Ritmi circadiani e qualita

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Esperienze di cronoterapia presso l universita
dellaquila

• Ritmi circadiani e qualita di vita Actigrafia e
  nuovi orizzonti nel carcinoma della mammella

28 novembre 2008
Dott.ssa Alessandra Santomaggio Oncologia
medica P.O. San Salvatore Università Degli Studi
DellAquila
Consorzio Interuniversitario Nazionale per la
Bio-Oncologia
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Infusione cronomodulata del 5-FU

• la tossicità del 5-FU è maggiore nellanimale da
  laboratorio quando lanimale 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

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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 286(21)1608-17.
CRONO FLAT
5-FU 600-700 l-OHP 20-25 AF 300 5 gg 3 w 5-FU 600-700 l-OHP 20-25 AF 300 5 gg 3 w
45 patients 47 patients
G3-4 Stomatitis 18 G3-4 Stomatitis 89
HF s. 4 HF s. 11
5-FU median dose 700 5-FU median dose 500
RR 53 TTP 11 OS 19 RR 32 TTP 8 OS 14.9
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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
6350(9079)681-6.
CRONO FLAT
5-FU 700 l-OHP 25 AF 300 5 gg 3 w 5-FU 700 l-OHP 25 AF 300 5 gg 3 w
93 pazienti 93 pazienti
G3-4 Stomatitis 14 G3-4 Stomatitis 76
Neurotoxicity 16 Neurotoxicity 31
5-FU median dose 700 5-FU median dose 500
RR 51 TTP 10 OS 16 RR 29 TTP 8 OS 17
p 0,003 p lt 0.0001
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12-hour (from 10 pm to 10 am) Timed flat infusion
of 5-fluorouracil without folinic acid
.
.
.
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Treatment schedule of doublet 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
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Objective tumor responses 12-h tfi-Firi
As Treated analysis ()
n. assessable patients 24/33
CR 3 (12,5)
PR 6 (25)
SD 5 (21)
PD 10 (41,5)
AsT Overall Response Rate (ORR) 37,5 (a0.05 CI
? 20) AsT Disease Control Rate 58,5
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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
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Phase i-ii study of 12-h tfi-Firiobjective
tumor responses of cumulatively 52 patients
As Treated analysis ()
n. assessable patients 37/52
CR 3 (8)
PR 12 (32)
SD 12 (32)
PD 10 (28)
AsT Overall Response Rate (ORR) 40 (a0.05 CI ?
16) AsT Disease Control Rate 72
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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
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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
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12-hour (from 10 pm to 10 am) Timed flat infusion
of 5-fluorouracil without folinic acid and with
oxaliplatin
.
.
.
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Treatment schedule of triplet 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
