Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II study

S. R. Alberts1,+, P. M. Townley2, R. M. Goldberg1, S. S. Cha1, D. J. Sargent1, D. F. Moore3, J. E. Krook4, H. C. Pitot1, T. R. Fitch5, M. Wiesenfeld6 and J. A. Mailliard2

1 Mayo Clinic and Mayo Foundation, Rochester, MN; 2 Missouri Valley Cancer Consortium, Omaha, NE; 3 Wichita Community Clinical Oncology Program, Wichita, KS; 4 Duluth Community Clinical Oncology Program, Duluth, MN; 5 Scottsdale Community Clinical Oncology Program, Scottsdale, AZ; 6 Cedar Rapids Oncology Project Community Clinical Oncology Program, Cedar Rapids, IA, USA

Received 30 September 2002; revised 25 November 2002; accepted 13 January 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

This study was performed to determine the efficacy of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA).

Patients and methods:

Pancreatic ACA patients with previously untreated advanced or metastatic disease were enrolled in a phase II study of gemcitabine and oxaliplatin. Oxaliplatin was given i.v. on day 1 and gemcitabine i.v. on days 1 and 8 of a 3-week cycle. The primary end point of the trial was 6-month survival. Secondary end points included response rate, overall survival, median time to progression and toxicity.

Results:

A total of 47 patients were enrolled, 46 of whom were evaluable. Of those patients assessed for the primary end point 50% lived for >=6 months. The median time to progression was 4.53 months. Five confirmed responses were seen with a median duration of response of 2.7 months. Overall, the treatment was well tolerated. However, one patient died as a result of treatment-related hemolytic uremic syndrome.

Conclusions:

Gemcitabine and oxaliplatin, at doses of 1000 mg/m2 and 100 mg/m2, respectively, showed moderate activity in patients with pancreatic ACA. Based on the results of this study further evaluation of this combination is warranted.

Key words: gemcitabine, oxaliplatin, pancreatic cancer, phase II trial


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Pancreatic adenocarcinoma (ACA) remains a devastating cancer with few good treatment options. While pancreatic cancer is the tenth most common cancer, it is the fourth leading cause of cancer-related death in the USA [1]. Only ~10–15% of patients will be potentially resectable at the time of initial diagnosis [2]. For the majority of patients chemotherapy offers the only proven treatment option with potential palliative benefit. The drug gemcitabine has served as the standard of therapy, based on its superior activity in a phase III trial [3]. Potential benefits of gemcitabine include palliation of symptoms, increased overall survival and disease regression. However, despite its proven activity only one-quarter of patients derive a clinical benefit, and only ~5% have evidence of tumor regression. Thus, there is a need for new therapies for pancreatic ACA.

One potential new therapeutic option is the drug oxaliplatin (trans-l-1,2-diaminocyclohexane oxalatoplatinum), a novel antineoplastic platinum derivative with a 1,2-diaminocyclohexane carrier ligand. Oxaliplatin is more potent than cisplatin (CDDP) in vitro, requiring fewer DNA adducts to achieve an equal level of cytotoxicity [4]. It has also shown efficacy in preclinical studies against many tumor cell lines, including some that are resistant to CDDP and carboplatin. In a preclinical study, oxaliplatin showed potent in vitro cytotoxic activity against three different pancreatic cancer cell lines [5]. However, in limited clinical evaluation oxaliplatin, used as a single agent, appears to have minimal activity against pancreatic ACA.

Oxaliplatin appears to enhance the activity of gemcitabine and thus may improve responses to this agent in patients with pancreatic ACA. The combination of gemcitabine and oxaliplatin has shown supra-additive sequence-dependent synergy in human colon cancer cells [6]. The sequence of gemcitabine followed by oxaliplatin inhibited cell growth more effectively than the reverse sequence. Given evidence of the in vitro activity of gemcitabine and oxaliplatin as single agents against pancreatic ACA, we conducted a phase II trial of this combination. At the time this trial was initiated only limited information was available about the appropriate schedule of administration. We therefore conducted a phase I trial of gemcitabine and oxaliplatin prior to conducting the phase II trial through the North Central Cancer Treatment Group (NCCTG). The results of the phase I trial have previously been reported [7].


