Open-Label, Multicenter, Randomized Phase III Trial of Adjuvant

Transcription

VOLUME 30 䡠 NUMBER 33 䡠 NOVEMBER 20 2012
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Open-Label, Multicenter, Randomized Phase III Trial of
Adjuvant Chemoradiation Plus Interferon Alfa-2b Versus
Fluorouracil and Folinic Acid for Patients With Resected
Pancreatic Adenocarcinoma
Jan Schmidt, Ulrich Abel, Jürgen Debus, Sabine Harig, Katrin Hoffmann, Thomas Herrmann, Detlef Bartsch,
Justus Klein, Ulrich Mansmann, Dirk Jäger, Lorenzo Capussotti, Reiner Kunz, and Markus W. Büchler
See accompanying editorial on page 4049
Jan Schmidt, Ulrich Abel, Jürgen
Debus, Sabine Harig, Katrin Hoffmann,
Thomas Herrmann, Dirk Jäger, and
Markus W. Büchler, Ruprecht-KarlsUniversity, Heidelberg; Detlef Bartsch,
Hospital of Beilefeld, Bielefeld; Justus
Klein, Hospital of Herford, Herford;
Ulrich Mansmann, University of
Munich, Munich; Reiner Kunz, St
Joseph Hospital, Berlin, Berlin, Germany;
and Lorenzo Capussotti, Mauriziano
Hospital Umberto I, Torino, Italy.
Submitted September 20, 2011;
accepted July 11, 2012; published
online ahead of print at www.jco.org on
October 8, 2012.
Supported by a grant from the Manfred
Lautenschläger Foundation.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Clinical trial information:
ISRCTN62866759.
Corresponding author: Markus W.
Büchler, MD, Department of Surgery,
Im Neuenheimer Feld 110, 69120
Heidelberg, Germany; e-mail: Markus
[email protected].
© 2012 by American Society of Clinical
Oncology
A
B
S
T
R
A
C
T
Purpose
Adjuvant chemotherapy prolongs survival in patients with pancreatic cancer, but its benefit is
limited. Long-term survival times of up to 44 months after adjuvant chemoradioimmunotherapy in
phase II trials motivated the present study.
Patients and Methods
Between 2004 and 2007, 132 R0/R1 resected patients received either fluorouracil (FU), cisplatin,
and interferon alfa-2b (IFN ␣-2b) plus radiotherapy followed by two cycles of FU (arm A, n ⫽ 64)
or six cycles of FU monotherapy (arm B, n ⫽ 68). One hundred ten patients (arm A, n ⫽ 53; arm
B, n ⫽ 57) received at least one dose of the study medication, and these patients composed the
per-protocol (PP) population. Biomarkers were analyzed longitudinally for their predictive value.
Results
Median survival for all randomly assigned patients was 26.5 months (95% CI, 21.6 to 39.5 months)
in arm A and 28.5 months (95% CI, 20.4 to 38.6 months) in arm B. The hazard ratio was 1.04 (arm
A v arm B: 95% CI, 0.66 to 1.53; P ⫽ .99). Median survival for the PP population was 32.1 months
(95% CI, 22.8 to 42.2 months) in arm A and 28.5 months (95% CI, 19.5 to 38.6 months) in arm B
(P ⫽ .49). Eighty-five percent of patients in arm A and 16% of patients in arm B experienced grade
3 or 4 toxicity. The quality of life was temporarily negatively affected in arm A.
Conclusion
The FU, cisplatin, and IFN ␣-2b plus radiotherapy regimen did not improve the survival compared
with FU monotherapy. Given the substantial adverse effects, this treatment can currently not be
recommended. Nevertheless, the outcome in both arms represents the best survival, to our
knowledge, ever reported for patients with resected pancreatic cancer in randomized controlled
trials. Future studies will demonstrate whether immune response to IFN ␣-2b challenge has a
predictive value.
