Annals of Oncology Advance Access originally published online on October 9, 2006
Annals of Oncology 2007 18(1):82-87; doi:10.1093/annonc/mdl340
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© 2006 European Society for Medical Oncology
gastrointestinal tumors |
Gemcitabine, oxaliplatin and weekly high-dose 5-FU as 24-h infusion in chemonaive patients with advanced or metastatic pancreatic adenocarcinoma: a multicenter phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
1 First Department of Medicine, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
2 First Department of Medicine, Friedrich-Alexander-University Erlangen, Erlangen, Germany
3 Department of Medicine II, Friedrich-Schiller-University, Jena, Germany
4 First Department of Medicine, Johannes-Gutenberg-University Mainz, Mainz, Germany
5 Gastroenterology Practice, Halle (Saale), Germany
6 Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
* Correspondence to: A. D. Wagner M. D. First Department of Medicine, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120 Halle (Saale), Germany. Tel: +49 345-557-2661; Fax: +49 345-557-2253; E-mail: anna-dorothea.wagner{at}gmx.de
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Abstract |
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Background: Combinations of gemcitabine–oxaliplatin, gemcitabine–5-fluorouracil (5-FU) and 5-FU–oxaliplatin have synergistic activity and nonoverlapping adverse effect profiles. This trial assessed efficacy and safety of the triple combination gemcitabine–oxaliplatin and infusional 5-FU in patients with locally advanced (n = 11) or metastatic (n = 32) pancreatic adenocarcinoma.
Patients and methods: A total of 43 eligible patients were treated with intravenous infusions of gemcitabine (900 mg/m2 over 30 min), followed by oxaliplatin (65 mg/m2 over 2 h) and 5-FU (1500 mg/m2 over 24 h) on days 1 and 8 of a 21-day cycle.
Results: Among all 43 patients, the tumor response rate was 19% [95% confidence interval 7% to 30%]. Nine patients were nonassessable for response because they did not complete the first two cycles of chemotherapy due to rapid disease progression, early death or treatment refusal. One patient was lost to follow-up. Median time to progression and overall survival were 5.7 and 7.5 months. Principal grade III/IV toxic effects were leucopenia in 11 (2%), thrombocytopenia in 13 (2%), nausea in 13 (0%), anorexia 16 (7%) and sensory neuropathy in 18 (0%) of patients. Unexpected cardiotoxicity was observed in this trial.
Conclusion: Response rates and survival of the three-drug combination compare favorably with single-agent gemcitabine, but do not exceed results for doublets.
Key words: combination chemotherapy, gemcitabine, oxaliplatin, pancreatic cancer, 5-FU
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Pancreatic cancer currently ranks seventh in global cancer mortality [1]. In the United States of America, it is the fourth leading cause of cancer-related death [2]. Because <10% of all patients undergo potentially curative resection, systemic chemotherapy is the major treatment option. Patients with metastatic disease have a median survival of 3–6 months. In addition, due to tumor-related symptoms, such as pain, weight loss, nausea and vomiting, their quality of life (QoL) is impaired significantly.
Gemcitabine is the first agent for which a benefit in survival (4.4 versus 5.6 months), as well as an improvement in disease-related symptoms, was demonstrated in a randomized study [3]. For this reason, single-agent chemotherapy with gemcitabine is currently considered as standard of care for patients with advanced pancreatic cancer [4, 5] and serves as reference in recently published trials. Nevertheless, results for single-agent gemcitabine are poor and urgently deserve further improvement. Recently, results for single-agent gemcitabine have been challenged by the combination of gemcitabine and erlotinib, which demonstrated an increase in median survival (6.4 versus 5.9 months; P = 0.03) for the combination of gemcitabine and erlotinib in a large randomized study [6]. Whether this difference is clinically meaningful is a matter of debate.
Due to a favorable toxicity profile and synergistic activity with a number of other drugs, gemcitabine serves as the basis for multiple combination therapies: Two-drug combinations of gemcitabine with cisplatin (CDDP) or oxaliplatin possess synergistic activity in preclinical studies [7–9] and demonstrated superiority in terms of time to progression and response rates in randomized clinical trials [10–12]. A survival benefit for gemcitabine–platinum combinations has been shown in a recent pooled analysis [13]. In addition, promising results in preclinical and phase II studies were published for combination chemotherapy with gemcitabine and 5-fluorouracil (5-FU)–leucovorin [14–16], as well as oxaliplatin–5-FU [17]. Combinations of gemcitabine and targeted drugs are subject of ongoing clinical trials. On the basis of its synergistic activity and nonoverlapping toxicity profile, we carried out this phase II study to investigate efficacy and toxicity of the triple gemcitabine, oxaliplatin and infusional 5-FU (GemFOx) combination chemotherapy in patients with locally advanced or metastatic pancreatic cancer.
