This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heinemann, V. Articles by Wilkowski, R. Search for Related Content PubMed PubMed Citation Articles by Heinemann, V. Articles by Wilkowski, R. Related Articles Related Correspondence

Randomized Phase III Trial of Gemcitabine Plus Cisplatin Compared With Gemcitabine Alone in Advanced Pancreatic Cancer

Volker Heinemann, Detlef Quietzsch, Frank Gieseler, Michael Gonnermann, Herbert Schönekäs, Andreas Rost, Horst Neuhaus, Caroline Haag, Michael Clemens, Bernard Heinrich, Ursula Vehling-Kaiser, Martin Fuchs, Doris Fleckenstein, Wolfgang Gesierich, Dirk Uthgenannt, Hermann Einsele, Axel Holstege, Axel Hinke, Andreas Schalhorn, Ralf Wilkowski

From the Medizinische Klinik und Poliklinik III, Klinikum Grosshadern; Krankenhaus Bogenhausen; Klinikum Neuperlach München; Krankenhaus München-Harlaching; Klinik für Strahlentherapie, Klinikum Grosshadern, Munich; Klinikum Chemnitz; Universitätsklinik Kiel, Kiel; Evangelisches Krankenhaus Dinslaken, Dinslaken; Klinikum Nürnberg Nord, Nürnberg; Klinikum Darmstadt, Darmstadt; Evangelisches Krankenhaus Düsseldorf, Düsseldorf; Medizinische Fakultät der TU Dresden, Dresden; Mutterhaus der Borromäerinnen Trier, Trier; Onkologische Praxis Augsburg, Augsburg; Onkologische Praxis Landshut; Klinikum Landshut, Landshut; Medizinische Universität zu Lübeck, Lübeck; Medizinische Klinik II, Universität Würzburg, Würzberg; Wissenchaftlicher Service Pharma (WiSP), Langenfeld, Germany

Address reprint requests to Volker Heinemann, MD, PhD, Medical Clinic III, Klinikum Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany; e-mail: Volker.Heinemann{at}med.uni-muenchen.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To compare the effectiveness and tolerability of gemcitabine plus cisplatin with single-agent gemcitabine as first-line chemotherapy for locally advanced or metastatic pancreatic cancer.

PATIENTS AND METHODS: Patients with advanced adenocarcinoma of the pancreas were randomly assigned to receive either gemcitabine 1,000 mg/m² and cisplatin 50 mg/m² given on days 1 and 15 of a 4-week cycle (GemCis arm) or gemcitabine alone at a dose of 1,000 mg/m² on days 1, 8, and 15 of a 4-week regimen (Gem arm). The primary end point was overall survival; secondary end points were progression-free survival, response rate, safety, and quality of life.

RESULTS: One hundred ninety-five patients were enrolled and showed baseline characteristics well balanced between treatment arms. Combination treatment in the GemCis arm was associated with a prolonged median progression-free survival (5.3 months v 3.1 months; hazard ratio [HR] = 0.75; P = .053). Also, median overall survival was superior for patients treated in the GemCis arm as compared with the Gem arm (7.5 v 6.0 months), an advantage which did not, however, reach statistical significance (HR = 0.80; P = .15). Tumor response rates were comparable between treatment arms (10.2% v 8.2%). The rate of stable disease was, however, greater in the combination arm (60.2% v 40.2%; P < .001). Grade 3 to 4 hematologic toxicity did not exceed 15% in both treatment arms.

CONCLUSION: These results support the efficacy and safety of an every-2-weeks treatment with gemcitabine plus cisplatin. Median overall survival and progression-free survival were more favorable in the combination arm as compared with gemcitabine alone, although the difference did not attain statistical significance.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Cancer of the exocrine pancreas remains a fatal disease for most patients. Because of its predominantly late diagnosis, most patients present with advanced disease.^1,2 Without effective treatment, these patients have a median survival of 3 to 4 months. Systemic chemotherapy with single-agent gemcitabine has evolved as a moderately active standard of care for treatment of locally advanced and metastatic pancreatic cancer.^3,4 Its wide acceptance is based not only on good tolerability but also on its potential to improve clinical benefit response.^5,6 In patients receiving gemcitabine, Karnofsky performance status (KPS) and stage of disease have been identified as important prognostic factors for treatment outcome.⁷

In an effort to improve therapeutic efficacy, numerous clinical studies have investigated gemcitabine (Gem) -based combination regimens. Some trials showed an improvement of overall response rates (ORR) and progression-free survival (PFS). However, a significant prolongation of overall survival (OS) has not been demonstrated when Gem was combined with platinum analogs,^8,9 antimetabolites,^10-13 or topoisomerase inhibitors.^14,15 This may be explained by the notably low chemosensitivity of pancreatic cancer, but it may also relate to the fact that knowledge on adequate patient selection for different treatment strategies is limited so far.