22 10 22 10
h
15 22 10 22 10
15 22 10 22 10
22 10 22 10
day
1 2
8 9
15 16
22 23
Submitted
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CLINICAL FEATURES OF PATIENTS ENROLLED 12-h
tfi-firfox
Total N. ()
No. of patients 36
Sex M/F 22/14
Age, years median range gt 65 years 62 39-74 14 (39)
WHO Performance Status 0 1-2 30 (83) 6 (17)
Primary tumor colon rectum 26 (72) 10 (28)
No. of involved sites 1 ? 2 26 (72) 10 (28)
Sites of metastases liver lung lynph nodes local Other 22 (61) 8 (22) 7 (19) 4 (11) 6 (17)
Liver metastases single Multiple 3 (8) 19 (53)
Previous adjuvant chemotherapy FA/5-FU bolus 5-FU bolus i.c. Irinotecan/5FU 9 (25) 6 (17) 2 (6) 1 (3)
Previous radiotherapy RT alone RTCT (5-FU i.c.) 2 (6) - 2 (6)
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Dose-limiting toxicities according to the
dose-escalation scheme
Dose levels CPT11 (mg/m2 d1,15)- l-OHP (mg/m2 d8,22)- 5-FU (mg/m2/d d1-2, 8-9, 15-16, 22-23) No. patientsa (new patients) No. cycles No. Patients with DLTb/total patients () No. New patients with DLT/new patients () No. cycles with DLT/total cycles () DLTs
I 180-70-700 2 (2) 2 - - - -
II 180-70-800 3 (1) 3 - - - -
III 180-70-900 3 (0) 3 - - - -
IV 180-80-900 7 (4) 12 1/7 (14) - 1 (8) G3 Diarrhea
V 180-80-1000 11 (6) 30 3/11 (27) 3/6 (50) 3 (10) G3 Diarrhea G1 Fever with delay gt 2 weeks G3 Hypotension
a intra- and inter-patient dose escalation
(Simon R. et al., JNCI 1997) b dose-limiting
toxicity
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Non Haematolgical toxicity (ctcae v 2.0)
Adverse events NCI-CTC grade () per Cycles NCI-CTC grade () per Cycles NCI-CTC grade () per Cycles NCI-CTC grade () per Cycles NCI-CTC grade () per Patients NCI-CTC grade () per Patients NCI-CTC grade () per Patients NCI-CTC grade () per Patients
1 2 3 4 1 2 3 4
Nausea 30 (24) 12 (9,5) - - 10 (43) 6 (26) - -
Vomiting 13 (10) 11 (9) - - 7 (30) 6 (26) - -
Diarrhea 18 (14) 18 (14) 11 (9) - 3 (13) 8 (35) 8 (35) -
Stomatitis 16 (13) 1 (1) - - 6 (26) 2 (9) - -
Asthenia 33 (26) 16 (13) 1 (1) - 9 (39) 9 (39) 1 (4) -
Neurotoxicity 54 (43) 6 (5) 1 (1) - 14 (61) 2 (9) 1 (4) -
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Haematological toxicity (ctcae v 2.0)
Adverse events NCI-CTC grade () per Cycles NCI-CTC grade () per Cycles NCI-CTC grade () per Cycles NCI-CTC grade () per Cycles NCI-CTC grade () per Patients NCI-CTC grade () per Patients NCI-CTC grade () per Patients NCI-CTC grade () per Patients
1 2 3 4 1 2 3 4
Anemia 13 (10) 3 (2) - - 5 (22) 3 (13) - -
Leucopenia 19 (15) 17 (13) - - 3 (13) 8 (35) - 1 (4)
Neutropenia 10 (8) 21 (17) 7 (5.5) 1 (1) 3 (13) 6 (26) 3 (13) 1 (4)
Thrombocytopenia 10 (8) 4 (3) - - 3 (13) 3 (13) - -
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Phase i-ii study of 12-h tfi-Firfoxobjective
tumor responses of cumulatively 36 patients
Intention to treat analysis () Assessable patients ()
n. patients 33 30
CR 2 (6) 2 (6.7)
PR 21 (63.6) 18 (60)
SD 3 (9) 3 (10)
PD 7 (21.2) 7 (23.3)
ITT Overall Response Rate (ORR) 69.6 (a0.05 CI
? 16) ITT Disease Control Rate 78.6 AsT Overall
Response Rate (ORR) 66.7 (a0.05 CI ? 17) AsT
Disease Control Rate 76.7
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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
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Phase I and ii studies of cpt-11/l-ohp/5-fu in
advanced colorectal cancer
Autore Fase Pts PDI CPT-11 mg/m2/w PDI OXP mg/m2/w PDI 5-FU mg/m2/w LV mg/m2 G3-4 diarrea ( of pts) Neutropenia febbrile ( of pts) RR
Falcone 2002 I 42 87,5 50 1900 48h ic 200 21 14 71.4
Ychou 2003 I 34 90 42,5 400 b 600 22 h ic or 400 b 2400 46 h ic 200 or 400 25-28 25-14 -
Goetz 2003 I 35 50 or 58 17 or 28 213 b or 320 b 20 16,6 - -
Abad 2004 I 18 75 42,5 1125 48 h ic - 33 - 77
Cals 2004 I 34 40 32 2400 24 h ic - - 16,6 50
Gil-Delgado 2004 I 34 90 42,5 400 b 600 22 h ic 200 12,5 12,5 44
Present Study I-II 29 90 40 1800 TFI - 37,5 - 57
Bécourarm 2001 II 32 45 21,2 400 b 600 22h ic 200 19 13 6
Calvo 2002 II 26 62,5 30 1300 24 h ic 500 34,5 - 69.2
Souglakos 2002 II 31 75 32,5 400 b 600 22h ic 200 32 6 58.1
Garufi 2003 II 35 60 26.7 933 150 28 - 22.9
Rosati 2004 II 40 44 32,5 1150 or 900 48 h ic 150 72,2 - 57.5
Masi 2004 II 32 82,5 42,5 1600 48 h ic 200 16 34 72
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Treatment schedule of poker (FIr-B/FOx)
CPT-11 160 mg/m2 Bevacizumab 5 mg/kg
l-OHP 60-70-80 mg/m2
CPT-11 160 mg/m2 Bevacizumab 5 mg/kg
l-OHP 60-70-80 mg/m2
5-FU 900 mg/m2/d
22 10 22 10
h
15 22 10 22 10
22 10 22 10
15 22 10 22 10
day
1 2
8 9
15 16
22 23
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CLINICAL FEATURES OF PATIENTS ENROLLED 12-h
tfi-fir-b/fox
Total N. ()
No. of patients 46
Sex M/F 28/18
Age, years median range gt 65 years 64 40-73 23 (50)
WHO Performance Status 0 1-2 44 (96) 2 (4)
Primary tumor colon rectum 22 (48) 24 (52)
No. of involved sites 1 ? 2 26 (57) 20 (43)
Sites of metastases liver lung lynph nodes local Other 31 (67) 11 (24) 17 (37) 9 (19) 5 (11)
Liver metastases single Multiple 10 (22) 21 (46)
Previous adjuvant chemotherapy FA/5-FU bolus Capecitabine Folfox4 9 (19) 4 (9) 1 (2) 4 (9)
Previous radiotherapy RT alone RTCT (5-FU i.c.) RTCT (XELOX) 6 (13) 2 (4) 3 (6) 1 (2)
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Dose-limiting toxicities according to the
dose-escalation scheme
Dose levels CPT11 (mg/m2 d1,15)- Bevacizumab (mg/kg d1,15)- l-OHP (mg/m2 d8,22)- 5-FU (mg/m2/d d1-2, 8-9, 15-16, 22-23) No. patientsa (new patients) No. cycles No. Patients with DLTb/total patients () No. New patients with DLT/new patients () No. cycles with DLT/total cycles () DLTs
I 900-160-5-60 9 (9) 12 1/9 (11) 1/9 (11) 1/12 (8) G3 Diarrhea
II 900-160-5-70 11 (3) 11 0/11 0/3 0/11 -
III 900-160-5-80 14 (3) 41 1/14 (7) 0/3 1/41 (2) G3 Mucositis G2 Diarrhea G2 Hypoalbumin.