J Clin Oncol 30:4077-4083. © 2012 by American Society of Clinical Oncology
0732-183X/12/3033-4077/$20.00
DOI: 10.1200/JCO.2011.38.2960
INTRODUCTION
Patients with pancreatic adenocarcinoma have an
especially poor prognosis. The 5-year overall survival (OS) rate is less than 5%, with a median survival time of 4 to 6 months. After surgical resection,
5-year OS rates of 25% have been reported for patients with adjuvant therapy.1 There are few randomized trials on adjuvant therapy for pancreatic
carcinoma. The European Study Group for Pancreatic Cancer (ESPAC) -1 trial assessed patients undergoing adjuvant chemotherapy with fluorouracil
(FU) and showed a significant survival benefit, with
a 5-year OS rate of 21% compared with 8% for
untreated controls.2 The CONKO-001 (Charité
Onkologie– 001) trial confirmed the role of adjuvant
treatment. This study comprised patients randomly
assigned to gemcitabine or best supportive care and
showed a significant increase in 5-year OS rate and
median OS time.3 Finally, the ESPAC-3 trial compared gemcitabine with FU and found no difference
in median OS.4
Investigators from the Virginia Mason Clinic
published data of a phase II trial of 43 patients undergoing combined therapy with cisplatin, FU, interferon alfa-2b (IFN ␣-2b), and external-beam
© 2012 by American Society of Clinical Oncology
Downloaded from ascopubs.org by 78.47.27.170 on January 15, 2017 from 078.047.027.170
Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
4077
Schmidt et al
radiation after pancreaticoduodenectomy and reported a 5-year OS
rate of 55%.5 The American College of Surgeons Oncology Group trial
investigated this regimen in a multicenter study, but because of
toxicity, the trial was stopped. However, recruitment was almost
complete at this point. The reported median survival was 27
months.6 We decided to evaluate this adjuvant regimen in a randomized, controlled, prospective, multicenter phase III trial compared with FU plus folinic acid.
The inclusion of IFN ␣-2b was supported by our in vitro data,
which indicated a relevant potential of IFN ␣-2b to modulate the
tumor behavior.7-11 Specifically, IFN ␣-2b had inhibitory effects on
tumor cell growth,12,13 radiotherapy- and chemotherapy-sensitizing
effects,14,15 and antiangiogenic properties16,17; enhanced the immunogenicity of tumors13; and modulated the immune system.13,18-20
patient in oral and written form before inclusion in the trial. The trial was
registered at the International Standard Randomised Controlled Trial Number Register (ISRCTN62866759) and monitored by an independent contract
research organization.
PATIENTS AND METHODS
Study Treatment
Patients in study arm A were treated as outpatients with FU (200 mg/m2
per day, continuous infusion), cisplatin (30 mg/m2 per week), and 3 million
units of IFN ␣-2b (three times a week) for 5.5 weeks combined with externalbeam radiation (50.4 Gy in 28 fractions) followed by two cycles of continuous
FU (days 64 to 101 and days 120 to 161). Patients treated in arm A were
challenged 4 to 6 days before therapy with a single dose of IFN ␣-2b. Nonsteroidal anti-inflammatory drugs and corticosteroids were avoided if possible
during IFN ␣-2b treatment. Because major combined electrolyte deficiency
was observed in some patients, an intensive electrolyte monitoring and prophylactic substitution treatment was performed.22 Patients in study arm B
were treated with bolus injections of folinic acid (FA; 20 mg/m2) and FU (425
mg/m2) given on 5 consecutive days every 28 days for six cycles; for a detailed
overview see Knaebel et al.21
Study Design and Patients
Patients with histologically proven resected (R0 or R1) pancreatic adenocarcinoma and Karnofsky performance score ⱖ 70 were eligible for enrollment within 12 weeks after operation. One hundred thirty-two patients were
randomly assigned (intent-to-treat [ITT] population: arm A, n ⫽ 64; arm B,
n ⫽ 68). Of these, 110 patients (arm A, n ⫽ 53; arm B, n ⫽ 57) receiving at least
one dose of study treatment formed the per-protocol (PP) population. Patients with known hypersensitivity to IFN ␣-2b, autoimmune disease, or
depression were excluded; for a detailed overview, see Knaebel et al.21 The final
protocol was approved by the Ethics Committee of the University of Heidelberg, Medical School (L-042/2003). Informed consent was obtained from each
Assessments
Laboratory and physical evaluations were performed before the start
and at the end of any therapy cycle. In the post-treatment period, patients
were seen every 3 months in the first 2 years, every 4 months in the third
year, and every 6 months during the fourth and fifth post-treatment years.
Computed tomography imaging was performed every 6 months and
whenever clinically indicated.
The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30; the EORTC QLQPAN26 pancreatic cancer module assessing disease-specific symptoms; and
the Center for Epidemiologic Studies Depression Scale, a 20-item self-report
Assessed for eligibility
(N = 510)
Excluded
Did not meet inclusion
criteria
Declined to participate
Other reasons
(n = 378)
(n = 227)
(n = 151)
(n = 0)
Randomly allocated
(n = 132)
Allocated to Arm A
Received allocated
intervention
Did not receive allocated
intervention
criteria
Withdrawal
(n = 64)
(n = 53)
Lost to follow-up (withdrew
before treatment start)
Discontinued intervention
due to recurrence
(n = 2)
(n = 11)
(n = 7)
(n = 4)
(n = 7)
Analyzed
ITT population (including
(n = 64)
two pts with early censoring)
PP population (did not
(n = 53)
receive at least one dose)
4078
Allocated to Arm B
Received allocated
intervention
Did not receive allocated
intervention
criteria
Withdrawal
(n = 68)
(n = 57)
Lost to follow-up (withdrew
before treatment start)
Discontinued intervention
due to recurrence
(n = 0)
Analyzed
ITT population
PP population (did not
receive at least one dose)
(n = 11)
Fig 1. CONSORT flow chart. ITT, intentto-treat; PP, per-protocol.