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
This study was approved by the Mayo Institutional Review Board (IRB) and the IRBs of the individual members of the NCCTG that elected to participate in this study. A signed written informed consent was obtained from all patients prior to initiating therapy. This study was funded through the NCCTG grant from the National Cancer Institute (NCI). There was no direct industrial funding for this study.

Patients with locally advanced pancreatic ACA, not amenable to treatment with chemoradiotherapy, or metastatic pancreatic ACA were eligible for enrollment in this trial. Prior chemotherapy, when used as a radiosensitizer with adjuvant therapy or for local disease, was allowed. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of <=2 and life expectancy of >=12 weeks. Inclusion criteria included: absolute neutrophil count >=1500/mm2; bilirubin <=1.5 mg/dl; aspartate aminotransferase (AST) and alkaline phosphatase levels <=3x the institutional upper limits of normal; creatinine <=2 mg/dl; and a negative pregnancy test for women of childbearing potential. Exclusion criteria included: chemotherapy or radiotherapy for metastatic disease; radiation to >25% of the bone marrow; pregnancy or lactation; uncontrolled infections; chronic debilitating diseases; and central nervous system metastases.

Pretreatment evaluation and follow-up studies
History and physical examination were performed prior to enrollment and before each subsequent course of chemotherapy. Studies carried out at the time of registration included: complete blood count (CBC); measurement of serum AST and alkaline phosphatase; total and direct bilirubin, calcium, creatinine, sodium, potassium and glucose measurements; and a chest X-ray. CBCs were repeated weekly and chemistries were repeated prior to each subsequent cycle of therapy.

Drug administration
Gemcitabine was commercially purchased (Eli Lilly, Indianapolis, IN) as a lyophilized powder in 200 mg and 1000 mg vials and stored at room temperature. It was reconstituted with normal saline to yield a concentration of 40 mg/ml and administered as an i.v. infusion in 250 ml normal saline over 30 min. Oxaliplatin was supplied by Sanofi-Synthelabo Research (Paris, France) through a Cooperative Research and Development Agreement with the NCI as a lyophilized powder in 50 and 100 mg vials and stored at room temperature in a light-protected package. It was reconstituted with 5% dextrose to yield a concentration of 5 mg/ml and administered as an i.v. infusion in 250–500 ml 5% dextrose water over 2 h following gemcitabine. Both drugs were administered on day 1 and gemcitabine was given alone on day 8 of a planned 3-week cycle. Cycles of treatment were repeated every 3 weeks if patients met the criteria for retreatment.

Disease assessment
Patients were considered to have a complete response (CR) to therapy if evidence of the tumor disappeared. A partial response (PR) was defined as a >=50% reduction in the sum of the products of the largest perpendicular diameters of the indicator lesion, single or multiple sites, chosen prior to therapy. A regression was defined as a reduction in the size of evaluable tumor that did not fit the definition of either a CR or PR. A response to therapy was only accepted as confirmed if it persisted on two or more consecutive scans at least 4 weeks apart. Progression was considered as an increase in the size of any pretreatment lesion for evaluable disease or at least a 25% increase in the size of any measurable lesion prior to pretreatment. Appearance of new lesion(s) constituted disease progression.

Statistical considerations
The primary end point of this trial was the proportion of patients alive at 6 months. All patients meeting the eligibility criteria then signed a consent form and began treatment and were followed for at least 6 months. The study design used a maximum of 40 patients to test the null hypothesis that the true proportion of patients alive at 6 months from study entry is at most 40%, with 80% power to detect a proportion alive at 6 months of 60%, at a 0.05 level of significance. If 21 or fewer of 40 patients lived at least 6 months from study entry, we would conclude that this treatment has insufficient activity in this disease. If 22 or more patients lived 6 months from entry, this was to be considered adequate evidence of efficacy of this treatment to recommended further testing in subsequent studies.

Secondary end points included overall survival, time to disease progression, response rate and toxicity. Survival time was defined as the time from registration to death due to any cause. The distribution of survival time was estimated using the Kaplan–Meier method [8]. Time to disease progression was defined as the time from registration to documentation of disease progression. The distribution of time to progression was also estimated using the Kaplan–Meier method. If a patient died without a documentation of disease progression, the patient was considered to have had tumor progression at the time of their death unless there was sufficient documented evidence to conclude no progression occurred prior to death. If a patient was considered to have had a major treatment violation or was taken off the study as a non-protocol failure, the patient was censored on the date they were removed from treatment.

