Download 2010-01-05 Seminar 5FU

2010/01/05
F1 吳教恩醫師
VS 陳仁熙醫師
 Introduction of 5-FU
 Beginning ~ FDA approval
 1960s, 1970s, Bolus 5FU (and Oral 5FU)
 1980s, Infusional 5-FU
 1990s, Modulated 5-FU
 Dose intensity
 Pharmacokinetics
 About the future
去氧核醣核酸
A
T
核醣核酸
C
G
U
 5-FU is an analogue of uracil with a fluorine atom at the
C-5 position in place of hydrogen.
80-85%
Shoft half-life:8-14min
TS: thymidylate synthase
CH2THF: 5,10-methylenetetrahydrofolate
de novo pathway
去氧
加磷
加磷
Ternary complex
加磷
加磷
Daniel B. Longley et al, Nature 2003
1954
1957
1958
1960
1962
 Rat hepatomas used the uracil more rapidly than normal
tissues
Rutman, R. J., et al, Cancer Res. 14, 119 (1954).
1954
1957
1958
1960
1962
Charles Heidelberger
1920/12/23-1983/01/18
Uracil
5-Fluorouracil
Heidelberger C , et al, Nature 179(4561):663-666, 1957.
1954
1957
1958
1960
1962
0.25 mg/kg/day X 5
↓
↓
↓
Much ↑
toxicity
15 mg/kg/day X 5
Toxicity?
None
↓
15 mg/kg/day X 7
↓
15 mg/kg/day X 5 
7.5mg/kg/day q3d until mild
slight but definite stomatitis
or bone marrow depression
Mild to Moderate
↓
15 mg/kg/day X 5
Severe toxicity
Interval: 30 days, until PD
Curreri, A. K, et. al, Cancer Res. 18:478-484. 1958.
1954
1957
1958
1960
1962
1. < 8 mg/kg/day x 5: minimal toxic effects.
2. 15 mg/kg/day x 5: no severe toxicity
3. The two deaths in this series might have
been avoided if stomatitis had been used as a
guide for termination of therapy.
Curreri, A. K, et. al, Cancer Res. 18:478-484. 1958.
1954
1957
1958
1960
1962
 Toxicity: relatively short duration once the drug is withdrawn
Curreri, A. K, et. al, Cancer Res. 18:478-484. 1958.
1954
1957
1958
1960
1962
Tumor regression was noted only in those
patients manifesting severe toxicity
9 / 35 receiving adequate therapeutic dosage
showed objective regression of neoplasms
Curreri, A. K, et. al, Cancer Res. 18:478-484. 1958.
1954
1957
1958
1960
1962
 Brennan confirmed the results in 155 patient.
Brennan, hl. J., et al Cancer Chmiothrr. Rep. 6.8- I I. 1960.
1954
1957
1958
1960
1962
 Approval of flourouracil (5FU) for the palliative treatment of
colon, rectal, breast, gastric, and pancreatic cancers.
 Because the patent on 5FU expired and generic versions of
5FU are available, drug companies have not submitted data to
update the 5FU drug label for additional indications.
 5FU use is, however, described in the labels of other drugs for
adjuvant, first-line and subsequent therapies for colorectal
cancer, in combination with leucovorin, levamisole, camptosar
or oxaliplatin.
Adjuvant
First-Line
Recurrent
-Levamisole
(with 5FU)
-Leucovorin
(with 5FU)
-Irinotecan
1990
1991
1996,1998
-Irinotecan
(with 5FU/LV)
-Oxaliplatin
(with 5FU/LV)
2000
2002
-Capecitabine
2001
Less toxic regimen
1962
1977
1964
 1,091 patient in past 5 yrs, slight toxicity
 428 measurable lesions, 91 improve, mean TTP: 9 m
 Most responsive: Cancer of the breast, colon or rectum,
stomach, cervix, ovary, and malignant hepatoma
 Unresponsive: SqCC of H&N, carcinoma of the lung,
hypernephroma, and malignant melanoma
Ansfield, F. J., et al, JAMA 181 :295-299. 1962.
1962
1977
1964
 In 1962, 1091 patients, 15mg/kg/day x 5 followed by
7.5g/kg/day q2-3d
 Maximum mortality rate of 2.9%
 12mg/kg/day x 5 followed by 6mg/kg/day q2-3d
 1/202 toxic death (0.5%)
 as good remission rate as 15mg/kg/day
Ansfeld, F. J., JAMA 190:686-688. 1964.
