Japanese Journal of Clinical Oncology 31:7-12 (2001)
© 2001 Foundation for Promotion of Cancer Research
Phase I Trial of Gemcitabine in Patients with Advanced Pancreatic Cancer
1Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo and 2Hepatobiliary and Pancreatic Oncology Division, National Cancer Center East Hospital, Chiba, Kashiwa, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIX 1APPENDIX 2AcknowledgmentsREFERENCES |
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Background: Gemcitabine is the most promising new agent currently being tested in pancreatic cancer. The present study was conducted to confirm the tolerability of a weekly schedule of gemcitabine at a dose of 1000 mg/m2 in Japanese patients with advanced pancreatic cancer.
Methods: The primary end-point was to evaluate the frequency of dose-limiting toxicity. Gemcitabine 1000 mg/m2 was administered over 30 min weekly in two schedules: gemcitabine x3 every 4 weeks (Schedule 1) and gemcitabine x7 followed by a week of rest and then gemcitabine x3 every 4 weeks thereafter (Schedule 2). At least three patients entered each schedule and three additional patients were treated in the presence of dose-limiting toxicity.
Results: Eleven chemo-naive patients with a good Karnofsky performance status of 
80 points and distant metastasis were entered into this trial. In Schedule 1, no dose-limiting toxicity was observed in the three patients. In Schedule 2, the evaluation of dose-limiting toxicity was complete in six of the eight enrolled patients and two patients showed dose-limiting toxicity in this Schedule; one patient experienced both grade 4 leukocytopenia and grade 4 neutropenia, and both grade 4 neutropenia and grade 3 GOT/GPT increased in another patient. Two patients (18%) showed a partial response and a clinical benefit response was also achieved in two (29%) of the seven evaluable patients.
Conclusion: Gemcitabine 1000 mg/m2 weekly x7 followed by a week of rest and weekly x3 every 4 weeks thereafter may be tolerated in Japanese patients with advanced pancreatic cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIX 1APPENDIX 2AcknowledgmentsREFERENCES |
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Pancreatic cancer (PC) is difficult to treat, with most patients surgically unresectable at the time of diagnosis (1,2). The prognosis of these unresectable PC patients is extremely poor, mainly because currently available chemotherapeutic agents are largely ineffective. Accordingly, there is a clear need for new, effective agents to improve the prognosis of PC.
Gemcitabine (GEM), which is a deoxycytidine analogue of arabinosylcytosine (ara-C), is one of the most promising new chemotherapeutic agents in recent years (3). GEM is activated by intracellular phosphorylation to the 5'-triphosphate (dFdCTP) with resultant inhibition of DNA synthesis. Compared with ara-C, a more prolonged inhibition both of cell synthetic function and of progression through the cell cycle can be expected, since dFdCTP accumulation occurs rapidly and the intracellular elimination is slow (4,5). Therefore, GEM has the potential for activity against human solid tumors, including PC, that are refractory to established anti-cancer agents.
Based on the results of previous phase I trials of GEM, the weekly schedule (30 min infusion, once weekly for three consecutive weeks followed by a week’s rest) at a dose of 800 mg/m2/week has generally been selected for further clinical trials (6–8). However, in the trials of GEM for advanced PC, a dose of 1000 mg/m2 has been used and approved in Western countries including the USA (9,10). Therefore, we conducted a phase I trial to confirm the tolerability of weekly schedule GEM at a dose of 1000 mg/m2 in Japanese patients with advanced PC.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIX 1APPENDIX 2AcknowledgmentsREFERENCES |
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Patients
Patients eligible for study entry had pathologically or clinically confirmed PC. Each patient was required to meet the following eligibility criteria: no indication of pancreatic resection or radiotherapy; no history of prior anti-cancer treatment except pancreatic resection; 20–74 years of age; Karnofsky performance status (KPS) of
50 points; estimated life expectancy 3 months; adequate renal function (normal serum creatinine and blood urea nitrogen levels), liver function [total bilirubin level 
2 times upper normal limit (UNL) (or 3 times UNL after biliary drainage if the patient had obstructive jaundice) and serum transaminases (GOT, GPT) levels 2.5 times UNL (or 3 times UNL in the patients with liver metastases and/or obstructive jaundice), bone marrow reserve (white blood cell count 4000–12 000/mm3, neutrophil count 2000/mm3, platelet count 100 000/mm3 and hemoglobin level 9.5g/dl) and pulmonary function (PaO2 70 mmHg); written informed consent. The exclusion criteria were as follows: pulmonary fibrosis or interstitial pneumonia; marked pleural or pericardial effusion or marked peripheral edema; severe heart disease; diabetes mellitus which is difficult to control; active infection; pregnant or lactating females; females of childbearing age unless using effective contraception; severe drug hypersensitivity; metastases of the central nervous system; severe neurological impairment or mental disorder; active concomitant malignancy; other serious medical conditions.
Pretreatment evaluation included complete history and physical examination. In addition, complete blood count, biochemistry tests, urinalysis, electrocardiogram and chest radiography were performed. Patients were clinically assessed weekly and laboratory tests were also performed weekly.
At least three patients were treated in each schedule and three more patients were enrolled in the presence of dose-limiting toxicity (DLT; see below for definition). Patients were hospitalized and observed during the first course, but further treatment could be delivered on an outpatient basis when the general condition of the patients remained good and no serious adverse effects were observed. Patients were removed from the study if it was difficult to continue GEM treatment because of the development of serious adverse effects and/or complications. Other reasons for withdrawal included progressive disease and a request to withdraw.
Treatments
GEM was supplied by Eli Lilly Japan (Kobe, Hyogo, Japan) as a lyophilized powder in vials containing 200 and 1000 mg of GEM as hydrochloride salt. First, 1000 mg/m2 GEM diluted in 100 ml of normal saline was administered weekly as an intravenous 30 min infusion. In Schedule 1, GEM was administered for 3 weeks with 1 week of rest (Fig. 1). In Schedule 2, GEM was administered seven times followed by 1 week of rest and then GEM three times every 4 weeks thereafter. The treatment was continued until there was evidence of disease progression or unacceptable toxicity including DLT.
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When patients experienced adverse effects such as grade 3 hematological toxicity, serum creatinine of 1.5–2.0 times UNL, grade 3 nausea/vomiting, total bilirubin level of 4.0–5.0 times UNL or grade 2 non-hematological toxicities other than anorexia, fatigue or alopecia on the treatment day, GEM administration was omitted on that day and postponed to the next scheduled treatment day. Patients who experienced the above adverse effects possibly received 800 mg/m2 in subsequent courses, although no dose adjustment was allowed during the same course.
There was no routine prophylactic administration of anti-emetics or granulocyte colony-stimulating factors. However, patients who experienced grade 2 nausea/vomiting were pretreated with anti-emetics in subsequent courses. With respect to leukocytopenia and/or neutropenia, lenograstim (Neutrogin; Chugai Pharmaceuticals, Tokyo, Japan) was administered subcutaneously when grade 4 toxicity or grade 3 toxicity with high fever (38.0°C) occurred. Platelet transfusion was performed when the platelet count decreased to <25 000/mm3.
Toxicity and Response Evaluation
The primary end-point of this trial was to evaluate the frequency of DLT and the secondary end-point was to evaluate objective tumor response and clinical benefit response. The criteria of DLT included non-hematological toxicity of grade 3 (except nausea/vomiting, anorexia and fatigue), grade 3 leukocytopenia and/or neutropenia with high fever (38.0°C) and grade 4 leukocytopenia and/or neutropenia or grade 4 thrombocytopenia. In addition, DLT was recognized when administration of GEM was omitted twice in succession owing to toxicity. The dose schedule of GEM was considered tolerable according to the general method used for the phase I trial of anti-cancer agents, in which the frequency of DLT was not more than 50%.
The objective tumor response was assessed at least every 3–4 weeks. In the present study, the sizes of metastatic lesions were measured to evaluate tumor response to GEM; however, pancreatic masses were not considered to be measurable, because imaging modalities including ultrasonography and computed tomography may be insufficient to determine accurately the tumor size of pancreatic masses (11). All responses were strictly judged by extramural review.
The clinical benefit responses to GEM therapy were evaluated by KPS and pain, as described elsewhere (9,10,12). KPS was recorded weekly by physicians. Pain was evaluated by measuring changes from the baseline in pain intensity and morphine consumption. Each patient recorded pain intensity on a pain assessment card every day. Patients who met at least one of the following criteria were defined as eligible for the evaluation of the clinical benefit response: (1) a baseline KPS of 50–70 points, (2) baseline pain intensity of 20 (out of 100) as measured by the pain assessment card and (3) baseline morphine consumption of 10 mg/day.
The duration of both tumor response and clinical benefit response was calculated from the first day of treatment and the duration of survival was also calculated from the first day of treatment using the Kaplan–Meier method. We used the Japan Society for Cancer Therapy criteria, which are fundamentally similar to the World Health Organization criteria and NCI Common Toxicity Criteria, for evaluating the tumor responses and the adverse effects (13,14). A monitoring committee was arranged independently to assess the evaluation of efficacy and safety of the study. This trial was performed after the approval of the investigational review board of each hospital had been given.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIX 1APPENDIX 2AcknowledgmentsREFERENCES |
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Patients and Treatments
Eleven chemo-naive patients were entered into this trial at two different schedule levels from the two hospitals of the National Cancer Center between June 1998 and February 1999. The diagnosis of PC was confirmed by histological examination in nine patients and in the remaining two patients it was based on typical radiographic findings of PC. Three patients entered Schedule 1 and a total of eight patients were enrolled in Schedule 2, because the GEM therapy was stopped owing to progressive disease and DLT was not evaluated completely in two patients.
The baseline characteristics of the 11 eligible patients are summarized in Table 1. There were eight males and three females with a median age of 58 years (range, 35–73 years). All patients showed a good KPS of 80 points and distant metastasis. The major sites of distant metastasis were the liver and lymph nodes. One patient had a history of a pancreatectomy for PC. Before chemotherapy, two patients underwent biliary drainage for obstructive jaundice.
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The 11 patients were given a total of 34 courses, with a median of two courses each (range, 1–8). The median cumulative dose of GEM received was 8000 mg/m2, with a range of 3000–25 000 mg/m2. The reasons for treatment discontinuation were disease progression (eight patients; 73%), DLT (one patient; 9%) and both (one patient; 9%). One (3%) of 39 planned GEM injections in Schedule 1 and four (5%) of 81 injections in Schedule 2 were omitted owing to adverse effects including grade 3 leukocytopenia and neutropenia, grade 2 skin rash and grade 2 GPT increase. However, no patients required dose modification in subsequent courses because of these toxicities.
Toxicity
All 11 patients received at least one dose of GEM and were therefore evaluable for toxicity. The GEM therapy was generally well tolerated and no treatment-related toxic death occurred. Hematological toxicity, most notably leukocytopenia and/or neutropenia, was the most common severe toxicity of GEM in this schedule, although no patient presented life-threatening complications.
Table 2 summarizes the hematological toxicity for each cohort of patients in both schedules. A greater severity of leukocytopenia and neutropenia was observed in Schedule 2; grade 3–4 toxicities occurred in three (38%) and four (50%) of the patients, respectively, in this schedule. However, these toxicities were brief and reversible, although the patients with grade 4 leukocytopenia and/or neutropenia received lenograstim; the median time to the nadir of the neutropenia was 14 days and the median time from the nadir to recovery (2000/mm3) was 8 days. A neutropenic fever, defined as high fever (38°C) concomitant with grade 3 neutropenia, was not observed. Anemia was more common in Schedule 2 (75%) than in Schedule 1 (33%). Thrombocytopenia was frequently observed, but it was mild and rarely significant.
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The non-hematological toxicities of GEM, which did not appear to be schedule dependent, were again mild and well tolerated, with only one patient (9%) having grade 4 toxicity (anorexia) (Table 3). Anorexia, fatigue, nausea/vomiting and liver function abnormalities were the most common non-hematological toxicities. Although the majority of these adverse effects were mild, it was
grade 3 in ~10–30%. Other common toxicities consisted of hypoxia, hypertension, skin rash, fever, proteinuria and glycosuria, but these were both mild and transient. Despite having received no prophylactic premedication, no patient experienced hypotension, flu-like symptoms or hemolytic–uremic syndrome. No cumulative tendency of hematological and non-hematological toxicities was noted as the treatment courses continued.
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In Schedule 1, no DLT was observed in three patients. In Schedule 2, two of six evaluable patients showed DLT after three doses of the first course; one patient experienced grade 4 leukocytopenia and grade 4 neutropenia and another patient had grade 4 neutropenia and grade 3 GOT/GPT increased. However, Schedule 2 was considered tolerable, because the frequency of DLT was not greater than 50% even in this schedule.
Response
All 11 patients were evaluable for objective tumor response. Two patients (one patient in each schedule) achieved a partial response which lasted 2 and 6 months, respectively, giving an overall response rate of 18% (95% CI, 2–52%). Four patients (36%) showed no change and the remaining five (45%) demonstrated progressive disease. Moreover, two (27%) of the seven eligible patients achieved a clinical benefit response in Schedule 2; the duration periods of the responses were 2 and 7 months, respectively. After GEM therapy, these two responders felt no pain without morphine treatment, although their baseline morphine consumption had been 60 and 90 mg/day, respectively. No patient was eligible in the evaluation of KPS, because all patients had had a good KPS of 80 points at study entry.
All but one patient had died at the time of analysis, while two patients had survived for more than 1 year (392 and 517+ days). Although all patients had metastatic disease, the overall survival of patients was relatively good, with a median survival time of 191 days (95% CI, 108–310 days).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIX 1APPENDIX 2AcknowledgmentsREFERENCES |
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At present, chemotherapy for PC has only limited value in clinical practice, because only a small proportion of patients will achieve real benefit from chemotherapy (1,2). The fundamental problem with chemotherapy for patients with PC is the lack of any individual drug with a truly high level of activity. Therefore, new agents are required before there will be any breakthroughs in the development of a truly effective chemotherapeutic regimen. Phase II trails of new agents are attempting to identify compounds with activity in patients with advanced PC. However, the majority of single agents tested have been found to be either ineffective or to lead to significant levels of toxicity (15).
GEM is a deoxycytidine analogue capable of inhibiting DNA replication and repair and it bears structural and metabolic similarities to ara-C (3). In contrast to ara-C, GEM has greater cell permeability and target enzyme affinity, as well as prolonged cellular retention (4,5). Clinical trials of GEM have demonstrated that it has significant and consistent anti-tumor activities in a variety of solid tumors, including non-small cell lung cancer, breast cancer and ovarian cancer (16–18). Hence GEM is chemically similar to ara-C, but is clinically different. With regard to PC, GEM is currently the most promising new agent being tested.
An early phase II trial in patients with advanced PC revealed a lower tumor response rate, but frequent subjective symptomatic improvement (clinical benefit response) was observed, often in the absence of a tumor response (19). Based on these observations, two subsequent trials of GEM were initiated, in which clinical benefit response was employed as the primary end-point (9,10). In the randomized trial comparing GEM with 5-fluorouracil (5-FU), GEM therapy showed significantly better results in clinical benefit response rates and survival (10). Moreover, the phase II trial in patients with 5-FU-refractory PC also demonstrated similar effects on disease-related symptoms (9). Accordingly, GEM has been accepted as first-line chemotherapy for PC in Western countries. In these trials, GEM at a dose of 1000 mg/m2 was administered seven times followed by 1 week of rest and then GEM three times every 4 weeks thereafter.
In the present trial, 11 chemo-naive patients with metastatic PC were treated weekly with GEM (1000 mg/m2) to confirm the tolerability of this dose schedule in Japanese patients with advanced PC. Hematological toxicity, particularly leukocytopenia and/or neutropenia, was the most common severe toxicity of GEM with this schedule, although non-hematological toxicities were mild and well tolerated. There was no DLT observed in Schedule 1, but two of six evaluable patients showed DLT in Schedule 2. With regard to anti-tumor activity of GEM, two patients achieved a partial response, giving an overall response rate of 18%. Moreover, two (27%) of the seven eligible patients achieved a clinical benefit response. These findings regarding toxicity and anti-tumor effect of GEM therapy were consistent with those of previous trials using the same dose schedule of GEM. Consequently, in Japanese patients with PC, further trials of GEM can be conducted with Schedule 2.
