A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Camptosar Pharmacology, Pharmacokinetics, Studies, Metabolism - Irinotecan hydrochloride
Camptosar Pharmacology, Pharmacokinetics, Studies, Metabolism - Irinotecan hydrochloride
CLINICAL PHARMACOLOGY
Irinotecan is a derivative of camptothecin. Camptothecins interact
specifically with the enzyme topoisomerase I which relieves torsional strain
in DNA by inducing reversible single-strand breaks. Irinotecan and its active
metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation
of these single-strand breaks. Current research suggests that the cytotoxicity
of irinotecan is due to double-strand DNA damage produced during DNA synthesis
when replication enzymes interact with the ternary complex formed by topoisomerase
I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair
these double-strand breaks. Irinotecan serves as a water-soluble precursor of
the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated
cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino
side chain. SN-38 is approximately 1000 times as potent as irinotecan as an
inhibitor of topoisomerase I purified from human and rodent tumor cell lines.
In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan
varies from 2- to 2000-fold. However, the plasma area under the concentration
versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38
is 95% bound to plasma proteins compared to approximately 50% bound to plasma
proteins for irinotecan (see Pharmacokinetics). The precise contribution of
SN-38 to the activity of CAMPTOSAR is thus unknown. Both irinotecan and SN-38
exist in an active lactone form and an inactive hydroxy acid anion form. A pH-dependent
equilibrium exists between the two forms such that an acid pH promotes the formation
of the lactone, while a more basic pH favors the hydroxy acid anion form.
Administration of irinotecan has resulted in antitumor activity
in mice bearing cancers of rodent origin and in human carcinoma xenografts of
various histological types.
Pharmacokinetics
After intravenous infusion of irinotecan in humans, irinotecan
plasma concentrations decline in a multiexponential manner, with a mean terminal
elimination half-life of about 6 to 12 hours. The mean terminal elimination
half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives
of the lactone (active) forms of irinotecan and SN-38 are similar to those of
total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.
Over the recommended dose range of 50 to 350 mg/m2, the AUC of irinotecan
increases linearly with dose; the AUC of SN-38 increases less than proportionally
with dose. Maximum concentrations of the active metabolite SN-38 are generally
seen within 1 hour following the end of a 90-minute infusion of irinotecan.
Pharmacokinetic parameters for irinotecan and SN-38 following a 90-minute infusion
of irinotecan at dose levels of 125 and 340 mg/m2 determined in two
clinical studies in patients with solid tumors are summarized in Table 1:
Table 1. Summary Of Mean (± Standard Deviation) Irinotecan And
SN-38 Pharmacokinetic Parameters In Patients With Solid Tumors
|
Dose
(mg/m2)
|
Irinotecan
|
SN-38
|
|
Cmax (ng/mL)
|
AUC0-24 (ng·h/mL)
|
t½ (h)
|
Vz (L/m2)
|
CL (L/h/m2)
|
Cmax (ng/mL)
|
AUC0-24 (ng·h/mL)
|
t½ (h)
|
|
125
|
1,660
|
10,200
|
5.8a
|
110
|
13.3
|
26.3
|
229
|
10.4a
|
|
(N=64)
|
± 797
|
± 3,270
|
± 0.7
|
± 48.5
|
± 6.01
|
± 11.9
|
± 108
|
± 3.1
|
|
340
|
3,392
|
20,604
|
11.7b
|
234
|
13.9
|
56.0
|
474
|
21.0b
|
|
(N=6)
|
± 874
|
± 6,027
|
± 1.0
|
± 69.6
|
± 4.00
|
± 28.2
|
± 245
|
± 4.3
|
Cmax - Maximum plasma concentration
AUC0-24 - Area under the plasma concentration-time
curve from time 0 to 24 hours after the end of the 90-minute infusion
t½ - Terminal elimination half-life
Vz - Volume of distribution of terminal elimination
phase
CL - Total systemic clearance
a Plasma specimens collected for 24 hours following
the end of the 90-minute infusion.
b Plasma specimens collected for 48 hours following
the end of the 90-minute infusion. Because of the longer collection period,
these values provide a more accurate reflection of the terminal elimination
half-lives of irinotecan and SN-38.