Weekly 5FU with loading dose
1962
1.
2.
Toxicity is necessary
for efficacy
1977
15 mg/kg/day X 4-5
↓
7.5 mg/kg/day q3d
Weekly regimen
↓
WBC < 4000
Resting
↓
WBC > 4000
↓
15 mg/kg/day BIW
↓
15 mg/kg/day QW
Loading dose
Weekly
bolus
Kuchlin, D. B, et al, Ann.. Surg . 156:105-113, 1962.
Weekly 5FU without loading dose
1962
1964
WCCCG study
548 patients
disseminated cancer
5-FU IV weekly
without a loading dose
15 mg/kg weekly x 4
↓
Single dose ≦ 1000mg
20 mg/kg weekly x 4
Response
Toxicity
Keep adequate dose
Toxicity
1977
1971
↓ dose 5mg/kg
Relapse
↑ dose
Jacobs. E. M., Cancer 27: 1302- 1305, 1971 .
Weekly 5FU 1962
1964
1977
1971
Loading
No loading
RR
11-28%
27.7%
Severe
toxicity
60-70%
47/430
(10.9%)
Drug
related
death
3-24%
0%
Effective and Safe
Jacobs. E. M., Cancer 27: 1302- 1305, 1971 .
 A number of physicians claimed success with the injection
of 500 mg once weekly without loading course
 This appealed to many physicians as it produced no
toxicity.
1962
1977
1971
WCCCG Data Processing Center
107 p’t disseminated adenocarcinoma
of gastrointestinal, pancreatic, biliary
tract, hepatic, breast, ovarian, or of
unknown primary origin
R
IV 5FU 15-20mg/kg
(n=52)
RR (%)
PO 5 FU 15-20mg/kg (n=55)
Cumulative
dose
Duration of response
Objective
Subjective
IV
8/38(21%)
56mg/kg
3.40
3.69
PO
14/35(40%)
47mg/kg
2.97
3.32
Bateman, J. R.,et al, Cancer 28:907-913, 1971.
1962
1971
1977
IV group: more hematologic toxicity
PO group: more GI toxicity
Bateman, J. R.,et al, Cancer 28:907-913, 1971.
1962
1971
1977
Oral administration of 5-FU was found safe and
effective in metastatic colorectal carcinoma.
2. Of a total of 14 cases of liver metastases, there were 11
responses, three of whom showed complete response.
3. A larger study is indicated to evaluate adequately the
relative response rate in different metastatic sites.
1.
Bateman, J. R.,et al, Cancer 28:907-913, 1971.
1962
1966
1968
1971
1977
462 colon, rectum, and breast cancer
361 acceptable evaluation
Treatment 1
Loading course
Treatment 2
Weekly IV 5FU
Treatment 3
Nontoxic schedule
Treatment 4
Oral 5FU
12 mg/kg/day x 4-5
(≦800mg)
↓
half doses q2-3d
until toxicity
↓
15mg/kg weekly
(≦1000mg)
15 mg/kg weekly x 4
↓ if no toxicity
20 mg/kg weekly
500mg/day x 4
↓
500mg weekly
(in diluted juice)
15 mg/kg/day x 6
↓
15mg/kg weekly
Ansfield F, et al, Cancer 39:34-40, 1977.
1962
1966
1968
1971
1977
Treatment 1
Loading course
Treatment 2
Weekly IV 5FU
Treatment 3
Nontoxic schedule
Treatment 4
Oral 5FU
12 mg/kg/day
x 4-5
> 50%
(≦800mg)
reduction
↓ area
of
half doses q2-3d
until toxicity
↓
15mg/kg weekly
(≦1000mg)
15 mg/kg weekly x 4
↓ if no toxicity
20 mg/kg weekly
500mg/day x 4
↓
500mg weekly
(in diluted juice)
15 mg/kg/day x 6
↓
15mg/kg weekly
Ansfield F, et al, Cancer 39:34-40, 1977.
1962
Duration of response in CRC
OS in CRC
1966
1968
1971
1977
TTP in CRC
OS in Breast
Ansfield F, et al, Cancer 39:34-40, 1977.