The previous phase I trial conducted in Japan demonstrated that the recommended dose schedule of GEM was 800 mg/m2 weekly x3 followed by 1 week of rest, with leukocytopenia as DLT (20). However, the current trial may indicate that Schedule 2 (1000 mg/m2 GEM weekly x7 followed by a week of rest and then GEM x3 every 4 weeks thereafter) may be tolerated in patients with advanced PC. The reason for the different results remains to be elucidated, although a once weekly schedule for seven consecutive weeks had not been tested in the previous trial. The differences in patient characteristics such as performance status and a history of chemotherapy between these two trials are the most likely explanation for this inconsistency. Only chemo-naive patients had been enrolled and all had a good KPS of 80 points in our trial, while 11 (39%) of 28 patients had a poor performance status of 2–3 and 23 patients (82%) had a history of chemotherapy in the previous phase I trial.
In conclusion, GEM 1000 mg/m2 weekly x7 followed by a week of rest and weekly x3 every 4 weeks thereafter may be tolerated in Japanese patients with advanced PC.
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APPENDIX 1 |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIX 1APPENDIX 2AcknowledgmentsREFERENCES |
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Judgment Committee
Minoru Kurihara Department of Gastroenterology, Toyosu Hospital, Showa University School of Medicine
Seiki Matsuno Department of Surgery I, Tohoku University School of Medicine
Noriyuki Moriyama Diagnostic Radiology Division, National Cancer Center Hospital
Tetsuo Hayakawa Department of Internal Medicine II, Nagoya University School of Medicine
Shuichi Okada Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital
Yusuke Tanigawara Department of Hospital Pharmacy, School of Medicine, Keio University
Yasuo Ohashi Department of Epidemiology and Biostatistics, School of Health Science and Nursing, Faculty of Medicine, University of Tokyo
Jun Kato Medical Drug Information, Eli Lilly Japan
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APPENDIX 2 |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIX 1APPENDIX 2AcknowledgmentsREFERENCES |
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Efficacy and Safety Evaluation Committee
Shigeru Tsukagoshi Cancer Chemotherapy Center
Toshihiko Kotake Osaka Medical Center
Yoichi Saito Osaka Saiseikai Nakatsu Hospital
Kiyokazu Yoshida Saitama Prefectural Cancer Center
Advisors for efficacy evaluation:
Tetsuo Taguchi Japan Society for Cancer Chemotherapy
Jou Ariyama Juntendo Hospital, Juntendo University School of Medicine
Advisor for medical statistics:
Yasuo Ohashi Department of Epidemiology and Biostatistics, School of Health Science and Nursing, Faculty of Medicine, University of Tokyo
Advisor for pharmacokinetics and person responsible for its data analysis:
Yusuke Tanigawara Department of Hospital Pharmacy, School of Medicine, Keio University
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIX 1APPENDIX 2AcknowledgmentsREFERENCES |
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This study was sponsored by Eli Lilly Japan. We thank Ms Yuko Saito, Ms Keiko Kondo and Ms Toshiko Kaneko for help with data management and manuscript preparation. Special thanks are due to Dr Yasutsuna Sasaki and Dr Hironobu Minami (National Cancer Center East Hospital) as sub-investigators.
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FOOTNOTES |
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+ For reprints and all correspondence: Shuichi Okada, Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, 5–1–1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Abbreviations: ara-C, arabinosylcytosine; DLT, dose-limiting toxicity; 5-FU, 5-fluorouracil; GEM, gemcitabine; KPS, Karnofsky performance status; PC, pancreatic cancer; UNL, upper normal limit
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIX 1APPENDIX 2AcknowledgmentsREFERENCES |
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Received September 12, 2000; accepted October 20, 2000.
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