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1179
A Comprehensive Review of 5-Fluorouracil and
Leucovorin in Patients with Metastatic Colorectal
Carcinoma
David Machover,
BACKGROUND. Colorectal carcinoma is the third leading cause of cancer-related
M.D.
Department of Hematology and Oncology, Hôpital Paul Brousse, Villejuif, France.
death. The primary treatment for patients with metastatic colorectal carcinoma is
systemic chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV), a biomodulator of 5-FU that has been shown to enhance its activity. Optimal dosing and
administration strategies remain to be determined.
METHODS. This article is a review of recent studies reporting on the use of high dose
and low dose LV as a biomodulator of 5-FU in patients with advanced colorectal
carcinoma.
RESULTS. Studies of LV plus 5-FU demonstrated response rates of 7–58% in patients who had not received prior chemotherapy. A survival advantage was recorded in some trials. LV plus 5-FU produces mild and transient hematologic
toxicity. The most common toxicities from LV plus 5-FU were gastrointestinal and
schedule-dependent, but generally resolved within a few days.
CONCLUSIONS. The combination of LV and 5-FU provides a favorable treatment
regimen for patients with metastatic colorectal carcinoma. Growing evidence suggests that altering the dose and schedule of both LV and 5-FU can impact positively
on the response rate. However, controversy remains regarding the optimal dosing
regimen. Therefore, continued study of LV plus 5-FU is urged and a favorable
impact on survival is requisite before definitive conclusions are drawn, particularly
in relation to LV dosage. Cancer 1997;80:1179–87.
q 1997 American Cancer Society.
KEYWORDS: advanced colorectal carcinoma, metastatic colorectal carcinoma, chemotherapy, 5-fluorouracil, biomodulation, leucovorin, folinic acid.
C
Supported by Wyeth-Ayerst International, Inc.
Address for reprints: David Machover, M.D.,
Hôpital Paul Brousse, 12 avenue P.V. CouturierBP 200, 94804 Villejuif Cedex, France.
Received January 28, 1997; revision received
April 28, 1997; accepted April 28, 1997.
olorectal carcinoma is the third leading cause of death from cancer
in industrialized nations.1 In the U. S. alone, an estimated 53,500
patients died of colorectal carcinoma in 1995.2 Nevertheless, between
1950 and 1990, there was a 30% decrease in mortality from colorectal
carcinoma in the U. S.,3 which may be attributed to advances in early
detection, improvements in treatment, and changes in lifestyle including diet and nutrition. Similarly, a substantial decline in colon
carcinoma mortality occurred in the southern European countries of
Spain, Italy, Greece, and Portugal between 1975 and 1988.1
Prognosis and survival for patients with colorectal carcinoma is
largely dependent on early detection. The prognosis of colorectal carcinoma is directly related to the extent of tumor penetration through
the bowel wall and the presence or absence of lymph node involvement. In patients with Dukes Stage D disease (stage characterized as
disease beyond the limit of surgical resection),4,5 median survival is
approximately 8 – 12 months. In patients with Dukes Stage C disease
q 1997 American Cancer Society
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W: Cancer
1180
CANCER October 1, 1997 / Volume 80 / Number 7
(indicating involvement of lymph nodes, regardless of
the extent of bowel wall penetration),6 the probability
of survival at 5 years is 45 – 55%. Metastatic colorectal
carcinoma represents a therapeutic challenge that has
seen some progress, although primarily in symptom
palliation, through the use of chemotherapy. Although
new drugs continually are being studied in clinical
trials, there is increasing interest in evaluating new
routes and schedules of administration for established
cytostatics and drug modulation, such as the combination of 5-fluorouracil (5-FU) and leucovorin (folinic
acid, d,l-5-formyltetrahydrofolate) (LV).
Since its introduction 40 years ago by Heidelberg
et al. the drug of choice for the treatment of metastatic
colorectal carcinoma has been 5-FU, a fluorinated analog of uracil.7 Clinical responses are observed in
õ 25% of patients treated with systemic 5-FU as a
single agent.8 One clinical study has suggested that a
therapeutic benefit may be gained by targeting the
optimal 5-FU area under the curve to maximize antitumor activity.9 Despite innovative techniques, such as
protracted continuous infusions (CI), significant
breakthroughs in disease control and long term survival have not been observed with single-agent 5-FU
in the treatment of patients with metastatic colorectal
carcinoma.