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patients and methods |
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patients
Patients were eligible for entry into the study if they met the following criteria: histologically confirmed, locally advanced [International Union Against Cancer (UICC) stage III, T1–4, N1] or metastatic (UICC stage IV, T1–4, N1, M1) pancreatic cancer or recurrence after resection; bidimensionally measurable tumor lesion; age 18–75 years; Eastern Cooperative Oncology Group (ECOG) status 0-1; estimated life expectancy
3 months and adequate bone marrow function (white blood cell count 3.5 x 109/l, platelets 100 x 109/l). Exclusion criteria were borderline tumors, serious concomitant disorders, bilirubin 1.5 times upper limit of normal, alanine amino transaminase and aspartate amino transaminase levels greater than five and 2.5 times upper limit of normal in patients with and without liver metastases, creatinine clearance exceeding 200 µmol/l, pregnant and lactating women, prior chemotherapy, patients with cerebral metastases and a peripheral sensory neuropathy. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all patients before entering the study. The protocol was approved by the ethics committee of the Medical Faculty, Martin-Luther-University Halle-Wittenberg, Germany, as well as the responsible ethics committees for the participating institutions.
study design and treatment
In this nonrandomized, multicenter phase II study, patients were treated according to the results of our prior phase I study [18] with gemcitabine (Gemzar®, Eli Lilly and Company, Indianapolis, USA) 900 mg/m2 as a 30-min infusion, followed by oxaliplatin (Eloxatin®, Sanofi-Syntelabo, Paris, France) 65 mg/m2 as a 2-h infusion and 5-FU (1500 mg/m2) without folinic acid as a 24-h continuous infusion on days 1 and 8 of a 21-day schedule. Treatment was continued until disease progression, until unacceptable toxicity, or at the request of the patient or investigator. Doses were modified on the basis of blood counts carried out before each chemotherapy administration in order to maintain a tolerable safety profile. Treatment was interrupted as long as leucopenia or diarrhea >grade I or any other toxicity (except alopecia) >grade II were observed. If the time to recovery from any toxicity was >1 week, subsequent doses were reduced to 80%. In patients experiencing a sensory neuropathy lasting longer than 7 days, oxaliplatin was administered at 80% of the initial dose in subsequent cycles. In case of sensory neuropathy with functional impairment not relieved by the time of the scheduled administration of the next cycle, treatment with oxaliplatin was withheld until recovery.
baseline and treatment assessments
Pretreatment evaluations consisted of a complete medical history, physical examination, assessment of ECOG status, blood count and blood chemistry including CA 19-9 and urine analysis. Tumor measurements were carried out with either computerized tomography or magnetic resonance imaging. Quality of life was assessed with European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and PAN-26 [19, 20] questionnaires. Tumor measurements and QoL assessments were repeated before every second cycle. Tumor response was classified according to World Health Organization criteria and had to be confirmed in a second computerized tomography or magnetic resonance imaging scan at least 4 weeks after the primary examination documenting the response. Blood counts were carried out before every chemotherapy administration, serum chemistry and urine analysis before every new cycle. Toxicity was classified according to National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0. After discontinuation of treatment, follow-up was scheduled every 3 months.
statistical methods and analysis
According to study protocol, we defined three populations for analysis.
- 1 The Safety population: all patients who received the study medication at least once.
- 2 The intention-to-treat (ITT) population: all eligible patients who received the study medication at least once.
- 3 The per-protocol (PP) population: the primary end point of the study, the objective response rate, was assessed in a PP population, which included all patients who completed at least two cycles of chemotherapy.
- 2 The intention-to-treat (ITT) population: all eligible patients who received the study medication at least once.
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results |
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patient's baseline characteristics
A total of 46 patients were enrolled in nine participating institutions from February 2002 to August 2003. At the time of this analysis, median follow-up was 7.5 months. One patient was excluded from all analyses because he did not receive the study medication. Two patients were excluded from the ITT analysis because histology was not confirmed. Thus, 45 patients were included in safety analysis, and 43 patients in the ITT analysis. The clinical characteristics of 43 patients included in the ITT analysis are summarized in Table 1.
