QUIMIOTERAPIA DE INDUCCION EN TUMORES DE CABEZA Y CUELLO

Transcripción

1 QUIMIOTERAPIA DE INDUCCION EN TUMORES DE CABEZA Y CUELLO TODAVIA EN DISCUSION? SEOM, SALAMANCA 2013 Ricardo Hitt CENTRO INTEGRAL ONCOLOGIA CIOCC. MADRID Ricardo Hitt 1

2 DISEÑO ENSAYOS CLINICOS Ensayos Fases II: en ocasiones demuestran una evidencia de beneficio en los pacientes tratados llegando a ser un tratamiento estándar sin estudios de confirmación. Ejemplos: MOPP enf Hodgkin, Glevec en Gist, BEP tumores germinales. Suelen ser estudios con población seleccionada y en centros de referencia Ricardo Hitt 2

3 DISEÑO ENSAYOS ENSAYOS FASES III : cuales son los objetivos actualmente? Incremento supervivencia: la mayoría de las enfermedades se tratan en 2º, 3º, ó 4º líneas Tiempo a la progresión: aplicable en tumores metastásicos Intervalo libre de enfermedad: mas real cuando se valora la Remisión Completa Preservación de órganos: válido solo en enfermedades resecables y CURABLES con cirugía. Ricardo Hitt 3

4 DISEÑO ENSAYOS CLINICOS META ANÁLISIS: que nivel de evidencia se puede tener en poblaciones heterogéneas? En puntuales MA se mezclan estudios diseñados para diferentes enfermedades, con pronósticos diferentes, localizaciones diversas, tratamientos dispares y conclusiones que difieren de las observadas en la práctica clínica. Ejemplo: MACH (Pignon), incluye: tumores resecables, irresecables, Laringe, Orofaringe, Cavidad Oral, Platinos, Platinos subóptimos, No Platinos, diferentes técnicas y dosis de Radioterapia, etc Ricardo Hitt 4

5 DISEÑO ENSAYOS CLINICOS En Tumores de Cabeza y Cuello (TCC) que esta demostrado?: Ensayos Fases II: beneficios de la inducción en centros y población seleccionada, Ejemplos: PPF, TPF + QTRT, se consiguen mejores resultados en las diferentes supervivencias. Desventajas : en ocasiones datos no reproducibles, requiere una amplia experiencia y un importante manejo de soporte. Ricardo Hitt 5

6 DISEÑO ENSAYOS CLINICOS ENSAYOS FASES III : datos concluyentes Tumores Resecables : EORTC, VETERANOS: la quimioterapia de Inducción seguida de Rt permite reemplazar a la cirugía en tumores de laringe e hipofaringe, logrando semejante supervivencia pero con preservación de órganos. ECOG Forastiere: QTI, RT, QTRT demuestran igual supervivencia global pero mejor tasa de preservación de laringe con QTRT y QTI. A 10 años mejoría de ILE con QTI Ricardo Hitt 6

7 DISEÑO ENSAYOS CLINICOS ENSAYOS FASES III : datos concluyentes Esquemas de inducción con Taxanos superior a PF clásico. Ejemplos : PPF vs PF seguido QTRT estándar (Hitt et al JCO 2005) TPF vs PF seguido de QTRT no estándar(posner and Vermonken NEJM 2007) Ricardo Hitt 7

8 GETTEC, French Cisplatin 100mg/m2, D1 5-FU 1000mg/m2, D1-D5 q3w, 3 cycles 318, HNSCC, oropharynx stage II-IV Operable: Surgery RT Induction C/T Inoperable: RT Operable: Surgery RT Inoperable: RT British Journal of Cancer 2000; 83: Ricardo Hitt 8

9 GETTEC, French chemotherapy Overall survival p=0.03 No chemotherapy chemotherapy Dz-free survival p=0.11 No chemotherapy Ricardo Hitt 9

10 GSTTC, Italy Cisplatin 100mg/m2, D1 5-FU 1000mg/m2, D1-D5 q3w, 4 cycles 237, HNSCC, stage III/IV B A Operable: Surgery RT Induction C/T Inoperable: RT Operable: Surgery RT Inoperable: RT Oral cavity Oropharynx A B Hypopharynx Para-nasal sinus Operable 29% 27% Inoperable 71% 73% Journal of the National Cancer Institute 1994; 86: Journal of the National Cancer Institute 2004; 96: Ricardo Hitt 10

11 All pts 3-yr distant metastasis rate Overall survival Inoperable Operable A 24% 3% B 42% 31% p value Operable group Overall survival Inoperable group Overall survival Ricardo Hitt 11

