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Published Ahead of Print on September 24, 2012 as 10.1200/JCO.2011.38.2960
Open-Label, Multicenter, Randomized Phase III Trial ofAdjuvant Chemoradiation Plus Interferon Alfa-2b VersusFluorouracil and Folinic Acid for Patients With ResectedPancreatic Adenocarcinoma Jan Schmidt, Ulrich Abel, Ju¨rgen Debus, Sabine Harig, Katrin Hoffmann, Thomas Herrmann, Detlef Bartsch,Justus Klein, Ulrich Mansmann, Dirk Ja¨ger, Lorenzo Capussotti, Reiner Kunz, and Markus W. Bu¨chler See accompanying editorial doi: 10.1200/JCO.2012.38.45.1799 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
Joseph Hospital, Berlin, Berlin, Germany; 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 ϭ 64) or six cycles of FU monotherapy (arm B, n ϭ 68). One hundred ten patients (arm A, n ϭ 53; arm B, n ϭ 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 ϭ .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 ϭ .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 comparedwith 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 J Clin Oncol 30. 2012 by American Society of Clinical Oncology a 5-year OS rate of 21% compared with 8% for INTRODUCTION
untreated controls.2 The CONKO-001 (Charite´ Patients with pancreatic adenocarcinoma have an Onkologie– 001) trial confirmed the role of adjuvant especially poor prognosis. The 5-year overall sur- treatment. This study comprised patients randomly vival (OS) rate is less than 5%, with a median sur- assigned to gemcitabine or best supportive care and vival time of 4 to 6 months. After surgical resection, showed a significant increase in 5-year OS rate and 5-year OS rates of 25% have been reported for pa- median OS time.3 Finally, the ESPAC-3 trial com- tients with adjuvant therapy.1 There are few ran- pared gemcitabine with FU and found no difference domized trials on adjuvant therapy for pancreatic carcinoma. The European Study Group for Pancre- Investigators from the Virginia Mason Clinic atic Cancer (ESPAC) -1 trial assessed patients un- published data of a phase II trial of 43 patients un- dergoing adjuvant chemotherapy with fluorouracil dergoing combined therapy with cisplatin, FU, in- (FU) and showed a significant survival benefit, with terferon alfa-2b (IFN ␣-2b), and external-beam 2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on September 25, 2012. For personal use only. No other uses without permission.
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Schmidt et al
radiation after pancreaticoduodenectomy and reported a 5-year OS patient in oral and written form before inclusion in the trial. The trial was rate of 55%.5 The American College of Surgeons Oncology Group trial registered at the International Standard Randomised Controlled Trial Num- investigated this regimen in a multicenter study, but because of ber Register (ISRCTN62866759) and monitored by an independent contract toxicity, the trial was stopped. However, recruitment was almost complete at this point. The reported median survival was 27 Study Treatment
months.6 We decided to evaluate this adjuvant regimen in a ran- Patients in study arm A were treated as outpatients with FU (200 mg/m2 domized, controlled, prospective, multicenter phase III trial com- 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 external- The inclusion of IFN ␣-2b was supported by our in vitro data, beam radiation (50.4 Gy in 28 fractions) followed by two cycles of continuous which indicated a relevant potential of IFN ␣-2b to modulate the FU (days 64 to 101 and days 120 to 161). Patients treated in arm A were tumor behavior.7-11 Specifically, IFN ␣-2b had inhibitory effects on challenged 4 to 6 days before therapy with a single dose of IFN ␣-2b. Non-steroidal anti-inflammatory drugs and corticosteroids were avoided if possible tumor cell growth,12,13 radiotherapy- and chemotherapy-sensitizing during IFN ␣-2b treatment. Because major combined electrolyte deficiency effects,14,15 and antiangiogenic properties16,17; enhanced the immu- was observed in some patients, an intensive electrolyte monitoring and pro- nogenicity of tumors13; and modulated the immune system.13,18-20 phylactic substitution treatment was performed.22 Patients in study arm Bwere treated with bolus injections of folinic acid (FA; 20 mg/m2) and FU (425mg/m2) given on 5 consecutive days every 28 days for six cycles; for a detailed PATIENTS AND METHODS
Study Design and Patients
Assessments
Patients with histologically proven resected (R0 or R1) pancreatic ade- Laboratory and physical evaluations were performed before the start nocarcinoma and Karnofsky performance score Ն 70 were eligible for enroll- and at the end of any therapy cycle. In the post-treatment period, patients ment within 12 weeks after operation. One hundred thirty-two patients were were seen every 3 months in the first 2 years, every 4 months in the third randomly assigned (intent-to-treat [ITT] population: arm A, n ϭ 64; arm B, year, and every 6 months during the fourth and fifth post-treatment years.