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treatment
A total of 311 cycles of the study therapy were started; 292 have been completed. The median number of cycles per patient was 5.5 (range 0–25). Dose reductions and treatment interruptions due to toxicity were necessary on 23.7% and 7.6% of treatment days.
efficacy
The tumor response rate was 19% (95% CI 7% to 30%) (Table 2), median overall and progression-free survival were 7.5 (95% CI 4.3–10.5) and 5.7 (95% CI 3.5–7.6) months and the 1-year survival rate was estimated to be 33% (95% CI 19% to 47%) (Figure 1) in the ITT population (N = 43). For patients with locally advanced and metastatic disease, median overall survival (OS) was 10.2 (95% CI 7.4–23.7) and 5.2 (95% CI 3.7–10.5) months, respectively. Out of 33 patients assessable for response, the tumor response rate was 24% (95% CI 10% to 39%). The median duration of response was 6.4 months. Ten patients were not eligible for assessment of response according to the protocol because they did not complete two cycles of therapy for the following reasons: two because of clinically evident rapid disease progression, two because of deterioration of their performance status and two rejected further treatment. Three patients died before the completion of the first two cycles due to sudden death, neutropenic pneumonia or a suspected cerebral thromboembolic event. One additional patient was lost to follow-up before completion of the second cycle. Thus, the PP population included 33 patients. Among these, two could not be assigned a response category because their tumors were not reevaluated.
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adverse events
Most common treatment-related adverse events (NCI-CTC) are reported in Table 3. Treatment was well tolerated in the majority of patients. One patient experienced a treatment-related death due to neutropenia and pneumonia. Most serious adverse events were not interpreted as treatment associated by the investigators. However, 5-FU-associated cardiac toxicity may have caused the following events: (i) An acute coronary syndrome, which developed 2 days after treatment with the study medication in a patient with prior diabetes mellitus. (ii) An acute myocardial infarction in a patient with a metabolic syndrome, which developed in the evening after receiving the study treatment and resulted in death on the same day despite cardiopulmonary resuscitation. (iii) A sudden death 5 days after study therapy in a patient with a history of deep venous thrombosis. This event was interpreted as a death due to pulmonary embolism. However, autopsy was not carried out. (iv) A death of respiratory failure 5 days after treatment with the study medication. Again, autopsy was not carried out. Apart from a cardiovascular event—related or unrelated to 5-FU—a gemcitabine-induced pulmonary toxicity needs to be considered as a possible cause.
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quality of life
EORTC QLQ-C30 QoL questionnaires were administered at baseline, after three cycles of therapy and every two cycles thereafter. Questionnaires from 79%, 47% and 42% of patients were available for evaluation at baseline, after two and four cycles of therapy, with a further decrease thereafter. Results for questions about global health status/QoL are presented in Figure 2. Mean global QoL remained stable at these evaluations. Figure 2 presents a graphical display of the individual paths of the global health status/QoL during the course of treatment.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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This multicenter phase II study was initiated to assess efficacy and safety of the GemFOx triple chemotherapy combination in patients with locally advanced and metastatic pancreatic cancer. An objective response rate of 19%, OS of 7.6 months and 1-year survival rate of 33% for the ITT population are superior to reported results for single-agent gemcitabine and in line with results from randomized studies for two-drug combinations, such as gemcitabine–CDDP [10, 11] or gemcitabine–oxaliplatin [12]. To qualify for further evaluation, a three-drug combination should be expected to exceed results of doublets. For this reason, according to the protocol, a response rate of 30% had to be achieved for further development of the three-drug combination. This criterion was not met in our study. Even when considering other outcomes, such as TTP and median survival, results of our study do not support the hypothesis that addition of 5-FU to the doublet of gemcitabine–oxaliplatin confers a relevant therapeutic advantage. Instead, despite preclinical synergism, promising results from phase II studies [15, 16] and—albeit limited—single-agent activity, neither did the addition of 5-FU to gemcitabine improve results for gemcitabine alone in randomized studies [21, 22] nor do results from other recent phase II trials investigating the three-drug combination of gemcitabine–CDDP and 5-FU in different schedules [23–25] consistently show more favorable results (TTP 3.0–7.2 months, OS 8.6–10.6 months and a 1-year survival rate between 26% and 46%) than those reported for two-drug combinations [11, 12, 15, 16] in comparable trials. For this reason, despite its rational design, results for this three-drug combination do not suggest a survival advantage for the overall population of patients with pancreatic cancer when compared with results from phase II and phase III studies of gemcitabine–platinum combinations without 5-FU.