12 Aldelstein DJ et al 100 pts, HNSCC stage III/IV Oral cavity 4% Oropharynx 44% RT alone CCRT RT: 66-72Gy, conventional, 1.8-2Gy/fx Cisplatin: 20mg/m2/d 5FU: 1000mg/m2/d Residual dz or recurrence Infusion, D1-D4 D22-D25 Hypopharynx 16% Larynx 36% Primary site resection +/- neck dissection 5yr OS RFS Dist. Metsfree survival OS with primary site preserve Local control without resection RT 48% 51% 75% 34% 45% CCRT 50% 62% 84% 42% 77% p value <0.001 Survival benefit from better local control Ricardo Hitt Cancer 2000; 88:

13 Veterans Affairs Laryngeal Cancer Study Group 332 pts, laryngeal SCC stage III/IV Surgery Adjuvant RT RT: 5000cGy/25fx RT: cGy T1/T2 9% T3 65% T4 26% C/T x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w C/T x 1 Poor respond Definitive RT Surgery +/- RT Residual disease Glottis 37% Supraglottis 63% 2yr DFS OS Recur at primary Recur at regional Distant mets Surgery 75% 68% 2% 5% 17% Laryngectomyfree survival C/T RT 65% 68% 12% 8% 11% 39% p value NS New England Journal of Medicine 1991; 324: Ricardo Hitt 13

14 EORTC 194 pts, hypopharynx SCC stage II/III/IV T2 20% T3 75% T4 5% Surgery C/T x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w Adjuvant RT C/T x 1 Poor respond Surgery +/- RT RT: 5000cGy/25fx RT: 7000cGy Definitive RT Residual disease Pyriform sinus Aryepiglottic fold 78% 22% 5yr DFS OS Recur at local Recur at regional Distant mets Surgery 32% 35% 17% 23% 36% Laryngectomyfree survival C/T RT 25% 30% 12% 19% 25% 35% p value NS NS NS NS Journal of National Cancer Institute 1996; 8: Ricardo Hitt 14

15 RTOG RT alone 518 pts, laryngeal SCC III/IV CCRT CCRT: RT 7000cGy/35fx Cisplatin 100mg/m2, q3w T2 12% T3 78% T4 10% C/T x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w C/T x 1 Poor respond RT Surgery +/- RT Residual disease Supraglottis 69% Glottis 31% Speech/swallow : similar 5yr DFS OS Intact larynx LR control Distant mets A: RT 27% 56% 70% 56% 22% B: CCRT 36% 54% 88% 78% 12% C: C/T RT 38% 55% 75% 61% 15% 0.02(C v A) 0.005(B v C) 0.004(B v C) 0.03(B v A) 0.001(B v A) Ricardo Hitt 15 p 0.006(B v A) NS 0.001(B v A) New England Journal of Medicine 2003; 349:

16 UNRESECTABLE SCCHN Paccagnella JNCI (Nov 2004) OVERALL SURVIVAL 5 years: CF 23%; control : 19% (ns) 10 years: CF 16% vs 9% (ns) unresectable 5 years: 21% vs. 16% P= years: 8% vs. 6% Ricardo Hitt 16

17 Hitt R et al, Spain Paclitaxel 175mg/m2, D1 Cisplatin 100mg/m2, D2 5FU 500mg/m2/d, D2-D6 PCF x 3 q3w Cisplatin 100mg/m2, q3w RT 7000cGy/35fx 382 pts, HNSCC stage III/IV CR or PR>80% CCRT CF x 3 Oral cavity 13% Oropharynx 34% Hypopharynx 23% Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d, D1-D5 q3w Poor responder Larynx 30% Resectable 35% Unresectable 65% Journal of Clinical Oncology 2005; 23: Salvage surgery Ricardo Hitt 17

18 Hitt R et al, Spain Induction CR neutropenia mucositis Median survival Time to tx failure PCF 33% 37% 53% 43m 36m CF 14% 36% 16% 37m 26m p value <0.001 < Dose density Cisplatin 5FU Paclitaxel PCF 91% 98% 99% CF 81% 91% p value <0.001 <0.001 Journal of Clinical Oncology 2005; 23: Ricardo Hitt 18

19 Time to Treatment Failure PF (n= 193), 112 Events PFT (n= 190), 93 Events Log-rank, p=0.024 PF (median)= 17.7 ( ) PFT (median)= 21.7 ( ) Ricardo Hitt 19

20 Final results of a randomized Phase III trial comparing induction chemotherapy (ICT) with cisplatin/5-fu (PF) or docetaxel/cisplatin/5-fu (TPF) followed by chemoradiotherapy (CRT) versus CRT alone as first-line treatment of unresectable locally advanced head and neck cancer (LAHNC) SPANISH HEAD AND NECK CANCER GROUP Hitt et.al ASCO 2009 BEST OF ASCO. Annals of Oncology (in press) Ricardo Hitt 2020

