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Phase II Study of Gemcitabine, Cisplatin, and Infusional Fluorouracil in Advanced Pancreatic Cancer

B.F. El-Rayes, M.M. Zalupski, A.F. Shields, U. Vaishampayan, L.K. Heilbrun, V. Jain, V. Adsay, J. Day, P.A. Philip

From the Karmanos Cancer Institute, Wayne State University, Detroit; and University of Michigan, Ann Arbor, MI.

Address reprint requests to Philip A. Philip, MD, PhD, FRCP, Karmanos Cancer Institute, Wayne State University, 4100 John R St, Detroit, MI 48201; email: philipp{at}karmanos.org.

	ABSTRACT

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Purpose: This phase II study was undertaken to determine the efficacy of adding infusional fluorouracil (FU) to the chemotherapy doublet of gemcitabine and cisplatin in patients with advanced pancreatic cancer.

Patients and Methods: The eligibility criteria included histologically or cytologically confirmed adenocarcinoma of the pancreas that was either unresectable or metastatic. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1,000 mg/m² intravenously (IV) on days 1, 8, and 15; cisplatin 50 mg/m² IV on days 1 and 15; and FU 175 mg/m²/d from days 1 to 15 by continuous IV infusion. Cycles were repeated every 28 days. Objective tumor response and toxicity were evaluated according to the World Health Organization criteria.

Results: A total of 47 patients (median age, 57 years; males, 59%) were enrolled. Sixteen patients had locally advanced (LA) disease, and 31 patients had metastatic disease. A total of 183 cycles of chemotherapy were administered. In patients with metastatic disease (n = 31), the probability of survival at 6 and 12 months was 66% and 34%, respectively. Objective partial response or stable disease was observed in 26% (90% confidence interval [CI], 0.14 to 0.41) and 61% (90% CI, 0.45 to 0.74) of patients, respectively. In patients with LA disease (n = 16), there were three partial responses (19%; 90 CI, 0.07 to 0.39). One patient in this group was successfully resected after FU-based radiotherapy. The most common grade 3 to 4 toxicities were neutropenia (60%), thrombocytopenia (42%), and anemia (26%). Thirteen patients were hospitalized for treatment-related complications.

Conclusion: The combination of gemcitabine, cisplatin, and infusional FU has significant activity in patients with advanced pancreatic cancer.

	INTRODUCTION

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PANCREATIC CANCER is the fourth leading cause of cancer death in the United States.¹ Despite increased understanding of the biology of pancreatic cancer, the 5-year survival rate of patients with newly diagnosed disease remains 5%.² This poor survival rate is attributed to the high incidence of metastatic disease at diagnosis and the relative chemoresistance of this tumor. Therefore, improvement in the outcome of patients with pancreatic cancer depends on the development of effective systemic therapies.

Gemcitabine is the most common cytotoxic agent used in this disease. However, the objective response rate of patients with pancreatic cancer treated with this drug is less than 10%.^3,4 Thus, combination chemotherapy has been introduced in an attempt to improve the response rate and survival of patients with advanced pancreatic cancer. In vitro and in vivo studies of gemcitabine and cisplatin have demonstrated synergy.⁵ Clinical trials have demonstrated significant activity of this combination in other malignancies.^6–8 Encouraged by these results, phase II trials of gemcitabine and cisplatin in advanced pancreatic cancer have been conducted.^9,10 Objective response rates of 11% to 31% and median survival times of 7 to 8 months have been reported. A phase III study comparing gemcitabine versus gemcitabine and cisplatin showed that the median time to disease progression and the overall response rate were significantly higher in the combination arm.¹¹ Although median survival was prolonged in the combination arm compared with gemcitabine alone (30 v 20 weeks, respectively), this result did not achieve statistical significance.

