nach oben

Targeted Oncology

Erschienen in:

29.03.2017 | Systematic Review

Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis

verfasst von: Xiu-Wei Zhang, Yu-Xiang Ma, Yang Sun, Yu-Bo Cao, Qin Li, Chong-An Xu

Erschienen in: Targeted Oncology | Ausgabe 3/2017

Einloggen, um Zugang zu erhalten

Abstract

Background

It remains controversial whether the addition of a second cytotoxic agent can further improve the therapeutic effect of gemcitabine monotherapy in advanced or metastatic pancreatic cancer (LA/MPC).

Objective

The objective of the present systematic review and meta-analysis was to investigate the efficacy and safety of gemcitabine-based doublet chemotherapy regimens compared to single-agent gemcitabine in the first-line treatment of unresectable LA/MPC.

Methods

We searched for randomized controlled trials (RCTs) of gemcitabine monotherapy versus gemcitabine in combination with a second cytotoxic agent in patients with LA/MPC. The last search date was December 31, 2016.

Results

Twenty-seven RCTs were identified and included in the present systematic review and meta-analysis, involving a total of 7343 patients. The meta-analysis showed that gemcitabine-based combination therapy significantly improved overall survival (OS) (HR: 0.89; 95% confidence interval (CI): 0.85-0.94; P < 0.0001), progression-free survival (PFS) (HR: 0.80; 95% CI: 0.73-0.88; P < 0.0001), and overall response rate (ORR) (RR: 1.83; 95% CI: 1.62-2.07; P < 0.0001) in comparison to single-agent gemcitabine. Subgroup analysis suggested that the antitumor activity differed between gemcitabine-based combination regimens: doublet regimens of gemcitabine plus a taxoid, and gemcitabine plus a fluoropyrimidine, in particular an oral fluoropyrimidine, resulted in a significant OS benefit for the patients. However, the combination of gemcitabine with other cytotoxic agents, such as platinum compounds or topoisomerase inhibitors failed to reduce the mortality risk. Combination therapy caused more grade 3/4 toxicities, including neutropenia, thrombocytopenia, vomiting, diarrhea, and fatigue.

Conclusions

Gemcitabine-based doublet regimens demonstrated superiority over gemcitabine monotherapy in overall efficacy, but were associated with increased toxicity. Different gemcitabine-based combinations showed different antitumor activity, and doublet regimens of gemcitabine in combination with a taxoid or a fluoropyrimidine, in particular an oral fluoropyrimidine provided significant survival benefits in the first-line treatment of unresectable LA/MPC.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.CrossRefPubMed

Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(14):2913–21.CrossRefPubMed

Fryer RA, Galustian C, Dalgleish AG. Recent advances and developments in treatment strategies against pancreatic cancer. Curr Clin Pharmacol. 2009;4:102–12.CrossRefPubMed

Hackert T, Buchler MW. Pancreatic cancer: advances in treatment, results and limitations. Dig Dis. 2013;31(1):51–6.CrossRefPubMed

Rosewicz S, Wiedenmann B. Pancreatic carcinoma. Lancet. 1997;349(9050):485–9.CrossRefPubMed

Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17.CrossRefPubMed

Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. 2010;7(3):163–72.CrossRefPubMed

Yeo CJ, Cameron JL. Improving results of pancreaticoduodenectomy for pancreatic cancer. World J Surg. 1999;23(9):907–12.CrossRefPubMed

Burris 3rd 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. Clin Oncol. 1997;15:2403–13.CrossRef

10.

NCCN guidelines for pancreatic cancer. [Accessed January 30, 2016]. Available from:http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf.

11.

Rocha Lima CM, Flores AM. Gemcitabine doublets in advanced pancreatic cancer: should we move on? J Clin Oncol. 2006;24(3):327–9.CrossRefPubMed

12.

Welch SA, Moore MJ. Combination chemotherapy in advanced pancreatic cancer: time to raise the white flag? J Clin Oncol. 2007;25(16):2159–61.CrossRefPubMed

13.

Sun C, Ansari D, Andersson R, et al. Does gemcitabine-based combination therapy improve the prognosis of unresectable pancreatic cancer? World J Gastroenterol. 2012;18(35):4944–58.CrossRefPubMedPubMedCentral

14.

Ciliberto D, Botta B, Correale P, et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer. 2013;49:593–603.CrossRefPubMed

15.

Von Hoff DD, Ervin T, Arena FP, Chiorean EG, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.CrossRef

16.

Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817.CrossRefPubMed

17.

Jadad AR, Moore RA, Carroll D, Jenkinson C, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.CrossRefPubMed

18.

Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–34.CrossRefPubMed

19.

Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.CrossRefPubMedPubMedCentral

20.