 The standard 5-FU administration schedule in the 1960s
and 1970s
 a weekly bolus with/without loading dose
 a 5-day bolus administered at 4- or 5-week intervals.
 (Oral 5-FU)
+ LV
•The Mayo Clinic or NCCTG regimen (5-FU and low-dose LV):
–Bolus 5-FU-(450 mg/m2)-leucovorin (20 mg/m2) daily for 5 days
every 28 days for 6 cycles (6 months)
•The Roswell Park or NSABP regimen (5-FU and high-dose leucovorin):
–Bolus 5-FU-(500 mg/m2)-leucovorin (500 mg/m2) weekly for 6
consecutive weeks every 8 weeks for 4 cycles (8 months)
 1960, 1962, Sullivan RD  1g/day for 36 days
 1972 Moertel, C. G.
 IV x 5D vs IVF 2 hr x 5D  ↓ toxicity, ↑dose
  may extend to 24 hr
 1975 Seifert P.
 IV x 5D vs IVF x 120 hr  ↓ toxicity , ↑RR, may ↑ OS
Sullivan RD, et al, Cancer Treat Res 1960; 8:77-83.
Sullivan RD , et al, Cancer Chemother Rep 1962; 16:499-510.
Moertel, C. G., et al, Cancer Rcs. 32:2717-27 19, 1972
Seifert P, et al, Cancer 36:123-128, 1975.
 Short half-life: 8-14 mins
 S-phase specific
 Safe venous access procedures and the
availability of portable drug delivery pump
mechanisms  ambulatory patients
1978
1980
1981
1983
1984
1985
mean half-life was 11.4min
William E, et al, Cancer Res 1978;38:3479-3482
1978
1980
1981
1984
1983
1985
 Previous study: route-dependent toxicity, IV: myelosupression, IVF GI toxicity
 PO: 5 p’t, 500mg/m2 x 5 days q4w
PO
 IV: 7 p’t, single dose, 500-900mg/m2
 IVF: 6 p’t 96 hr, 3 p’t 1100mg/m2/day, 3 p’t 1000mg/m2/day
IV
plasma
BM ~ 100X
BM
IVF
IV
PO
IVF
Fraile RJ, et al, Cancer Res 1980; 40: 2223–2228.
1978
1980
1981
1983
1984
1985
 要決定>30天以上的dose
 Patients were entered at
the following dose levels:
200, 300, 350, 400, and
600 mg/m2/day.
 Stomatitis  DC, 50%
dose next course
Lokich JJ, et al, Cancer 48:2565-2568, 1981.
1978
1980
1981
1983
1984
1985
 1983, Lokich JJ, Phase II study: RR 38%
 1984, Lokich JJ, palmar-plantar erythrodysesthesia
syndrome
 1985, Belt RJ, confirmation of activity, RR 30-50%
Lokich JJ, et al, Proceedings, 13th International Congress of Chemotherapy, Vienna, Austria, August, 1983.
Lokich JJ, et al, Ann Intern Med 101:789-800, 1984.
Belt RJ, et al, Proc Am Soc Clin Oncol 4:349 (abstr), 1985.
(1) Maximum tolerated dose (MTD) for protracted infusion
of ≧ 10 weeks was 300 mg/m2/day
(2) ↑ dose rate by 15% (300350mg/m2)  ≦ 3 weeks
(3) Dose-limiting toxicity is stomatitis
(diarrhea and hematologic effects
are not observed)
(4) Hand-foot syndrome: 25% to 30%
Lokich JJ, et al, Cancer 48:2565-2568, 1981.
Lokich JJ, et al, Ann Intern Med 101:789-800, 1984.
Jacob Lokich, Oncology 12(Suppl 7):19-22, 1998
 1,219 patients included in six randomized trials
 RR: 22% vs 14%, OR: 0.55, P = .0002
 OS: 12.1 months vs 11.3 months, HR 0.88, P = .04
Phase II only
With LV, not 5FU only
Meta-analysis Group in Cancer, J Clin Oncol 16(1):301-308, 1998.
RR: OR: 0.55, P = .0002
OS: HR 0.88, P = .04
Meta-analysis Group in Cancer, J Clin Oncol 16(1):301-308, 1998.