The rationale for a combined use of Gem and cisplatin (Cis) is based on the preclinical evidence that Gem not only increases Cis-induced DNA cross links, but also effectively inhibits their repair. Synergistic cytotoxicity observed in vitro clearly relates to this drug interaction.^16-19 In pancreatic cancer, several clinical studies suggest that the combination of Gem and Cis is active and may improve ORR, PFS, and OS.^8,20-22 The present trial compares a biweekly application of Gem and Cis to a regimen where single-agent Gem was administered weekly for 3 weeks in a 4-week regimen.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Patient Population
This trial included patients with pathologically confirmed, locally advanced or metastatic pancreatic cancer (adenocarcinoma or poorly differentiated) not amenable to surgical resection. Tumor lesions had to be bidimensionally measurable with a minimum size of 1 cm x 1 cm. Prior chemotherapy was not allowed. Prior radiotherapy was permitted only when the irradiated lesion was not the target lesion. Other eligibility criteria included age at least 18 years, life expectancy at least 12 weeks, and KPS at least 70%. Patients must have had adequate bone marrow and organ function tests.

Patient Assignment
Written informed consent was provided by all patients before study entry. Central random assignment was performed before the start of treatment, and patients were assigned to one of the treatment arms.

Treatment
In this open-label multicenter trial, treatment was applied in an out- or inpatient setting according to the decision of the respective medical facility. In the experimental arm, patients received Gem (1,000 mg/m², 30-minute intravenous [IV] infusion) plus Cis (50 mg/m², 1 hour IV infusion). Both agents were administered on days 1 and 15 of a 4-week cycle. In the control arm, patients received single-agent Gem (1,000 mg/m², 30-minute IV infusion) administered on days 1, 8, and 15 of a 4-week cycle. Doses could be adjusted according to prespecified dose reduction tables to maintain an acceptable toxicity profile.

Efficacy Evaluation
The intent-to-treat population was defined by the recruited patients. The efficacy-analyzable population was defined by all recruited patients who had completed at least one cycle of Gem-based chemotherapy. The primary outcome measure was OS, which was determined for all randomly assigned patients from the date of random assignment to the date of death or last contact. Patients alive and patients lost to follow-up were censored at the last date of contact. Among secondary outcome measures, PFS was defined as the time from random assignment until death or evidence of tumor progression. Patients who discontinued treatment on the study without documented progression were censored at their last date of tumor assessment. ORR (according to WHO criteria) was defined as the best tumor response during treatment. Assessment of ORR was carried out every two cycles (every 8 weeks) applying the initially used imaging procedure.

Safety Evaluation
Before entering the study, patients had a full blood count and analysis of blood chemistry, including liver and renal function tests. A full blood count was taken each day of treatment, and blood chemistry at the start of each cycle. According to the protocol, the safety analysis included all patients who had received at least one dose of Gem.

Quality-of-Life Evaluation
Before and during the course of treatment, quality of life was determined using the quality-of-life (QOL) index according to Spitzer et al.²³ QOL was assessed by the patients before start of treatment on study and at each new cycle of therapy.

Statistical Methods
The study was designed to detect a 60% improvement in median survival from 5 to 8 months with a power of 80% and an overall significance level of 5%. Time-to-event curves were estimated according to the method of Kaplan and Meier and were compared using the log-rank test. Results from Peto’s adaptation of the Wilcoxon test variant for censored data are provided for comparison, in case of distinct deviation from the proportional hazard assumption. Fisher’s exact test was used to compare categoric characteristics and response rates. The midrank Wilcoxon test was applied to compare the distributions of dose-intensity, toxicity, and quality of life between treatment arms. The Cox proportional hazards model was applied for multivariate analysis. All P values result from two-sided tests.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Patient Characteristics
Between December 1997 and January 2002, a total of 195 patients (intent-to-treat population) were enrolled onto the study from 34 different centers (see Online Only Appendix). Five patients (three in the GemCis arm and two in the Gem arm) did not receive treatment per protocol and further follow-up was omitted. According to the protocol, 190 patients (95 in the GemCis arm and 95 in the Gem arm) were assessable and were included into the population of analyzable patients.