The response rate was estimated by the number of patients who have documented objective responses (maintained for a minimum of 4 weeks) divided by the total number of patients evaluable for response. Standard criteria were used to evaluate patients’ objective tumor status <=14 days prior to registration and prior to every other course of treatment. Patients who died (or were lost to follow-up) without progression were considered to have progressed at the date of death (or last contact) unless documentation proved otherwise, in which case they would be considered as having no progression at the date of last tumor evaluation. Duration of response is calculated from the date of the patient’s first best objective status of CR, PR or regression, to the date of progression.

This study utilized the NCI Common Toxicity Criteria version 2.0 for adverse event monitoring and reporting. Toxicity was evaluated prior to each cycle of treatment. The maximum grade for each type of toxicity was recorded for each patient and frequency tables were used to determine toxicity patterns.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between March and December 2000, 47 patients were enrolled in this study through the NCCTG, with one patient declared ineligible. We include in these 47 patients three who were treated at these same dose levels in the phase I portion of the trial. The characteristics of the 46 eligible patients are outlined in Table 1. Twenty-six of the patients were men and 20 were women, with a median age of 62.5 years (range 38–76). All the patients had metastatic disease. Twenty-eight percent of patients had previously undergone surgery and 6.5% had received prior radiochemotherapy for localized disease. The majority of patients had an ECOG performance status of 0 or 1 (76%).


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Table 1. Characteristics of patients receiving oxaliplatin and gemcitabine for pancreatic adenocarcinoma
 
Outcome measures
The primary end point of this study was 6-month survival. Fifty percent of the patients enrolled in this study survived >=6 months [95% confidence interval (CI) 34% to 66%]. The median overall survival (Figure 1) was 6.22 months (95% CI 5.4–8.9 months). Twenty of the first 40 patients entered onto the phase II portion of the trial were alive at 6 months from study entry, which did not meet our predefined criteria for success. The median time to progression (Figure 2) was 4.53 months (95% CI 3.4–5.5 months).



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Figure 1. Overall survival for patients receiving gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma.

 


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Figure 2. Time to progression for patients receiving gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma.

 
All 46 patients were evaluable for response. The overall confirmed response rate was 10.9% (95% CI 3.6% to 23.6%), which consisted of four PRs and one CR. The median duration of response (for these five patients) was 2.7 months. Two additional patients experienced a response (one PR, one CR) that was not confirmed on a subsequent scan. The patient with the CR died as a result of hemolytic uremic syndrome (HUS), as discussed below, prior to confirmation of the CR.

Dose intensity
A median of 5.5 cycles of therapy were given (range 1–17). Of the 42 patients receiving a second cycle of therapy, six required a dose reduction for their second cycle. Dose reduction by cycle is shown in Table 2.


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Table 2. Frequency of dose reductions for patients receiving oxaliplatin and gemcitabine for pancreatic adenocarcinoma
 
Toxicity
The most common grade 3–4 toxicity was neutropenia (Table 3). Nearly one-quarter of the patients had grade 4 neutropenia. Grade 3 febrile neutropenia occurred in 6.7% of patients. One death occured in a patient showing response to therapy. This patient died as a result of HUS. The patient developed classical symptoms associated with HUS including thrombocytopenia and acute renal failure. No other potentially life threatening (grade 4) toxicities were seen. Hematological and non-hematological toxicities related to therapy are outlined in Table 3.


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Table 3. Treatment-related toxicities for all cycles of therapy with gemcitabine and oxaliplatin
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The combination of gemcitabine and oxaliplatin, at doses of 1000 mg/m2 and 100 mg/m2, respectively, showed evidence of activity in this phase II trial of patients with metastatic pancreatic ACA. However, the predetermined level of success for the primary end point in this trial was not met, suggesting that the combination, as given in this study, may not be more active than gemcitabine alone. The sample size for this trial was based on having adequate power to detect >=60% of the patients alive after >=6 months. Only 50% of patients treated in this study reached this end point; this is comparable to 46% for gemcitabine alone. The median overall survival for patients receiving gemcitabine and oxaliplatin was also only slightly higher than that reported for patients receiving gemcitabine alone (6.2 versus 5.6 months, respectively).

