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© 2003 American Society for Clinical Oncology Combining Capecitabine and Gemcitabine in Patients With Advanced Pancreatic Carcinoma: A Phase I/II Trial
From the University Hospitals of Basel, Berne, and Geneva; the Cantonal Hospital of St. Gallen; and the Hospital St. Clara-Basel, Switzerland. Address reprint requests to Richard Herrmann, MD, University Hospital of Basel, Petersgraben 4, CH-4031 Basel, Switzerland; email: rherrmann{at}uhbs.ch.
Purpose: Preclinical studies indicate positive interactions between capecitabine, an oral fluorouracil precursor, and gemcitabine, the current standard treatment for advanced pancreatic carcinoma (APC). In this study, we investigated the addition of capecitabine to gemcitabine treatment for patients with APC.
Patients and Methods: This multicenter study included patients naïve to chemotherapy who had histologically or cytologically confirmed, nonresectable or metastatic pancreatic carcinoma. Gemcitabine was given at a fixed dose of 1,000 mg/m2 on days 1 and 8 of a 21-day cycle. Capecitabine was given in increasing doses orally bid for 14 days followed by a 1-week rest. The maximum-tolerated dose (MTD) was defined as one dose level below the dose causing dose-limiting toxicity (DLT) in Results: Thirty-six patients were included. DLT occurred at a dose of 800 mg/m2 bid of capecitabine and consisted of myelotoxicity and mucositis. Hand-foot syndrome was not observed, and other toxic effects were mild. Thus, in this regimen, the recommended dose of capecitabine is 650 mg/m2 bid. In 27 patients with measurable disease, we observed one complete and four partial remissions. In addition, significant drops (> 50% from baseline value) of the tumor marker CA 19–9 occurred in 14 of 24 assessable patients. Conclusion: The combination of capecitabine and gemcitabine is well tolerated, with apparent efficacy in patients with APC. Therefore, it is currently being compared with gemcitabine monotherapy in a phase III study.
CHEMOTHERAPY FOR patients with advanced pancreatic carcinoma (APC) improves clinical symptoms and overall survival.1 Still, life expectancy for the majority of these patients is short, with a median survival between 4 and 10 months.2–4 Until 1997, fluorouracil (5-FU) was the drug most widely used for APC, with an objective response rate of 0% to 7%.3,5 Burris et al3 provided evidence for better symptom control with the use of gemcitabine as a monotherapy. It is worth noting that, in this study, no objective responses were observed in the patients treated with 5-FU, but this finding may be related to the power of the study or the mode of administration of 5-FU rather than to a lack of activity of 5-FU in APC. Combination regimens of gemcitabine and 5-FU in the treatment of APC were found to be well tolerated and as effective as gemcitabine monotherapy in several phase I/II trials.6–11 However, adding weekly intravenous bolus 5-FU to weekly gemcitabine did not confer a significant survival benefit in a randomized trial,12 but there are no randomized data on the combination of infusional 5-FU with gemcitabine in APC. Capecitabine is an oral precursor of 5-FU. It has several advantages over 5-FU, the most important of which is its easy oral administration. As conversion of capecitabine to 5-FU is dependent on an enzyme (thymidine phosphorylase) preferentially expressed in malignant cells, it is thought to exert its main effect locally within the tumor.13 Phase II clinical data provided evidence for activity of capecitabine in APC,14 and data from a xenograft model15 indicated synergistic activity of capecitabine and gemcitabine. The aim of this study was to find the appropriate dose of capecitabine in combination with gemcitabine for patients with unresectable or metastatic pancreatic carcinoma. We also sought to evaluate the safety and efficacy of this combination.
Patients were eligible if they were naïve to chemotherapy and had histologically or cytologically proven, surgically unresectable, locally advanced or metastatic adenocarcinoma of the pancreas. Additional inclusion criteria were age 18 to 80 years, Karnofsky performance status  60%, life expectancy > 3 months, and adequate organ functions (leukocyte count > 3,500/µL, platelet count > 100,000/µL, hemoglobin > 10.0g/dL, serum creatinine < 1.25 times upper limit of normal [ULN], transaminases and alkaline phosphatase < 2.5 times ULN or < 5 times ULN in patients with liver metastasis, bilirubin < 1.5 times ULN, prothrombin time < 12.0 seconds, and calcium < 2.88 mmol/L). Written informed consent was obtained from each patient. Patients with central nervous system involvement or other significant medical conditions were excluded. The protocol and the informed consent form were approved by the local institutional review boards at each participating center.