The meta-analysis of 1381 patients in nine randomized clinical trials confirmed the advantage of
treatment with the combination of 5-FU plus LV over
5-FU alone in terms of objective response. The response rate of the combination of 5-FU plus LV, as
compared with 5-FU as a single agent, was 23% versus
11% (P õ 1007). This benefit was documented in trials
involving weekly and daily schedules of administration
with both high dose LV (¢ 200 mg/m2/day) (HDLV)
and low dose LV (° 25 mg/m2/day) (LDLV).8
The meta-analysis did not reveal any advantage
for survival when comparing 5-FU alone with 5-FU
plus LV.8 In fact, none of the nine trials included in
the meta-analysis showed a statistically significant difference in survival after follow-up. Among the reasons
discussed for this lack of survival advantage in light of
an improved objective response with 5-FU plus LV
were: 1) the short duration of tumor response, 2) the
small numbers of patients with a complete response
(approximately 3%), 3) the small numbers of patients
with any response (23%), and 4) the high proportion
of crossover patients treated with 5-FU plus LV after
failure of single-agent 5-FU. This article will present
an overview of the preclinical rationale and of recent
studies investigating the use of HDLV and LDLV plus
5-FU in the treatment of patients with advanced colorectal carcinoma.
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Biomodulation of 5-FU by LV
Preclinical Studies
The modulation of 5-FU-based chemotherapy by LV is
based on evidence from preclinical studies. Variables
used to determine the maximal potentiation of 5-FU by
LV include the dose, the concentration achieved, and
the schedule of administration of both compounds. LV
is a precursor of 5,10-methylene tetrahydrofolate
(CH2FH4), the cofactor involved in the interaction of
fluorodeoxyuridine monophosphate (FdUMP) with its
target enzyme, thymidylate synthase (TS). In the presence of the reduced folate cofactor CH2FH4, FdUMP
forms a stable covalent ternary complex of TS-FdUMPCH2FH4 with concomitant inactivation of the enzyme.
The cytotoxicity of 5-FU is enhanced by this mechanism.10,11
The effectiveness of LV in potentiating the cytotoxicity of 5-FU depends partly on its conversion to a
polyglutamate.12 – 16 Polyglutamates of CH2FH4 are better for the tight binding of FdUMP to TS and are more
active than the monoglutamate in increasing 5-FU cytotoxicity.15,16 The number of glutamate residues on
the newly synthesized reduced folate has been correlated to both the duration of exposure to, and the
dose of, LV.13,14 Prolonged exposure to low levels of LV
produces increased intracellular levels of the longer
chain polyglutamates compared with a short, high
dose exposure.17
Preclinical studies suggested a relationship between LV dosage and the intracellular levels of CH2FH4
that are achieved.13,14,18,19 However, the intracellular
amounts of CH2FH4 that were achieved in these experiments were of a variable magnitude, depending on
the cell lines studied. Most studies have found higher
intracellular reduced folate levels at increasing doses
of LV. Moreover, higher doses of LV expanded intracellular polyglutamate pools and were frequently associated with superior tumor growth inhibition in combination with 5-FU.14
The influence of the method of LV administration
and the dose of LV on 5-FU-mediated inhibition of TS
was evaluated in a series of studies of immunedeprived mice bearing human colon adenocarcinomas
from different cell lines.13,14 LV (500 mg/m2) was administered to the mice via bolus, using a 4-hour or
24-hour infusion.13 The concentration of polyglutamates in tumor tissue was similar for all three methods
of administration.13
Additional synergism between LV and 5-FU may
be achieved by sequential rather than simultaneous
administration of these two agents. To further potentiate the cytotoxicity of 5-FU, the timing of its administration should correspond to the peak concentration
of polyglutamates.12 This may be unique for each cell
W: Cancer
5-FU and Leucovorin in Colorectal Carcinoma/Machover
line or tumor type. In National Cancer Institute H630
colon carcinoma cells, the highest concentration of
the ternary complex TS-FdUMP-CH2FH4 was observed
when 5-FU was administered 18 hours after LV and
the concentration of polyglutamates was at its peak.12
In contrast, the peak concentration of polyglutamates
occurred at only 4 hours after LV administration in
MCF-7 breast carcinoma cells. Because the length of
exposure to LV, the concentration, and the interval
between LV administration and 5-FU treatment all
play a critical role in enhancing the formation of the
ternary complex, no single fixed-dose schedule is likely
to be optimal for all tumors. Additional studies are
necessary to better characterize 5-FU/LV regimens
with optimal cytotoxicity.