Median follow-up for patients treated in the GemCis arm was 7.4 months (range, 0.2 to 48.6 months), whereas it was 6.0 months (range, 0.3 to 48.5 months) for those in the Gem arm. At the time of final analysis, 92.3% of patients had died. Patient characteristics are shown in Table 1.

Adherence to the treatment protocol was comparable in both treatment arms. In the GemCis arm, 1,013 cycles were analyzed; dose reductions were performed in 5.3%, dose delays in 2.7%, and omissions of doses in 1.5% of cycles. In the Gem arm, a total of 772 cycles were applied; dose reductions, delays, and omissions were reported in 7.5%, 4.6%, and 2.3%, respectively. The analysis of relative dose-intensity during a range of 1 to 10 treatment cycles indicated that more than 90% of chemotherapy doses were applied as scheduled with no significant difference between treatment arms. The median relative dose-intensity was 93% to 99% for Gem and 92% to 99% for Cis in the GemCis arm, whereas it was 92% to 97% in the Gem arm.

Second-Line Therapy
After failure of first-line treatment, 31 patients (16.1%; 15.8% in the GemCis arm and 16.5% in the Gem arm) received second-line therapy. Fifteen patients (8%) received fluoropyrimidine-based therapy, 12 patients (6%) single-agent Gem, and 4 patients (2%) were treated with GemCis.

Safety Results
The overall tolerability of both regimens was equally acceptable (Table 2). Hematologic toxicity was low, and WHO grade 3 to 4 events remained below 15% for both arms. Also, nonhematologic toxicity was predominantly mild to moderate, and WHO grade 3 to 4 adverse events were observed in less than 15% of patients. Only nausea and vomiting were significantly more frequent in the GemCis arm (22.2% v 5.9%; P = .0002; Table 2).

PFS. GemCis caused a superior PFS (5.3 v 3.1 months; P = .053) compared with Gem (Fig 1). In a post hoc subset analysis, the superiority of GemCis was even more pronounced in locally advanced disease (8.6 v 3.2 months; P = .0053), whereas only a moderate advantage was detected in patients with metastatic disease (4.2 v 3.1 months; P = .31). A further subset analysis revealed that GemCis was superior to Gem in patients with a KPS of 90% to 100% (7.7 v 2.8 months; P = .013), whereas no advantage was observed in patients with a KPS of 70% to 80%.

View larger version (11K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimates of progression-free survival (PFS). GemCis, gemcitabine plus cisplatin; Gem, gemcitabine alone.

View larger version (12K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimates of overall survival (OS). GemCis, gemcitabine plus cisplatin; Gem, gemcitabine alone.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

In the randomized trial, tolerability was acceptable in both treatment arms, which is reflected by a high relative dose-intensity (> 90%). In view of the low number of reduced, delayed, or omitted doses (< 10%, respectively) the presently used biweekly regimen of Gem and cisplatin showed a better tolerability than the previously used schedule (Gem administered on days 1, 8, 15 plus cisplatin administered on days 1 and 15 every 4 weeks).²¹ Compared with the GemOx regimen (fixed–dose rate Gem plus oxaliplatin) previously reported by Louvet et al,⁹ toxicity associated with GemCis was comparable with the exception of nausea and vomiting observed at a higher rate in the cisplatin-based regimen and peripheral sensory neuropathy occurring more frequently with oxaliplatin-based therapy.

QOL has gained acceptance as a surrogate end point of treatment efficacy due to the trials reported by Burris and Rothenberg.^5,6 Their work on clinical benefit response as a composite parameter of pain, performance status, and weight not only demonstrated that Gem was superior over bolus fluorouracil, but also showed that this end point related to a significantly improved survival. Using the five-item QOL index described by Spitzer al,²³ it could be shown in this trial that treatment with GemCis, despite a higher overall incidence of adverse effects, did not impair QOL when compared with treatment with Gem alone. A trend toward an improved QOL score was equally observed in both treatment arms during the initial two cycles of therapy.

It is a general notion that response evaluation by imaging is difficult in pancreatic cancer and may be limited by desmoplastic and inflammatory reactions of the tumor. For this reason, DCR may give a more reliable reflection of drug efficacy than ORR alone. Previous reports had indicated that Gem induced a DCR of 42% to 44%,^5,8 whereas the combination of Gem and Cis consistently increased DCR to a range of 55% to 68%.^8,20-22 These data are essentially confirmed by the present randomized trial where in the intent-to-treat analysis a DCR of 70.4% was reached in the GemCis arm, whereas DCR in the Gem arm was 48.5%. From the viewpoint of preventing initial PD, GemCis was 2.4-fold more effective than Gem (PD = 18.4% v 43.3%; P < .001).

Patients treated in the GemCis arm showed a marked (71%) prolongation of PFS compared with Gem alone (5.3 v 3.1 months). Although this improvement suggests a distinctly greater efficacy of the GemCis combination, it failed to reach the level of significance when all patients were evaluated. A significantly superior effect of the GemCis regimen was, however, demonstrated in a post hoc analysis of patients with locally advanced pancreatic cancer (8.6 v 3.2 months; P = .0053). So far, there is no good explanation as to why the PFS advantage observed in locally advanced disease did not translate into a corresponding survival benefit (10.3 v 10.4 months). Comparable results have also been reported by Louvet et al⁹; their GemOx regimen improved PFS but had no effect on survival compared with standard-dose Gem. A further hypothesis-generating subset analysis suggests that patients with a good KPS (90% to 100%) may be those who benefit most from a relevant prolongation of PFS in the GemCis as compared with the Gem arm (7.7 v 2.8 months; HR = 0.54; P = .013).

The primary end point of this trial was OS. The 25% (7.5 v 6.0 months) increase of OS induced by GemCis compares with a 50% (7.5 v 5.0 months) increase observed by the Italian group⁸ and also relates to the 27% (9.0 v 7.1 month) increase reported for the GemOx regimen by the French/Italian group.⁹ Although it appears that platinum-based regimens consistently prolonged survival, none of the trials so far showed a statistically significant superiority of the combination. Most likely, this is a result of the underpowered design of the trials. In view of the consistency of results, the question of whether the outcome of the aforementioned trials should rightfully be considered a negative one needs to be asked. Not only a meta-analysis of the available studies, but also the upcoming data from an Eastern Cooperative Oncology Group (ECOG) trial comparing GemOx with fixed-dose rate and standard-dose Gem may help to clarify this topic.

The interpretation of trial results may also depend on subgroups of patients with different prognosis. A multivariate analysis performed in this trial suggests that not only stage of disease, but also performance status are independent prognostic factors for survival. Moreover, evidence from a post hoc analysis leads to the hypothesis that specifically patients with a good KPS (90% to 100%) will draw the greatest benefit from combination therapy with Gem and Cis, whereas those patients with a worse performance status should receive single-agent therapy with Gem.

Also, second-line therapy evolves as an important confounder of survival analysis. So far, second-line therapy has not been established in pancreatic cancer. Although in this trial, centers were encouraged to allow cross-over when treatment failed in one arm, only 16% of patients actually received second-line therapy, which did not have an impact on outcome. By comparison, already 55% of patients received further treatment in the French/Italian trial.⁹

In conclusion, the combination of Gem with Cis has significantly improved disease control rate and induced an improved, but not statistically significant, prolongation of PFS and OS. The perspective for further development in pancreatic cancer therapy is set by the development of targeted agents. First results indicate the superiority of gemcitabine in combination with erlotinib.²⁴ Future trials must define those subgroups of patients who will benefit most from targeted therapy alone or in conjunction with single-agent or combination chemotherapy.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
We thank all the following investigators for their contribution to this randomized multicenter trial: Prof Aul (Würzburg), Dr Berchem (Freiburg), D. Bosse (München), Prof Clemens (Trier), Dr Fleckenstein (Munich), Dr Frick (Regensburg), Dr Gesierich (München), Prof Gieseler (Kiel), Dr Gonnermann (Dinslaken), Dr Haag (Dresden), Dr Harich (Bad Trissl), Dr Heinrich (Augsburg), Dr Hinke (Langenfeld), Dr Hoffmann (Norderstedt), Prof Holstege (Landshut), Dr Hurtz (Halle), Dr Jechart (Augsburg), Dr Junhold (Hof), Dr Krödel (Fulda), Prof Neuhaus (Düsseldorf), PD Dr Quietzsch (Chemnitz), Dr Rost (Darmstadt), Prof Schalhorn (München), Prof Schepp (Munich), Dr Schlotzauer (Hagen), Dr Schmohl (Munich), Dr Schönekäs (Nürnberg), Dr Schulz (Garmisch-Partenkirchen), M. Szymala (Munich), Dr Uthgenannt (Lübeck), Dr Vehling-Kaiser (Landshut), Dr Wilkowski (Munich), and M. Wolff (Munich).

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Volker Heinemann Eli Lilly Germany (B) Eli Lilly Germany (A) Eli Lilly Germany (C) Detlef Quietzsch Eli Lilly Germany (A) Michael Gonnermann Eli Lilly Germany (A) Andreas Rost Hoffmann-La Roche Germany (A); Eli Lilly Germany (A); Merck Pharma Germany (A) Bernard Heinrich Eli Lilly Germany (A) Axel Holstege Hoffmann-La Roche Germany (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Volker Heinemann, Andreas Schalhorn Administrative support: Volker Heinemann Provision of study materials or patients: Volker Heinemann, Detlef Quietzsch, Frank Gieseler, Herbert Schönekäs, Andreas Rost, Horst Neuhaus, Michael Clemens, Bernard Heinrich, Ursula Vehling-Kaiser, Martin Fuchs, Doris Fleckenstein, Wolfgang Gesierich, Dirk Uthgenannt, Axel Holstege, Andreas Schalhorn, Ralf Wilkowski Collection and assembly of data: Volker Heinemann, Detlef Quietzsch, Frank Gieseler, Michael Gonnermann, Herbert Schönekäs, Andreas Rost, Horst Neuhaus, Caroline Haag, Michael Clemens, Bernard Heinrich, Martin Fuchs, Doris Fleckenstein, Dirk Uthgenannt Data analysis and interpretation: Volker Heinemann, Detlef Quietzsch, Frank Gieseler, Herbert Schönekäs, Hermann Einsele, Axel Hinke Manuscript writing: Volker Heinemann, Frank Gieseler Final approval of manuscript: Volker Heinemann, Detlef Quietzsch, Frank Gieseler, Herbert Schönekäs, Andreas Rost, Michael Clemens, Bernard Heinrich, Dirk Uthgenannt, Hermann Einsele, Axel Hinke, Andreas Schalhorn, Ralf Wilkowski

 

	NOTES

 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
1. Evans DB, Abbruzzese JL, Willett CG: Cancer of the pancreas, in De Vita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 6). Philadelphia, PA, Lippincott Williams and Wilkins, 2001, pp 1126-1161

2. Rosewicz S, Wiedenmann B: Pancreatic carcinoma. Lancet 349: 485-489, 1997[CrossRef][Medline]

3. Haller DG: Chemotherapy for advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 56: 16-23, 2003 (suppl 4)[CrossRef][Medline]

4. Heinemann V: Gemcitabine-based combination treatment of pancreatic cancer. Semin Oncol 29: 25-35, 2002 (suppl 3)[Medline]

5. Burris HA, 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]

6. 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]

7. Storniolo AM, Enas MH, Brown CA, et al: An investigational new drug treatment program for patients with gemcitabine. Cancer 85: 1261-1268, 1999[CrossRef][Medline]

8. 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 Oncologico dell’Italia Meridionale. Cancer 94: 902-910, 2002[CrossRef][Medline]

9. Louvet C, Labianca R, Hammel P, et al: Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23: 3509-3516, 2005[Abstract/Free Full Text]

10. Berlin J, Catalano P, Thomas J, et al: A phase III study of gemcitabine in combination with 5-FU vs gemcitabine alone in patients with advanced pancreatic carcinoma (E2297): An Eastern Cooperative Oncology Group (ECOG) trial. J Clin Oncol 20: 3270-3275, 2002[Abstract/Free Full Text]