Fluorouracil (FU)-based regimens were shown to be superior to the best supportive care.^12,13 Bolus FU has been compared with gemcitabine in advanced pancreatic cancer in a randomized study.³ The clinical benefit response and 1-year survival rate was significantly higher with gemcitabine. Gemcitabine plus bolus FU was recently compared with gemcitabine alone in advanced pancreatic cancer.¹⁴ No statistically significant improvement in response rate or median survival with the combination was observed. Studies have generally used bolus administration schedules of FU in the treatment of pancreatic cancer. Nevertheless, the biologic activity of FU is schedule-dependent, and infusional FU may have an improved therapeutic index compared with bolus FU.¹⁵ Both FU and gemcitabine inhibit de novo synthesis of thymidine ribonucleotide, and preclinical data has demonstrated synergy between gemcitabine and FU in HT-29 colon cancer cell lines.¹⁶ Phase II trials of infusional FU and either cisplatin or gemcitabine have shown higher response rates and longer median survivals than historical control patients.^17–19 Furthermore, infusional FU is less myelosuppressive, allowing it to be combined with gemcitabine, which can cause significant myelotoxicity.

This phase II study was undertaken to determine the efficacy of the triple-drug combination of gemcitabine, cisplatin, and infusional FU in patients with locally advanced (LA) or metastatic pancreatic cancer. The primary end points of the study were survival at 6 months for patients with metastatic disease and conversion of unresectable patients to resectable in patients without metastasis.

	PATIENTS AND METHODS

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Patient Eligibility
Patients were eligible to enter the study if they had histologic or cytologic diagnosis of an adenocarcinoma of the pancreas that was either unresectable or metastatic. Participants were required to have a Southwest Oncology Group performance status of 0 to 2, a life expectancy of at least 3 months, and adequate hematologic, renal, and hepatic functions defined by the following parameters: neutrophil count 1,500/µL, platelet count 100,000/µL, creatinine 1.5 mg/dL, total serum bilirubin 3.0 mg/dL, and AST less than 2.5 times the upper limit of the institutional normal range (ULN). Patients were excluded if they had another active cancer within the preceding year except for adequately treated basal cell cancer, squamous cell skin cancer, or in situ cervical cancer. Additional exclusion criteria included previous chemotherapy for pancreatic cancer within the preceding 6 months or any prior therapy with gemcitabine. Before initiation of study treatment, all patients provided written informed consent in accordance with the guidelines of the Human Investigation Committees of Wayne State University and the University of Michigan.

Study Design and Treatment Plan
All treatment was delivered in the outpatient setting. Gemcitabine (Gemzar; Eli Lilly, Indianapolis, IN) was administered intravenously (IV) on days 1, 8, and 15 of each treatment cycle at a dose of 1,000 mg/m². Cisplatin 50 mg/m² was administered IV on days 1 and 15 after gemcitabine infusion and hydration. FU was administered as a continuous IV infusion via an indwelling venous catheter at a dose of 175 mg/m²/d from days 1 to 15. Cycles were repeated every 28 days.

Dose reductions were made on days 8 and 15 based on the toxicity encountered within a cycle as follows: gemcitabine, cisplatin, and FU were held for a neutrophil count or platelet count less than 500/µL or less than 25,000/µL, respectively, and full-dose chemotherapy was administered for a neutrophil count 500/µL and platelet count 25,000/µL. FU was dose-reduced by 20% for any grade 1 nonhematologic toxicity (excluding nausea, alopecia, or nephrotoxicity) encountered during a cycle of treatment. FU was held for a grade 2 nonhematologic toxicity. All three drugs were held for grade 3 or 4 nonhematologic toxicity.

A new cycle of therapy could begin if the neutrophil count was 1,500/µL, the platelet count was 100,000/µL, and all relevant nonhematologic toxicities were grade 2 or lower. Adjustment of the dose of each drug on day 1 of each cycle was dependent on the presence and the extent of toxicity in the preceding cycle. Dose adjustments on day 1 were as follows: a 20% dose reduction for gemcitabine and cisplatin for a nadir neutrophil count less than 1,000/µL or platelet count less than 75,000/µL. For nonhematologic toxicities, excluding alopecia, nephrotoxicity, nausea, or vomiting, only the FU dose was adjusted as follows: for grade 1 to 2 and 3 to 4 toxicities, the dose was reduced by 20% and 40%, respectively. Treatment for patients with renal toxicity was guided by the serum creatinine levels on the day of cisplatin administration. Patients with a serum creatinine of 1.6 to 2.0 mg/dL had a dose reduction of 50%. Patients with a serum creatinine greater than 2.1 mg/dL had the cisplatin dose held. Cisplatin dose was also adjusted based on the highest serum creatinine level during the previous cycle. For a creatinine of 2.1 to 3.0 mg/dL, the cisplatin dose was reduced by 25% in subsequent cycles, provided that the serum creatinine level had recovered to less than 1.5 mg/dL. Patients with a serum creatinine of 3.5 to 4.5 mg/dL had the subsequent dose of cisplatin reduced by 50% if the serum creatinine level on the day of the next treatment was less than 1.5 x ULN. When the serum creatinine level was greater than 4.5 x ULN, no additional therapy with cisplatin was allowed. The use of growth factor was permitted. When doses were reduced for toxicity, re-escalation of dose was not permitted.

