CHIMIOTHÉRAPIE ORALE MÉTRONOMIQUE PERSPECTIVES EC ANTOINE ISHH, PARIS MONACO VENDREDI 5 FÉVRIER 2016
Metronomic chemotherapy is an reasonable treatment option, for patients not requiring rapid tumor response. LoE: 1 B 88,3% The better studied regimen is CM (low dose oral cyclophosphamide and methotrexate); other regimens are being evaluated (including capecitabine and vinorelbine). Randomized trials are needed to accurately compare metronomic CT with standard dosing regimens.
chimiothérapie en Phase métastatique Proposition Statut Niveau de preuve Votes (#1 - n = 43) (#2 - n = 44) Oui Non Abst. La chimiothérapie métronomique est une option thérapeutique raisonnable chez les patientes ne nécessitant pas une réponse tumorale rapide. Nouveau 1B 88,4 % 7,0 % 4,6 % Même prescrites en adjuvant, si la dose cumulée n a pas été atteinte et en l absence de contre-indications cardiaques, les anthracyclines peuvent être réutilisées en situation métastatique, surtout si l intervalle libre est d au moins 1 an. Nouveau 1C 93,2 % 2,3 % 4,5 %
Les chimiothérapies métronomiques en clinique (ex du cancer du sein) Metronomic protocol Study design Patients (N) ORR (%) Clinical benefit (%) Median TTP (months) Median OS (months) mctx + mmtx Phase II 64 19 32 3 mctx + mmtx versus mctx + mmtx-thalidomide Phase III 86 85 mctx + mmtx-dalteparin- Prednisone Phase I/II 41 17 24 2 12 mctx + mmtx-cxb Phase II 67 0 31 2 8 mctx + mmtx-trastuzumab Phase II 22 18 46 6 mctx-pegylated Doxorubicin Phase II 29 62 96 mctx + CAP Phase II 66 30 53 5 17 21 12 mctx + CAP Phase II 45 44 58 12* Not reached mcap Phase II 60 24 62 7 17 m5fu-eniluracil Phase II 33 48 78 7 mcap-mtxt-cxb Phase II 38 34 42 4 10 mvrl Phase II 34 elderly 38 70 8 16 m5fu-megestrol acetate Phase II 29 31 41 7 13 mctx-letrozole versus Letrozole Phase II R mcap-mctx-bev Phase II 46 48 68 10 57 57 mcap-mctx-bev-erlotinib Phase II 24 62 75 11 25 mcap-mmtx-bev Phase II 24 32 64 7* 14 mvrl-bev Phase II 13 8 54 4* 88 72 41 41 97 95 4 4 18 17 Romiti A et al. Cancer Chemother Pharmacol 2013;72:13 33
Blood Conc (ng/ml) Blood Conc (ng/ml) Vinorelbine orale vs Intra-veineuse: Une «Bioéquivalence» validée. 10000 1000 100 30 mg/m² I.V. versus 80 mg/m² Oral 10000 1000 100 25 mg/m² I.V. versus 60 mg/m² Oral 10 10 1 0 12 24 36 Time (h) 1 0 12 24 36 Time (h) Equivalent AUCs : I.V. Oral 30 mg/m² 80 mg/m² 25 mg/m² 60 mg/m² Marty, Ann. Oncol. 2001
Vinorelbine orale en monothérapie, Schéma Conventionnel. Etude Freyer Etude de phase II multicentrique en 1 ère ligne de CSM (n=64) Schéma thérapeutique: NAVELBINE Oral 60 mg/m 2 /semaine pendant les 3 premières semaines, puis 60 mg/m 2 /semaine selon la toxicité Taux de RO: 31% (Obj principal) PFS: 4,3 mois OS de 23,9 mois Tolérance Enregistrement Freyer, JCO 2003;
Clin Cancer Res 2009;15:6454-6461 3 responders received nonstop treatment for over 3 years without over toxicity. Metronomic administration of oral vinorelbine is feasible at doses up to 50 mg thrice a week
Phase I trial of metronomic oral vinorelbine in patients with advanced cancer Lakshmi Rajdev, Abdissa Negassa, Qun Dai, Gary Goldberg, Kathy Miller, Joseph A. Sparano Cancer Chemother Pharmacol (2011) 68:1119 1124 Oral vinorelbine may be given using a metronomic schedule, 50 mg thrice weekly for three of 4 weeks, with minimal toxicity in patients with advanced cancer.