n ϭ 68). Of these, 110 patients (arm A, n ϭ 53; arm B, n ϭ 57) receiving at least Computed tomography imaging was performed every 6 months and one dose of study treatment formed the per-protocol (PP) population. Pa- tients with known hypersensitivity to IFN ␣-2b, autoimmune disease, or The European Organisation for Research and Treatment of Can- depression were excluded; for a detailed overview, see Knaebel et al.21 The final cer (EORTC) Quality of Life Questionnaire (QLQ) C30; the EORTC QLQ- protocol was approved by the Ethics Committee of the University of Heidel- PAN26 pancreatic cancer module assessing disease-specific symptoms; and berg, Medical School (L-042/2003). Informed consent was obtained from each the Center for Epidemiologic Studies Depression Scale, a 20-item self-report Fig 1. CONSORT flow chart. ITT, intent-
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Adjuvant Chemoradioimmunotherapy for Pancreatic Cancer
measure of depression that emphasizes the emotional dimension for depres- However, the definition of the primary efficacy analysis population changed sion, were used as quality-of-life (QoL) instruments.23,24 Questionnaires were during the course of the study. According to the final decision, all patients who provided at baseline and at every follow-up visit. Patients in arm A had further did not receive at least one dose of the study treatment were to be excluded assessments in the middle and at the end of cycle 1 and at the end of cycles 2 and from the primary analysis set and to be replaced. In total, 132 patients were 3. Documentation of clinical follow-up data in this trial was restricted to randomly assigned (ITT population: group A, n ϭ 64; group B, n ϭ 68). Of patients who received at least one dose of the study treatment.
these, 110 patients (PP population: group A, n ϭ 53; group B, n ϭ 57) startedthe study treatment. Data on disease-free survival, QoL, and toxicity were Statistical Analyses
available only for patients in the PP population.
The sample size calculation was based on the assumption (under H ) of Random assignment was central. A separate randomization list (block a constant monthly hazard rate of 0.044 in group B (FU/FA) and a constant randomization, 1:1) was prepared for each participating center. The primary monthly hazard rate of 0.021 in arm A. These hazard values were derived from efficacy end point was survival time; the secondary efficacy end point was 2-year survival rates of 35% in arm B and 60% in arm A, assuming exponential disease-free survival. The end points to be included in the analysis of QoL were survival curves. Assuming an accrual period of 18 months and a (total) the single items of the QoL instruments, except where aggregate scales were follow-up of 42 months (18 ϩ 24 months), testing for the aforementioned difference in hazard rates at a level of ␣ ϭ 5% and with a power of 80% yielded Standard methods for survival analysis were used in the analysis of a study size of 96 evaluable patients (48 patients per treatment group). Origi- time-to-event end points, including Kaplan-Meier estimates of the survivor nally, patients not completing the treatment were planned to be excluded from functions, Greenwood’s formula for estimating the SE of event rates, the Cox analysis. With an anticipated number of 14 patients stopping the treatment proportional hazards model, and the log-rank test for comparing two survival prematurely, a total of 110 patients were planned to be randomly assigned.
Table 1. Demographics and Baseline Clinical Characteristics for All Patients
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.