DerSimonian R, Levine RJ. Resolving discrepancies between a meta-analysis and a subsequent large controlled trial. JAMA, J Am Med Assoc. 1999;282(7):664–70.CrossRef

21.

DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 2007;28(2):105–14.CrossRefPubMed

22.

Boston RC, Sumner AE. STATA: a statistical analysis system for examining biomedical data. Adv Exp Med Biol. 2003;537:353–69.CrossRefPubMed

23.

Omuro Y, Ikari T, Ishii H, et al. A randomized phase II study of gemcitabine plus S-1 versus gemcitabine alone in patients with unresectable pancreatic cancer. J Clin Oncol. 2011;29 Suppl 15:4029.CrossRef

24.

Vogel A, Penenberg D, McGovern D, et al. 2358 Efficacy and safety of nab-Paclitaxel (nab-P) plus gemcitabine (Gem) vs gem alone in patients (Pts) with metastatic pancreatic cancer (MPC) treated to progressive disease (PD) in the phase III MPACT trial. Eur J Cancer. 2015;51:S455.CrossRef

25.

Palacio S, Akunyili II, Ernani V, et al. Gemcitabine (Gem) and nab-paclitaxel (nab-P) in patients (pts) with refractory advanced pancreatic cancer. J Clin Oncol. 2015;33(3):413.CrossRef

26.

Riess H, Helm A, Niedergethmann M, et al. A randomised, prospective, multicenter, phase III trial of gemcitabine, 5-fluorouracil (5-FU), folinic acid vs. gemcitabine alone in patients with advanced pancreatic cancer. Cancer J. 2010;8(3):255–62.

27.

O’ Reilly EM, Aboualfa 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 (APC). J Clin Oncol. 2004;22 Suppl 14:4006.CrossRef

28.

Bernhard J, Dietrich D, Scheithauer W, 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. 2008;26:3695–701.CrossRefPubMed

29.

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. 2002;20(20):3270–5.CrossRefPubMed

30.

Di Costanzo F, Carlini P, Doni L, et al. Gemcitabine with or without continuous infusion 5-FU in advanced pancreatic cancer: a randomized phase II trial of the Italian oncology group for clinical research (GOIRC). Br J Cancer. 2005;93(2):185–9.CrossRefPubMedPubMedCentral

31.

Ohkawa S. Randomized controlled trial of gemcitabine in combination with UFT versus gemcitabine alone in patients with advanced pancreatic cancer. J Clin Oncol. 2004;22 Suppl 14:4131.CrossRef

32.

Scheithauer W, Schull B, Ulrich-Pur H, et al. Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol. 2003;14(1):97–104.CrossRefPubMed

33.

Herrmann R, Bodoky G, Ruhstaller T, 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. Clin Oncol. 2007;25:2212–7.CrossRef

34.

Cunningham D, Chau I, Stocken D, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27(33):5513–8.CrossRefPubMed

35.

Ioka T, Ikeda M, Ohkawa S, et al. Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer (PC) in Japan and Taiwan: GEST study. J Clin Oncol. 2011;29 Suppl 15:4007.CrossRef

36.

Nakai Y, Isayama H, Sasaki T, et al. A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study. Br J Cancer. 2012;106(12):1934–9.CrossRefPubMedPubMedCentral

37.

Ozaka M. et al.Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study). Cancer Chemother Pharmacol. 2012;69(5):1197–204.CrossRefPubMed

38.

Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013;31(13):1640–8.CrossRefPubMed

39.

Sudo K, Ishihara T, Hirata N, et al. Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer. Cancer Chemother Pharmacol. 2014;73(2):389–96.CrossRefPubMed

40.

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. 2005;23(15):3509–16.CrossRefPubMed

41.

Poplin E, Feng YJ. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27(23):3778–85.

42.

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. 2002;94:902–10.CrossRefPubMed

43.

Wang X, Ni Q, et al. Gemcitabine or gemcitabine plus cisplatin for in 42 patients with locally advanced or metastatic pancreatic cancer. Zhonghua Zhong Liu Za Zhi. 2002;24(4):404–7.PubMed

44.

Viret F, Ychou M, Lepille D, et al. Gemcitabine in combination with cisplatin (GP) versus gemcitabine (G) alone in the treatment of locally advanced or metastatic pancreatic cancer: Final results of a multicenter randomized phase II study. J Clin Oncol. 2004;22 Suppl 14:4118.CrossRef

45.

Li CP, Chao Y. A prospective randomized trial of gemcitabine alone or gemcitabine + cisplatin in the treatment of metastatic pancreatic cancer. J Clin Oncol. 2004;22 Suppl 14:4144.

46.

Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006;24(24):3946–52.

47.

Colucci G, Labianca R, Di Costanzo F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010;28(10):1645–51.CrossRefPubMed

48.