Patients requiring a delay in therapy of longer than 2 weeks or requiring more than two dose reductions were removed from the study. In addition, patients were removed from the study for any of the following reasons: disease progression, unacceptable toxicity, withdrawal of consent, or initiation of chemoradiotherapy or surgery for patients with LA disease.

On-Study Evaluation
Standard treatment efficacy end points in relation to survival, objective response, time to disease progression, and duration of response were determined. Survival was defined as the time from the initiation of therapy to the date of death or last follow-up. Imaging studies, including computerized tomography, were performed at baseline, after every two cycles of therapy, and when there was clinical suspicion of disease progression. Tumor responses were categorized as complete, partial, progression, or stable. Complete response was defined as the disappearance of all measurable and assessable disease without the appearance of any new lesions. Partial response was defined as a 50% or greater reduction in the sum of the products of all measurable lesions compared with baseline measurements. Objective response required one confirmatory follow-up scan at least 3 weeks after the first documentation of response. Progressive disease was defined as a 25% or greater increase in the sum of the products of any measurable lesion, relative to either the baseline or the maximal response, or the appearance of any new lesions. Stable disease was defined as any change in tumor size that did not meet criteria for progressive disease or partial response and that persisted at the 4-month evaluation. Duration of response was defined as the time from complete or partial response until first objective evidence of disease progression or death from any cause. Duration of response was censored for patients who were removed from the study or who received antitumor therapy other than gemcitabine, cisplatin, and FU, including chemoradiotherapy or surgery. Time to progression was defined as the time from enrollment onto the study until progression or death. Toxicities were evaluated, at a minimum, on days 1, 8, and 15 of each cycle and graded according to the World Health Organization toxicity criteria.

Statistical Methods
This phase II trial was planned with two Fleming two-stage designs,²⁰ one design for LA patients and a separate design for metastatic patients. For the LA patients, we wished to determine whether the true resectability rate was 0.01 or less versus 0.15 or more. We used only the response-assessable LA patients because only they would be appropriate to determine whether the chemotherapy had rendered them surgically resectable. The two-stage design called for a maximum of 19 response-assessable patients, 10 in stage 1 and nine in stage 2. The design had a type I error of 0.015 and a power of 0.801. After accruing 12 LA patients, 10 were response-assessable and, thus, resectability assessable. With only one patient among them having been resected, the trial portion for LA patients was terminated without proceeding to stage 2. Final case review (with supplemental clinical information) indicated that four patients initially regarded as metastatic were actually LA, thus yielding 16 patients in total, 13 of whom were resectability assessable. The conclusion persisted that the revised sample proportion (one of 13 patients, 8%) better supported the null hypothesis that the true resectability rate was at most 0.01.

For the metastatic patients, we wished to determine whether the true 6-month survival rate was 0.50 or less versus 0.75 or more. For this end point, we used all registered patients with metastatic disease. The two-stage design called for a maximum of 30 patients, 15 in stage 1 and 15 in stage 2. The design had a type I error of 0.022 and a power of 0.796. At least nine, but at the most 12, 6-month survivors among the first 15 patients were required to proceed to stage 2. After the accrual of 15 patients, nine of them survived for at least 6 months, thus stage 2 was begun, and we enrolled another 15 metastatic patients. Final case review (with supplemental clinical information) indicated that one patient initially regarded as LA was actually metastatic, thus yielding 31 metastatic patients in total. Our conclusion was that the sample proportion (21 of 31 patients, 68%) better supported the alternative hypothesis that the true 6-month survival rate was at least 0.75.

