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Circadian Rhythms and Quality of Life in Breast Cancer: Chronotherapy Experiences

Discover the impact of chronotherapy on breast cancer treatment, explore actigraphy, and new perspectives in cancer care. Learn about innovative treatment timings and their effects on patient health.

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Circadian Rhythms and Quality of Life in Breast Cancer: Chronotherapy Experiences

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  1. Ritmi circadiani e qualita’ di vita: Actigrafia e nuovi orizzonti nel carcinoma della mammella 28 novembre 2008 Esperienze di cronoterapia presso l’ universita’ dell’aquila Dott.ssa Alessandra Santomaggio Oncologia medica P.O. San Salvatore Università Degli Studi Dell’Aquila Consorzio Interuniversitario Nazionale per la Bio-Oncologia

  2. Infusione cronomodulata del 5-FU • la tossicità del 5-FU è maggiore nell’animale da laboratorio quando l’animale è nella fase di attività rispetto alla fase di riposo • incremento della attività a metà notte, nelle cellule mononucleate periferiche dell'uomo, della diidropirimidina deidrogenasi (DPD) • riduzione nell'uomo, della sintesi del DNA da parte delle cellule del midollo osseo e della mucosa orale e gastrointestinale, nella prima metà della notte (tra le ore 24.00 e le ore 4.00) rispetto alla prima metà della fase di attività

  3. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. Levi FA, Zidani R, Vannetzel JM, Perpoint B, Focan C, Faggiuolo R, Chollet P, Garufi C, Itzhaki M, Dogliotti L, et al. J Natl Cancer Inst. 1994 Nov 2;86(21):1608-17.

  4. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Levi F, Zidani R, Misset JL. Lancet. 1997 Sep 6;350(9079):681-6. * p 0,003 § p < 0.0001

  5. 12-hour (from 10 pm to 10 am) Timedflatinfusionof5-fluorouracil withoutfolinic acid Chronomodulatedinfusionof 5-fu 12-h TimedFlatInfusion TFI/5-FU 12-h timedflatinfusion tfi-5fu LV …. 5-FU continousinfusion Flatinfusion LV 5-FU bolus …. 5-FU 22-h continousinfusion De gramont LV …. 5-FU 2800 mg/mq 46-h continousinfusion Modified De gramont 10 AM 4 PM 10 PM 4 AM 10 AM

  6. Treatment scheduleofdoublet “Firi” CPT-11 180 mg/m2 CPT-11 180 mg/m2 5-FU 600-1200 mg/m2/d 22 10 22 10 22 10 22 10 h 22 10 22 10 22 10 22 10 day 1 2 3 4 15 16 17 18 Ficorella C Oncol Rep 2006

  7. Objective tumor responses 12-h tfi-Firi AsT Overall Response Rate (ORR) 37,5% (α0.05; CI  20) AsT Disease Control Rate 58,5%

  8. survival At median follow-up of 17 months, we observed: Median Time to Progression (TTP)* 10 months (Range months 2-28+) Median Overall Survival (OS)* 25 months (Range months 3 - 42) *calculated with method of Kaplan and Meier

  9. Phase i-ii study of 12-h tfi-Firi:objective tumor responses of cumulatively 52 patients AsT Overall Response Rate (ORR) 40% (α0.05; CI  16) AsT Disease Control Rate 72%

  10. survival At median follow-up of 19 months, we observed: Median Time to Progression (TTP)* 10 months (Range months 2-32+) Median Overall Survival (OS)* 21 months (Range months 3 – 47+) *calculated with method of Kaplan and Meier

  11. L-OHP, 5-FU e AF in infusione cronomodulata La migliore tollerabilità di L-OHP si verifica a 16 HALO (hours after light onset) negli animali trattati

  12. 12-hour (from 10 pm to 10 am) Timedflatinfusionof5-fluorouracil withoutfolinic acid and withoxaliplatin Chronomodulatedinfusionofl-ohp Chronomodulatedinfusionof 5-fu l-OHP 12-h TimedFlatInfusion TFI/5-FU 3PM to 5PM timedflatinfusionl-ohp 12-h timedflatinfusion tfi-5fu LV …. 5-FU continousinfusion Flatinfusion LV 5-FU bolus …. 5-FU 22-h continousinfusion De gramont LV …. 5-FU 2800 mg/mq 46-h continousinfusion Modified De gramont 10 AM 4 PM 10 PM 4 AM 10 AM

  13. Treatment scheduleoftriplet “FIr/Fox” CPT-11 180 mg/m2 l-OHP 70-80 mg/m2 CPT-11 180 mg/m2 l-OHP 70-80 mg/m2 5-FU 800-1300 mg/m2/d h 22 10 22 10 15 22 10 22 10 15 22 10 22 10 22 10 22 10 day 1 2 8 9 15 16 22 23 Submitted