Treatment Plan Adverse events were recorded according to the National Cancer Institute of Canada common toxicity criteria (NCIC-CTC). The maximum-tolerated dose (MTD) was defined as one dose level below the dose level at which two or more of six patients experienced dose-limiting toxicity (DLT), which was defined as neutropenia and/or thrombocytopenia grade 4 or any nonhematologic grade 3 or 4 toxic effect occurring during the first two treatment courses. The MTD represents the dose recommended for further studies.
The capecitabine and/or gemcitabine dosage was adjusted, delayed, or omitted for toxic effects
Assessment of Safety and Efficacy
Statistics
Thirty-six patients with APC from five Swiss centers were included between December 1998 and April 2001 (Table 1  ).
Nine patients were assigned to dose level 1 (500 mg/m2 bid), 21 patients to dose level 2 (650 mg/m2 bid), and six patients to dose level 3 (800 mg/m2 bid). A total of nine patients had to be included in this first cohort to obtain enough safety data to allow dose escalation. During the first treatment cycle, two patients requested to drop out, and one patient showed early progression of disease. One patient in this cohort experienced a febrile neutropenia. Of the 21 patients treated at dose level 2 (650 mg/m2 bid), six were included during the dose-finding (phase I) part of this study. One of these patients experienced a grade 4 neutropenia during cycle 1. The other 15 patients were recruited in the second (phase II) part of this study, once the MTD was defined at this level. At dose level 3 (800 mg/m2 bid), two of six patients experienced DLT, which consisted of grade 3 mucositis in one patient and a febrile grade 4 neutro- and thrombocytopenia and grade 3 mucositis in a second patient. Therefore, the previous dose level, that is, 650 mg/m2 bid of oral capecitabine, was found to be the MTD. Dose reduction of both drugs was necessary in five patients, four of whom were treated at the highest dose level.
The 21 patients who were treated at the MTD experienced mild toxic effects (Table 2
Of 27 patients with measurable disease, one patient had a complete remission (dose level 3), four patients had partial remissions (one at dose level 1, one at dose level 2, and two at dose level 3), and 11 patients had stable diseases (two at dose level 1 and nine at dose level 2). Six of the 11 patients with stable disease had a minor response, with more than 25% reduction in tumor size. The tumor marker CA 19–9 was elevated (> 35 U/l) in 27 patients at baseline; in 24 of these patients, a follow-up value after treatment was available: CA 19–9 dropped more than 50% in 14 (58%) patients and more than 90% in six patients (25%). An increase of CA 19–9 occurred in five patients (21%). The median survival was 191 days (95% confidence interval [CI], 148 to 234), and 1- and 2-year survival rates were 33% (±16%) and 17% (±13%), respectively. In this small study, there was no apparent correlation between initial performance status and toxic effects or response. There seemed to be a trend toward better response and survival in patients with locally advanced disease as compared with patients with metastatic disease.
The current standard regimen for patients with APC consists of single-agent gemcitabine.3 As yet, the combination regimen of capecitabine and gemcitabine for patients with APC has not been investigated. Therefore, the primary objective of this trial was to find the appropriate dose of capecitabine in this combination and to test its safety. We recommend a twice-daily dose of capecitabine of 650 mg/m2 for further testing. The overall toxicity was mild at the dose level recommended for future studies. DLT included myelosuppression and mucositis, both of which are consistent with the toxicity profiles of each individual drug. It is noteworthy that no hand-foot syndrome was observed. This often painful, paraesthetic erythema of the palmar and plantar skin is reported to occur in up to 52% (all grades) of patients with APC treated with single-agent capecitabine (1,250 mg/m2 bid).14 Mild nausea was the most common side effect, but it never impaired oral intake of capecitabine. Nine patients received more than six treatment cycles (range, 8 to 35). There appears to be no cumulative toxicity. In line with the preclinical observation of synergy,15 lower than single-agent doses of both agents still achieved a promising preliminary antitumor effect. Interestingly, Schilsky et al17 found that a higher dose (capecitabine 830 mg/m2 bid for 21 days and gemcitabine 1,000 mg/m2 weekly x 3 repeated every 4 weeks) was tolerated by 40 pretreated patients with a variety of solid tumors, including three patients with APC, in their phase I study. We believe, however, that we have truly reached the limit of dose escalation for our study population at the top dose, because not only did the two DLTs occur but also two additional patients treated at the top dose needed a dose reduction because of toxicity. The population of patients with APC, although naïve to chemotherapy, seems to be particularly susceptible to treatment toxicity. Neither dihydropyrimidine dehydrogenase expression nor pharmacokinetics was obtained in the patients experiencing DLT. The question of whether the dose recommended here is sufficiently high to be effective in a large number of patients will be answered after completion of the current phase III trial. Oral administration of capecitabine rather than infusional 5-FU, with its potential risks of central-line infection and thrombosis, contributes to fewer hospital visits during this outpatient treatment. This result is important not only for reasons of cost-effectiveness but also in light of the limited life expectancy of patients with APC.