a intra- and inter-patient dose escalation
(Simon R. et al., JNCI 1997) b dose-limiting
toxicity
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Non Haematolgical toxicity (ctcae v 3.0)
Patients Patients Patients Patients Cycles Cycles Cycles Cycles
Number 46 46 46 46 196 196 196 196
NCI-CTC Grade 1 2 3 4 1 2 3 4
Nausea () 22 (48) 12 (26) 3 (7) - 66 (34) 19 (10) 4 (2) -
Vomiting () 9 (20) 6 (13) 2 (4) - 18 (9) 9 (5) 2 (1) -
Diarrhea () 19 (41) 13 (28) 11 (24) - 58 (30) 26 (13) 12 (6) -
Hypoalbuminemia () 2 (4) 1 (2) - - 2 (1) 1 (0.5) - -
Constipation () 15 (33) 1 (2) - - 20 (10) 1 (0.5) - -
Stomatitis/mucositis () 14 (30) 2 (4) 3 (6.5) - 24 (12) 3 (1.5) 3 (1.5) -
Erythema () 1 (2) - 1 (2) - 3 (1.5) - 1 (0.5) -
Asthenia () 11 (24) 19 (41) 2 (4) - 32 (16) 30 (15) 2 (1) -
Neurotoxicity () 31 (67) 5 (11) - - 101 (52) 6 (3) - -
Hypertension () 12 (26) 4 (9) 1 (2) - 22 (11) 4 (2) 1 (0.5) -
Hypotension () 1 (2) - - - 1 (0.5) - - -
Hematuria () 2 (4) 1 (2) - - 3 (1.5) 1 (0.5) - -
Gengival recession/gengivitis () 7 (15) - - - 10 (5) - - -
Rhinitis () 32 (70) - - - 86 (44) - - -
Epistaxis () 25 (54) 2 (4) - - 59 (30) - - -
HFS () 1 (2) - - - 1 (0.5) - - -
Headache () 5 (11) - - - 8 (4) - - -
Hypokalemia () 3 (6.5) 1 (2) - - 2 (1) - 1 (0.5) -
Hypertransaminasemy () 3 (6.5) 1 (2) 1 (2) 1 (2) 7 (15) 3 (1.5) 1 (0.5) 1 (0.5)
Hyperpigmentation () 6 (13) 2 (4) - - 11 (6) 2 (1) - -
Fever without infection () 10 (22) - - - 11 (6) - - -
Alopecia () 3 (6.5) 8 (17) 2 (4) - 7 (4) 12 (6) 5 (3) -
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Haematological toxicity (ctcae v 3.0)
Patients Patients Patients Patients Cycles Cycles Cycles Cycles
Number 46 46 46 46 196 196 196 196
NCI-CTC Grade 1 2 3 4 1 2 3 4
Anemia () 7 (15) 1 (2) - - 13 (7) 1 (0.5) - -
Leucopenia () 12 (26) 11 (24) - - 37 (19) 16 (8) - -
Neutropenia () 8 (17) 11 (24) 4 (9) - 28 (14) 18 (9) 7 (4) -
Trhombocitopeny () 5 (11) 1 (2) - - 14 (7) 1 (0.5) - -
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Objective tumor response
Intention to treat analysis () As Treated analysis ()
n. assessable patients 39 35
CR 2 (5) 2 (6)
PR 30 (77) 27 (77)
SD 2 (5) 2 (6)
PD 5 (13) 4 (11)
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
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Objective tumor responses
Intention to treat analysis () As Treated analysis ()
n. assessable patients 39 35
CR 2 (5) 2 (6)
PR 30 (77) 27 (77)
SD 2 (5) 2 (6)
PD 5 (13) 4 (11)
ITT Overall Response Rate (ORR) 82 (a0.05 CI ?
12) ITT Disease Control Rate 87 AsT Overall
Response Rate (ORR) 83 (a0.05 CI ? 13) AsT
Disease Control Rate 89
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Received Dose-intensity
BEV BEV 5-FU 5-FU CPT-11 CPT-11 L-OHP L-OHP
Mediana (range) Media (C.I. a 0,05) Mediana (range) Media (C.I. a 0,05) Mediana (range) Media (C.I. a 0,05) Mediana (range) Media (C.I. a 0,05)
DI/ciclo mg/m2(Kg)/w 2,25 (1-2,5) 2,1 (? 0,06) 1575 (720-1800) 1519 (? 47,1) 72 (25-80) 68 (? 2,1) 35 (14-40) 33 (?1,05)
DI/pz mg/m2(Kg)/w 2,1 (1,7-2,5) 2 (? 0,08) 1530 (955-1800) 1514 (? 66) 67 (50-80) 68 (? 2,9) 33 (21-38) 32 (?1,45)
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.
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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
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Surgery after treatment
Total N. ()
No. of patients 6/46 (13)
Sites liver single multiple liver and lung primary tumor and lymph nodes 3/6 (50) 2/3(67) 1/3 (33) 1/6 (17) 2/6 (33)
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Treatment schedule of dTX/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.