Grade 3 or 4
hematologic toxicity
Hand-foot
syndrome
Bolus
31%
(most leukopenia, rare
anemia and
thrombocytopenia)
13%
CI
4%
P < 10 -16
34%
P < 10 -7
Other nonhematologic
toxicity
14%
13%
Meta-analysis Group in Cancer, J Clin Oncol 16(1):301-308, 1998.
 Protracted infusion, as developed by Lokich et al.,
provides 5-FU at a low daily dose rate but a high
cumulative dose for up to 10 weeks. The rationale is
based on the principle that maximizing cell exposure to 5FU over time results in greater tumoricidal effect.
 The “super” bolus 24- or 48-hr infusion popularized in
Europe administers a high-dose weekly or biweekly to
capitalize on the dose-response effect.
 Intermediate infusion durations for 5-7 days also employ a
maximally tolerated dose concept, and were introduced
initially to be used in conjunction with radiation therapy.
 Sparing of host toxicity
 Allopurinol : Uncertain results
 Uridine: Impossible to reach required drug concentration
 Chronomodulation: Difficult to reproduce
 Increased tumor toxicity
 Methotrexate: Mixed results
 Leucovorin: Consistent benefit
 PALA: RCT showed no benefit
 Platinum analogues: Oxaliplatin ↓TS expression:
combination
 Irradiation: CCRT
Daniel B. Longley et al, Nature 2003
Chronomodulated administration
Circadian Variation:
DPD activity, decreased S phase
susceptibility 0000 h and 0400 h in
BM, skin, mucosa
 less toxic and more effective, ↑RR, ↓Toxicity
Francis Levi, et al, Lancet 1997; 350: 681–86
Leucovorin
RR: OR: 0.53, P < .0001
OS: HR 0.90, P = .004
The Meta-Analysis Group in Cancer , J Clin Oncol 22:3766-3775, 2004
Methotrexate
RR: OR: 0.51, P < .0001
OS: HR 0.87, P = .024
Advanced Colorectal Cancer Meta-Analysis Project, J Clin Oncol 12:960-969, 1994
RR(%)
P
OR
OS(m)
P
HR
14
22
11
P = .0002
OR 0.55
P < .0001
11.3
12.1
10.5
P=0.04
HR 0.88
P =.004
5FU + LV
21
5FU
10
5FU + MTX 19
OR 0.53
P < .0001
OR 0.51
11.7
9.1
10.7
HR 0.90
P= .024
HR 0.87
Bolus
Infusional
5FU
Meta-analysis Group in Cancer, J Clin Oncol 16(1):301-308, 1998.
The Meta-Analysis Group in Cancer , J Clin Oncol 22:3766-3775, 2004
Advanced Colorectal Cancer Meta-Analysis Project, J Clin Oncol 12:960-969, 1994
Dose intensity
Pharmacokinetics
BSA based
(mg/m2)
Dose
intensity
If PK stable
Plasma
level
AUC
Effect
Toxicity
 The data suggest that the dose-intensity response line is
steep, once a threshold dose intensity has been surpassed.
Dose intensity
↑ total dose
time
Response
Rate
Hryniuk WM, et al, Sem Oncol 14(4):3-11, 1987.
 Weekly bolus (500 mg/m2) or daily x 5 (525 mg/m2)
 5 day infusion or protracted 28-day infusion (2.1 g)
1000 x 5
300 x 28
5000/4
8400/4
3-4 X
↑ RR
J. Lokich, et al, Annals of Oncology 8: 15-25, 1997.
Schedules
Dose intensity
RR
24-hour infusion weekly
2.6 g/m2/week
25%
48-hour infusion weekly or biweekly
2.4 g/m2/week
30%
120-hour infusion at 4-5-week intervals
1.25g/m2/week
3%
14-day infusion
1.225 g/m2/week
12%
protracted infusions continuously for 10 weeks or more
2.1g/m2/week
30%
Lokich J, Anderson N, Cancer 70:998-1002, 1992.