Many patients treated for APC experience a benefit from chemotherapy in terms of better symptom control, whereas their tumor imaging does not change significantly. Other than the WHO objective response criteria have therefore been recognized as valuable surrogates for treatment evaluation. A decrease of the tumor marker CA 19–9 has been shown to identify patients who benefit from treatment.18 Halm et al 19 showed that patients with a greater than 20% drop in CA 19–9 levels during the first 8 weeks of treatment had a significantly longer median survival than did patients with a rise or a decrease of In summary, this combination, which is well tolerated at the recommended dose level, has apparent efficacy and is currently being compared with gemcitabine single-agent therapy in a phase III trial.
This study was supported by Roche Pharma Schweiz. Presented in part at the 36th annual meeting of the American Society of Clinical Oncology, New Orleans, May 20–23, 2000.
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3. Burris HA, III, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403–2413, 1997 4. Storniolo AM, Enas NH, Brown CA, et al: An investigational new drug treatment program for patients with gemcitabine: Results for over 3,000 patients with pancreatic carcinoma. Cancer 85:1261–1268, 1999[CrossRef][Medline] 5. Cullinan S, Moertel CG, Wieand HS, et al: A phase III trial on the therapy of advanced pancreatic carcinoma: Evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer 65:2207–2212, 1990[CrossRef][Medline] 6. Cascinu S, Silva RR, Barni S, et al: A combination of gemcitabine and 5-fluorouracil in advanced pancreatic cancer: A report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Br J Cancer 80:1595–1598, 1999[CrossRef][Medline] 7. Berlin JD, Adak S, Vaughn DJ, et al: A phase II study of gemcitabine and 5-fluorouracil in metastatic pancreatic cancer: An Eastern Cooperative Oncology Group Study (E3296). Oncology 58:215–218, 2000[CrossRef][Medline]
8. Hidalgo M, Castellano D, Paz-Ares L, et al: Phase I–II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer. J Clin Oncol 17:585–592, 1999
9. Oettle H, Arning M, Pelzer U, et al: A phase II trial of gemcitabine in combination with 5-fluorouracil (24-hour) and folinic acid in patients with chemonaive advanced pancreatic cancer. Ann Oncol 11:1267–1272, 2000 10. Matano E, Tagliaferri P, Libroia A, et al: Gemcitabine combined with continuous infusion 5-fluorouracil in advanced and symptomatic pancreatic cancer: A clinical benefit-oriented phase II study. Br J Cancer 82:1772–1775, 2000[CrossRef][Medline] 11. Rauch DP, Maurer CA, Aebi S, et al: Activity of gemcitabine and continuous infusion fluorouracil in advanced pancreatic cancer. Oncology 60:43–48, 2001[CrossRef][Medline]
12. Berlin J, Catalano P, Thomas J, et al: Phase III study of gemcitabine in combination with 5-FU vs gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 20:3270–3275, 2002 13. Schilsky RL: Pharmacology and clinical status of capecitabine. Oncology (Huntingt) 14:1297–1306; discussion 1309–1311, 2000[Medline]
14. Cartwright TH, Cohn A, Varkey JA, et al: Phase II Study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 20:160–164, 2002 15. Sawada N, Fujimoto-Ouchi K, Ishikawa T, et al: Antitumour activity of combination therapy with capecitabine plus vinorelbine, and capecitabine plus gemcitabine in human tumor xenograft models. Proc Am Assoc Cancer Res 2002 (abstr 5388) 16. WHO: Handbook of Reporting Results of Cancer Treatment. Publication No 48:Geneva, Switzerland, World Health Organization, 1979
17. Schilsky RL, Bertucci D, Vogelzang NJ, et al: Dose-escalating study of capecitabine plus gemcitabine combination therapy in patients with advanced cancer. J Clin Oncol 20:582–587, 2002 18. Heinemann V, Schermuly MM, Stieber P, et al: CA19-9: A predictor of response in pancreatic cancer treated with gemcitabine and cisplatin. Anticancer Res 19:2433–2435, 1999[Medline] 19. Halm U, Schumann T, Schiefke I, et al: Decrease of CA 19-9 during chemotherapy with gemcitabine predicts survival time in patients with advanced pancreatic cancer. Br J Cancer 82:1013–1016, 2000[CrossRef][Medline] Submitted April 3, 2002; accepted September 18, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
20%. In this study a greater than 50% decrease of CA 19–9 level was observed in 14 of 24 assessable patients. 