The importance of defining optimal treatment
strategies for the administration of the fluoropyrimidines, 5-FU and 5-fluoro-2*-deoxyuridine (FdUrd), in
combination with LV, was suggested in a study of rats
bearing Ward colorectal carcinomas.18 This clinically
relevant model system appears to mimic both the efficacy and the toxicity of the current 5-FU plus LV
dosing schemes.18 Three treatment schedules were
employed, each schedule examining HDLV, LDLV, or
no LV:
1. Four-day (96-hour) CI of 5-FU or FdUrd with or
without a daily 2-hour CI of LDLV (20 mg/kg) or
HDLV (200 mg/kg).
2. Daily 1 4 5-FU or FdUrd intravenous push (IVP)
with or without a daily 2-hour CI of LDLV (20 mg/
kg) or HDLV (200 mg/kg). The fluoropyrimidine was
administered after the first hour of LV treatment.
3. Weekly 5-FU or FdUrd IVP given for 3 weeks with
or without a 2-hour CI of LDLV (20 mg/kg) or HDLV
(200 mg/kg). The fluoropyrimidine was administered after the first hour of LV treatment.
Greater therapeutic efficacy, as measured by more
complete tumor regression, was achieved with HDLV
than with LDLV when combined with 5-FU given
weekly (P õ 0.005) or as a 4-day CI.18 More complete
responses were observed with HDLV plus FdUrd than
with LDLV plus FdUrd on all three schedules (P õ 0.05
for Schedule 1, and P õ 0.001 for Schedules 2 and 3).
The results also demonstrated that toxicity (stomatitis
and diarrhea) was independent of the LV dose.18 These
data suggest that antitumor activity may be influenced
by LV dose in relation to the schedule of fluoropyrimidine administration.
From the studies presented earlier, it appears that
maximum potentiation of 5-FU by LV may be dependent on the dose of LV, the intracellular concentration
of reduced folate achieved, and on the schedule of
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1181
administration, although the optimal regimen has not
yet been defined.
Clinical Experience
Schedules of Administration of LV
Various schedules of administration of 5-FU plus LV
have been explored to improve efficacy and minimize
toxicity (Table 1). Four schedules of administration for
5-FU currently in use account for the majority of recent clinical trials in this area. LV frequently is administered as an intravenous (IV) rapid infusion or 2-hour
CI. In the biweekly or 24-hour CI regimens, only HDLV
has been used.26,27
Efficacy
Response rates reported in recent comparative trials
examining 5-FU plus LV for the treatment of patients
with metastatic colorectal carcinoma have been lower
than those reported in the pivotal trials examined in
the meta-analysis8 (Table 2). No significant increases
in survival were reported for any dose or schedule of 5FU plus LV for the nine trials included in the analysis.8
However, survival advantage was reported in one trial
that was not included in the meta-analysis.21 Preliminary results from recent comparative trials include reports of increased survival for LV plus 5-FU over single
agent 5-FU. An interim analysis of a Phase III trial
comparing daily 1 5 LDLV plus 5-FU treatment with
single agent 5-FU reported a median survival of 13.8
months (n Å 126) versus 10.0 months (n Å 120), respectively (P Å 0.02).29
A comprehensive Phase II clinical trial comparing
seven combinations of single agent 5-FU and 5-FU
plus LV at various doses and schedules found no significant differences between the regimens in response
rate or survival.38 However, the response rate for single
agent 5-FU (500 mg/m2/d, daily x 5, IVB) in this trial
was 24%, compared with the historic range of 10 –
15%.8,27 The response rate for LV-containing regimens
was 17% for the daily 1 5 LDLV plus 5-FU every 4
weeks, and 14% for weekly 1 6 HDLV plus 5-FU.38
These two regimens were directly compared in a
large multicenter clinical trial reported in 1994, with
response rates of 35% and 31%, respectively.30 As
shown in Table 2, the response rates initially reported
were 42 – 43% for daily 1 5 LDLV plus 5-FU every 4
weeks 21,22 and 30.3 – 44% for weekly 1 6 HDLV plus 5FU.24,25 In a recent review of 48 patients treated with
the daily 1 5 LDLV plus 5-FU every 4 weeks regimen
for metastatic colorectal carcinoma, the response rate
was 33%, which is within the range established in the
studies discussed earlier.31
A recently published multicenter trial of 291
assessable patients with advanced colorectal carci-
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1182
CANCER October 1, 1997 / Volume 80 / Number 7
TABLE 1
Schedule of Administration and Typical Doses of 5-Fluorouracil and Leucovorin
5-FU
LV
Regimen
Frequency
Duration
mg/m2/day
Duration
mg/m2/day
Daily 1 five 5-FU plus HDLV20–23
Daily 1 five 5-FU plus LDLV21,22
Weekly 5-FU plus HDLV24,25
Weekly 5-FU plus LDLV25
Biweekly 5-FU plus HDLV26
Daily 1 5 every 3–5 wks
Daily 1 5 every 3–5 wks
Weekly 1 6 with a 2-wk rest
Weekly 1 6 with a 2-wk rest
Days 1–2, every 2 wks
200
20
500
20–25
200
Weekly
370–400
370–425
600
500–600
300–400
300–600
2600
IVB
IVB
2-hr CIV
IVB
2-hr CIV
Weekly 24-hr CI 5-FU plus HDLV27
IVB
IVB
IVB
IVB
IVB then
22-hr CI
24-hr CI
2–24-hr CIV
500
5-FU: 5-fluorouracil; LV: leucovorin; HDLV: high dose leucovorin; LDLV: low dose leucovorin; CI: continuous infusion; IVB: intravenous bolus; CIV: continuous intravenous infusion.