Chao Y, Wu CY, Wang JP. et al.A randomized controlled trial of gemcitabine plus cisplatin versus gemcitabine alone in the treatment of metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2013;72(3):637–42.CrossRefPubMed

49.

Kulke MH, Tempero MA, Niedzwiecki D, et al. Randomized phase II study of docetaxel, or irinotecan in patients with metastatic pancreatic cancer:CALGB 89904. J Clin Oncol. 2009;27:5506–12.CrossRefPubMedPubMedCentral

50.

Lohr JM, Haas SL, Bechstein WO, et al. Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: randomized controlled phaseIItrial. Ann Oncol. 2012;23:1214–22.CrossRefPubMed

51.

Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol. 2006;24(27):4441–7.

52.

Rocha Lima CM, Green MR, Rotche R, Miller Jr WH, 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. 2004;22(18):3776–83.CrossRefPubMed

53.

Stathopoulos GP, Syrigos KG, Polyzos A, et al. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer. 2006;95(5):587–92.CrossRefPubMedPubMedCentral

54.

Oettle H, Richards D, Ramanathan RK, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol. 2005;16:1639–45.CrossRefPubMed

55.

Burris 3rd HA. Recent updates on the role of chemotherapy in pancreatic cancer. Semin Oncol. 2005;32(4 Suppl 6):S1–3.CrossRefPubMed

56.

Bria E, Milella M, et al. Gemcitabine-based combinations for inoperable pancreatic cancer: have we made real progress? Cancer. 2007;110(3):525–33.CrossRefPubMed

57.

de Xie R, Liang HL, Wang Y, Guo SS. Meta-analysis of inoperable pancreatic cancer: gemcitabine combined with cisplatin versus gemcitabine alone. Chin J Dig Dis. 2006;7:49–54.CrossRef

58.

Petrelli F, Coinu A, Borgonovo K, et al. Polychemotherapy or gemcitabine in advanced pancreatic cancer: A meta-analysis. Dig Liver Dis. 2014;46(5):452–9.CrossRefPubMed

59.

Hu J, Zhao G, Wang HX, et al. A meta-analysis of gemcitabine containing chemotherapy for locally advanced and metastatic pancreatic adenocarcinoma. J Hematol Oncol. 2011;4(2):11.CrossRefPubMedPubMedCentral

60.

Hoff PM, Cassidy J, Schmoll HJ. The evolution of fluoropyrimidine therapy: from intravenous to oral. Oncologist. 2001;6 Suppl 4:3–11.CrossRefPubMed

61.

Yardley DA. Nab-paclitaxel mechanisms of action and delivery. J Control Release. 2013;170:365–72.CrossRefPubMed

62.

Von Hoff DD, Ramanathan RK. Gemcitabine plus nab-pacltaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29(34):4548–54.CrossRef

63.

Heinemann V, Boeck S, et al. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer. 2008;8:82.

64.

Reni M, Cordio S, Milandri C, et al. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005;6:369–76.CrossRefPubMed

65.

Fine RL, Fogelman DR, Schreibman SM,et al. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis.Cancer Chemother Pharmacol. 2008;61:167–175.

66.

De Jesus-Acosta A, Oliver GR, Blackford A,et al. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2012;69:415–424.

67.

Yang ZY, Yuan JQ, et al. Gemcitabine plus erlotinib for advanced pancreatic cancer: a systematic review with meta-analysis. Plos One. 2013;8(3):e57528.CrossRefPubMedPubMedCentral

68.

Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B(CALGB80303). J Clin Oncol. 2010;28:3617–22.CrossRefPubMedPubMedCentral

69.

Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010;28:3605–10.CrossRefPubMedPubMedCentral

70.

Gonçalves A, Gilabert M, François E, et al. BAYPAN study: a double blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012;23:2799–805.CrossRefPubMed

71.

Boeck S, Hinke A, et al. Importance of performance status for treatment outcome in advanced pancreatic cancer. World J Gastroenterol. 2007;13(2):224–7.CrossRefPubMedPubMedCentral

Titel: Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis
verfasst von: Xiu-Wei Zhang
Yu-Xiang Ma
Yang Sun
Yu-Bo Cao
Qin Li
Chong-An Xu
Publikationsdatum: 29.03.2017
Verlag: Springer International Publishing
Erschienen in: Targeted Oncology / Ausgabe 3/2017
Print ISSN: 1776-2596
Elektronische ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-017-0486-5

Neu im Fachgebiet Onkologie

24.04.2024 | DGIM 2024 | Nachrichten

Springer Medizin

Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis

Abstract

Background

Objective

Methods

Results

Conclusions

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie

Springer Medizin

Abstract

Background

Objective

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2017

CRNDE Expression Positively Correlates with EGFR Activation and Modulates Glioma Cell Growth

Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma

A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer

Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors

Immune Checkpoint Inhibitor-Induced Colitis: Diagnosis and Management

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie