consorzio interuniversitario nazionale per la bio-oncologia dott.ssa alessandra santomaggio...
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Consorzio Interuniversitario Nazionale
per la Bio-Oncologia
Dott.ssa Alessandra SantomaggioOncologia medicaP.O. San SalvatoreUniversità Degli Studi Dell’Aquila
28 novembre 2008
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
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.
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
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
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
4 AM
10 AM
10 AM
10 PM
4 PM
5-FU 22-h continous infusion
5-FU bolus
5-FU 2800 mg/mq 46-h continous infusion
LV
LV
LV
5-FU continous infusion
12-h Timed Flat Infusion TFI/5-FU
1 2 3 4
CPT-11 180 mg/m2
5-FU 600-1200 mg/m2/d
h
day
22 10 22 10 22 10 22 10
15 16 17 18
CPT-11 180 mg/m2
Ficorella C Oncol Rep 2006
22 10 22 10 22 10 22 10
As Treated analysis
(%)n. assessable patients
24/33
CR3
(12,5)
PR6
(25)
SD5
(21)
PD10
(41,5)
AsT Overall Response Rate (ORR) 37,5% (α0.05; CI 20)
AsT Disease Control Rate 58,5%
12
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
As Treated analysis
(%)n. assessable patients
37/52
CR3
(8)
PR12
(32)
SD12
(32)
PD10
(28)
AsT Overall Response Rate (ORR) 40% (α0.05; CI 16)
AsT Disease Control Rate 72%
15
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
La migliore tollerabilità di L-OHP si verifica a 16 HALO (hours after light onset) negli animali trattati
4 AM
10 AM
10 AM
10 PM
4 PM
5-FU 22-h continous infusion
5-FU bolus
5-FU 2800 mg/mq 46-h continous infusion
LV
LV
LV
5-FU continous infusion
12-h Timed Flat Infusion TFI/5-FUl-OHP
22 10 22 10
1 2
CPT-11 180 mg/m2
5-FU 800-1300 mg/m2/d
h
day
15 22 10 22 10
8 9
l-OHP 70-80 mg/m2
22 10 22 10
15 16
CPT-11 180 mg/m2
1515 22 10 22 10
22 23
l-OHP 70-80 mg/m2
Submitted
Total N. (%)No. of patients 36Sex M/F 22/14
Age, years median range > 65 years
6239-74
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 RT+CT (5-FU i.c.)
2 (6)-
2 (6)
Dose levels
CPT11 (mg/m2 d1,15)-l-OHP (mg/m2 d8,22)-5-FU (mg/m2/dd1-2, 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 180-70-7002
(2)2 - - - -
II 180-70-8003
(1)3 - - - -
III 180-70-9003
(0)3 - - - -
IV 180-80-9007
(4)12 1/7 (14%) - 1 (8%) G3 Diarrhea
V 180-80-100011(6)
30 3/11 (27%) 3/6 (50%) 3 (10%)
G3 DiarrheaG1 Fever with delay > 2 weeksG3 Hypotension
a intra- and inter-patient dose escalation (Simon R. et al., JNCI 1997)b dose-limiting toxicity
Adverse eventsNCI-CTC grade (%)
per CyclesNCI-CTC grade (%)
per Patients
1 2 3 4 1 2 3 4
Nausea30
(24)12
(9,5)- -
10(43)
6(26)
- -
Vomiting13
(10)11(9)
- -7
(30)6
(26)- -
Diarrhea18
(14)18
(14)11(9)
-3
(13)8
(35)8
(35)-
Stomatitis16
(13)1
(1)- -
6(26)
2(9)
- -
Asthenia33
(26)16
(13)1
(1)-
9(39)
9(39)
1(4)
-
Neurotoxicity54
(43)6
(5)1
(1)-
14(61)
2(9)
1(4)
-
Adverse eventsNCI-CTC grade (%)
per CyclesNCI-CTC grade (%)
per Patients
1 2 3 4 1 2 3 4
Anemia13
(10)3
(2)- -
5(22)
3(13)
- -
Leucopenia19
(15)17
(13)- -
3(13)
8(35)
-1
(4)
Neutropenia10(8)
21(17)
7(5.5)
1(1)
3(13)
6(26)
3(13)
1(4)
Thrombocytopenia10(8)
4(3)
- -3
(13)3
(13)- -
Intention to treat analysis
(%)
Assessable patients
(%)
n. patients
33 30
CR2 (6)
2 (6.7)
PR21
(63.6)18 (60)
SD3 (9)
3 (10)
PD7
(21.2)7
(23.3)
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%
24
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
Autore Fase PtsPDICPT-11mg/m2/w
PDIOXPmg/m2/w
PDI5-FUmg/m2/w
LVmg/m2
G3-4 diarrea(% of pts)
Neutropenia febbrile(% of pts)
RR%
Falcone2002
I 42 87,5 50 1900 48h ic 200 21 14 71.4
Ychou2003
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 -*
Goetz2003
I 35 50 or 58 17 or 28213 b or 320
b 20 16,6 - -*
Abad2004
I 18 75 42,5 1125 48 h ic - 33 - 77
Cals2004
I 34 40 32 2400 24 h ic - - 16,6 50#