Exact, minimum-width 90% confidence intervals (CIs) for response and toxicity rates were calculated using the Casella method,²¹ as implemented in StatXact software (Cytel Software Corporation, Cambridge, MA). ²² Standard Kaplan-Meier estimates of the censored response duration and censored survivorship functions were computed. Because of the small sample sizes, survival statistics were estimated more conservatively using linear interpolation among successive event times on the Kaplan-Meier curves.²³

	RESULTS

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Patient Characteristics
The characteristics of the patients on the study are listed in Table 1. Forty-seven patients were enrolled onto the study between April 1999 and November 2001. The median age at study entry was 57 years (range, 28 to 78 years). There were more men (59%) than women. Ninety-one percent of patients had a performance status of 0 to 1. Sixteen patients had LA disease that was surgically unresectable. Thirty-one patients had metastatic disease (liver, n = 28, 90%; lung, n = 2, 7%; or other site, n = 1, 3%). No patient had received prior chemotherapy or radiation treatment.

Survival
The median survival time for the whole group of the treated patients was 8.6 months (90% CI, 6.8 to 11.2 months). The Kaplan-Meier estimate of survival is shown in Figure 1. The 6-month and 1-year survival rates were 69% and 36%, respectively (Table 2). Among the patients who died, the longest survival was 27.9 months. Eight patients are still alive, for a censoring rate of 17%.

View larger version (16K): [in this window] [in a new window]   Fig 1. The Kaplan-Meier estimate of the overall survival duration in the 47 patients with advanced pancreatic cancer enrolled onto the study. The dashed lines represent the 90% confidence intervals (CI) for each successive estimate of the survival rate (solid line). The 1-year survival rate was 36% (90% CI, 0.23 to 0.47).

View larger version (14K): [in this window] [in a new window]   Fig 2. The Kaplan-Meier estimate of overall survival by disease extent. The solid line represents the 31 patients with metastatic disease, and the dashed line represents the 16 patients with locally advanced disease.

Of the 31 patients with metastatic disease, eight patients (26%; 90% CI, 0.14 to 0.41) had a partial response, and 19 (61%; 90% CI, 0.45 to 0.74) had stable disease. Of the 16 patients with LA disease, the objective partial response rate was 19% (90% CI, 0.07 to 0.39). Fifty percent of these patients (90% CI, 0.30 to 0.70) had stable disease. Ten of 16 patients without metastasis subsequently received chemoradiotherapy. Three patients underwent surgical exploration, and one had resection. Although the resected specimen had viable tumor, the patient is alive and continues to be disease-free at 30 months.

Time to Disease Progression
The median time to progression in all 47 patients was 7.2 months (90% CI, 5.0 to 9.5 months). The median time to disease progression in the patients with metastatic and LA disease were 5.7 months (90% CI, 3.0 to 9.1 months) and 7.2 months (90% CI, 4.1 to 11.0 months), respectively.

Toxicity
One registered patient did not receive any treatment and is not assessable for toxicity. Treatment was generally well tolerated in the outpatient setting. Two treatment-related deaths were reported. One patient suffered a gall bladder perforation in the first week of chemotherapy. Another patient died of overwhelming sepsis after a fourth cycle of chemotherapy. Thirteen patients required hospitalization for treatment-related complications (pneumonia, n = 3; electrolyte imbalance, n = 3; sepsis, n = 2; stroke, n = 1; renal failure, n = 1; mucositis, n = 1; gastritis, n = 1; and perforated gall bladder, n = 1). Grade 4 toxicities were observed in 17 patients, and 20 episodes of grade 4 toxicity were reported. The most common grade 3 to 4 toxicities were neutropenia (60%) and thrombocytopenia (42%). Thirteen patients required RBC transfusions, and two patients required platelet transfusions. Table 3 lists the toxicities encountered in this study.

	DISCUSSION

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The lack of any single effective therapy to date has justified the performance of additional phase II trials with the hope of identifying a more active regimen. Studies have suggested that combinations of gemcitabine and platinum compounds have superior antitumor effects compared with gemcitabine alone in patients with advanced pancreatic cancer.^9–11,30 Infusional FU or capecitabine produces response rates and median survivals in patients with advanced pancreatic cancer comparable with gemcitabine.^29,31 This study tested the hypothesis that the addition of infusional FU to the gemcitabine/cisplatin regimen would result in a more efficacious combination in pancreatic cancer. The trial design assumed that infusional FU has a better therapeutic index than bolus FU.¹⁵ Therefore, the addition of infusional FU to the gemcitabine/cisplatin regimen was based on the activity of this agent in advanced pancreatic cancer and its nonoverlapping toxicities with the gemcitabine/cisplatin combination.