11. Riess A, Helm M, Niedergethmann, et al : A randomised, prospective, multicenter, phase III trial of gemcitabine, 5-fluorouracil, folinic acid versus gemcitabine alone in patients with advanced pancreatic cancer. J Clin Oncol 24: 310s, 2005 (suppl; abstr LBA4009)

12. Herrmann R, Bodoky G, Ruhstaller T, et al: Gemcitabine plus capecitabine versus gemcitabine alone in locally advanced or metastatic pancreatic cancer: A randomized phase III study of the Swiss Group for Clinical Cancer Res (SAKK) and the Central European Cooperative Group (CECOG). J Clin Oncol 24: 310s, 2005 (suppl; abstr LBA4010)

13. Richards DA, Kindler HL, Oettle H, et al: A randomized phase III study comparing gemcitabine + pemetrexed versus gemcitabine in patients with locally advanced and metastatic pancreas cancer. J Clin Oncol 23: 315s, 2004 (suppl; abstr 4007)

14. Rocha Lima CM, Green MR, Rotche R, et al: Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22: 1430-1438, 2004[Abstract/Free Full Text]

15. O’ Reilly EM, Abou-Alfa GK, Letourneau R, et al: A randomized phase III trial of DX-8951f (exatecan mesylate; DX) and gemcitabine (GEM) vs. gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 23: 315s, 2004 (suppl; abstr 4006)

16. Peters GJ, Bergman AM, Ruiz van Haperen VW, et al: Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 22: 72-79, 1995 (suppl 4)[Medline]

17. Van Moorsel CJA, Veerman G, Bergman AM, et al: Combination chemotherapy studies with gemcitabine. Semin Oncol 24: S7-S23, 1997 (suppl 7)[Medline]

18. Yang LY, Li L, Jiang H, et al: Expression of ERCC1 antisense RNA abrogates gemicitabine-mediated cytotoxic synergism with cisplatin in human colon tumor cells defective in mismatch repair but proficient in nucleotide excision repair. Clin Cancer Res 6: 773-781, 2000[Abstract/Free Full Text]

19. Achanta G, Pelicano H, Feng L, et al: Interaction of p53 and DNA-PK in response to nucleoside analogues: Potential role as a sensor complex for DNA damage. Cancer Res 61: 8723-8729, 2001[Abstract/Free Full Text]

20. Cascinu S, Labianca R, Catalano V, et al: Weekly gemcitabine and cisplatin chemotherapy: A well-tolerated but ineffective chemotherapeutic regimen in advanced pancreatic cancer patients—A report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Ann Oncol 14: 205-208, 2003[Abstract/Free Full Text]

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

22. 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]

23. Spitzer WO, Dobson AJ, Hall J, et al: Measuring the quality of life of cancer patients: A concise QL-index for use by physicians. J Chron Dis 34: 585-597, 1981[CrossRef][Medline]

24. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. J Clin Oncol 23: 1s, 2005 (suppl; abstr 1)[CrossRef][Medline]

Submitted January 18, 2006; accepted June 20, 2006.

Related Correspondence

• Gemcitabine Plus Cisplatin in Advanced Pancreatic Cancer
  Robert R. McWilliams and Steven R. Alberts
  JCO 2007 25: 1142 [Full Text]

This article has been cited by other articles:

				J. Bernhard, D. Dietrich, W. Scheithauer, D. Gerber, G. Bodoky, T. Ruhstaller, B. Glimelius, E. Bajetta, J. Schuller, P. Saletti, et al. Clinical Benefit and Quality of Life in Patients With Advanced Pancreatic Cancer Receiving Gemcitabine Plus Capecitabine Versus Gemcitabine Alone: A Randomized Multicenter Phase III Clinical Trial--SAKK 44/00-CECOG/PAN.1.3.001 J. Clin. Oncol., August 1, 2008; 26(22): 3695 - 3701. [Abstract] [Full Text] [PDF]

				M. S. Pino, M. Balsamo, F. Di Modugno, M. Mottolese, M. Alessio, E. Melucci, M. Milella, D. J. McConkey, U. Philippar, F. B. Gertler, et al. Human Mena+11a Isoform Serves as a Marker of Epithelial Phenotype and Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Pancreatic Cancer Cell Lines Clin. Cancer Res., August 1, 2008; 14(15): 4943 - 4950. [Abstract] [Full Text] [PDF]