Irinotecan exhibits moderate plasma protein binding (30% to
68% bound). SN-38 is highly bound to human plasma proteins (approximately 95%
bound). The plasma protein to which irinotecan and SN-38 predominantly binds
is albumin. Metabolism and Excretion: The metabolic conversion of irinotecan
to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily
occurs in the liver. SN-38 subsequently undergoes conjugation to form a glucuronide
metabolite. SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity
assays using two cell lines in vitro. The disposition of irinotecan has not
been fully elucidated in humans. The urinary excretion of irinotecan is 11%
to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and
urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide)
over a period of 48 hours following administration of irinotecan in two patients
ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).
Pharmacokinetics in Special Populations
Geriatric: In studies using the weekly schedule, the terminal
half-life of irinotecan was 6.0 hours in patients who were 65 years or older
and 5.5 hours in patients younger than 65 years. Dose-normalized AUC0-24
for SN-38 in patients who were at least 65 years of age was 11% higher than
in patients younger than 65 years. No change in the starting dose is recommended
for geriatric patients receiving the weekly dosage schedule of irinotecan. The
pharmacokinetics of irinotecan given once every 3 weeks has not been studied
in the geriatric population; a lower starting dose is recommended in patients
70 years or older based on clinical toxicity experience with this schedule (see
DOSAGE AND ADMINISTRATION). Pediatric:
Information regarding the pharmacokinetics of irinotecan is not available. Gender:
The pharmacokinetics of irinotecan do not appear to be influenced by gender.
Race: The influence of race on the pharmacokinetics of irinotecan has not been
evaluated. Hepatic Insufficiency: The influence of hepatic insufficiency on
the pharmacokinetic characteristics of irinotecan and its metabolites has not
been formally studied. Among patients with known hepatic tumor involvement (a
majority of patients), irinotecan and SN-38 AUC values were somewhat higher
than values for patients without liver metastases (see PRECAUTIONS).
Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics
of irinotecan has not been evaluated.
Drug-Drug Interactions
In a phase 1 clinical study involving irinotecan, 5-fluorouracil
(5-FU), and leucovorin (LV) in 26 patients with solid tumors, the disposition
of irinotecan was not substantially altered when the drugs were co-administered.
Although the Cmax and AUC0-24 of SN-38, the active
metabolite, were reduced (by 14% and 8%, respectively) when irinotecan was followed
by 5-FU and LV administration compared with when irinotecan was given alone,
this sequence of administration was used in the combination trials and is recommended
(see DOSAGE AND ADMINISTRATION). Formal
in vivo or in vitro drug interaction studies to evaluate the influence of irinotecan
on the disposition of 5-FU and LV have not been conducted. Possible pharmacokinetic
interactions of CAMPTOSAR with other concomitantly administered medications
have not been formally investigated.
CLINICAL STUDIES
Irinotecan has been studied in clinical trials in combination
with 5-fluorouracil (5-FU) and leucovorin (LV) and as a single agent (see DOSAGE
AND ADMINISTRATION). When given as a component of combination-agent
treatment, irinotecan was either given with a weekly schedule of bolus 5-FU/LV
or with an every-2-week schedule of infusional 5-FU/LV. Weekly and a once-every-3-week
dosage schedules were used for the single-agent irinotecan studies. Clinical
studies of combination and single-agent use are described below.
First-Line Therapy in Combination with 5-FU/LV for the Treatment
of Metastatic Colorectal Cancer
Two phase 3, randomized, controlled, multinational clinical
trials support the use of CAMPTOSAR Injection as first-line treatment of patients
with metastatic carcinoma of the colon or rectum. In each study, combinations
of irinotecan with 5-FU and LV were compared with 5-FU and LV alone. Study 1
compared combination irinotecan/bolus 5-FU/LV therapy given weekly with a standard
bolus regimen of 5-FU/LV alone given daily for 5 days every 4 weeks; an irinotecan-alone
treatment arm given on a weekly schedule was also included. Study 2 evaluated
two different methods of administering infusional 5-FU/LV, with or without irinotecan.