In this study, triple-agent combination therapy with gemcitabine, cisplatin, and infusional FU resulted in a 6-month survival rate of 66% and a median survival of 8.5 months in patients with metastatic pancreatic cancer. This result compares favorably with the results in patients treated with single-agent gemcitabine.^3,14 In our previous trial with gemcitabine/cisplatin, we reported a median survival time of 7.1 months in 38 patients with metastatic disease.⁹ Additionally, the long median time to progression (5.7 months) and the number of 1-year survivors (34%) indicates the meaningful activity of this combination in metastatic disease. Of note, previous trials with the gemcitabine/cisplatin combination have resulted in a median survival time of greater than 7 months in all studies thus far. Ultimately, a conclusion regarding the utility of combination chemotherapy in pancreatic cancer, including an evaluation of this triple-drug therapy, requires a randomized phase III study. If undertaken, it will need to be powered to detect the expected increase in median survival approximated by the results of phase II studies (ie, a 2- to 3-month improvement).

Combination chemotherapy in patients with advanced pancreatic cancer is associated with increased toxicity.³² It has been suggested that a burden from treatment should not be added to those suffering with this disease. However, it has been amply demonstrated that quality of life parallels the disease process. Balancing the toxicity and activity of a therapy is the art of palliative treatment. The combination of gemcitabine, cisplatin, and infusional FU was associated with moderate to severe toxicity, and hospitalization during therapy was a frequent event. Thirteen patients required hospitalization, a result not unexpected in this patient population.^14,29,32 Grade 3 to 4 myelotoxicity was frequent and resulted in dose reductions, but therapy could be continued. No bleeding complications occurred secondary to thrombocytopenia. The incidence rates of grade 3 to 4 toxicities were comparable with those reported with the gemcitabine and cisplatin combination.

Activity of a chemotherapy combination in advanced disease might be expected to have little impact on survival in that population, but the treatment may be more useful in earlier-stage disease. Chemotherapy in LA or resectable pancreatic cancer may increase operability, improve local control, and eliminate occult systemic metastasis. This triplet combination, although not permitting resection of unresectable patients in our trial, may reasonably be incorporated into multimodality therapy. One patient in this study was rendered resectable after this relatively intensive induction chemotherapy regimen and a course of chemoradiotherapy. Of note, this patient has enjoyed a relatively prolonged disease-free survival (30+ months), despite the fact that he did not achieve a complete pathologic response.

In conclusion, the activity and tolerability of the triplet gemcitabine, cisplatin, and infusional FU compares favorably with single-agent gemcitabine and gemcitabine-based doublets. This regimen should be further studied and its utility in advanced disease confirmed in a phase III trial. Despite suggestions of improvement with combination chemotherapy in pancreatic cancer, systemic disease control remains poor.

	NOTES

 
Supported in part by Cancer Center Support grant no. CA-22453 from the National Cancer Institute, Bethesda, MD, and by Eli Lilly Oncology, Indianapolis, IN.

	REFERENCES

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1. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer J Clin 52:23–47, 2002[Abstract/Free Full Text]

2. Evans DB, Abbruzese JL, Rich TA: Cancer of the Pancreas (ed 6). Philadelphia, PA, Lippincott-Raven Publishers, 1997

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[Abstract/Free Full Text]

4. Rothenberg ML, Moore MJ, Cripps MC, et al: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7:347–353, 1996[Abstract/Free Full Text]

5. Kanzawa F, Saijo N: In vitro interaction between gemcitabine and other anticancer drugs using a novel three-dimensional model. Semin Oncol 24:S7-8–S7-16, 1997 (suppl)

6. Crino L, Scagliotti G, Marangolo M, et al: Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: A phase II study. J Clin Oncol 15:297–303, 1997[Abstract/Free Full Text]

7. Hitt R, Castellano D, Hidalgo M, et al: Phase II trial of cisplatin and gemcitabine in advanced squamous-cell carcinoma of the head and neck. Ann Oncol 9:1347–1349, 1998[Abstract/Free Full Text]