Vinorelbine orale en schéma métronomique Etude Briasoulis (dose optimale) VRL concentration (ng/ml) Steady state VRL levels over time (all patients) 10 30 mg 40 mg 50 mg 5 0 5 0 2 4 6 8 10 12 16 20 30 36 Briasoulis E et al. BMC Cancer 2013;13:263 10
Progression-free survival (%) Survival (%) Metronomic oral vinorelbine monotherapy has clinical activity as first-line therapy in Breast Cancer Patients. Dosing: 70 mg/m 2 split in 3 doses / week Schedule: days 1, 3, and 5; 3 weeks on/ 1 week off (maximum 12 cycles) Duration: maximum 12 cycles Age > 70 years PFS (median value) = 7.7 months (95% CI: 6.9 9.1) Response measure Number of patients (%) Complete response 2 (6) Partial response 11 (32) Overall response rate 13 (38) No change 11 (32) Disease control rate 23 (68) Progressive disease 10 (29) Total 34 (100) 100 80 60 40 20 0 100 80 60 40 20 Overall survival Median: 15.9 months (95% CI: 13.1 15.9 months) 5 10 15 20 25 Time (months) PFS according to Karnofsky performance status (KPS) >80 KPS 80 KPS P=0.03 0 5 10 15 20 25 Months after treatment Addeo R, Sgambato A, Cennamo G et al. Clin Breast Cancer 2010;10:301 6
Survie sans progression : principaux protocoles de première ligne Anthra adjuvants 30-55% Anthra adjuvants 100% Anthra adjuvants 30-55% Docetaxel Paclitaxel Paclitaxel Docetaxel Paclitaxel Docetaxel Docetaxel & capecitabine Paclitaxel & bévacizumab Paclitaxel & lapatinib Docetaxel & bevacizumab* Paclitaxel & bevacizumab 4,2 3,98 4,2 5,2 3,9 5,9 5,2 5,9 6,1 6,7 7 6,1 7 6,7 8 8 8,8 8,7 8,8 8,7 11,8 11,9 O Shaugnessy 2002 Miller 2007 Dileo 2008 Miles 2008 Albain 2009 Sparano 2009 O Shaugnessy 2002 Miller 2007 Dileo 2008 Miles 2008 Miles 2008 Anthra adjuvants 70% Anthra adjuvants 100% Docetaxel & gemcitabine Docetaxel & capecitabine Paclitaxel & gemcitabine Docetaxel caelyx 6,1 6,14 8,0 7,9 8,05 7,98 9,8 9,8 Chan 2009 Chan 2009 Albain 2008 Sparano 2009 0 2 4 6 8 10 12 * Hors AMM Albain KS, JCO 26:3950 3957 2008 DiLeo A, JCO 26:5544 5552, 2008 O'Shaughnessy J, JCO 20:2812 2823 2002 Miller K, NEJM 357:2666 2676, 2007 Miles, Abstract LBA1011 ASCO 2008 Sparano J, Abstract SABCs 2008 Chan S, J Clin Oncol 1753
Metronomic oral vinorelbine monotherapy is well tolerated as first-line therapy Dosing: 70 mg/m 2 Schedule: Days 1, 3, and 5; 3 weeks on/1 week off (maximum 12 cycles) Duration: maximum 12 cycles Age > 70 years By patient (n=34) (%) By cycle (n=186) (%) Adverse event Grades 1 2 Grade 3 Grade 4 Overall Grades 1 2 Grade 3 Grade 4 Overall Haematological Neutropenia 16 (47) 3 (9) 0 19 (57) 27 (15) 8 (4) 0 35 (19) Anaemia 7 (29) 3 (9) 0 9 (26) 22 (12) 7 (4) 0 60 (16) Thrombocytopenia 4 (12) 1 (3) 0 5 (15) 16 (9) 3 (2) 0 19 (10) Febrile neutropenia 1 (3) 0 1 (3) 7 (4) 2 (1) 0 9 (5) Non-haematological Febrile infection 7 (21) 2 (6) 0 9 (26) 7 (4) 6 (3) 0 13 (7) Diarrhoea 6 (18) 1 (3) 0 7 (21) 7 (4) 1 (5) 0 8 (4) Nausea 14 (41) 1 (3) 0 15 (44) 24 (13) 5 (3) 0 29 (16) Vomiting 6 (17) 1 (3) 0 7 (21) 15 (8) 3 (2) 0 18 (10) Stomatitis 4 (12) 1 (3) 0 5 (15) 9 (5) 0 0 9 (5) Fatigue 4 (12) 0 0 4 (12) 7 (4) 0 0 7 (4) Constipation 4 (12) 0 0 4 (12) 7 (4) 0 0 7 (4) Neuromotor/sensory 2 (6) 0 0 2 (6) 3 (2) 0 0 3 (2) Alopecia 27 (79) 0 0 27 (79) NA 0 0 NA Addeo R, Sgambato A, Cennamo G et al. Clin Breast Cancer 2010;10:301 6
RANDOMISATION Tempo-Breast1 randomized phase II trial ( first-line MBC chemo ) weekly schedule 3-week cycles Oral Vinorelbine 80 mg/m² weekly (first cycle at 60) metronomic schedule Oral Vinorelbine 50 mg total dose 3 times per week continuously MBC ER-positive and HER2-negative Pretreated by hormone therapy Treatment until disease progression