  14. CLINICAL FEATURES OF PATIENTS ENROLLED 12-htfi-firfox

  15. Dose-limitingtoxicitiesaccordingto the dose-escalation scheme a intra- and inter-patient dose escalation (Simon R. et al., JNCI 1997) b dose-limiting toxicity

  16. Non Haematolgicaltoxicity(ctcae v 2.0)

  17. Haematological toxicity (ctcae v 2.0)

  18. Phase i-ii study of 12-h tfi-Firfox:objective tumor responses of cumulatively 36 patients ITT Overall Response Rate (ORR) 69.6% (α0.05; CI  16) ITT Disease Control Rate 78.6% AsT Overall Response Rate (ORR) 66.7% (α0.05; CI  17) AsT Disease Control Rate 76.7%

  19. survival With a median follow-up of 19 months (range 1-31), we observed: Median Time to Progression (TTP)* 12 months (Range months 3+ - 61+) Median Overall Survival (OS)* 20 months (Range months 3+ - 61+) *calculated with method of Kaplan and Meier

  20. Phase I and ii studies of cpt-11/l-ohp/5-fu in advanced colorectal cancer

  21. Treatment scheduleof poker (FIr-B/FOx) CPT-11 160 mg/m2Bevacizumab 5 mg/kg l-OHP 60-70-80 mg/m2 CPT-11 160 mg/m2Bevacizumab 5 mg/kg l-OHP 60-70-80 mg/m2 5-FU 900 mg/m2/d h 22 10 22 10 15 22 10 22 10 22 10 22 10 15 22 10 22 10 day 1 2 8 9 15 16 22 23

  22. CLINICAL FEATURES OF PATIENTS ENROLLED 12-htfi-fir-b/fox

  23. Dose-limitingtoxicitiesaccordingto the dose-escalation scheme a intra- and inter-patient dose escalation (Simon R. et al., JNCI 1997) b dose-limiting toxicity

  24. Non Haematolgicaltoxicity(ctcae v 3.0)

  25. Haematological toxicity (ctcae v 3.0)

  26. Objective tumor response CR complete response; PR partial response; SD stable disease; PD progressive disease 1 pt lost to follow-up; 6 pts had not received at least 3 cycles of treatment; 4 pts evaluated after 2 cycles of treatment

  27. Objective tumor responses ITT Overall Response Rate (ORR) 82% (α0.05; CI  12) ITT Disease Control Rate 87% AsT Overall Response Rate (ORR) 83% (α0.05; CI  13) AsT Disease Control Rate 89%

  28. ReceivedDose-intensity BEV 84% of projected D.I. 5-FU 85% of projected D.I. CPT-11 84% of projected D.I. OXP 82% of projected D.I.

  29. survival With a median follow-up of 12 months (range 1-31), we observed: Median Progression Free Survival (PFS)* 12 months (Range months 1+ - 30+) Median Overall Survival (OS)* 28 months (Range months 1+ - 31+) *calculated with method of Kaplan and Meier

  30. Surgeryafter treatment

  31. Treatment scheduleofdTX/FU DTX 80-85 mg/mq 5-FU 700-900 mg/mq/d 1 2 3 4 5 day h 22 10 22 10 22 10 22 10 22 10 10pm-10amTFI traces the 12h circadian-timed infusion of 5-FU (10PM-10AM with maximum delivery at 4AM) and may contribute to increase its tolerability, using an easier administration than the chromodulated infusion.

  32. Phase i study of 12-h tfi-FU/DTx:objective tumor responses AsT Overall Response Rate (ORR) 61% (α0.05; CI  28) AsT Disease Control Rate 82%

  33. Phase I studies of docetaxel in combination with 5-FU in advanced breast cancer a MTD maximum-tolerated dose b DLT dose-limiting toxicity

  34. CLINICAL FEATURES OF PATIENTS ENROLLED 12-htfi-fU/DTX

  35. Haematological and Non Haematolgicaltoxicity (ctcae v 3.0) 2 cases (8%) of thrombosis related to the venous access dev

  36. Phase i study of 12-h tfi-FU/DTx:objective tumor responses AsT Overall Response Rate (ORR) 61% (α0.05; CI  28) AsT Disease Control Rate 82%

  37. survival We observed: Median Progression Free Survival (PFS)* 10 months (Range months 4 - 28) Median Overall Survival (OS)* 25 months (Range months 4 - 46+) *calculated with method of Kaplan and Meier

  38. Grazie per l’attenzione

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