				Y. J. Chua and J. R. Zalcberg Pancreatic cancer--is the wall crumbling? Ann. Onc., July 1, 2008; 19(7): 1224 - 1230. [Abstract] [Full Text] [PDF]

				J. Nieto, M. L. Grossbard, and P. Kozuch Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty? Oncologist, May 1, 2008; 13(5): 562 - 576. [Abstract] [Full Text] [PDF]

				S. Boeck and V. Heinemann Second-Line Therapy in Gemcitabine-Pretreated Patients With Advanced Pancreatic Cancer J. Clin. Oncol., March 1, 2008; 26(7): 1178 - 1179. [Full Text] [PDF]

				D. Laheru, E. Lutz, J. Burke, B. Biedrzycki, S. Solt, B. Onners, I. Tartakovsky, J. Nemunaitis, D. Le, E. Sugar, et al. Allogeneic Granulocyte Macrophage Colony-Stimulating Factor-Secreting Tumor Immunotherapy Alone or in Sequence with Cyclophosphamide for Metastatic Pancreatic Cancer: A Pilot Study of Safety, Feasibility, and Immune Activation Clin. Cancer Res., March 1, 2008; 14(5): 1455 - 1463. [Abstract] [Full Text] [PDF]

				H. Burris III and C. Rocha-Lima New Therapeutic Directions for Advanced Pancreatic Cancer: Targeting the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways Oncologist, March 1, 2008; 13(3): 289 - 298. [Abstract] [Full Text] [PDF]

				S. Boeck, T. Hoehler, G. Seipelt, R. Mahlberg, A. Wein, A. Hochhaus, H.-P. Boeck, B. Schmid, E. Kettner, M. Stauch, et al. Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer Ann. Onc., February 1, 2008; 19(2): 340 - 347. [Abstract] [Full Text] [PDF]

				M. A. Tempero How I Treat Pancreatic Ductal Adenocarcinoma J. Oncol. Pract, January 1, 2008; 4(1): 46 - 47. [Full Text] [PDF]

				S. P. Desai, E. Ben-Josef, D. P. Normolle, I. R. Francis, J. K. Greenson, D. M. Simeone, A. E. Chang, L. M. Colletti, T. S. Lawrence, and M. M. Zalupski Phase I Study of Oxaliplatin, Full-Dose Gemcitabine, and Concurrent Radiation Therapy in Pancreatic Cancer J. Clin. Oncol., October 10, 2007; 25(29): 4587 - 4592. [Abstract] [Full Text] [PDF]

				V. Heinemann, R. Labianca, A. Hinke, and C. Louvet Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study Ann. Onc., October 1, 2007; 18(10): 1652 - 1659. [Abstract] [Full Text] [PDF]

				H. Ueno, T. Okusaka, M. Ikeda, C. Morizane, T. Ogura, A. Hagihara, and T. Tanaka Phase II Study of Combination Chemotherapy with Gemcitabine and Cisplatin for Patients with Metastatic Pancreatic Cancer Jpn. J. Clin. Oncol., August 2, 2007; (2007) hym060v1. [Abstract] [Full Text] [PDF]

				R. Herrmann, G. Bodoky, T. Ruhstaller, B. Glimelius, E. Bajetta, J. Schuller, P. Saletti, J. Bauer, A. Figer, B. Pestalozzi, et al. Gemcitabine Plus Capecitabine Compared With Gemcitabine Alone in Advanced Pancreatic Cancer: A Randomized, Multicenter, Phase III Trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group J. Clin. Oncol., June 1, 2007; 25(16): 2212 - 2217. [Abstract] [Full Text] [PDF]

				E. Van Cutsem, C. Verslype, and P. A. Grusenmeyer Lessons Learned in the Management of Advanced Pancreatic Cancer J. Clin. Oncol., May 20, 2007; 25(15): 1949 - 1952. [Full Text] [PDF]

				R. R. McWilliams and S. R. Alberts Gemcitabine Plus Cisplatin in Advanced Pancreatic Cancer J. Clin. Oncol., March 20, 2007; 25(9): 1142 - 1142. [Full Text] [PDF]

				V. Heinemann and S. Boeck In Reply J. Clin. Oncol., March 20, 2007; 25(9): 1142 - 1143. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services