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Schmidt et al
curves.25 Follow-up was quantified using the Kaplan-Meier estimate ofpotential follow-up. The Cox proportional hazards model was used to investigate the influence of potentially important prognostic factors (base-line variables) on survival time and to adjust the treatment effect in the PP Patients and Treatment Compliance
population for imbalance in baseline variables. Briefly, the adjustment One hundred thirty-two patients were randomly assigned.
proceeded as follows. Screening was performed for potential confounders; Twenty-two patients did not receive any treatment as a result of variables were selected as potential confounders if their inclusion as a withdrawal or not meeting inclusion criteria (Fig 1). The two groups second variable in the model changed the estimated treatment effect by atleast 10%. For tumor marker values, logarithms were used. Then, the were well balanced regarding demographics and baseline characteris- variables selected in the screening process were included in a multivariable tics (Table 1). None of the group differences shown in Table 1 were model. In a backward selection, variables were dropped from this model statistically significant. Although the mean values of CA 19-9 differed using the same (10% change) criterion.
considerably, because of outliers, the median values (arm A, 208.9 No covariates were used in the primary efficacy analysis. Comparison of U/mL; arm B, 190.0 U/mL) were quite similar. Complete information treatment groups with respect to uncensored continuous variables was done on treatment compliance was available for 41 patients in arm A and 46 using the Wilcoxon rank sum test. Fisher’s exact test was used in case ofcategorical variables. Because most patients were recruited in one center, patients in arm B. Only one patient in arm A received the total planned center effects were not accounted for. Missing data were not replaced or dose compared with 32 patients (69.6%) in arm B. Dose reductions in imputed. QoL end points were analyzed along the lines described by Machin arm A were mainly performed for cisplatin and FU. On average, in and Weeden.26 Average areas under the curve (AUCs) were calculated as the cycle 1, 96% of the IFN ␣-2b, 98% of the radiation, 75% of the total AUC divided by the number of days in the interval. Only patients who cisplatin, and 72% of the FU planned doses were administered.
completed at least three QoL assessments were included in the calculation ofthe AUC.
One interim analysis was conducted 1 year after the start of patient Efficacy
enrollment. In case of a highly significant advantage (P Ͻ .001) for the group A Median follow-up for all randomly assigned patients (n ϭ 132) regimen, the treatment in group B was to be replaced with a regimen consisting was 42.7 months. The survival curves for these patients are shown in of chemoradiotherapy according to the cisplatin, FU, IFN ␣-2b, and external- Figure 2A. These curves were virtually undistinguishable, reflected by beam radiation (CapRI) regimen, but without the IFN ␣-2b treatment. The a hazard ratio (HR) of 1.04 for arm A versus arm B (95% CI, 0.66 to results of this analysis did not warrant any change in the trial conduction.
1.53; P ϭ .99). Median survival from date of resection was 26.5 Furthermore, the study included a stopping rule based on continuous moni-toring of treatment-related deaths. This rule, which used a Bayesian criterion months (95% CI, 21.6 to 39.5 months) in arm A and 28.5 months with uniform prior, stipulated that the study had to be stopped once the (95% CI, 20.4 to 38.6 months) in arm B.
posterior probability that the rate of treatment-related deaths exceeded 5% In the PP population, the median follow-up time was 45.9 was higher than 90%. Because no treatment-related deaths were reported, the months. The median OS time was 32.1 months (95% CI, 22.8 to 42.2 stopping rule was not activated. Given that the significance level used in the months) in arm A and 28.5 months (95% CI, 19.5 to 38.6 months) in interim analysis was low, no adjustment of the main evaluation for multiple arm B (Fig 2B). OS was not significantly different between treatment groups (P ϭ .49). When adjusting the treatment effect on survival for All statistical tests were two-tailed. The significance level was ␣ ϭ 5%.
SAS Version 9.1.3 (SAS Institute, Cary, NC) was used to conduct the analysis.
imbalance in covariates using the Cox proportional hazards model, Given the relatively small patient numbers, in this report, percentages are 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
Abbreviation: CTC, Common Toxicity Criteria.