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Phase i study of 12-h tfi-FU/DTxobjective tumor
responses
As Treated analysis ()
n. assessable patients 13/14
CR 2 (15)
PR 6 (46)
SD 3 (24)
PD 2 (15)
AsT Overall Response Rate (ORR) 61 (a0.05 CI ?
28) AsT Disease Control Rate 82
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Phase I studies of docetaxel in combination with
5-FU in advanced breast cancer
Recommended Dose Recommended Dose MTDa MTDa
Author pts 5-FU schedule docetaxel mg/m2 5-FU mg/m2/d docetaxel mg/m2 docetaxel mg/m2 5-FU mg/m2/d DLTb
Petit 22 37 bolus 60 d1 every 4 w 300 d1-3 or d1-5 every 4 w 75 d1 75 d1 300 d1-3 mucositis neutropenia
Ando 23 19 C.I. 50 d1 every 3 w 500 d1-5 every 3 w 60 d1 60 d1 500 d1-5 diarrhea neutropenia
Lortholary 24 32 C.I. 85 d1 every 3 w 750 d1-5 every 3 w 100 d1 100 d1 750 d1-5 stomatitis
Present study 14 12-h C.I. 85 d1 every 3 w 800 d1-5 every 3 w 85 d1 85 d1 900 d1-5 diarrhea
a MTD maximum-tolerated dose b DLT dose-limiting
toxicity
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CLINICAL FEATURES OF PATIENTS ENROLLED 12-h
tfi-fU/DTX
n ()
Number of patients Median age Range 18(100) 59 48-74
WHO performance status 0 ? 1 15(83) 3(16)
Surgery Mastectomy Lumpectomy 6(33) 12(68)
Adjuvant therapy Chemotherapy with anthracyclines Chemotherapy without anthracyclines Hormonal therapy Radiotherapy 9(53) 5(30) 5(30) 7(40)
Previous metastatic breast cancer therapy Hormonal therapy 2(13)
Disease sites Soft tissue and skin Liver Lung and pleura Bone Brain 1(6) 9(50) 9(50) 1 2(70) 2(11)
Number of organs involved 1 2 2(12) 15(83)
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Haematological and Non Haematolgical toxicity
(ctcae v 3.0)
Cycles 141 Cycles 141 Cycles 141 Cycles 141 Patients 18 Patients 18 Patients 18 Patients 18
Grade 1 2 3 4 1 2 3 4
Fever () - 4 (3) - - - 3 (23) - -
Neutropenia () 1 (1) 12 (8) 24 (17) 29 (20) - 1 (5) 2 (11) 13 (76)
Leucopenia () 4 (3) 20 (16) 28 (19) 8 (5) 1 (5) 1 (5) 9 (52) 5 (29)
Anemia () 8 (6) 1 (1) - - 4 (23) 1 (5) - -
Nausea () 11 (9) 5 (4) - - 4 (23) 4 (23) - -
Vomiting () 3 (2) 2 (1) - - 2 (11) 2 (11) - -
Diarrhea () 4 (3) 2 (1) - - 4 (23) 2 (11) - -
Stomatitis () 7 (5) 7 (5) 3 (2) 1 (1) 2 (11) 4 (23) 3 (17) 1 (1)
Neurotoxicity () 2 (1) - - - 2 (11) - - -
Dermatitis () - 2 (1) - - - 2 (11) - -
Fluid retention () 5 (4) - - - - 3 (17) - -
Asthenia () 1 (1) - - - - 1 (5) - -
Cardiotoxicity () - - - - - - - -
2 cases (8) of thrombosis related to the venous
access dev
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Phase i study of 12-h tfi-FU/DTxobjective tumor
responses
As Treated analysis ()
n. assessable patients 13/14
CR 2 (15)
PR 6 (46)
SD 3 (24)
PD 2 (15)
AsT Overall Response Rate (ORR) 61 (a0.05 CI ?
28) AsT Disease Control Rate 82
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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
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Grazie per lattenzione