Japanese Journal of Clinical Oncology Advance Access originally published online on November 22, 2005
Japanese Journal of Clinical Oncology 2005 35(12):733-738; doi:10.1093/jjco/hyi190
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© 2005 Foundation for Promotion of Cancer Research
Phase I Study of Fixed Dose Rate Infusion of Gemcitabine in Patients with Unresectable Pancreatic Cancer
1 Division of Hepatobiliary and Pancreatic Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba and 2 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
For reprints and all correspondence: Junji Furuse, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: jfuruse{at}east.ncc.go.jp
Received July 20, 2005; accepted September 24, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: The purpose of this study was to determine the feasible dose of gemcitabine when administered as a fixed dose rate infusion (10 mg/m2/min) on a weekly schedule to Japanese patients with unresectable advanced pancreatic cancer.
Methods: Patients were required to have histologically or cytologically proven locally advanced or metastatic pancreatic cancer for which they had received no previous chemotherapy. Gemcitabine was administered intravenously weekly for three consecutive weeks every 4 weeks. Patients at three dose levels were scheduled to receive escalating doses of gemcitabine: 1000 mg/m2 over 100 min (Level 1), 1200 mg/m2 over 120 min (Level 2) and 1500 mg/m2 over 150 min (Level 3).
Results: A total of 16 patients were enrolled in this study between December 2003 and September 2004. Maximum-tolerated dose was not reached during the first course. Dose-limiting toxicity was Grade 4 neutropenia. Grade 3 or 4 neutropenia was observed at Level 3 in all six patients in the first course, and administration of gemcitabine on Day 8 or 15 was skipped in all six patients. Non-hematologic toxicity was mild and the most common symptoms were anorexia, nausea and vomiting. Partial response was achieved in 1 of the 17 patients (7%). Median overall survival was 7.3 months.
Conclusions: Gemcitabine administered at a rate of 10 mg/m2/min was tolerated up to 1500 mg/m2, but 1200 mg/m2 represented a more appropriate recommended dose in further studies owing to neutropenia in Japanese patients with advanced pancreatic cancer.
Key Words: advanced pancreatic cancer • systemic chemotherapy • gemcitabine • fixed dose rate infusion
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Pancreatic cancer is the fifth most common cause of cancer death in Japan, with an estimated 19 000 deaths annually (1). Early-stage diagnosis of pancreatic cancer is difficult because of the lack of specific early symptoms, and surgery with curative intent can be performed in only 5–20% of patients (2). The prognosis for unresectable pancreatic cancer remains extremely poor.
Gemcitabine (2',2'-difluorodeoxycytidine) is a novel pyrimidine antimetabolite with a broad spectrum of antitumor activity against various solid tumors, such as pancreatic and lung cancer (3). This prodrug is initially phosphorylated by deoxycytidine kinase to gemcitabine monophosphate, with subsequent phosphorylation steps yielding gemcitabine di- and triphosphate (4). Gemcitabine triphosphate inhibits DNA synthesis by competing with deoxycytidine triphosphate for incorporation into DNA by DNA polymerase (5). A dose of 790 mg/m2 gemcitabine weekly for 3 weeks every 28 days was recommended for Phase II studies on the basis of a Phase I study in which gemcitabine was administered as a once-weekly 30 min bolus infusion (6). This dosing schedule was used in subsequent Phases II and III studies, and once-weekly 30 min infusion of the 1000 mg/m2 dose was subsequently selected as the standard schedule (7,8). In a randomized clinical trial, gemcitabine was confirmed to provide a survival advantage over 5-FU in addition to symptom-relieving benefits in patients with advanced pancreatic cancer (8). Based on these results, gemcitabine has generally been accepted as the standard chemotherapeutic agent for advanced pancreatic cancer. However, the advantages in terms of survival rate are inadequate, and various chemotherapeutic regimens have been investigated in clinical studies in efforts to prolong survival.
The cellular pharmacokinetics of the active metabolite, gemcitabine triphosphate, in mononuclear cells have been examined in previous studies, and the rate of gemcitabine triphosphate accumulation and peak intracellular concentration were highest at a dose rate of 350 mg/m2 over 30 min, during which steady-state gemcitabine levels of 15–20 µmol/l were achieved in plasma (6,9). A dose 
10 mg/m2/min that achieves plasma gemcitabine concentrations of 15–20 µmol/l would thus maximize the intracellular rate of accumulation for gemcitabine triphosphate. This schedule of gemcitabine administration, with fixed dose rate (FDR) infusion of 10 mg/m2/min, would enable exposure to higher concentrations of gemcitabine, and should improve clinical efficacy.