noma compared weekly 5-FU plus HDLV or LDLV in
a slightly modified regimen.28 The dose of 5-FU was
reduced to 500 mg/m2/day, compared with 600 mg/
m2/day in the studies previously discussed.24,25 In this
study, response rates in the two arms were similar:
21.6% for the weekly HDLV plus 5-FU arm, and 17.5%
for the weekly LDLV plus 5-FU arm. This is in contrast
to the previously reported results of HDLV plus 5-FU
(44%) versus LDLV plus 5-FU (18.8%) (P Å 0.046) and
may be due to the lower dose of 5-FU.24,25
One regimen that has given consistent results in
terms of response rate over the last 10 years is daily
1 5 HDLV plus 5-FU given every 3 – 4 weeks. The response rate for this regimen of 370 – 400 mg/m2/day
of 5-FU plus 200 mg/m2/day of LV, given by rapid IV,
has ranged from 26 – 38.9%.20 – 23,32
Recently, l-leucovorin rather than the usual d,l
mixture has been tested in clinical trials (Table 3). In
a small, Phase I-II trial, a French group reported a
response rate of 52% for daily 1 5 HDl-LV plus 5FU in 25 patients previously untreated for metastatic
colorectal carcinoma.40,41 A response rate of 18.5% using this schedule of administration, but a lower dose of
5-FU, was observed in a larger (n Å 119), international
Phase II study designed to be directly comparable to
an earlier trial.20,43 The same regimen led to a response
rate of 10.6% in a large, comparative Phase III trial
reported in a 1995 abstract (n Å 188).42 In the other
arm of this study (n Å 184), daily 1 5 LDl-LV plus 5FU, the response rate was similar, 11.4%. Again, the
lower response rates may be due to less overall exposure to 5-FU.
The daily 1 5 LDLV plus 5-FU regimen was chosen
as the comparator arm in a Phase III clinical trial examining the efficacy and safety of the biweekly HDLV
plus 5-FU regimen for the treatment of patients with
advanced colorectal carcinoma.35,36 The response rate
of 34% for biweekly HDLV plus 5-FU was significantly
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09-10-97 10:11:31
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greater (P Å 0.002) than the response rate (17%) for
daily 1 5 LDLV plus 5-FU.43 However, these two regimens are difficult to compare because the amount of
5-FU given to patients in the daily 1 5 LDLV plus 5FU arm over the course of 1 month is less than the
amount administered in the biweekly HDLV plus 5FU regimen. The range of response rates observed for
the biweekly HDLV plus 5-FU regimen in recent trials
was 26 – 54%.26,33 – 37
The last schedule of administration to be discussed in this review is a 24-hour CI of 5-FU paired
with HDLV, either as a 24-hour CI or as a 2-hour CI.
A small Phase II trial evaluated the response of previously untreated patients with advanced colorectal
carcinoma (n Å 12) and that achieved in those patients
who had prior chemotherapy (n Å 10). Response rates
were 58% and 30%, respectively.27 Preliminary results
from a slightly larger trial (n Å 31) indicate a response
rate of 39%.39
Table 4 summarizes the regimen and the range of
survival reported in the trials reviewed. Survival has
not changed significantly since the pivotal studies
forming the basis for the meta-analysis reported a median survival of 11.5 months for 5-FU plus LV.