In both studies, concomitant medications such as antiemetics, atropine, and
loperamide were given to patients for prophylaxis and/or management of symptoms
from treatment. In Study 2, a 7-day course of fluoroquinolone antibiotic prophylaxis
was given in patients whose diarrhea persisted for greater than 24 hours despite
loperamide or if they developed a fever in addition to diarrhea. Treatment with
oral fluoroquinolone was also initiated in patients who developed an absolute
neutrophil count (ANC) < 500/mm3, even in the absence of fever
or diarrhea. Patients in both studies also received treatment with intravenous
antibiotics if they had persistent diarrhea or fever or if ileus developed.
In both studies, the combination of irinotecan/5-FU/LV therapy
resulted in significant improvements in objective tumor response rates, time
to tumor progression, and survival when compared with 5-FU/LV alone. These differences
in survival were observed in spite of second-line therapy in a majority of patients
on both arms, including crossover to irinotecan-containing regimens in the control
arm. Patient characteristics and major efficacy results are shown in Table 2.
Table 2. Combination Dosage Schedule: Study Results
| |
Study 1
|
Study 2
|
|
Irinotecan + Bolus 5-FU/LV weekly x 4 q 6 weeks
|
Bolus 5-FU/LV daily x 5 q 4 weeks
|
Irinotecan weekly x 4 q 6 weeks
|
Irinotecan+ Infusional 5-FU/LV
|
Infusional 5-FU/LV
|
|
Number of Patients
|
231
|
226
|
226
|
198
|
187
|
|
Demographics and Treatment Administration
|
|
Female/Male (%)
|
34/65
|
45/54
|
35/64
|
33/67
|
47/53
|
|
Median Age in years (range)
|
62 (25-85)
|
61 (19-85)
|
61 (30-87)
|
62 (27-75)
|
59 (24-75)
|
|
Performance Status (%)
|
|
0
|
39
|
41
|
46
|
51
|
51
|
|
1
|
46
|
45
|
46
|
42
|
41
|
|
2
|
15
|
13
|
8
|
7
|
8
|
|
Primary Tumor (%)
|
|
Colon
|
81
|
85
|
84
|
55
|
65
|
|
Rectum
|
17
|
14
|
15
|
45
|
35
|
|
Median Time from Diagnosis to
|
|
Randomization
|
1.9
|
1.7
|
1.8
|
4.5
|
2.7
|
|
(months, range)
|
(0-161)
|
(0-203)
|
(0.1-185)
|
(0-88)
|
(0-104)
|
|
Prior Adjuvant 5-FU Therapy (%)
|
|
No
|
89
|
92
|
90
|
74
|
76
|
|
Yes
|
11
|
8
|
10
|
26
|
24
|
|
Median Duration of Study
|
|
Treatmenta (months)
|
5.5
|
4.1
|
3.9
|
5.6
|
4.5
|
|
Median Relative Dose Intensity (%)a
|
|
Irinotecan
|
72
|
--
|
75
|
87
|
--
|
|
5-FU
|
71
|
86
|
--
|
86
|
93
|
|
Efficacy Results
|
|
|
|
|
|
|
Confirmed Objective Tumor
|
39
|
21
|
18
|
35
|
22
|
|
Response Rateb (%)
|
(p<0.0001)c
|
|
(p<0.005)c
|
|
Median Time to Tumor Progressiond(months)
|
7.0
|
4.3
|
4.2
|
6.7
|
4.4
|
|
(p=0.004)d
|
|
(p<0.001)d
|
|
Median Survival (months)
|
14.8
|
12.6
|
12.0
|
17.4
|
14.1
|
|
(p <0.05)d
|
|
(p<0.05)d
|
a Study 1: N=225 (irinotecan/5-FU/LV), N=219 (5-FU/LV),
N=223 (irinotecan) Study 2: N=199 (irinotecan/5-FU/LV), N=186 (5-FU/LV)
b Confirmed ³ 4 to 6
weeks after first evidence of objective response
c Chi-square test
d Log-rank test
Improvement was noted with irinotecan-based combination therapy
relative to 5-FU/LV when response rates and time to tumor progression were examined
across the following demographic and disease-related subgroups (age, gender,
ethnic origin, performance status, extent of organ involvement with cancer,
time from diagnosis of cancer, prior adjuvant therapy, and baseline laboratory
abnormalities). Figures 1 and 2 illustrate the Kaplan-Meier survival curves
for the comparison of irinotecan/5-FU/LV versus 5-FU/LV in Studies 1 and 2,
respectively.