Phase I studies of FDR infusion of gemcitabine in the United States recommended a Phase II dose of 1500 mg/m2 (10,11). A subsequent randomized Phase II trial comparing this FDR gemcitabine infusion schedule and high-dose gemcitabine (2200 mg/m2) using a standard 30 min infusion showed improved median survival time for the FDR arm (12). The FDR infusion schedule is expected to become the optimal method of gemcitabine administration, but has not previously been assessed in Japan. We, therefore, conducted a Phase I study to determine whether FDR infusion of gemcitabine would be tolerated in Japanese patients with unresectable advanced pancreatic cancer. The primary objectives of this study were to confirm whether the recommended dose in the United States, 1500 mg/m2 over 150 min, would be feasible in Japanese patients and to determine the relationship between dose and toxicity for gemcitabine administered using the FDR infusion schedule. The secondary objective was to evaluate antitumor activity of the schedule.
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PATIENTS AND METHODS |
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PATIENTS ELIGIBILITY
Eligibility criteria for enrollment in the study were as follows: (i) histologically confirmed pancreatic ductal adenocarcinoma; (ii) unresectable locally advanced or metastatic disease; (iii) no previous treatment for pancreatic cancer except surgery; (iv) age
20 and 
74 years old; (v) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; (vi) adequate bone marrow (leukocyte count 4000 cells/mm3, platelet count 100 000 cells/mm3 and hemoglobin 9.0 g/dl), renal function (serum creatinine concentration upper limit of normal) and hepatic function (serum bilirubin level 2.0 mg/dl, serum albumin level 3.0 g/dl, serum aspartate and alanine transaminase (AST and ALT) levels 2.5 times upper limit of normal); (vii) life expectancy 8 weeks; and (viii) written informed consent from the patient. Percutaneous biliary drainage was performed in patients with obstructive jaundice, and these patients were required to have serum bilirubin levels of 2.0 mg/dl and serum AST and ALT levels 5 times the upper limit of normal before enrollment. Exclusion criteria comprised serious complications such as active infection, active gastrointestinal ulcer, cardiac disease or renal disease; central nervous system metastasis; marked pleural effusion or ascites; symptomatic interstitial pneumonitis; and pregnancy or lactation for women. This protocol was approved by the National Cancer Center's institutional review board for clinical investigation.
TREATMENT METHODS
Gemcitabine (Eli Lilly Japan K.K., Kobe, Japan) was administrated intravenously at 10 mg/m2/min, weekly, for three consecutive weeks, followed by a week of rest. This cycle was continued until disease progression or serious adverse effects developed or until the patient requested discontinuation. When patients developed leukopenia of <2000/mm3, neutropenia of <1000/mm3, thrombocytopenia of <70 000/mm3, total bilirubin >2.0 mg/dl or AST and ALT levels >5 times the upper limit of normal, gemcitabine administration was suspended until the patient recovered. If a rest period of >4 weeks was required owing to toxicity, the patient was withdrawn from the study.
STUDY DESIGNS
Patients at three dose levels were scheduled to receive escalating dose of gemcitabine. At the first dose level (Level 1), gemcitabine was administered at a dose of 1000 mg/m2. The dose level was increased to 1200 mg/m2 for Level 2 and 1500 mg/m2 for Level 3. Patient cohorts had a minimum of three patients at each level. If no dose-limiting toxicity (DLT) was observed in the initial three patients during the first cycle of treatment, the dose was advanced to the next level. If DLT occurred in the initial three patients, three additional patients were studied at the same dose level. If two or more of these six patients experienced DLT at that level, the dose was escalated to the next level. The maximum-tolerated dose (MTD) was defined as the highest dose level at which more than two of the six patients experienced DLT during the first cycle of treatment. If DLT occurred in three patients at Level 1, the dose was reduced to 800 mg/m2 (Level 0). DLT was defined as follows: (i) Grade 4 leukopenia or neutropenia; (ii) febrile neutropenia; (iii) Grade 4 thrombocytopenia or Grade 3 thrombocytopenia requiring transfusion; (iv) Grade 3 non-hematological toxicity with the exception of nausea, vomiting, anorexia, fatigue and constipation; and (v) any toxicity requiring two consecutive skips of administration or a >4 week delay in treatment. Toxicity was graded according to the National Cancer Institute common toxicity criteria version 2.0.
CLINICAL ASSESSMENTS
Physical examination, complete blood cell counts, serum chemistries and urinalysis were performed at baseline and at least once weekly after initiating treatment. Patients underwent dynamic computed tomography (CT) to evaluate response at 4–8 week intervals after start of treatment. CT was performed by obtaining contiguous transverse sections using the helical scanning method at a section thickness of 5 mm. Tumor response was assessed according to the World Health Organization criteria (13). Serum carbohydrate antigen (CA)19-9 levels were measured monthly by immunoradiometric assay. Progression-free survival was calculated from the first day of treatment until evidence of tumor progression, clinical progression or death owing to any cause. Overall survival was calculated from the first day of treatment until death owing to any cause. Survival data were analysed using the Kaplan–Meier method.