(n = 4)
(n = 7)
(n = 9)
(n = 68)
(n = 57)
Adjuvant Chemoradioimmunotherapy for Pancreatic Cancer
Statistical Analyses
The sample size calculation was based on the assumption (under H1) of
a constant monthly hazard rate of 0.044 in group B (FU/FA) and a constant
monthly hazard rate of 0.021 in arm A. These hazard values were derived from
2-year survival rates of 35% in arm B and 60% in arm A, assuming exponential
survival curves. Assuming an accrual period of 18 months and a (total)
follow-up of 42 months (18 ⫹ 24 months), testing for the aforementioned
difference in hazard rates at a level of ␣ ⫽ 5% and with a power of 80% yielded
a study size of 96 evaluable patients (48 patients per treatment group). Originally, patients not completing the treatment were planned to be excluded from
analysis. With an anticipated number of 14 patients stopping the treatment
prematurely, a total of 110 patients were planned to be randomly assigned.
Table 1. Demographics and Baseline Clinical Characteristics for All Patients
%
60.0
30.0-74.0
%
60.4
33.0-77.0
No. of
Patients
%
60.2
31.0-77.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Arm A
Arm B
0
19
34
36
64
29
24
55
45
30
27
37
19
53
47
66
34
49
61
66
43
45
55
61
39
1
2
49
1
2
4
92
2
0
1
55
1
0
2
96
2
1
3
104
2
1
3
95
2
11
42
21
79
12
45
21
79
23
87
21
79
2
40
11
4
75
21
1
44
12
2
77
21
3
84
23
3
76
21
35
66
39
69
74
67
4
14
8
26
11
7
19
12
15
21
14
19
36.5
8.0-74.0
39.3
7.0-83.0
38.0
7.0-83.0
882.3
1.0-15,641.0
407.8
0.6-3,258.8
638.7
0.6-15,641.0
23.3
15.1-41.7
24.0
16.5-37.0
23.6
15.1-41.7
Abbreviation: BMI, body mass index.
www.jco.org
No. of
Patients
Both Arms
(n ⫽ 110)
B
64
66
12
18
24
58
66
50
53
41
43
35
36
30
36
42
48
54
60
24
28
16
20
12
12
8
8
6
6
3
3
72
6
12
18
24
30
36
42
48
54
60
8
7
6
5
3
3
66
72
Time (months)
No. at risk
Arm A
Arm B
53
57
53
56
46
45
39
35
33
29
24
23
16
17
12
11
Arm A
Arm B
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
No. at risk
Arm A
Arm B
66
Arm A
Arm B
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
C
6
Time (months)
No. at risk
Arm A
Arm B
Overall Survival
(probability)
Age, years
Mean
Range
Sex
Female
Male
Resection
R0
R1
Tumor status
T1
T2
T3
T4
Node status
N0
N1
Grade
1
2
3
Pylorus-preserving
Whipple
procedure
Classic Whipple
procedure
Left resection
Treatment start,
days
Mean
Range
Preoperative CA
19-9, U/mL
Mean
Range
BMI, kg/m2
Mean
Range
No. of
Patients
Arm B
(n ⫽ 57)
A
Disease-Free
Survival (probability)
Demographic or
Clinical
Characteristic
Arm A
(n ⫽ 53)
However, the definition of the primary efficacy analysis population changed
during the course of the study. According to the final decision, all patients who
did not receive at least one dose of the study treatment were to be excluded
from the primary analysis set and to be replaced. In total, 132 patients were
randomly assigned (ITT population: group A, n ⫽ 64; group B, n ⫽ 68). Of
these, 110 patients (PP population: group A, n ⫽ 53; group B, n ⫽ 57) started
the study treatment. Data on disease-free survival, QoL, and toxicity were
available only for patients in the PP population.
Random assignment was central. A separate randomization list (block
randomization, 1:1) was prepared for each participating center. The primary
efficacy end point was survival time; the secondary efficacy end point was
disease-free survival. The end points to be included in the analysis of QoL were
the single items of the QoL instruments, except where aggregate scales were
proposed in the user manuals.
Standard methods for survival analysis were used in the analysis of
time-to-event end points, including Kaplan-Meier estimates of the survivor
functions, Greenwood’s formula for estimating the SE of event rates, the Cox
proportional hazards model, and the log-rank test for comparing two survival
Overall Survival
(probability)
measure of depression that emphasizes the emotional dimension for depression, were used as quality-of-life (QoL) instruments.23,24 Questionnaires were
provided at baseline and at every follow-up visit. Patients in arm A had further
assessments in the middle and at the end of cycle 1 and at the end of cycles 2 and
3. Documentation of clinical follow-up data in this trial was restricted to
patients who received at least one dose of the study treatment.