Second-Line Treatment for Recurrent or Progressive Metastatic
Colorectal Cancer After 5-FU-Based Treatment
Weekly Dosage Schedule
Data from three open-label, single-agent, clinical studies,
involving a total of 304 patients in 59 centers, support the use of CAMPTOSAR
in the treatment of patients with metastatic cancer of the colon or rectum that
has recurred or progressed following treatment with 5-FU-based therapy. These
studies were designed to evaluate tumor response rate and do not provide information
on actual clinical benefit, such as effects on survival and disease-related
symptoms. In each study, CAMPTOSAR was administered in repeated 6-week cycles
consisting of a 90-minute intravenous infusion once weekly for 4 weeks, followed
by a 2-week rest period. Starting doses of CAMPTOSAR in these trials were 100,
125, or 150 mg/m2, but the 150-mg/m2 dose was poorly tolerated
(due to unacceptably high rates of grade 4 late diarrhea and febrile neutropenia).
Study 1 enrolled 48 patients and was conducted by a single investigator at several
regional hospitals. Study 2 was a multicenter study conducted by the North Central
Cancer Treatment Group. All 90 patients enrolled in Study 2 received a starting
dose of 125 mg/m2. Study 3 was a multicenter study that enrolled
166 patients from 30 institutions. The initial dose in Study 3 was 125 mg/m2
but was reduced to 100 mg/m2 because the toxicity seen at the 125-mg/m2
dose was perceived to be greater than that seen in previous studies. All
patients in these studies had metastatic colorectal cancer, and the majority
had disease that recurred or progressed following a 5-FU-based regimen administered
for metastatic disease. The results of the individual studies are shown in Table
3.
Table 3. Weekly Dosage Schedule: Study Results
| |
Study
|
| |
1
|
2
|
3
|
|
Number of Patients
|
48
|
90
|
64
|
102
|
|
Starting Dose (mg/m2/wk x 4)
|
125a
|
125
|
125
|
100
|
|
Demographics and Treatment Administration
|
|
Female/Male (%)
|
46/54
|
36/64
|
50/50
|
51/49
|
|
Median Age in years (range)
|
63 (29-78)
|
63 (32-81)
|
61 (42-84)
|
64 (25-84)
|
|
Ethnic Origin (%)
|
|
White
|
79
|
96
|
81
|
91
|
|
African American
|
12
|
4
|
11
|
5
|
|
Hispanic
|
8
|
0
|
8
|
2
|
|
Oriental/Asian
|
0
|
0
|
0
|
2
|
|
Performance Status (%)
|
|
0
|
60
|
38
|
59
|
44
|
|
1
|
38
|
48
|
33
|
51
|
|
2
|
2
|
14
|
8
|
5
|
|
Primary Tumor (%)
|
|
Colon
|
100
|
71
|
89
|
87
|
|
Rectum
|
0
|
29
|
11
|
8
|
|
Unknown
|
0
|
0
|
0
|
5
|
|
Prior 5-FU Therapy (%)
|
|
|
|
|
|
For Metastatic Disease
|
81
|
66
|
73
|
68
|
|
6 months after Adjuvant
|
15
|
7
|
27
|
28
|
|
> 6 months after Adjuvant
|
2
|
16
|
0
|
2
|
|
Classification Unknown
|
2
|
12
|
0
|
3
|
|
Prior Pelvic/Abdominal Irradiation (%)
|
|
Yes
|
3
|
29
|
0
|
0
|
|
Other
|
0
|
9
|
2
|
4
|
|
None
|
97
|
62
|
98
|
96
|
|
Duration of Treatment with
|
|
CAMPTOSAR (median, months)
|
5
|
4
|
4
|
3
|
|
Relative Dose Intensityb (median %)
|
74
|
67
|
73
|
81
|
|
Efficacy
|
|
Confirmed Objective Response Rate (%)c
|
21
|
13
|
14
|
9
|
|
(95% CI)
|
(9.3 - 32.3)
|
(6.3 - 20.4)
|
(5.5 - 22.6)
|
(3.3 - 14.3)
|
|
Time to Response (median, months)
|
2.6
|
1.5
|
2.8
|
2.8
|
|
Response Duration (median, months)
|
6.4
|
5.9
|
5.6
|
6.4
|
|
Survival (median, months)
|
10.4
|
8.1
|
10.7
|
9.3
|
|
1-Year Survival (%)
|
46
|
31
|
45
|
43
|
a Nine patients received 150 mg/m2 as
a starting dose; two (22.2%) responded to CAMPTOSAR.