21 Safety: Adverse events Grade 3/4 AEs, % patients CRT (N=118) PF plus CRT (N=156) TPF plus CRT (N=153) Total ICT (TPF + PF) (N=309) Neutropenia Febrile neutropenia Thrombocytopenia Asthenia Mucositis Radiation Dermatitis Ricardo Hitt 21 21

22 Por protocolo Secondary endpoint: LCR p= % patients 51.7 CRT (N=119) Combined ICT + CRT (N=234) Ricardo Hitt 22 22

23 POR PROTOCOLO Tiempo libre de evento ICT + CRT; median 18.2 months CRT; median 13.3months HR=0.747;95% CI P= ICT + CRT CRT ICT + CRT CRT (months) Ricardo Hitt 23

24 POR PROTOCOLO Fracaso al tratamiento ICT + CRT; median 14.4 months CRT; median 6.1 months HR=0.646;95% CI P= <0.001 ICT + CRT CRT ICT + CRT CRT Ricardo Hitt 24

25 INTENCIÓN DE TRATAR Tiempo libre de evento ICT + CRT; median 14.3 months CRT; median 13.8 months Log-Rank p=0.426 ICT + CRT CRT (months) ICT + CRT CRT Ricardo Hitt 25

26 INTENCIÓN DE TRATAR Fracaso al tratamiento ICT + CRT; median 8.9 months CRT; median 7.1 months Log-Rank p= ICT + CRT CRT (months) ICT + CRT CRT Ricardo Hitt 26

27 Head and Neck Cancer Pretreatment considerations Comorbid chronic diseases Pulmonary Cardiovascular Digestive Malnutrition Resulting from poor dietary habits or symptoms Severe in over 25% of patients Oral health Periodontal disease, infections, and caries common Dental rehabilitation indicated prior to radiotherapy Schantz SP, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001; Ricardo Hitt 27

28 CRT: Significant increase in acute toxicity Mucositis p<0.01 Dermatitis p<0.05 Leukopenia RT alone (n=140) CRT (n=130) Nausea/emesis Xerostomia ns Acute adverse effects: Grade 3 Ricardo Hitt Wendt TG, et al. J Clin Oncol 1998;16:

29 Patients (%) CRT: Late toxicity Analysis of 230 patients receiving CRT in 3 studies (RTOG 91-11, 97-03, 99-14) Factors associated with development of severe late toxicity a o Older age (p=0.001), advanced T-stage (p=0.0036), larynx/hypopharynx primary (p=0.004), neck dissection after RT (p=0.018) % 30 27% % 12% 10% 0 Any severe late toxicity Feeding tube dependence >2 yrs post-rt Pharyngeal dysfunction Laryngeal dysfunction a Chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for feeding tube >2 years after registration and/or DeatH Ricardo potential treatment-related Hitt death within 3 years Machtay M, et al. J Clin Oncol 2008;26:

30 TREMPLIN study: Organ preservation with Erbitux + RT after induction TPF Previously untreated SCC larynx/hypopharynx Suitable for total laryngectomy 60 pts Cisplatin RT (70 Gy) TPF (3 cycles, q3w) (n=153) <PR PR R 116 (76%) pts Erbitux Total laryngectomy + postoperative RT 71% could receive the full Erbitux protocol 43% could receive the full cisplatin protocol q3w: every 3 weeks; R: randomized 56 pts RT (70 Gy) Primary endpoint: larynx preservation 3 months post treatment Secondary endpoints: Preservation of larynx function 18 months after end of treatment, OS, tolerance to and compliance with treatment, feasibility of salvage surgery Ricardo Hitt Lefebvre J, et al. J Clin Oncol 2013;31:

31 TREMPLIN study: High rate of protocol modification due to acute toxicity with Chemo + RT Cisplatin + RT n=58* (%) Erbitux + RT n=56 (%) Protocol modification due to acute toxicity 33 (57.0) 19 (33.9) Grade 3 4 mucositis 27 (46.6) 25 (44.6) Grade 3 4 in-field skin toxicity 15 (25.9) 32 (57.1) Grade 3 4 laryngoesophageal toxicity 5 (8.6) 5 (8.9) Renal toxicity (any grade) 9 (15.5) 0 (0.0) * 2 patients did not start treatment in the cisplatin arm Lefebvre J, et al. J Clin Oncol 2013;31: Ricardo Hitt 32

