Consorzio Interuniversitario Nazionale per la Bio-Oncologia Dott.ssa Alessandra Santomaggio...

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


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:


10 months (Range months 2-32+)


21 months (Range months 3 – 47+)


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:


12 months (Range months 3+ - 61+)




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) - -


(%)

As Treated analysis


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


(%)

As Treated analysis


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%



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)*





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


13/14

CR2

(15)

PR6

(46)

SD3

(24)

PD2

(15)



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


13/14

CR2

(15)

PR6

(46)

SD3

(24)

PD2

(15)



47

We observed:

Median Progression Free Survival (PFS)*

10 months (Range months 4 - 28)


25 months (Range months 4 - 46+)


Grazie per l’attenzione

Consorzio Interuniversitario Nazionale per la Bio-Oncologia Dott.ssa Alessandra Santomaggio...

Documents

Transcript of Consorzio Interuniversitario Nazionale per la Bio-Oncologia Dott.ssa Alessandra Santomaggio...