b Relative dose intensity for CAMPTOSAR based on
planned dose intensity of 100, 83.3, and 66.7 mg/m2/wk corresponding
with 150, 125, and 100 mg/m2 starting doses, respectively.
c Confirmed =4 to 6 weeks after first evidence of
objective response.
In the intent-to-treat analysis of the pooled data across all
three studies, 193 of the 304 patients began therapy at the recommended starting
dose of 125 mg/m2. Among these 193 patients, 2 complete and 27 partial
responses were observed, for an overall response rate of 15.0% (95% Confidence
Interval [CI], 10.0% to 20.1%) at this starting dose. A considerably lower response
rate was seen with a starting dose of 100 mg/m2. The majority of
responses were observed within the first two cycles of therapy, but responses
did occur in later cycles of treatment (one response was observed after the
eighth cycle). The median response duration for patients beginning therapy at
125 mg/m2 was 5.8 months (range, 2.6 to 15.1 months). Of the 304
patients treated in the three studies, response rates to CAMPTOSAR were similar
in males and females and among patients older and younger than 65 years. Rates
were also similar in patients with cancer of the colon or cancer of the rectum
and in patients with single and multiple metastatic sites. The response rate
was 18.5% in patients with a performance status of 0 and 8.2% in patients with
a performance status of 1 or 2. Patients with a performance status of 3 or 4
have not been studied. Over half of the patients responding to CAMPTOSAR had
not responded to prior 5-FU. Patients who had received previous irradiation
to the pelvis responded to CAMPTOSAR at approximately the same rate as those
who had not previously received irradiation.
Once-Every-3-Week Dosage Schedule
Single-Arm Studies: Data from an open-label, single-agent,
single-arm, multicenter, clinical study involving a total of 132 patients support
a once every-3-week dosage schedule of irinotecan in the treatment of patients
with metastatic cancer of the colon or rectum that recurred or progressed following
treatment with 5-FU. Patients received a starting dose of 350 mg/m2 given
by 30-minute intravenous infusion once every 3 weeks. Among the 132 previously
treated patients in this trial, the intent-to-treat response rate was 12.1%
(95% CI, 7.0% to 18.1%). Randomized Trials: Two multicenter, randomized,
clinical studies further support the use of irinotecan given by the once-every-3-week
dosage schedule in patients with metastatic colorectal cancer whose disease
has recurred or progressed following prior 5-FU therapy. In the first study,
second-line irinotecan therapy plus best supportive care was compared with best
supportive care alone. In the second study, second-line irinotecan therapy was
compared with infusional 5-FU-based therapy. In both studies, irinotecan was
administered intravenously at a starting dose of 350 mg/m2 over 90
minutes once every 3 weeks. The starting dose was 300 mg/m2 for patients
who were 70 years and older or who had a performance status of 2. The highest
total dose permitted was 700 mg. Dose reductions and/or administration delays
were permitted in the event of severe hematologic and/or nonhematologic toxicities
while on treatment. Best supportive care was provided to patients in both arms
of Study 1 and included antibiotics, analgesics, corticosteroids, transfusions,
psychotherapy, or any other symptomatic therapy as clinically indicated. In
both studies, concomitant medications such as antiemetics, atropine, and loperamide
were given to patients for prophylaxis and/or management of symptoms from treatment.
