Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
MEDITERRANEAN SCHOOL OF ONCOLOGY Ritmi circadiani e qualità di vita: actigrafia e nuovi orizzonti nel carcinoma della mammella Roma, 28 Novembre 2008 Cronomodulazione e farmaci orali Giuseppe Tonini [email protected] Oncologia Medica Universita’ Campus Bio-Medico, Roma Chronobiology Chronobiology is the study of the temporal relationships of biological phenomena Rhythms that fluctuate on a 24-hour time scale are known as circadian rhythms. The best-known circadian rhythms body temperature hormone secretion metabolism sleep/wake cycle Physiology of Circadian Rhythmicity Prominent daily variations also occur in endocrine, thermoregulatory, cardiac, pulmonary, renal, gastrointestinal, neurobehavioral functions Harrison 3 Circadian rhytms in colorectal cancer patients Mormont MC et al, Chronobiol Int 2002 Properties of circadian rythms Ubiquitous (cyanobacterias, plants, rodents, humans) Endogenous (persist in the absence of environmental cycles) Circadian clock genes Circadian gene expression In vitro circadian expression of cell cycle genes Delaunay F et al, J Biol Chem 2001 Functional classes of cycling transcripts in cultured rat fibroblasts Delaunay F et al, J Biol Chem 2001 Chronobiology: implications for cancer therapy Chronotherapy aims to adapt the timing of drug administration according to the circadian rhythms of cancer and normal cells. Administration of drug at a circadian time when it is best tolerated can achieve best antitumour activity. Mormont and Levi, Cancer 2003 Chronobiology: implications for cancer therapy Circadian rhythms in anticancer drug tolerability in laboratory mice or rats. The least toxic dosing time is indicated as a function of the rest-activity cycle. Mormont and Levi, Cancer 2003 How administer chronotherapy: the multichannel pump Centralized programmation Any modulation of delivery rate 4 reservoirs (100-2000 ml) Rates from 1 to 3000 ml/h Safeties Alarms Very expensive!!!! New advances in chronotherapy Phase I, II, III trials are on-going and the results are interesting!!!! Oxaliplatin and capecitabine in vitro synergistic effect Chronomodulated Capecitabine Capecitabine Weekly infusion of oxaliplatin Phase II studies with weekly or biweekly oxaliplatin have demonstrated low levels of toxicity and high clinical activity (Rosati G, Ann Oncol. 2001 and Oncology, 2004; Santini D, Medical Oncology, 2004; Scheithauer W, Ann Oncol, 2003; Kemeny N, Ann Oncol, 2002; Chao Y et al, Br J cancer, 2004) The weekly oxaliplatin schedule leads to a higher dose-density and a higher total dose administered (Rosati G, Ann Oncol. 2001; Santini D, Medical Oncology, 2004) The weekly oxaliplatin schedule may lead to a better and more continous synergistic action with capecitabine administered for 14 days Toxicity and efficacy of chronomodulated chemotherapy Metastatic colorectal cancer (Folinic Acid, 5-FU, Oxaliplatin) Infusion flow Constant Chrono p Toxicity Oral mucositis gr 3-4 Neuropathy gr 2-3 Responding rate 74% 31% 30% 14% <10-4 16% <10-2 51% <10-3 Lévi et al. JNCI 1994 ; Lancet 1997 ; Lancet Onc 2001 Chronotherapy trials in metastatic breast cancer Author Phase Regimen Pts Results DepresBrummer et al (1995) I Mitoxantrone, 5FU/AF 18 Neutropenia was the most frequent toxicity (G3: 4 pts; G4: 7 pts), G3 mucositis: 1 pts; No G3/4 diarrhea, nausea, or vomiting. Coudert et al (2008) I Vinorelbine. 5FU (8 chrono schedules) 90 No significant results regarding an optimal time for vinorelbine administration Experiences of chronomodulated chemotherapy at Campus BioMedico Continuous infusion of oxaliplatin plus chronomodulated capecitabine in 5-fluorouracil- and irinotecan-resistant advanced colorectal cancer patients. Santini D, Vincenzi B, La Cesa A, Caricato M, Schiavon G, Spalletta B, Di Seri M, Coppola R, Rocci L and Tonini G. Oncology. 2005;69(1):27-34. Chronomodulated administration of oxaliplatin plus capecitabine (XELOX) as first line chemotherapy in advanced colorectal cancer patients: phase II study. Santini D, Vincenzi B, Schiavon G, Di Seri M, Virzi V, Spalletta B, Caricato M, Coppola R and Tonini G. Cancer Chemother Pharmacol. 2007 Apr;59(5):613-20. Treatment schedule Chronomodulated XELOX C.I. Oxaliplatin (70 mg/mq) Chronomodulated Capecitabine (2000 mg/mq) 1 8 8 a.m.-8 p.m. 8 a.m.