8. Moore MJ, Winquist EW, Murray N, et al: Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: A phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 17:2876–2881, 1999[Abstract/Free Full Text]

9. Philip PA, Zalupski MM, Vaitkevicius VK, et al: Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma. Cancer 92:569–577, 2001[CrossRef][Medline]

10. Heinemann V, Wilke H, Mergenthaler HG, et al: Gemcitabine and cisplatin in the treatment of advanced or metastatic pancreatic cancer. Ann Oncol 11:1399–1403, 2000[Abstract/Free Full Text]

11. Colucci G, Giuliani F, Gebbia V, et al: Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: A prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer 94:902–910, 2002[CrossRef][Medline]

12. Mallinson CN, Rake MO, Cocking JB, et al: Chemotherapy in pancreatic cancer: Results of a controlled, prospective, randomised, multicentre trial. BMJ 281:1589–1591, 1980[Abstract/Free Full Text]

13. Glimelius B, Hoffman K, Sjoden PO, et al: Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 7:593–600, 1996[Abstract/Free Full Text]

14. Berlin JD, Catalano P, Thomas JP, et al: Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 20:3270–3275, 2002[Abstract/Free Full Text]

15. Meta-Analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer: Meta-Analysis Group in Cancer. J Clin Oncol 16:301–308, 1998[Abstract/Free Full Text]

16. Schulz L, Schalhorn A, Wilmanns W, et al: Synergistic interaction of gemcitabine and 5-fluorouracil in colon cancer cells. Proc Am Soc Clin Oncol1998 (abstr 965)

17. Nicolson M, Webb A, Cunningham D, et al: Cisplatin and protracted venous infusion 5-fluorouracil (CF): Good symptom relief with low toxicity in advanced pancreatic carcinoma. Ann Oncol 6:801–804, 1995[Abstract/Free Full Text]

18. 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]

19. Rougier P, Zarba JJ, Ducreux M, et al: Phase II study of cisplatin and 120-hour continuous infusion of 5-fluorouracil in patients with advanced pancreatic adenocarcinoma. Ann Oncol 4:333–336, 1993[Abstract/Free Full Text]

20. Fleming TR: One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143–151, 1982[CrossRef][Medline]

21. Cassella G: Refining binomial confidence intervals. Can J Stat 14:113–129, 1987

22. Mehta C, Patel N: StatXact 5: Statistical Software for Exact Nonparametric Inference, User Manual. Cambridge, MA, Cytel Software Corporation, 1999, pp 429–433

23. Lee ET: Statistical Methods for Survival Data Analysis. New York, NY, Wiley & Sons, Inc, 1992, pp 77–78

24. 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[Abstract/Free Full Text]

25. Louvet C, Andre T, Lledo G, et al: Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: Final results of a GERCOR multicenter phase II study. J Clin Oncol 20:1512–1518, 2002[Abstract/Free Full Text]

26. Kurtz JE, Kohser F, Negrier S, et al: Gemcitabine and protracted 5-FU for advanced pancreatic cancer: A phase II study. Hepatogastroenterology 47:1450–1453, 2000[Medline]

27. Rocha Lima CM, Savarese D, Bruckner H, et al: Irinotecan plus gemcitabine induces both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. J Clin Oncol 20:1182–1191, 2002[Abstract/Free Full Text]

28. Scheithauer W, Kornek GV, Raderer M, et al: Phase II trial of gemcitabine, epirubicin and granulocyte colony-stimulating factor in patients with advanced pancreatic adenocarcinoma. Br J Cancer 80:1797–1802, 1999[CrossRef][Medline]

29. Maisey N, Chau I, Cunnigham D, et al: Multicenter randomized phase III trial of protracted venous infusion of 5-flourouracil with PVI 5-FU plus mitomycin in inoperable pancreatic cancer. J Clin Oncol 20:3130–3136, 2002[Abstract/Free Full Text]

30. Philip PA: Gemcitabine and platinum combinations in pancreatic cancer. Cancer 95:908–911, 2002[CrossRef][Medline]

31. 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[Abstract/Free Full Text]

32. Adsay NV, El-Rayes BF, Philip PA: Pancreatic cancer: The evolving role of systemic therapy. Expert Opin Pharmacother 2:1939–1947, 2001[CrossRef][Medline]

Submitted March 4, 2003; accepted May 9, 2003.

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