If late diarrhea persisted for greater than 24 hours despite loperamide, a 7-day
course of fluoroquinolone antibiotic prophylaxis was given. Patients in the
control arm of the second study received one of the following 5-FU regimens:
(1) LV, 200 mg/m2 IV over 2 hours; followed by 5-FU, 400 mg/m2
IV bolus; followed by 5-FU, 600 mg/m2 continuous IV infusion over
22 hours on days 1 and 2 every 2 weeks; (2) 5-FU, 250 to 300 mg/m2
/day protracted continuous IV infusion until toxicity; (3) 5-FU, 2.6 to 3 g/m2
IV over 24 hours every week for 6 weeks with or without LV, 20 to 500 mg/m2
/day every week IV for 6 weeks with 2-week rest between cycles. Patients were
to be followed every 3 to 6 weeks for 1 year.
A total of 535 patients were randomized in the two studies
at 94 centers. The primary endpoint in both studies was survival. The studies
demonstrated a significant overall survival advantage for irinotecan compared
with best supportive care (p=0.0001) and infusional 5-FU-based therapy (p=0.035)
as shown in Figures 3 and 4. In Study 1, median survival for patients treated
with irinotecan was 9.2 months compared with 6.5 months for patients receiving
best supportive care. In Study 2, median survival for patients treated with
irinotecan was 10.8 months compared with 8.5 months for patients receiving infusional
5-FU-based therapy. Multiple regression analyses determined that patients’ baseline
characteristics also had a significant effect on survival. When adjusted for
performance status and other baseline prognostic factors, survival among patients
treated with irinotecan remained significantly longer than in the control populations
(p=0.001 for Study 1 and p=0.017 for Study 2). Measurements of pain, performance
status, and weight loss were collected prospectively in the two studies; however,
the plan for the analysis of these data was defined retrospectively. When comparing
irinotecan with best supportive care in Study 1, this analysis showed a statistically
significant advantage for irinotecan, with longer time to development of pain
(6.9 months versus 2.0 months), time to performance status deterioration (5.7
months versus 3.3 months), and time to > 5% weight loss (6.4 months versus
4.2 months). Additionally, 33.3% (33/99) of patients with a baseline performance
status of 1 or 2 showed an improvement in performance status when treated with
irinotecan versus 11.3% (7/62) of patients receiving best supportive care (p=0.002).
Because of the inclusion of patients with non-measurable disease, intent-to-treat
response rates could not be assessed.
Table 4. Once-Every-3-Week Dosage Schedule: Study Results
| |
Study 1
|
Study 2
|
| |
Irinotecan
|
BSCa
|
Irinotecan
|
5-FU
|
|
Number of Patients
|
189
|
90
|
127
|
129
|
|
Demographics and Treatment Administration
|
|
Female/Male (%)
|
32/68
|
42/58
|
43/57
|
35/65
|
|
Median Age in years (range)
|
59 (22-75)
|
62 (34-75)
|
58 (30-75)
|
58 (25-75)
|
|
Performance Status (%)
|
|
0
|
47
|
31
|
58
|
54
|
|
1
|
39
|
46
|
35
|
43
|
|
2
|
14
|
23
|
8
|
3
|
|
Primary Tumor (%)
|
|
Colon
|
55
|
52
|
57
|
62
|
|
Rectum
|
45
|
48
|
43
|
38
|
|
Prior 5-FU Therapy (%)
|
|
For Metastatic Disease
|
70
|
63
|
58
|
68
|
|
As Adjuvant Treatment
|
30
|
37
|
42
|
32
|
|
Prior Irradiation (%)
|
26
|
27
|
18
|
20
|
|
Duration of Study Treatment (median, months) (Log-rank
test)
|
4.1
|
--
|
4.2 (p=0.02)
|
2.8
|
|
Relative Dose Intensity (median %)b
|
94
|
--
|
95
|
81-99
|
|
Survival
|
|
Survival (median, months)
|
9.2
|
6.5
|
10.8
|
8.5
|
|
(Log-rank test)
|
(p=0.0001)
|
|
(p=0.035)
|
|
a BSC = best supportive care
b Relative dose intensity for irinotecan based on
planned dose intensity of 116.7 and 100 mg/m2/wk corresponding with
350 and 300 mg/m2 starting doses, respectively.