10 X
10 X
Jacob Lokich, Oncology 12(Suppl 7):19-22, 1998
1. no scientific basis
2. Phase 1 study: MTD
BSA based
(mg/m2)
Dose
intensity
Variability, differences in
absorption, distribution,
metabolism, excretion
If PK stable
Plasma
level
AUC
Effect
Toxicity
DPD genotype
TS genotype
TS level
Lower TS level
 clinical response and
improved survival
DPD Deficiency
Partial 3% – 5%
Complete 0.1%
40-50%
Other unknown factors
Circadian Variation:
DPD activity
Plasma 5FU level
↓
effect and toxicity
Chronomodulated
administration: not
practical approach
Monitoring 5 FU
level
 “personalizing” the 5-FU dose
 more effective and less toxic
 Bolus: more difficult
 Infusional: only one sample (2hr to end)
 Css × TCI = AUC
Css: steady-state concentration
TCI: Time of continuous infusion in hours
 可換算成每個月的AUC來比較
M. Wasif Saif, et al, J Natl Cancer Inst 2009;101: 1543 – 1552
 AUC > 25 mg·h/L in CRC1,2
 Hematologic: neutropenia
 Nonhematologic: diarrhea, stomatitis, and hand – foot
syndrome
 AUC > 30 mg·h/L in H&N Cancer3-5
Different targeted
AUC in solid tumor
1. Ychou M, et al, Anticancer Res. 1999;19(3B):2229-2235.
2. Ychou M, et al, Cancer Chemother Pharmacol 2003;52(4):282-290.
3. Santini J, et al, Br J Cancer 1989;59(2):287-290.
4. Milano G, et al, J Clin Oncol 1994;12(6):1291-1295.
5. Vokes EE, et al, J Clin Oncol 1996;14(5):1663-1671.
Bolus 5FU/LV as
adjuvant
Next Slide
Di Paolo A, et al, 2008;14(9):2749-2755.
Grade 3, 4
Toxicity
5-FU
level
Narrow targeted AUC
interindividual variability
intraindividual variability
Variation in different regimen
 + LV, such as infusional LV5FU2: AUC 20 ~ 25 mg·h/L
 + CDDP in H&N: 25 ~ 30 mg·h/L.
 Consistent target range: 20 ~ 25 mg·h/L, despite different
administration modes (bolus vs infusion) and schedules
(several hours to several days)
Grade 3, 4
Toxicity
5-FU
Level
(mg·h/L)
25
Targeted AUC
Grade 3, 4
Toxicity
30
Targeted AUC
25
20
5-FU/LV in CRC
5-FU/CDDP in H&NC
A. Gamelin E, et al, Annual Meeting of American Society
of Clinical Oncology; 1998
B. Fety R, et al, Clin Cancer Res 1998; 4: 2039-45
C. Santini J, et al, Br J Cancer 1989; 59: 287-90
D. Lévi F, et al, Lancet 1997; 350: 681-6
Ploylearmsaeng SA , et al, Clin Pharmacokinet . 2006 ;45(6):567–592.
5 FU 1,500 mg/m2 + LV
200 mg/m2 IVF 8 hr weekly
mCRC
Total 802
At the target level
345 (42.7%)
Below target level
373 (46.3%)
Above target level
88 (11%)
57.3%
Gamelin E. Clin Colorectal Cancer 2007;7(6):411-413.
Fixed dose
N=104
N=208
mCRC
5 FU 1,500 mg/m2 + LV
200 mg/m2 IVF 8 hr weekly
R
Adjusted dose
N=104
Gamelin E , et al, J Clin Oncol .2008 ;26(13): 2099–2105 .
RR
OS
Fixed dose
18.3%
16m
1,500 mg/m2/wk
Adjusted dose
33.7%
22m
1,790 +- 386 mg/m2/wk (900 ~ 3,300 mg/m2/wk)
0.004
0.08
Gamelin E , et al, J Clin Oncol .2008 ;26(13): 2099–2105 .
 More frequent and severe in fixed dose(P .003).
Target concentration
of 600 μ g/L
Gamelin E, et al, Proc Am Soc Clin Oncol-GI 2009.
 A simple, cost-effective, and rapid testing method for 5-
FU levels
  shift BSA-guided to PK-guided
  adjust dosage earlier
 Phenotype, the sum of all the factors  guided to adjust
dosage
 Nearly all CRC, An even broader application for
therapeutic drug monitoring of any treatment regimen that
incorporates a fluoropyrimidine.
 Introduction of 5-FU
 Beginning ~ FDA approval
 1960s, 1970s, Bolus 5FU (and Oral 5FU)
 1980s, Infusional 5-FU
 1990s, Modulated 5-FU
 Dose intensity
 Pharmacokinetics
 About the future