It remains unclear whether other combinations of three or more drugs might be more efficient: At present, data from only one randomized phase III study comparing a polychemotherapy regimen (PEG-F: CDDP, epirubicin, fluorouracil and gemcitabine), for which a median survival of 10 months in a prior phase II study [26] was reported, with single-agent gemcitabine have been published [27]. Although there was a statistically significant difference between the two treatment groups in the primary end point of this study, which was progression-free survival at 4 months (60% versus 28%, hazard ratio (HR) 0.46), this did not translate into a significant difference in 1-year OS (38.5% versus 21.3%, P = 0.11) for patients treated with PEG-F. While the results of this trial confirm a certain—albeit limited—potential for improvement of therapeutic results with the use of a gemcitabine-based polychemotherapy combination, as long as progression-free survival is not established as a study end point in pancreatic cancer, the clinical relevance of these findings is uncertain. Interestingly, when comparing the survival curves in both treatment groups in this study, relevant differences were observed only after a follow-up of >9 months. Thus, a benefit from combination as compared with single-agent chemotherapy was observed only among those patients who survived longer than 9 months. Whether subgroups of patients, e.g. those with a good performance status, derive a greater benefit from combination chemotherapy remains an interesting question: Although they always need to be interpreted with caution, subgroup analyses of patients with a Karnofsky status of 90%–100% in two large randomized studies [21, 28] demonstrated a benefit in survival in patients with a good Karnofsky status (8.5 versus 6.2 months, P = 0.17 and 10.1 versus 7.5 months) for combinations of gemcitabine–5-FU and gemcitabine–capecitabine as compared with single-agent therapy with gemcitabine. In contrast, combination chemotherapy tended to shorten survival in patients with a lower performance status and results for the overall population did not differ significantly between treatment groups in these trials. The hypothesis that patients with a good performance status may have a greater benefit from treatment intensification is supported by a recent pooled analysis [13]. Thus, three- or four-drug combinations might be beneficial for selected patients with a good performance status. Due to their different toxicity profile, targeted drugs might be given either sequentially or simultaneously with combination chemotherapies and further enhance their therapeutic efficacy.
Evaluation of toxicity was another aim of our study. Although rates of hematologic and gastrointestinal grade III and IV toxic effects were remarkably low and compare favorably with other reports of three-drug combinations, an unexpectedly high rate of cardiovascular events has been observed in this trial. The temporal association with the administration of 5-FU may suggest a causal relationship. Cardiotoxicity of 5-FU usually consists of angina [29], but cases of cardiac arrest [30] and congestive heart failure have also been described. Usually, symptoms occur 2–5 days after the start of the infusion [31]. However, the number of patients included in our study is too small to make any definitive conclusions about these relatively rare events. While comparable observations have not been made in parallel phase II studies evaluating the same chemotherapy combination in patients with biliary tree and gall-bladder carcinoma in the same institution [32], the potential for cardiotoxicity of 5-FU in combinations including platinum derivatives and gemcitabine deserves consideration.
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Acknowledgements |
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We express our thanks to Lena Minning and Mareike Kunze (Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg) for data handling and management; Dirk Arnold (Department of Medicine IV, Martin-Luther-University Halle-Wittenberg) for discussion of the manuscript, and K. H. Pflueger, Diakoniekrankenhaus Bogenhausen; W. Schepp, Klinikum Bogenhausen, S. Hahnfeld, Onkologische Gemeinschaftspraxis Jena, and T. Herrmann, University of Heidelberg, for inclusion of one patient each in this study. This study was supported by grants from Lilly Deutschland GmbH, Bad Homburg, Germany, and Sanofi-Synthelabo, Paris, France. The Coordinating Centre for Clinical Trials, Martin-Luther-University Halle-Wittenberg, Germany (supported by the Ministry for Education and Research, grant number BMBF/FKZ: 01GH0105 KKS Halle), provided additional support. Preliminary results of this study were previously presented at the American Society of Clinical Oncology Annual Meeting 2004 (Abstr 4096).
Received for publication April 24, 2006. Revision received August 4, 2006. Accepted for publication August 14, 2006.
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