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RESULTS |
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PATIENT CHARACTERISTICS
Between December 2003 and September 2004, a total of 16 patients were enrolled in this study. Dose escalation schedule and the number of patients at each level are shown in Table 1. The first administration of 1200 mg/m2 of gemcitabine in one patient receiving Level 2 was later found to have been infused over 90 min, departing from the FDR of 10 mg/m2/min. As a result, an additional patient was added to Level 2 and ultimately seven patients were treated at Level 2. Patient characteristics are shown in Table 2. The 16 patients received 60 courses of gemcitabine. Median number of courses administered per patient was 3 (range 1–9 courses). All 16 patients were evaluable for toxicity, but the Level 2 patient not infused with gemcitabine at a rate of 10 mg/m2/min was excluded from the evaluation of DLT.
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TOXICITY
Toxicities of the 15 patients evaluated for DLT during the first course are shown in Table 3. The first three patients enrolled on Levels 1 and 2 did not experience any DLT, but one of the six patients at Level 3 experienced DLT. MTD was not reached in this study. However, since all six patients at Level 3 (1500 mg/m2 over 150 min) experienced Grade 3 or 4 neutropenia after Day 1 or 8 of the first course and did not receive the second or third dose of gemcitabine, an additional three patients were entered at Level 2 to accurately determine the recommended FDR for gemcitabine. Finally, no Grade 4 hematological toxicity was observed in any of the six patients at Level 2, and Grade 3 neutropenia developed in three of these patients. While five of the six patients received the full three doses of gemcitabine in the first course, the remaining patient did not receive the third dose owing to Grade 3 neutropenia. Level 2 (1200 mg/m2) was therefore selected as the recommended dose for further studies of this FDR gemcitabine regimen in Japan.
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Toxicities throughout the entire period of this protocol were assessed in all 16 patients enrolled in this study (Table 4). The most common toxicity was leukopenia, particularly neutropenia, with 13 of the 16 patients (81%) developing Grade 3 or 4 neutropenia during treatment. Non-hematological toxicities were generally mild at all levels, and one patient developed Grade 3 nausea, vomiting, and anorexia at Level 1 and Level 2, respectively. Skin rashes were mild, but tended to occur in a larger number of patients as the dose was escalated.
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TUMOR RESPONSE AND SURVIVAL
Partial response was achieved in 1 of the 16 patients (6.3%), but no complete responses were observed. Overall response rate was thus 6.3% (95% confidence interval = 0.2–30.2%). No change was noted in 12 patients (75.0%), and progressive disease was in two patients (12.5%). The patient with DLT was not evaluated for tumor response because she received standard gemcitabine chemotherapy as second-line chemotherapy before the evaluation. Serum CA19-9 levels were reduced to >50% in 2 of the 12 patients (16.7%) in whom pretreatment level was elevated to above the upper limit of normal.
Disease progression was finally observed in all patients and 12 of the 16 patients died of disease progression. Median progression-free survival was 3.2 months, and overall median survival time (MST) was 7.3 months (Figs 1 and 2).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Gemcitabine is a prodrug that requires initial intracellular phosphorylation by deoxycytidine kinase, ultimately undergoing phosphorylation to the active gemcitabine triphosphate, a cytotoxic agent that inhibits DNA synthesis. Tempero et al. (12) reported on intracellular concentrations of gemcitabine triphosphate in peripheral blood mononuclear cells in a randomized trial comparing FDR infusion over 150 min and high-dose gemcitabine (2200 mg/m2) using a standard 30 min infusion. The rate of gemcitabine triphosphate accumulation in patients who received conventional infusion decreased markedly after the end of infusion (30 min), whereas patients who received gemcitabine as FDR infusion exhibited linear accumulation of the triphosphate throughout the infusion. Intracellular gemcitabine triphosphate concentration in the FDR arm was 2-fold higher than that in the conventional infusion arm.
In the United States, two Phase I studies have been performed to determine the recommended dose for FDR infusion of gemcitabine (10,11). Brand et al. (11) conducted a Phase I study at dose levels of 1200 mg/m2, 1500 mg/m2 and 1800 mg/m2, administered on Days 1, 8 and 15 of a 28 day cycle. MTD was defined as 1500 mg/m2, with granulocytopenia and thrombocytopenia representing the DLTs. Brand et al. concluded that myelosuppression was more severe than anticipated based on previous reports regarding standard gemcitabine administration. Touroutoglou et al. (10) conducted the other Phase I study of FDR infusion of gemcitabine in which the weekly dose was escalated from 1200 to 2800 mg/m2 for 3 weeks every 4 weeks. They reported that MTD was 1800 mg/m2, and recommended a Phase II starting dose of 1500 mg/m2 owing to myelosuppressive effects.