-8 p.m. X X 15 21 X Treatment schedule Capecitabine chronomodulation 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% % dose 8 a.m. 6 p.m. 11 p.m. Patients characteristics Number of patients (%) 62 (100%) First line 26 Other lines 36 1-2 previous lines Median age, years (range) 16-20 65 (32-77) Male/Female 32/30 ECOG 0/1/2 36/22/4 Colon/rectal (%) 68/32 Single/> 1 metastatic sites (%) 48/52 >2 metastatic sites(%) 27.1% Metastatic sites (%) liver/lung 68.7/47.9 Best confirmed responses in first line chemotherapy (% patients) N Pts (%) 26 % cCR 2 7.7% cPR 15 57.7% RR% 17 65,4% cSD 7 26.9% cPD 2 7.7% D Stab. 24 92.3% Best confirmed responses in other lines of chemotherapy (% patients) N Pts (%) 36 (100%) CR 0 (0%) PR 11 (30.6%) SD 13 (36.1%) PD 12 (33.3%) CR-PR 11 (30.6%) Disease stabilization 24 (66.6%) (CR-PR-SD) Survival data in first line chemotherapy N Pts 26 Months (95% C.I.) Progression free survival 9.66 (6.88 - 12.45) Median survival 19.74 (15.92–23.56) 1-year survival rate 84.6% (22 Pts) Survival data in other lines of chemotherapy N Pts 36 Months (range) Progression free survival 6.7 (4.9-8.4) Median survival 11.3 (6.6-13.1) 1-year survival rate 53.8% Safety results (after dose reduction) toxicity per patient (47 patients) NCI Gr 3 Thrombocytopenia Neutropenia % patients 0 6.1 Febrile neutropenia 0 Anemia 0 Asthenia 21.2 Diarrhea 12.1 Stomatitis 3 Vomiting 6.1 Hand foot syndrome 3.0 Alopecia (Gr2) 3.0 Liver 3.0 Conclusions With high activity and good tolerability, chronomodulated XELOX compares favorably with standard XELOX High RR% in first and other lines TTP in first line comparable with the best schedules Favorable median survival Responses in oxaliplatin-pretreated patients Low incidence of severe neurotoxicity and hand foot syndrome Low incidence of severe diarrhea after dose reduction of capecitabine Bevacizumab plus chronomodulated capecitabine as first-line advanced colorectal cancer patients. (Unpublished data) Schedule Oxaliplatin: 70m/mq (gg 1-8q21) Bevacizumab: 7,5 mg/mq (gg1q21) Capecitabine: 1750 mg/mq (gg1-14q21): ¼ h 8, ¼ h 18, ½ h 23. Patients’ characteristics Total 19 Median Age 57 100% Primary Tumor Colon 10 52,6% Rectal 9 47,4% 1 9 47,4% 2 5 26,3% ≥3 5 26,3% Liver 13 Abdominal Lymph nodes 7 Lung 6 Peritoneum 5 Number of metastatic sites Metastasis localization Toxicity Toxicity Pts (%) Grade 1 Grade 2 Grade 3 Grade 4 Any Grade Hematological Anemia 6 (31,5) 1 (5,3) 1 (5,3) 0 8 (42,1) Leucopenia 3 (15,8) 1 (5,3) 0 0 4 (21) Neutropenia 0 4 (21) 1 (5,3) 0 5 (26,3) 4 (21) 0 1 (5,3) 0 5 (26,3) Thrombocytopenia Non Hematological Nausea/vomiting 4 (21) 5 (26,4) 0 0 9 (47,4) Stomatitis 10 (52,6) 1 (5,3) 1 (5,3) 0 12 (63,2) Neurotoxicity 14 (73,6) 3 (15,8) 1 (5,3) 0 18 (92,7) Diarrhea 7 (36,8) 2 (10,6) 3 (15,8) 0 12 (63,2) Asthenia 7 (36,8) 7 (36,8) 2 (10,6) 0 16 (84,2) H-F syndrome 6 (13,1) 1 (2,2) 0 0 7 (15,3) Hepatotoxicity 1 (5,2) 3 (15,8) 1 (5,3) 1 (5,3) 6 (31,4) Efficacy Pts (%) 1 (8,4%) 5 (41,6%) 3 (25%) 3 (25%) CR PR SD PD Response Duration Median 7 months 95% C.I. 4,987-9,899 TTP Median 9 months 95% C.I. 8,101-9,899 OS Not reached RR 6 (50%) DCR 9 (75%) Phase I study of intermittent and chronomodulated oral therapy with capecitabine in patients with advanced and/or metastatic cancer. Santini D, Vincenzi B, Schiavon G, La Cesa A, Gasparro S, Vincenzi A and Tonini G. BMC Cancer. 2006; 24;6:42 Schedules and end-points Schedule: Capecitabine 1500-2750 mg/mq (gg1-14q21): ¼ h 8, ¼ h 18, ½ h 23. Endpoints: • Maximum-tolerated dose • Dose-limiting toxicities • Safety Patients’ characteristics Results Most common toxicities: fatigue, diarrhoea and hand foot syndrome. Only 1/9 pts treated at capecitabine dose of 2,750 mg/m2 had DLT toxicities (fatigue G4). No other episodes of DLT were observed at the same dose steps and at lower doses of capecitabine. The dose of 2,750 mg/m2 is recommended for further study. Tumor responses were observed in patients with metastatic breast (6 PR) and colorectal cancer (3 PR). Conclusions Conclusions Circadian rhythms modulate cell functions relevant for: - anticancer agent pharmacology - Cancer processes New advances in cancer chronotherapy : • Programmable drug delivery devices • Relevance shown in Phase I, II & III clinical trials Conclusions In our experience chronomodulated chemotherapy is effective and well tolerated Our results clearly highlight the need for new trials to verify the real clinical impact of this new way of chronomodulated capecitabine administration in combination with other active drugs in solid tumors. Oncologia Medica Università Campus Bio-Medico, Roma Giuseppe Tonini Daniele Santini Bruno Vincenzi Annalisa La Cesa Claudia Grilli Sara Galluzzo Simona Gasparro Vladimir Virzì Gaia Schiavon Valentina Leoni Marianna Silletta Francesco Pantano Maria Elisabetta Fratto Alice Calvieri Olga Venditti Chiara Spoto Salvatore Intagliata Calogero Gucciardino Laura Rocci Federica Uzzalli Marzia Mazzaroni