Safety and Toxicity
The percentage of patients experiencing toxicity
greater than Grade 2 for leukopenia, stomatitis/mucositis, and diarrhea in recent trials is summarized in
Table 5. The large Phase II clinical trial comparing
seven combinations of single agent 5-FU, 5-FU plus
LV, or other biomodulators of 5-FU found more severe
hematologic toxicity associated with the rapid IV than
with the CI arms of the study. Diarrhea was most frequent in the weekly 1 6 arm compared with the daily
1 5 arms or the CI arms. Of the eight treatment-related
deaths in this trial, two occurred on the daily 1 5
W: Cancer
5-FU and Leucovorin in Colorectal Carcinoma/Machover
1183
TABLE 2
Efficacy of 5-Fluorouracil/Leucovorin in Patients with Advanced Colorectal Carcinoma
Petrelli et al. 198724
Petrelli et al. 198925
Jäger et al. 199628
Poon et al. 198921
Poon et al. 199122
Borner et al. 199629
Buroker et al. 199430
Fried et al. 199531
Machover et al. 198623
No prior chemo
Prior chemo
Erlichman et al. 198820
Petrioli et al. 199532
de Gramont et al. 198826
Johnson et al. 199133
Bécouarn et al. 199534
de Gramont et al. 1995,35 199736
Beerblock et al. 199637
Leichman et al. 199538
Ardalan et al. 199127
No prior chemo
Prior chemo
Köhne et al. 199539
5-FU dose
(mg/m2/day)
LV dose (mg/
m2/day)
450, IVB
600, IV
500, IVB
600, IVB
600, IVB
500, IVB
500, IVB
370, IVB
370–425, IVB
370, IVB
425, IVB
400, IVB
400, IVB
425, IVB
600, IVB
425, IVB
340–400 CIV
15 mins
None
500, 2-hr CIV
370–425, IVB
370, IVB
400, IVB
400, IVB
300–500, IVB, then
300–500, 22-hr
CIV
400, IVB then 400,
22-hr CIV
400, IVB then 600,
22-hr CIV
425, IVB
400, IVB then 600,
22-hr CIV
3000–4000, 48-hr CIV
2600, 24-hr CIV
500, IVB
425, IVB
600, IVB
2600, 24-hr CIV
2600, 24-hr CIV
Frequency
Daily 1 5 every 4 wks
Weekly 1 6; 2-wk rest
Daily 1 5 every 4 wks
Weekly 1 6; 2-wk rest
Weekly 1 6; 2-wk rest
Weekly
Weekly
Daily 1 5 every 4–5 wks
Daily 1 5 every 4–5 wks
Daily 1 5 every 4–5 wks
Daily 1 5 every 4–5 wks
Daily 1 5 every 4 wks
Daily 1 5 every 4 wks
Daily 1 5 every 4–5 wks
Weekly 1 6; 2-wk rest
Daily 1 5 every 4 wks
Daily 1 5 every 21 days
500, IVB
25, IVB
500, 2-hr CIV
20, 2-hr CIV
200, IVB
20, IVB
200, IVB
20, IVB
20, IVB
20, IVB
500, 2-hr CIV
20, IVB
200, IVB
Evaluable
patients
Response rate
(CR / PR)
Median survival
(mos)
19
25
107
109
112
148
143
68
70
75
81
126
120
183
179
48
11%
44%
12.1%
30.3%
18.8%
21.6%
17.5%
26%
43%
33%
42%
ND
ND
35%
31%
33%
11
12
11.5
13.75
11.25
12.9
12.6
12.2
12.0
12.7
12.7
10.0
13.8
9.3
10.7
8.5
38.9%
21.9%
7%
33%
33.3%
18.6%
54.1%
17
12
9.6
12.6
13.5
7.5
18
200, IVB
200, IVB
None
200, 2-hr CIV
Daily 1 5 every 28 days
Daily 1 5 every 28 days
Daily 1 5 every 3 wks
Daily 1 5 every 4 wks
Daily 1 2 every 2 wks
54
32
61
64
81
86
37
200, 2-hr CIV
Daily 1 2 every 2 wks
47
24%
17.3
200, 2-hr CIV
Daily 1 2 every 2 wks
86
38.3%
10.3
20, 2-hr CIV
200, 2-hr CIV
Daily 1 5 every 4 wks
Daily 1 2 every 2 wks
147
159
17%
34%
13.3
14.3
500, 22-hr CIV
None
None
20, IVB
500, 3-hr CIV
500, 24-hr CIV
Every 2 wks
Weekly
Daily 1 5 every 5 wks
Daily 1 5 every 4–5 wks
Weekly 1 6; 2-wk rest
Weekly
92
83
88
85
85
33.7%
13% (15%)
24% (29%)
17% (27%)
14% (21%)
ND
15
13
14
13
12
10
31
58%
30%
39%
ú22
10
ND
500, 2-hr CIV
Weekly 1 6; 2-wk rest
5-FU: 5-fluorouracil; LV: leucovorin; CR: complete response; PR: partial response; IVB: intravenous bolus; IV: intravenous; CIV: continuous intravenous infusion; ND: not defined; chemo: chemotherapy.