6
12
18
24
45
49
27
28
23
20
20
16
30
36
42
48
54
60
7
4
6
3
3
1
66
72
Time (months)
53
57
13
11
11
7
8
4
Fig 2. Overall survival in the (A) intent-to-treat and (B) per-protocol populations
and (C) disease-free survival in the per-protocol population.
4079
Schmidt et al
curves.25 Follow-up was quantified using the Kaplan-Meier estimate of
potential follow-up. The Cox proportional hazards model was used to
investigate the influence of potentially important prognostic factors (baseline variables) on survival time and to adjust the treatment effect in the PP
population for imbalance in baseline variables. Briefly, the adjustment
proceeded as follows. Screening was performed for potential confounders;
variables were selected as potential confounders if their inclusion as a
second variable in the model changed the estimated treatment effect by at
least 10%. For tumor marker values, logarithms were used. Then, the
variables selected in the screening process were included in a multivariable
model. In a backward selection, variables were dropped from this model
using the same (10% change) criterion.
No covariates were used in the primary efficacy analysis. Comparison of
treatment groups with respect to uncensored continuous variables was done
using the Wilcoxon rank sum test. Fisher’s exact test was used in case of
categorical variables. Because most patients were recruited in one center,
center effects were not accounted for. Missing data were not replaced or
imputed. QoL end points were analyzed along the lines described by Machin
and Weeden.26 Average areas under the curve (AUCs) were calculated as the
total AUC divided by the number of days in the interval. Only patients who
completed at least three QoL assessments were included in the calculation of
the AUC.
One interim analysis was conducted 1 year after the start of patient
enrollment. In case of a highly significant advantage (P ⬍ .001) for the group A
regimen, the treatment in group B was to be replaced with a regimen consisting
of chemoradiotherapy according to the cisplatin, FU, IFN ␣-2b, and externalbeam radiation (CapRI) regimen, but without the IFN ␣-2b treatment. The
results of this analysis did not warrant any change in the trial conduction.
Furthermore, the study included a stopping rule based on continuous monitoring of treatment-related deaths. This rule, which used a Bayesian criterion
with uniform prior, stipulated that the study had to be stopped once the
posterior probability that the rate of treatment-related deaths exceeded 5%
was higher than 90%. Because no treatment-related deaths were reported, the
stopping rule was not activated. Given that the significance level used in the
interim analysis was low, no adjustment of the main evaluation for multiple
testing was performed.
All statistical tests were two-tailed. The significance level was ␣ ⫽ 5%.
SAS Version 9.1.3 (SAS Institute, Cary, NC) was used to conduct the analysis.
Given the relatively small patient numbers, in this report, percentages are
rounded to whole numbers.
RESULTS
Patients and Treatment Compliance
One hundred thirty-two patients were randomly assigned.
Twenty-two patients did not receive any treatment as a result of
withdrawal or not meeting inclusion criteria (Fig 1). The two groups
were well balanced regarding demographics and baseline characteristics (Table 1). None of the group differences shown in Table 1 were
statistically significant. Although the mean values of CA 19-9 differed
considerably, because of outliers, the median values (arm A, 208.9
U/mL; arm B, 190.0 U/mL) were quite similar. Complete information
on treatment compliance was available for 41 patients in arm A and 46
patients in arm B. Only one patient in arm A received the total planned
dose compared with 32 patients (69.6%) in arm B. Dose reductions in
arm A were mainly performed for cisplatin and FU. On average, in
cycle 1, 96% of the IFN ␣-2b, 98% of the radiation, 75% of the
cisplatin, and 72% of the FU planned doses were administered.
Efficacy
Median follow-up for all randomly assigned patients (n ⫽ 132)
was 42.7 months. The survival curves for these patients are shown in
Figure 2A. These curves were virtually undistinguishable, reflected by
a hazard ratio (HR) of 1.04 for arm A versus arm B (95% CI, 0.66 to
1.53; P ⫽ .99). Median survival from date of resection was 26.5
months (95% CI, 21.6 to 39.5 months) in arm A and 28.5 months
(95% CI, 20.4 to 38.6 months) in arm B.
In the PP population, the median follow-up time was 45.9
months. The median OS time was 32.1 months (95% CI, 22.8 to 42.2
months) in arm A and 28.5 months (95% CI, 19.5 to 38.6 months) in
arm B (Fig 2B). OS was not significantly different between treatment
groups (P ⫽ .49). When adjusting the treatment effect on survival for
imbalance in covariates using the Cox proportional hazards model,
age, type of surgery, log(carcinoembryonic antigen), and log(CA
19-9) were retained as potential confounders in the final model. The
Table 2. Adverse Events
Cycle 1, Arm A
(n ⫽ 53)
Cycle 2, Arm A
(n ⫽ 51)
Adverse Event
No.