Gil-Delgado2004
I 34 90 42,5400 b +
600 22 h ic 200 12,5 12,5 44
Present Study
I-II 29 90 401800TFI
- 37,5 - 57
Bécourarm2001
II 32 45 21,2400 b +
600 22h ic 200 19 13 6#
Calvo2002
II 26 62,5 30 1300 24 h ic 500 34,5 - 69.2
Souglakos2002
II 31 75 32,5400 b +
600 22h ic 200 32 6 58.1
Garufi2003
II 35 60 26.7§ 933§ 150 § 28 - 22.9#
Rosati2004
II 40 44 32,51150 or
900 48 h ic 150 72,2 - 57.5
Masi2004
II 32 82,5 42,5 1600 48 h ic 200 16 34 72
22 10 22 10
1 2
CPT-11 160 mg/m2 Bevacizumab 5 mg/kg
5-FU 900 mg/m2/d
h
day
15 22 10 22 10
8 9
l-OHP 60-70-80 mg/m2
22 10 22 10
15 16
CPT-11 160 mg/m2 Bevacizumab 5 mg/kg
15 22 10 22 10
22 23
l-OHP 60-70-80 mg/m2
Total N. (%)
No. of patients 46Sex M/F 28/18Age, years median range > 65 years
6440-73
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 RT+CT (5-FU i.c.) RT+CT (XELOX)
6 (13)2 (4)3 (6)1 (2)
Dose levels
CPT11 (mg/m2 d1,15)-Bevacizumab (mg/kg d1,15)-l-OHP (mg/m2 d8,22)-5-FU (mg/m2/dd1-2, 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 900-160-5-609
(9)12
1/9(11%)
1/9(11%)
1/12(8%)
G3 Diarrhea
II 900-160-5-7011(3)
11 0/11 0/3 0/11 -
III 900-160-5-8014(3)
411/14(7%)
0/31/41(2%)
G3 MucositisG2 Diarrhea + G2 Hypoalbumin.
a intra- and inter-patient dose escalation (Simon R. et al., JNCI 1997)b dose-limiting toxicity
Patients Cycles
Number 46 196
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) -
Patients Cycles
Number 46 196
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) - -
Intention to treat analysis
(%)
As Treated analysis
(%)n. assessable patients
39 35
CR2 (5)
2 (6)
PR30 (77)
27 (77)
SD2 (5)
2 (6)
PD5
(13)4
(11)
CR complete response; PR partial response; SD stable disease; PD progressive disease1 pt lost to follow-up; 6 pts had not received at least 3 cycles of treatment; 4 pts evaluated after 2 cycles of treatment
Intention to treat analysis
(%)
As Treated analysis
(%)n. assessable patients
39 35
CR2 (5)
2 (6)
PR30 (77)
27 (77)
SD2 (5)
2 (6)
PD5
(13)4
(11)
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%
BEV 5-FU CPT-11 L-OHP
Mediana (range)
Media(C.I.
α 0,05)
Mediana(range)
Media (C.I.
α 0,05)
Mediana
(range)
Media (C.I.
α 0,05)
Mediana (range)
Media (C.I.
α 0,05)
DI/ciclomg/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/pzmg/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)
33
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.
34
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
35
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)
DTX 80-85 mg/mq
5-FU 700-900 mg/mq/d
22 10 22 10 22 10 22 10 22 10
1 2 3 4 5day
h
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.
As Treated analysis
(%)n. assessable patients
13/14
CR2
(15)
PR6
(46)
SD3
(24)
PD2
(15)
AsT Overall Response Rate (ORR) 61% (α0.05; CI 28)
AsT Disease Control Rate 82%
Recommended Dose MTDa
Author pts 5-FUschedule
docetaxelmg/m2
5-FUmg/m2/d
docetaxelmg/m2
5-FUmg/m2/d
DLTb
Petit [22] 37 bolus 60 d1every 4 w
300 d1-3 or d1-5
every 4 w
75 d1 300 d1-3 mucositisneutropenia
Ando [23] 19 C.I. 50 d1every 3 w
500 d1-5every 3 w
60 d1 500 d1-5 diarrheaneutropenia
Lortholary [24] 32 C.I. 85 d1every 3 w
750 d1-5every 3 w
100 d1 750 d1-5 stomatitis
Present study 14 12-h C.I. 85 d1every 3 w
800 d1-5every 3 w
85 d1 900 d1-5 diarrhea
a MTD maximum-tolerated dose b DLT dose-limiting toxicity
n (%)
Number of patientsMedian 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)
12(70)2(11)
Number of organs involved: 1 ≥2
2(12)15(83)
Cycles141
Patients18
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
As Treated analysis
(%)n. assessable patients
13/14
CR2
(15)
PR6
(46)
SD3
(24)
PD2
(15)
AsT Overall Response Rate (ORR) 61% (α0.05; CI 28)
AsT Disease Control Rate 82%
47
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
Grazie per l’attenzione