32 TREMPLIN study: Erbitux preserves organ function in locally advanced SCCHN Larynx preservation Primary endpoint* Larynx function preservation Overall survival Patients (%) Secondary endpoints** Erbitux + RT Chemo + RT Chemo + RT is associated with acute and long-term toxicity Erbitux + RT shows a manageable, well-tolerated profile *3 months after end of treatment **18 months after end of treatment For patients who were randomized (n=116 [76%]) Lefebvre J, et al. J Clin Oncol 2013;31: Ricardo Hitt 33

33 Overall survival in % TREMPLIN study: Overall survival (ITT) Erbitux + RT Chemo + RT Up to 18 months HR: 0.98 (95% CI: 0.26, 3.66), log-rank: p=0.68 Up to 36 months HR: 0.84 (95% CI: 0.34, 2.08), log-rank: p= Months Patients at risk Chemo + RT (0.93) 51 (0.84) 32 (0.78) 13 (0.70) Erbitux + RT (0.93) 45 (0.82) 25 (0.71) 11 (0.71) ITT: intent to treat Lefebvre J, et al. J Clin Oncol 2013;31: Ricardo Hitt 34

34 TREMPLIN study: Pronounced late toxicity profile for Chemo + RT Cisplatin n=58* (%) Erbitux n=56 (%) Residual renal dysfunction at last evaluation (all grade 1) 4 cycles 5 cycles 6 cycles 13 (22.4) 0 (0.0) 3% 5% 14% Grade 3/4 mucosal toxicity 2 (3.5) 1 (1.8) Grade 3/4 osteoradionecrosis 1 (1.7) 1 (1.8) Grade 3/4 xerostomia 6 (10.3) 5 (8.9) Grade 3/4 subcutaneous fibrosis 4 (7.0) 1 (2.0) Grade 3/4 neuropathy 2 (3.4) 0 (0.0) * 2 patients did not start treatment in the cisplatin arm Lefebvre J, et al. J Clin Oncol 2013;31: Ricardo Hitt 35

35 DISEÑO ENSAYOS CLINICOS META ANÁLISIS : Datos Concluyentes Taxane-Cisplatin-Fluorouracil As Induction Chemotherapy in Locally Advanced Head and Neck Cancers: An Individual Patient Data Meta- Analysis of the Meta-Analysis of Chemotherapy in Head and Neck Cancer Group Pierre Blanchard, Jean Bourhis, Benjamin Lacas, Marshall R. Posner, Jan B. Vermorken, Juan J. Cruz Hernandez, Abderrahmane Bourredjem, Gilles Calais, Adriano Paccagnella, Ricardo Hitt, and Jean-Pierre Pignon, on behalf of the Meta-Analysis of Chemotherapy in Head and Neck Cancer, Induction Project, Collaborative Group JCO Aug 10, 2013: ; DOI: /JCO Ricardo Hitt 35

36 Survival curves for (A) overall survival, (B) progressionfree survival, (C) locoregional failure, and (D) distant failure. Blanchard P et al. JCO 2013;31: Ricardo Hitt 36

37 ROLE OF PRIMARY CHEMOTHERAPY Neoplasms in which Chemotherapy is the Primary Therapeutic Modality for Localized Tumors -Large cell lynphoma -Lymphoblastic lymphoma -Wilms tumor -Embryonal rhabdomyosarcoma -Small cell lung cancer? -Central nervous system lymphoma DeVita 2004 Ricardo Hitt 37

38 ROLE OF PRIMARY CHEMOTHERAPY Neoplasms in which Primary Chemotherapy Can Allow Less Mutilating Surgery: -Anal carcinoma -Bladder carcinoma -Breast cancer -Laryngeal cancer -Osteogenic sarcoma -Soft tissue sarcoma Ricardo Hitt 38

39 ROLE OF PRIMARY CHEMOTHERAPY Neoplasms in which Clinical Trials Indicate an Expanding Role for Primary Chemotherapy in the Future -Non-small cell lung cancer -Bladder cancer -Cervical cancer -Gastric cancer -Head and Neck Cancer -Pancreas cancer -Prostate cancer Ricardo Hitt 39

40 CONCLUSIONES La quimioterapia de inducción en tumores de cabeza y cuello tras 20 años de desarrollo ha demostrado: PERMITIR PRESERVACIÓN DE ÓRGANOS MEJORÍA DE SUPERVIVENCIA EN TUMORES IRRESECABLES MEJOR CONTROL LOCO-REGIONAL EN TUMORES IRRESECABLES INCREMENTO DE TOXICIDAD CUANDO SE COMBINA CON QTRT SER FACTIBLE SOLO EN POBLACIÓN SELECCIONADA Y CENTROS CON EXPERIENCIA SE PODRÍA PLANTEAR ESQUEMAS MENOS TÓXICOS CON CETUXIMAB EN INDUCCIÓN? Ricardo Hitt 40