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Adjuvant Chemoradioimmunotherapy for Pancreatic Cancer
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 Table 3. EORTC QLQ-C30, Summary Statistics for the AUC
months) in arm A and 11.5 months (95% CI, 9.8 to 17.6 months) in Arm A (n ϭ 53) Arm B (n ϭ 57) Total (n ϭ 110) Pء arm B (P ϭ .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% 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 ϭ .007). Node-positive patients had a median survival of 25.3 months compared with 49.8 months for node- negative patients (HR, 0.57; P ϭ .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 ϭ .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
NOTE. Statistics only shown for parameters with significant or borderline With regard to the AUC, significant differences between groups included global health status, role functioning, nausea/vomiting, and Abbreviations: AUC, area under the curve; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Question- 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 ءWilcoxon rank sum test; in accordance with the specification for the EORTC for global health status over time is shown in Figures 3A and 3B. No 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 significant differences between groups with respect to AUC were for role functioning, social functioning, and the global health status.
found for any parameter in the EORTC QLQ-PAN26 (data notshown). Depression score as measured by the Center for Epidemio-logic Studies Depression Scale is shown in Figure 3C for arm A andFigure 3D for arm B. No QoL measurements have been performedduring the different courses of treatment for arm B patients. However, DISCUSSION
although no comparison with arm B is possible, a clear deteriorationduring cycle 1 of arm A is obvious. Patients started to recover at the Pancreatic adenocarcinoma has a dismal prognosis even after curative beginning of cycle 2 of arm A and were back at baseline when cycle 3 resection. The concept of adjuvant treatment has been proven within the last decade with a reported increase in median survival from 15months to 23 months.2-4 However, further improvement is needed.
The strategy of chemoradioimmunotherapy was investigated by Pi- Treatment After Recurrence
cozzi et al5 in a phase II trial with impressive outcome. On the basis of Approximately 72% of the 88 patients who experienced recur- these data, we designed the CapRI trial choosing the best known rence underwent palliative treatment. Fifty-one patients (58%) re- chemotherapy at that time (FU) as comparator.
ceived gemcitabine monotherapy as recommended in the trial The chemoradioimmunotherapy regimen has been controver- protocol, and seven patients received other chemotherapy (gemcit- sial because of its toxicity. This was especially true when the American abine plus oxaliplatin, n ϭ 4; gemcitabine plus capecitabine, n ϭ 1; College of Surgeons Oncology Group Z05031 trial reported a grade 3 infusional FU, leucovorin, and oxaliplatin, n ϭ 1; FU, n ϭ 1). Five or 4 GI toxicity rate of 93%, leading to a premature stop of the trial.6 patients received other treatments (resection, n ϭ 1; chemoemboliza- Our experience was similar; although toxicity in our study was lower tion, n ϭ 1; percutaneous radiotherapy, n ϭ 1; chemoradiotherapy than that reported by the US centers, we still observed substantial not further specified, n ϭ 2). Four patients were classified as having toxicity throughout all CapRI centers. Toxicity was mainly of hema- tologic origin but manageable. There may be several reasons for the 2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on September 25, 2012. For personal use only. No other uses without permission.
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Schmidt et al
V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8 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 Ն 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 There were no differences in the CapRI trial with respect to OS.
adverse effects. First, modern radiotherapy was applied with narrow mar- Although the CapRI trial was originally powered only to find a fairly large gins, sparing vulnerable organs. Second, because treatment with IFN- difference in 2-year survival rates (25 percentage points), the power of this based chemoradiotherapy is challenging, patients included in the trial trial as actually performed, with a longer accrual time (42 months instead were treated at high-volume centers by a multidisciplinary team, includ- of 18 months) and larger sample size (132 patients instead of 96 patients), ing surgeons, oncologists, and a radio-oncologist, who had undergone was Ն 80% for a 20% increase in 2-year survival rates, irrespective of the specific training before the study began in every center. However, even rate in the control group. Taking into account the available study results, under these conditions, significantly more patients receiving the investi- even smaller effects can reasonably be excluded. More specifically, if the gational treatment suffered grade 3 and 4 toxicities than patients in the true 2-year survival rate in arm B is assumed to lie between 35% and 65%, control arm. Patients’ QoL was mostly affected during the first cycle of then based on results for the HR and its 95% CI found for the ITT arm A, but most patients recovered soon after the end of cycle 1.
population in this study, a true difference of more than 15% in favor of Survival rates for adjuvant chemotherapy have not substantially arm A can be excluded at the ␣ ϭ 5% level.