%
No.
Patients experiencing CTC grade 3 or 4
event
Grade 3 and 4 toxicities
Neutropenia
Hypovolemia/electrolyte disturbances
Nausea/vomiting
Anemia
Diarrhea
Thrombocytopenia
Other
Grade 4 toxicities
Acute renal insufficiency
Neutropenia
Hypovolemia/electrolyte disturbances
Hand-foot syndrome
Nausea/vomiting
Diarrhea
36
93
52
10
8
3
4
2
14
11
1
7
1
1
1
67.9
2
2
2
55.9
10.8
8.6
3.2
4.3
2.2
15.4
%
3.9
Cycle 3, Arm A
(n ⫽ 46)
No.
%
2
2
4.3
Arm B
(n ⫽ 57)
No.
%
9
13
15.8
1
1
7.7
7.7
10
76.9
1
1
7.7
100
2
100
9.1
63.6
9.1
9.1
9.1
1
100
Abbreviation: CTC, Common Toxicity Criteria.
4080
resulting HR of arm A versus arm B was 1.2 (95% CI, 0.49 to 2.95).
Median disease-free survival was 15.2 months (95% CI, 10.3 to 24.8
months) in arm A and 11.5 months (95% CI, 9.8 to 17.6 months) in
arm B (P ⫽ .61; Fig 2C). Time from recurrence to death was 12.3
months (95% CI, 9.3 to 14.4 months) in arm A and 10.2 months (95%
CI, 7.6 to 13.0 months) in arm B.
Prognostic Markers
Preoperative CA 19-9 levels were identified as a prognostic
marker. Patients with a preoperative CA 19-9 level greater than 250
U/mL had a median survival time of 19.3 months compared with 38.7
months in patients with a CA 19-9 level less than 250 U/mL (HR, 0.49;
95% CI, 0.29 to 0.82; P ⫽ .007). Node-positive patients had a median
survival of 25.3 months compared with 49.8 months for nodenegative patients (HR, 0.57; P ⫽ .035). Furthermore, patients starting
for any reason later than 8 weeks after surgery had a median survival of
25.4 months compared with 39.9 months for early starters (P ⫽ .067).
Safety and Adverse Event Profile
Grade 3 or 4 toxicity was observed in 85% of the patients in arm
A (mainly neutropenia and dehydration) and 16% of patients in arm
B (mainly diarrhea). Grade 4 toxicity was more prevalent in arm A
than arm B (29% v 2%, respectively; Table 2). Toxicity occurred
mainly in cycle 1 of arm A. Twelve percent and 4% of arm A patients
experienced grade 3 or 4 toxicity during cycles 2 and 3, respectively.
There were no adverse events resulting in death.22
QoL
With regard to the AUC, significant differences between groups
included global health status, role functioning, nausea/vomiting, and
appetite loss (Table 3). For all parameters shown in Table 3, QoL
tended to be worse in arm A. QoL as measured by EORTC QLQ-C30
for global health status over time is shown in Figures 3A and 3B. No
significant differences between groups with respect to AUC were
found for any parameter in the EORTC QLQ-PAN26 (data not
shown). Depression score as measured by the Center for Epidemiologic Studies Depression Scale is shown in Figure 3C for arm A and
Figure 3D for arm B. No QoL measurements have been performed
during the different courses of treatment for arm B patients. However,
although no comparison with arm B is possible, a clear deterioration
during cycle 1 of arm A is obvious. Patients started to recover at the
beginning of cycle 2 of arm A and were back at baseline when cycle 3
was started.
Treatment After Recurrence
Approximately 72% of the 88 patients who experienced recurrence underwent palliative treatment. Fifty-one patients (58%) received gemcitabine monotherapy as recommended in the trial
protocol, and seven patients received other chemotherapy (gemcitabine plus oxaliplatin, n ⫽ 4; gemcitabine plus capecitabine, n ⫽ 1;
infusional FU, leucovorin, and oxaliplatin, n ⫽ 1; FU, n ⫽ 1). Five
patients received other treatments (resection, n ⫽ 1; chemoembolization, n ⫽ 1; percutaneous radiotherapy, n ⫽ 1; chemoradiotherapy
not further specified, n ⫽ 2). Four patients were classified as having
recurrence at time of death.