LDLV plus 5-FU arm and involved sepsis. No deaths
occurred in the weekly HDLV plus 5-FU arm.38
Investigators found significant differences in the
toxicity profiles of two regimens (daily 1 5 LDLV plus
5-FU and weekly 1 6 HDLV plus 5-FU) in a large,
multicenter, comparative trial.30 Significantly more severe leukopenia and stomatitis were observed in the
daily 1 5 LDLV plus 5-FU arm (P õ 0.01), whereas
significantly more diarrhea was observed in the weekly
HDLV plus 5-FU arm (P õ 0.01). Five treatment-re-
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lated deaths occurred on the daily 1 5 LDLV plus 5FU regimen compared with two deaths on the weekly
HDLV plus 5-FU regimen (P Å 0.26).30 These deaths
may be related in part to the greater dose of 5-FU
given to patients as rapid IV in the daily 1 5 LDLV
plus 5-FU arm.
In the multicenter clinical trial that compared
both HDLV plus 5-FU and LDLV plus 5-FU on a weekly
schedule of administration, the observed toxicities
were similar in both arms. Although more diarrhea
W: Cancer
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CANCER October 1, 1997 / Volume 80 / Number 7
TABLE 3
Efficacy of 5-Fluorouracil and l-Leucovorin
Machover et al. 1992,40 199341
Valsecchi et al. 199542
Erlichman et al. 199643
5-FU dose
(mg/m2/day)
l-LV dose
(mg/m2/day)
Frequency
Evaluable
patients
Response rate
(CR / PR)
Median survival
(mos)
350–550 2-hr CIV
350–550 2-hr CIV
370, IVB
370, IVB
370, IVB
100, IVB
100, IVB then 250, CIV
100, IVB
10, IVB
100, IVB
Daily 1 5 every 21 days
Daily 1 5 every 21 days
Daily 1 5 every 28 days
Daily 1 5 every 28 days
Daily 1 5 every 28 days
25
27
188
184
119
52%
37%
10.6%
11.4%
18.5%
73%a
67%a
10
10
12.6
5-FU: 5-fluorouracil; LV: leucovorin; CR: complete response; PR: partial response; IVB: intravenous bolus; CIV: continuous intravenous infusion.
a
Percent of patients surviving after 12 months.
Treatment groups other than 5-fluorouracil or 5-fluorouracil plus leucovorin are not shown.
TABLE 4
Survival for Previously Untreated Patients Reported by Regimen
Regimen
Survival range
(mos)
Daily 1 five LDLV plus 5-FU (3 wks)
Daily 1 five HDLV plus 5-FU (4 wks)
Daily 1 five HDl-LV plus 5-FU
Weekly LDLV plus 5-FU
Weekly HDLV plus 5-FU
Biweekly HDLV plus 5-FU
Weekly HDLV plus 24-hr CI 5-FU
9.3–14
12.2–13.5
10–12.6
11.5–12.6
10.7–13.75
10.3–18
ú 22
LDLV: low dose leucovorin; 5-FU: 5-fluorouracil; HDLV: high dose leucovorin; HDl-LV: high dose
l-leucovorin; CI: continuous infusion.
was associated with the HDLV plus 5-FU arm, the occurrence of Grade 4 diarrhea was comparable (four
patients in the HDLV plus 5-FU arm and three patients
in the LDLV plus 5-FU arm). No toxic deaths were
observed in this study.28
The dose-limiting toxicities, stomatitis/mucositis, and diarrhea, observed for both the 5-FU plus
HDLV 20 – 23,32 and the 5-FU plus HDl-LV daily 1 5
regimens (Table 6), were consistent across several
trials.40,41,43
Significant differences in toxicity between daily 1
5 LDLV plus 5-FU and biweekly HDLV plus 5-FU were
reported in preliminary results from a Phase III clinical
trial.35,36 Eighteen patients (9.2%) receiving biweekly
HDLV plus 5-FU reported Grade 3/4 toxicities compared with 41 patients (21.5%) receiving the daily 1 5
LDLV plus 5-FU regimen (P Å 0.0004). The administration of 5-FU by CI rather than by rapid infusion in the
biweekly HDLV plus 5-FU arm may account for the
decreased 5-FU – related toxicities observed. In three
other clinical trials investigating the safety of the biweekly HDLV plus 5-FU regimen for the treatment of
patients with advanced colorectal carcinoma, õ 5% of
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the patients experienced severe leukopenia or diarrhea; the incidence of stomatitis/mucositis was õ