Overall, the chemotherapy given in this trial was well tolerated. With the exception of neutropenia, grade 4 toxicity was very uncommon. No episodes of neutropenic fever or sepsis occurred. Most patients, receiving more than one cycle of therapy, were able to receive full doses of both gemcitabine and oxaliplatin (Table 2). One patient did die as a result of treatment-related HUS. The development of HUS has been associated with both gemcitabine [9] and oxaliplatin [10]. However, this complication of treatment with either of the drugs appears to be quite rare.

One potential explanation of the limited benefit from the addition of oxaliplatin to gemcitabine may be the schedule and doses we chose to use. Since initiating this study, a variety of phase I schedules have been assessed by other groups (Table 4). Varying doses of gemcitabine and oxaliplatin were used. Prior studies with oxaliplatin have suggested that dose intensity is important [11]. It is therefore possible that the dose of 100 mg/m2 used in our study provided insufficient oxaliplatin to produce a significant benefit. However, in our phase I trial it was not possible to achieve full dose oxaliplatin in combination with gemcitabine [7]. Further studies will need to be performed to evaluate the importance of dose intensity.


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Table 4. Varying schedules and doses of gemcitabine and oxaliplatin as determined in other studies
 
The appropriate method for administering gemcitabine has also been questioned. The traditional 30-min infusion of gemcitabine does not appear to optimize the pharmacokinetics of this drug. In previous studies comparing the optimal infusion rate, the pharmacokinetics of gemcitabine suggested that a fixed dose-rate infusion of ~10 mg/m2/min achieves a higher intracellular level of the active metabolite than the standard 30-min infusion [1214]. In a phase II randomized trial of these two approaches to gemcitabine administration, in patients with pancreatic ACA, the fixed dose-rate infusion showed more promising results [15].

One other study has assessed the combination of gemcitabine and oxaliplatin in patients with locally advanced or metastatic pancreatic ACA [16]. In this study, gemcitabine was given as a fixed dose-rate infusion (Table 4). The dose intensity of oxaliplatin was also higher than that achieved in our study. The overall response rate was 30%, with similar response rates for both locally advanced and metastatic disease. The median overall survival for the patients with metastatic disease was 8.7 months.

Based on the results of the studies carried out thus far, including our study and that of Louvet et al. [16], it appears that the combination of gemcitabine and oxaliplatin warrants additional study. The manner in which these two drugs are given appears to influence the regimen’s efficacy. A planned phase III study by the ECOG should help to better clarify both the benefit of a fixed dose-rate infusion of gemcitabine and the added benefit of oxaliplatin.


    Acknowledgements
 
This study was conducted as a trial on behalf of the North Central Cancer Treatment Group and Mayo Clinic, and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-35269, CA-60276, CA-52352, CA-63849, CA-37417, CA-35195, CA-35101, CA-35103, CA-35448, CA-35113 and CA-35415 from the National Cancer Institute Department of Health and Human Services.

Additional participating institutions include: Medcenter One Health Systems, Bismarck, ND (F. Addo); Carle Cancer Center, Urbana, IL (K.M. Rowland); Iowa Oncology Research Assocation Community Clinical Oncology Program (CCOP), Des Moines, IA (R.F. Morton); Meritcare Hospital CCOP, Fargo, ND (R. Levitt); Geisinger Clinic and Medical Center CCOP, Danville, PA (S. Nair); Illinois Oncology Research Association CCOP, Peoria, IL (J.W. Kugler); Toledo Community Hospital Oncology Program CCOP, Toledo, OH (P.L. Schaefer); Sioux Community Cancer Consortium, Sioux Falls, SD (L.K. Tschetter); CentraCare Clinic, St Cloud, MN (H.E. Windschitl); Siouxland Hematology-Oncology Associates, Sioux City, IA (J.C. Michalak).


    Footnotes
 
+ Correspondence to: Dr S. R. Alberts, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1-507-284-8964; Fax: +1-507-538-0823; E-mail: alberts.steven{at}mayo.edu Back


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 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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