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Table 3. EORTC QLQ-C30, Summary Statistics for the AUC
Measure
Dyspnea
No. of patients
Mean score
Range
Role functioning
No. of patients
Mean score
SD
Social functioning
No. of patients
Mean score
SD
Global health status
No. of patients
Mean score
SD
Nausea/vomiting
No. of patients
Mean score
SD
Appetite loss
No. of patients
Mean score
Range
25th percentile
75th percentile
Constipation
No. of patients
Mean score
Range
Arm A (n ⫽ 53) Arm B (n ⫽ 57) Total (n ⫽ 110)
Pⴱ
50
24.3
0.0-70.1
35
18.2
0.0-93.4
85
21.8
0.0-93.4
.053
50
55.6
22.6
35
69.5
22.5
85
61.4
23.5
.008
50
64.5
24.0
35
74.5
19.4
85
68.6
22.7
.061
50
55.8
16.4
36
62.8
14.6
86
58.7
16.0
.024
50
15.9
15.1
36
8.2
13.3
86
12.7
14.8
.001
50
29.8
0.0-90.5
10.8
41.0
36
18.2
0.0-71.3
0.0
31.0
86
25.0
0.0-90.5
5.8
39.5
.004
50
13.6
0.0-64.9
36
9.2
0.0-50.0
86
11.8
0.0-64.9
.055
NOTE. Statistics only shown for parameters with significant or borderline
significant group differences.
Abbreviations: AUC, area under the curve; EORTC QLQ-C30, European
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30; SD, standard deviation.
ⴱ
Wilcoxon rank sum test; in accordance with the specification for the EORTC
QLQ-C30, higher values correspond to a worse quality of life for dyspnea,
nausea/vomiting, appetite loss, and constipation and to a better quality of life
for role functioning, social functioning, and the global health status.
DISCUSSION
Pancreatic adenocarcinoma has a dismal prognosis even after curative
resection. The concept of adjuvant treatment has been proven within
the last decade with a reported increase in median survival from 15
months to 23 months.2-4 However, further improvement is needed.
The strategy of chemoradioimmunotherapy was investigated by Picozzi et al5 in a phase II trial with impressive outcome. On the basis of
these data, we designed the CapRI trial choosing the best known
chemotherapy at that time (FU) as comparator.
The chemoradioimmunotherapy regimen has been controversial because of its toxicity. This was especially true when the American
College of Surgeons Oncology Group Z05031 trial reported a grade 3
or 4 GI toxicity rate of 93%, leading to a premature stop of the trial.6
Our experience was similar; although toxicity in our study was lower
than that reported by the US centers, we still observed substantial
toxicity throughout all CapRI centers. Toxicity was mainly of hematologic origin but manageable. There may be several reasons for the
4081
Schmidt et al
N
52
49
49
48
41
28
23
22
19
16
16
9
11
100
B
Global Health Status / QoL
Global Health Status / QoL
A
75
50
25
0
N
53
42
31
23
18
19
V1
V8
FU 1
FU 2
FU 3
FU 4 FU 5
10
FU 6
FU 7
FU 8
13
11
FU 6
FU 7
25
0
46
41
46
39
37
23
22
Visit
19
18
15
14
10
10
D
N
50
50
40
40
30
30
Score
Score
11
50
Visit
N
15
75
V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8
C
14
100
20
43
41
29
20
12
19
13
V1
V8
FU 1
FU 2
FU 3
FU 4 FU 5
8
20
10
10
0
0
V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8
Visit
FU 8
Visit
Fig 3. Box plots for the development of the global health status measured by European Organisation for Research and Treatment of Cancer Quality of Life
Questionnaire C30 for (A) arm A and (B) arm B. Top line shows time in weeks. Box plots for Center for Epidemiologic Studies Depression Scale scores (self-monitored,
cutoff for depression is a score ⱖ 16) for (C) arm A and (D) arm B. Top line shows time in weeks. FU, follow-up; QoL, quality of life; V, visit.
difference between the US and European studies regarding the severity of
adverse effects. First, modern radiotherapy was applied with narrow margins, sparing vulnerable organs. Second, because treatment with IFNbased chemoradiotherapy is challenging, patients included in the trial
were treated at high-volume centers by a multidisciplinary team, including surgeons, oncologists, and a radio-oncologist, who had undergone
specific training before the study began in every center. However, even
under these conditions, significantly more patients receiving the investigational treatment suffered grade 3 and 4 toxicities than patients in the
control arm. Patients’ QoL was mostly affected during the first cycle of
arm A, but most patients recovered soon after the end of cycle 1.
Survival rates for adjuvant chemotherapy have not substantially
changedduringthelastdecade.ESPAC-1reportedamediansurvivaltime
for FU chemotherapy of 20 months.2 Four years later, CONKO-001
reported a median survival time for gemcitabine of 23 months,3 and 2
years later, ESPAC-3 reported identical median survival data for gemcitabine and for FU of 23 months.4 Finally, in the CapRI study, the median
survival for FU/FA was 28.5 months, and the 2-year survival rate was 54%
(recruitment period: August 2004 to December 2007). There might be
several reasons for this. The improvement in imaging may allow more
accurate exclusion of patients with metastasis. In addition, palliative treatment options extend survival after recurrence, which, in our study, was
12.3 months in arm A and 10.2 months in arm B.