In the two randomized studies, the EORTC QLQ-C30 instrument
was utilized. At the start of each cycle of therapy, patients completed a questionnaire
consisting of 30 questions, such as "Did pain interfere with daily activities?"
(1 = Not at All, to 4 = Very Much) and "Do you have any trouble taking
a long walk?" (Yes or No). The answers from the 30 questions were converted
into 15 subscales, that were scored from 0 to 100, and the global health status
subscale that was derived from two questions about the patient’s sense of general
well being in the past week. In addition to the global health status subscale,
there were five functional (i.e., cognitive, emotional, social, physical, role)
and nine symptom (i.e., fatigue, appetite loss, pain assessment, insomnia, constipation,
dyspnea, nausea/vomiting, financial impact, diarrhea) subscales. The results
as summarized in Table 5 are based on patients’ worst post-baseline scores.
In Study 1, a multivariate analysis and univariate analyses of the individual
subscales were performed and corrected for multivariate testing. Patients receiving
irinotecan reported significantly better results for the global health status,
on two of five functional subscales, and on four of nine symptom subscales.
As expected, patients receiving irinotecan noted significantly more diarrhea
than those receiving best supportive care. In Study 2, the multivariate analysis
on all 15 subscales did not indicate a statistically significant difference
between irinotecan and infusional 5-FU.
Table 5. EORTC QLQ-C30: Mean Worst Post-Baseline Scorea
|
QLQ-C30 Subscale
|
Study 1
|
Study 2
|
| |
Irinotecan
|
BSC
|
p-value
|
Irinotecan
|
5-FU
|
p-value
|
|
Global Health Status
|
47
|
37
|
0.03
|
53
|
52
|
0.9
|
|
Functional Scales
|
|
Cognitive
|
77
|
68
|
0.07
|
79
|
83
|
0.9
|
|
Emotional
|
68
|
64
|
0.4
|
64
|
68
|
0.9
|
|
Social
|
58
|
47
|
0.06
|
65
|
67
|
0.9
|
|
Physical
|
60
|
40
|
0.0003
|
66
|
66
|
0.9
|
|
Role
|
53
|
35
|
0.02
|
54
|
57
|
0.9
|
|
Symptom Scales
|
|
Fatigue
|
51
|
63
|
0.03
|
47
|
46
|
0.9
|
|
Appetite Loss
|
37
|
57
|
0.0007
|
35
|
38
|
0.9
|
|
Pain Assessment
|
41
|
56
|
0.009
|
38
|
34
|
0.9
|
|
Insomnia
|
39
|
47
|
0.3
|
39
|
33
|
0.9
|
|
Constipation
|
28
|
41
|
0.03
|
25
|
19
|
0.9
|
|
Dyspnea
|
31
|
40
|
0.2
|
25
|
24
|
0.9
|
|
Nausea/Vomiting
|
27
|
29
|
0.5
|
25
|
16
|
0.09
|
|
Financial Impact
|
22
|
26
|
0.5
|
24
|
15
|
0.3
|
|
Diarrhea
|
32
|
19
|
0.01
|
32
|
22
|
0.2
|
aFor the five functional subscales and global health
status subscale, higher scores imply better functioning, whereas, on the nine
symptom subscales, higher scores imply more severe symptoms. The subscale scores
of each patient were collected at each visit until the patient dropped out of
the study.
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