9%.33,34,37
Only two small trials have reported toxicity associated with HDLV plus 24-hour CI 5-FU. No Grade 3/4
leukopenia was observed. The percentage of patients
experiencing severe diarrhea and stomatitis/mucositis
ranged from 9 – 14% and 4.5 – 14%, respectively. The
reported incidence of hand/foot syndrome appeared
to be greater with the 24-hour CI of 5-FU than with
rapid infusion of 5-FU.27,39
Conclusions
The limited efficacy of chemotherapy in the treatment
of patients with metastatic colorectal carcinoma encourages oncologists to continue to test new therapies
in randomized trials. The combination of 5-FU and
LV has been shown to be an active treatment with
acceptable toxicity for patients with metastatic colorectal carcinoma who have not received prior chemotherapy.8,20 Despite the number of clinical trials, the
optimal dose, method of administration, and schedule
for LV plus 5-FU has yet to be determined.44
Studies of LV biomodulation of 5-FU demonstrate
that prolonged exposure to LV enhances the stability
of the TS complex formation by increasing intracellular
concentrations of reduced folate polyglutamates.12 In
some cell lines, 5-FU and LDLV produce optimal antitumor effects, whereas higher concentrations of LV (up
to 10 mM) are required in other cells lines to achieve
comparable effects.12 Because response to chemotherapy is not uniform among neoplasms, tumor type also
may have an impact on LV potentiation of cell kill by 5FU. Clearly, the mechanism by which LV modulates the
activity of 5-FU needs further study. Over the long term,
increased understanding of this process may define the
role of LV in combination with 5-FU.
The two most common treatment regimens currently in use (daily 1 5 LDLV plus 5-FU and weekly
W: Cancer
5-FU and Leucovorin in Colorectal Carcinoma/Machover
1185
TABLE 5
Safety of 5-Fluorouracil/Leucovorin in Patients with Advanced Colorectal Carcinoma
% of patients with ú Grade 2 toxicity
Petrelli et al. 1987
24
Petrelli et al. 198925
Jåger et al. 199628
Poon et al. 198921
Poon et al. 199122
Borner et al. 199629
Buroker et al. 199430
Fried et al. 199531
Machover et al. 198623
Erlichman et al. 198820
Petrioli et al. 199532
de Gramont et al. 198826
Johnson et al. 199133
Bécouarn et al. 199534
de Gramont et al. 1995,35 199736
Beerblock et al. 199637
Leichman et al. 199538
Ardalan et al. 199127
Köhne et al. 199539
Frequency
No. of
evaluable
patients
Leukopenia
Mucositis,
stomatitis
Diarrhea
20, IVB
20, IVB
500, 2-hr CIV
20, IVB
200, IVB
None
200, IVB
200, IVB
None
200, 2-hr CIV
Daily 1 5 every 4 wks
Weekly 1 6; 2-wk rest
Daily 1 5 every 4 wks
Weekly 1 6; 2-wk rest
Weekly 1 6; 2-wk rest
Weekly
Weekly
Daily 1 5 every 4–5 wks
Daily 1 5 every 4–5 wks
Daily 1 5 every 4–5 wks
Daily 1 5 every 4–5 wks
Daily 1 5 every 4 wks
Daily 1 5 every 4 wks
Daily 1 5 every 4–5 wks
Weekly 1 6; 2-wk rest
Daily 1 5 every 4 wks
Daily 1 5 every 21 days
Daily 1 5 every 28 days
Daily 1 5 every 28 days
Daily 1 5 every 3 wks
Daily 1 5 every 4 wks
Daily 1 2 every 2 wks
19
25
107
109
112
148
143
68
70
75
81
126
120
183
179
48
86
61
64
81
86
37
37%
10%
27%
8%
4%
0.7%
1.4%
19%
21%
15%
22%
ND
ND
29%
5%
ND
10%
ND
ND
3.7%
2.3%
3%
10%
10%
15%
4%
0%
0%
0%
30%
26%
28%
28%
ND
ND
24%
2%/
22%
18%
ND
ND
13.4%
8.1%
0%
23%
40%
9%
25%
13%
27%
16.1%
9%
14%
19%
16%
ND
ND
18%
32%
11%
11%
ND
ND
11.1%
8.1%
16%
200, 2-hr CIV
Daily 1 2 every 2 wks
62
0%
0%
0%
200, 2-hr CIV
Daily 1 2 every 2 wks
86
3.5%
8.1%
2.3%
20, 2-hr CIV
200, 2-hr CIV
Daily 1 5 every 4 wks
Daily 1 2 every 2 wks
147
159
7.9%
2%
9.9%
1.5%
4.7%
3.1%
500, 22-hr CIV
None
None
20, IVB
500, 3-hr CIV
500, 24-hr CIV
500, 2-hr CIV
Every 2 wks