4082
There were no differences in the CapRI trial with respect to OS.
Although the CapRI trial was originally powered only to find a fairly large
difference in 2-year survival rates (25 percentage points), the power of this
trial as actually performed, with a longer accrual time (42 months instead
of 18 months) and larger sample size (132 patients instead of 96 patients),
was ⱖ 80% for a 20% increase in 2-year survival rates, irrespective of the
rate in the control group. Taking into account the available study results,
even smaller effects can reasonably be excluded. More specifically, if the
true 2-year survival rate in arm B is assumed to lie between 35% and 65%,
then based on results for the HR and its 95% CI found for the ITT
population in this study, a true difference of more than 15% in favor of
arm A can be excluded at the ␣ ⫽ 5% level.
To our knowledge, the median survival times of 26.5 and 28.5
months are the highest ever reported for these patients in a randomized setting. An underlying selection bias seems unlikely because the
patient cohort in the CapRI trial seems to be representative of the
patient population being treated for pancreatic cancer in the adjuvant
setting.27 The treatment outcome of resected pancreatic carcinoma
was substantially improved in this study independent of the study
group. Thus, it seems likely that factors other than the type of adjuvant
therapy are responsible for this improvement. One factor could be a
center effect. Most patients (113 of 132 patients) in this trial were
recruited from Heidelberg, where surgery is performed with a rather
aggressive soft tissue clearance. Thus, the possibility that the type of
surgery has a larger influence on survival than assumed cannot be
ruled out.
Better and targeted therapies for systemic control of pancreatic cancer are needed. Prognostic markers for pancreatic adenocarcinoma, such
as the impact of nodal status and the level of CA 19-9, have been confirmed in the CapRI trial. In conclusion, the CapRI trial showed no
difference in OS between chemoradioimmunotherapy and FU plus folinic acid in the adjuvant treatment of pancreatic carcinoma. Future studies have to address the question of whether responders in the
chemoradioimmunotherapygroupandtheFUgrouparethesamesubset
of patients. Only if they are different could one justify the substantially
higher toxicity with personalized chemoradioimmunotherapy.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Employment or Leadership Position: None Consultant or Advisory
Role: Jürgen Debus, Merck Serono (C) Stock Ownership: None
REFERENCES
1. Raraty MG, Magee CJ, Ghaneh P, et al: New
techniques and agents in the adjuvant therapy of
pancreatic cancer. Acta Oncol 41:582-595, 2002
2. Neoptolemos J, Stocken D, Friess H, et al:
The final results of the European Study Group for
Pancreatic Cancer randomized controlled trial of
adjuvant chemoradiotherapy and chemotherapy in
patients with resectable pancreatic cancer. N Engl
J Med 350:1200-1210, 2004
3. Oettle H, Post S, Neuhaus P, et al: Adjuvant
chemotherapy with gemcitabine vs observation in
patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA
297:267-277, 2007
4. Neoptolemos JP, Stocken DD, Bassi C, et al:
Adjuvant chemotherapy with fluorouracil plus folinic
acid vs gemcitabine following pancreatic cancer
resection: A randomized controlled trial. JAMA 304:
1073-1081, 2010
5. Picozzi VJ, Kozarek RA, Traverso LW: Interferonbased adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J
Surg 185:476-480, 2003
6. Picozzi J, Abrams R, Traverso L, et al:
ACOSOG Z05031: Report on a multicenter, phase II
trial for adjuvant therapy of resected pancreatic
cancer using cisplatin, 5- FU, and alpha-interferon.
J Clin Oncol 26:214s, 2008 (suppl; abstr 4505)
7. Ma JH, Patrut E, Schmidt J, et al: Synergistic
effects of interferon-alpha in combination with
chemoradiation on human pancreatic adenocarcinoma. World J Gastroenterol 11:1521-1528, 2005
8. Schmidt J, Patrut EM, Ma J, et al: Immunomodulatory impact of interferon-alpha in combination with
chemoradiation of pancreatic adenocarcinoma (CapRI).