The present study evaluated the safety of FDR infusion of gemcitabine and identified the feasible dose for Japanese patients with unresectable advanced pancreatic cancer. This Phase I study was conducted using dose levels of 1000, 1200 and 1500 mg/m2, administered on Days 1, 8 and 15 of the 28 day cycle. DLT was observed in only one patient at Level 3, and MTD was not reached in this study. However, all six patients displayed Grade 3 or 4 neutropenia during the first course at Level 3, and no patient received all three doses of gemcitabine during the first course. In contrast, three patients at Level 2 experienced Grade 3 neutropenia, and only one patient had to skip the dose of gemcitabine on Day 15. Based on these results, the recommended dose should be 1200 mg/m2 in further studies of FDR infusion of gemcitabine in Japan from the perspective of dose intensity for gemcitabine.
Preclinical data, using primary human tumor cell lines including pancreatic carcinoma, have suggested a possible dose–response relationship, and exposure to high concentrations of gemcitabine, independent of infusion duration, might correlate with improved cytoxicity and enhanced clinical effectiveness (12). Thus, a randomized trial of gemcitabine comparing high-dose gemcitabine (2200 mg/m2) administered using a standard 30 min infusion to FDR infusion of 1500 mg/m2 over 150 min was conducted in patients with locally advanced or metastatic pancreatic cancer according to the results of two Phase I studies in the United States (10–12). Although no difference in tumor response was noted between the 30 min infusion and FDR arms, MST was reported as 5.0 months in the 30 min infusion arm and 8.0 months in the FDR arm (P = 0.013), and 1 and 2 year survival rates were 9.0 and 2.2%, respectively, in the 30 min infusion arm, and 28.8 and 18.3%, respectively, in the FDR arm. In the study conducted by Burris et al. (8), MST for gemcitabine using the standard 30 min infusion of 1000 mg/m2 was 5.7 months, and 1 and 2 year survival rates were 18 and 0%, respectively. A retrospective analysis reported that the MST of patients in Japan treated with gemcitabine by standard infusion of 1000 mg/m2 was 5.7 months (14). In comparison, survival outcomes of patients treated using the standard 30 min infusion are similar, and MST is <6 months. In contrast, in a study with a limited number of patients using FDR infusion, MST was 7.3 months and similar to MST in the FDR arm of the randomized trial in the United States (12).
The most common toxicity for FDR infusion was myelosuppression, particularly neutropenia, as noted in a randomized trial by Tempero et al. (12). In our study, Grade 3 or 4 neutropenia developed in 81.3% of patients, and Grade 3 or 4 leukopenia and thrombocytopenia were observed in 62.5 and 18.8%, respectively. By contrast, a Phase I study for the standard infusion of gemcitabine in Japan reported rates of Grade 3 or 4 neutropenia, leukopenia and thrombocytopenia of 36.4, 27.3 and 0%, respectively (15). The FDR infusion schedule thus seems more hematologically toxic. Conversely, the non-hematological toxicity of FDR infusion was relatively mild. Grade 3 nausea and vomiting that occurred in 12.5% of patients on FDR infusion resembled the results obtained with standard infusion in the Japanese Phase I study, in which 9.1% of patients developed Grade 3 nausea and vomiting. Skin rashes were more frequent with FDR infusion, with 50% of patients developing Grade 1 or 2 skin rashes, than with standard infusion, in which 27.3% of patients developed Grade 1 or 2 skin rashes.
Various regimens of gemcitabine in combination with potentially synergistic drugs have been trialed to improve prognosis in patients with unresectable pancreatic cancer (16–22), and FDR infusion of gemcitabine has also been applied to combination chemotherapy with other anticancer drugs (20–22). A Phase III study comparing standard infusion of gemcitabine, FDR infusion of gemcitabine and combined FDR infusion of gemcitabine and oxaliplatin is under way as an ECOG study in the United States. The results of that study should be awaited before deciding whether FDR infusion of gemcitabine alone can be used as the standard treatment for unresectable pancreatic cancer. However, data from the present study confirm that FDR infusion of gemcitabine is tolerated by Japanese patients, and continued evaluation of FDR infusion, alone or in combination with other agents, is warranted in Japan.
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Acknowledgments |
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This study was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan.
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References |
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