changed during the last decade. ESPAC-1 reported a median survival time To our knowledge, the median survival times of 26.5 and 28.5 for FU chemotherapy of 20 months.2 Four years later, CONKO-001 months are the highest ever reported for these patients in a random- reported a median survival time for gemcitabine of 23 months,3 and 2 ized setting. An underlying selection bias seems unlikely because the years later, ESPAC-3 reported identical median survival data for gemcit- patient cohort in the CapRI trial seems to be representative of the abine and for FU of 23 months.4 Finally, in the CapRI study, the median patient population being treated for pancreatic cancer in the adjuvant survival for FU/FA was 28.5 months, and the 2-year survival rate was 54% setting.27 The treatment outcome of resected pancreatic carcinoma (recruitment period: August 2004 to December 2007). There might be was substantially improved in this study independent of the study several reasons for this. The improvement in imaging may allow more group. Thus, it seems likely that factors other than the type of adjuvant accurate exclusion of patients with metastasis. In addition, palliative treat- therapy are responsible for this improvement. One factor could be a ment options extend survival after recurrence, which, in our study, was center effect. Most patients (113 of 132 patients) in this trial were 12.3 months in arm A and 10.2 months in arm B.
recruited from Heidelberg, where surgery is performed with a rather 2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on September 25, 2012. For personal use only. No other uses without permission.
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Adjuvant Chemoradioimmunotherapy for Pancreatic Cancer
aggressive soft tissue clearance. Thus, the possibility that the type of Honoraria: None Research Funding: Ju¨rgen Debus, Merck Serono
surgery has a larger influence on survival than assumed cannot be Expert Testimony: None Other Remuneration: None
Better and targeted therapies for systemic control of pancreatic can- AUTHOR CONTRIBUTIONS
cer are needed. Prognostic markers for pancreatic adenocarcinoma, suchas the impact of nodal status and the level of CA 19-9, have been con- Conception and design: Jan Schmidt, Ulrich Abel, Ju¨rgen Debus,
firmed in the CapRI trial. In conclusion, the CapRI trial showed no Thomas Herrmann, Detlef Bartsch, Ulrich Mansmann, Dirk Ja¨ger, difference in OS between chemoradioimmunotherapy and FU plus fo- Markus W. Bu¨chler
Administrative support: Markus W. Bu¨chler
linic acid in the adjuvant treatment of pancreatic carcinoma. Future stud- Provision of study materials or patients: Thomas Herrmann, Detlef
ies have to address the question of whether responders in the Bartsch, Justus Klein, Dirk Ja¨ger, Lorenzo Capussotti, Reiner Kunz, chemoradioimmunotherapy group and the FU group are the same subset of patients. Only if they are different could one justify the substantially Collection and assembly of data: Jan Schmidt, Ulrich Abel, Ju¨rgen
higher toxicity with personalized chemoradioimmunotherapy.
Debus, Sabine Harig, Katrin Hoffmann, Thomas Herrmann, Detlef
Bartsch, Justus Klein, Dirk Ja¨ger, Lorenzo Capussotti, Reiner Kunz,
Markus W. Bu¨chler
Data analysis and interpretation: Jan Schmidt, Ulrich Abel, Ju¨rgen
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
Debus, Katrin Hoffmann, Thomas Herrmann, Detlef Bartsch, Justus OF INTEREST
Klein, Ulrich Mansmann, Dirk Ja¨ger, Lorenzo Capussotti, Reiner Kunz,Markus W. Bu¨chler Employment or Leadership Position: None Consultant or Advisory
Manuscript writing: All authors
Role: Ju¨rgen Debus, Merck Serono (C) Stock Ownership: None
Final approval of manuscript: All authors
9. Hoffmann K, Mehrle S, Schmidt J, et al:
and upregulates proliferation-associated IL-2Ralpha, REFERENCES
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ule of interferon alpha combined with gemcitabine J Clin Oncol 26:214s, 2008 (suppl; abstr 4505) Research. London, United Kingdom, Chapman & induces apoptosis in tumor-associated endothelial 7. Ma JH, Patrut E, Schmidt J, et al: Synergistic
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trials for adjuvant treatment of pancreatic adenocar- Cancer Immunol Immunother 55:1396-1405, 2006 Interferon-alpha activates multiple STAT proteins Acknowledgment
We thank Karin Ho¨rner for the excellent support.
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