Cancer Immunol Immunother 55:1396-1405, 2006
Honoraria: None Research Funding: Jürgen Debus, Merck Serono
Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Jan Schmidt, Ulrich Abel, Jürgen Debus,
Thomas Herrmann, Detlef Bartsch, Ulrich Mansmann, Dirk Jäger,
Markus W. Büchler
Administrative support: Markus W. Büchler
Provision of study materials or patients: Thomas Herrmann, Detlef
Bartsch, Justus Klein, Dirk Jäger, Lorenzo Capussotti, Reiner Kunz,
Markus W. Büchler
Collection and assembly of data: Jan Schmidt, Ulrich Abel, Jürgen
Debus, Sabine Harig, Katrin Hoffmann, Thomas Herrmann, Detlef
Bartsch, Justus Klein, Dirk Jäger, Lorenzo Capussotti, Reiner Kunz,
Markus W. Büchler
Data analysis and interpretation: Jan Schmidt, Ulrich Abel, Jürgen
Debus, Katrin Hoffmann, Thomas Herrmann, Detlef Bartsch, Justus
Klein, Ulrich Mansmann, Dirk Jäger, Lorenzo Capussotti, Reiner Kunz,
Markus W. Büchler
Manuscript writing: All authors
Final approval of manuscript: All authors
9. Hoffmann K, Mehrle S, Schmidt J, et al:
Interferon-alpha restitutes the chemosensitivity in pancreatic cancer. Anticancer Res 28:1499-1507, 2008
10. Zhu Y, Tibensky I, Schmidt J, et al: Interferonalpha in combination with chemotherapy has potent
antiangiogenic properties in an orthotopic mouse
model for pancreatic adenocarcinoma. J Immunother 31:28-33, 2008
11. Zhu Y, Tibensky I, Schmidt J, et al: Interferonalpha enhances antitumor effect of chemotherapy in
an orthotopic mouse model for pancreatic adenocarcinoma. J Immunother 31:599-606, 2008
12. Iacopino F, Ferrandina G, Scambia G, et al:
Interferons inhibit EGF-stimulated cell growth and
reduce EGF binding in human breast cancer cells.
Anticancer Res 16:1919-1924, 1996
13. Pfeffer LM, Dinarello CA, Herberman RB, et
al: Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons. Cancer Res 58:2489-2499, 1998
14. Holsti LR, Mattson K, Niiranen A, et al: Enhancement of radiation effects by alpha interferon in
the treatment of small cell carcinoma of the lung. Int
J Radiat Oncol Biol Phys 13:1161-1166, 1987
15. Kurzrock R, Talpaz M, Guttermann J: Interferons:
Clinical Applications. Philadelphia, PA, Lippincott, 1991
16. Decatris M, Santhanam S, O’Byrne K: Potential of interferon-alpha in solid tumours: Part 1.
BioDrugs 16:261-281, 2002
17. Solorzano CC, Hwang R, Baker CH, et al:
Administration of optimal biological dose and schedule of interferon alpha combined with gemcitabine
induces apoptosis in tumor-associated endothelial
cells and reduces growth of human pancreatic carcinoma implanted orthotopically in nude mice. Clin
Cancer Res 9:1858-1867, 2003
18. Marrack P, Kappler J, Mitchell T: Type I interferons keep activated T cells alive. J Exp Med
189:521-530, 1999
19. Matikainen S, Sareneva T, Ronni T, et al:
Interferon-alpha activates multiple STAT proteins
and upregulates proliferation-associated IL-2Ralpha,
c-myc, and pim-1 genes in human T cells. Blood
93:1980-1991, 1999
20. Paquette RL, Hsu NC, Kiertscher SM, et al:
Interferon-alpha and granulocyte-macrophage colonystimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. J Leukoc Biol
64:358-367, 1998
21. Knaebel HP, Märten A, Schmidt J, et al: Phase
III trial of postoperative cisplatin, interferon alpha-2b,
and 5-FU combined with external radiation treatment versus 5-FU alone for patients with resected
pancreatic adenocarcinoma – CapRI: Study protocol
[ISRCTN62866759]. BMC Cancer 5:37, 2005
22. Hoffmann K, Märten A, Lindel K, et al: Major
combined electrolyte deficiency during therapy with lowdose cisplatin, 5-fluorouracil and interferon alpha: Report
on several cases and review of the literature
[ISRCTN62866759]. BMC Cancer 6:128, 2006
23. Fitzsimmons D, Johnson CD, George S, et al:
Development of a disease specific quality of life
(QoL) questionnaire module to supplement the
EORTC core cancer QoL questionnaire, the QLQC30 in patients with pancreatic cancer: EORTC
Study Group on Quality of Life. Eur J Cancer 35:939941, 1999
24. Radloff L: The CES-D scale: A new self report
depression scale for research in the general population. Appl Psych Meas 1:385-401, 1977
25. Collett D: Modelling Survival Data in Medical
Research. London, United Kingdom, Chapman &
Hall, 1994
26. Machin D, Weeden S: Suggestions for the
presentation of quality of life data from clinical trials.
Stat Med 17:711-724, 1998
27. Sorg C, Schmidt J, Büchler M, et al: Examination of external validity in randomized controlled
trials for adjuvant treatment of pancreatic adenocarcinoma. Pancreas 38:542-550, 2009
■ ■ ■
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Open-Label, Multicenter, Randomized Phase III Trial of Adjuvant

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