addition, most trials have focused almost entirely on cancer-related outcome measures such as survival, response rate, and safety. Also, the outcome measures that are of major importance for elderly patients, such as quality of life, functional decline, and cognitive functioning, have hardly been studied. Improving lung cancer care for the elderly will only be possible if trials are conducted with a more patient-centered approach instead of merely disease-centered.

42 (N Engl J Med 1999;341: ) Ensayos SEER

43 41% vs 56% NO HA CAMBIADO 40 % vs 70%

44 EVALUACIÓN INTEGRAL DEL PACIENTE ANCIANO CON CÁNCER DE PULMÓN
OBJETIVOS DE LOS ENSAYOS MÁS ADECUADOS EVALUACIÓN INTEGRAL DEL TUMOR

45