Weekly
Daily 1 5 every 5 wks
Daily 1 5 every 4–5 wks
Weekly 1 6; 2-wk rest
Weekly
Weekly 1 6; 2-wk rest
92
83
88
85
85
22
31
4.3%
1%
16%
17%
4%
0%
0%
3.2%
1%
4%
12%
1%
4.5%
14%
2.2%
9%
9%
10%
23%
9%
14%
5-FU dose
(mg/m2/day)
LV dose
(mg/m2/day)
450, IVB
600, IV
500, IVB
600, IVB
600, IVB
500, IVB
500, IVB
370, IVB
370–425 IVB
370, IVB
425, IVB
400, IVB
400, IVB
425, IVB
600, IVB
425, IVB
340–400, CIV 15 mins
425, IVB
370, IVB
400, IVB
400, IVB
300, IVB then 300,
22-hr CIV then
escalated
400, IVB then 400,
22-hr CIV
400, IVB then 600,
22-hr CIV
425, IVB
400, IVB then 600,
22-hr CIV
3000–4000, 48-hr CIV
2600, 24-hr CIV
500, IVB
425, IVB
600, IVB
2600, 24-hr CIV
2600, 24-hr CIV
None
500, 2-hr CIV
None
500, IVB
25, IVB
500, IVB
20, IVB
200, IVB
20, IVB
200, IVB
20, IVB
5-FU: 5-fluorouracil; LV: leucovorin; IVB: intravenous bolus; IV: intravenous; CIV: continuous intravenous infusion; ND: not defined.
Treatment groups other than 5-fluorouracil or 5-fluorouracil plus leucovorin are not shown.
HDLV plus 5-FU) have yielded similar response rates
but different toxicity profiles.30,38 The main dose-limiting toxicity of 5-FU plus HDLV given as a weekly
rapid infusion is diarrhea, whereas the predominant
dose-limiting toxicity of the daily 1 5 regimen is mucositis/stomatitis.38,44 Both the incidence and severity of
toxicities appear to be independent of the dose of LV.
Based on the pharmacologic properties of the enantiomers of LV, researchers hypothesized that using
only the l stereoisomer of LV might enhance antitumor
efficacy.23 However, the results of clinical trials using
/ 7b71$$1340
09-10-97 10:11:31
cana
l-LV also were within the range of efficacy and toxicity
previously established for the d,l mixture.40 – 43
The important parameters in defining a combined
regimen are the dose, methods, and length of administration for both agents. Based on recent preclinical
studies, different tumors may need specific regimens
for an optimal response to 5-FU plus LV combination
therapy.12,45 Continuous or intermittent infusion of 5FU, resulting in an overall higher dose of 5-FU administered with less concomitant toxicity, also may lead
to an improved response.27,33,46,47
W: Cancer
1186
CANCER October 1, 1997 / Volume 80 / Number 7
TABLE 6
Toxicity of 5-Fluorouracil and l-Leucovorin
% of patients with ú Grade 2 toxicity
5-FU dose
(mg/m2/day)
l-LV dose
(mg/m2/day)
Machover et al. 1992, 1993
350–550, 2-hr CIV
350–550, 2-hr CIV
Valsecchi et al. 199542
370, IVB
370, IVB
370, IVB
100, IVB
100, IVB then 250,
2-hr CIV
100, IVB
10, IVB
100, IVB
40
Erlichman et al. 199643
41
Frequency
Evaluable
patients
Leukopenia
Mucositis,
stomatitis
Diarrhea
Daily 1 5 every 21 days
Daily 1 5 every 21 days
25
27
ND
ND
15%
31%
31%
45%
Daily 1 5 every 28 days
Daily 1 5 every 28 days
Daily 1 5 every 28 days
188
184
119
ND
ND
15.9%
ND
ND
17.6%
ND
ND
23.2%
5-FU: 5-fluorouracil; LV: leucovorin; IVB: intravenous bolus; CIV: continuous intravenous infusion; ND: not defined.
Treatment groups other than 5-fluorouracil or 5-fluorouracil plus leucovorin are not shown.
For patients with metastatic colorectal carcinoma,
chemotherapy has been the primary therapeutic option. The combination of 5-FU plus LV provides improved efficacy of 5-FU and tolerable adverse effects,
while achieving symptom palliation. Intense effort
through a decade of clinical trials has provided evidence in favor of the clinical efficacy of 5-FU modulation by LV. The remaining questions regarding the optimal doses and treatment regimens for these agents
require additional investigation. The answers might
not be easily obtained in the setting of advanced disease.
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