|Year : 2016 | Volume
| Issue : 5 | Page : 104-108
Meta-analysis of gemcitabine and cisplatin combination chemotherapy versus gemcitabine alone for pancreatic cancer
Diyu Huang1, Jie Fang2, Gaojian Luo3
1 Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
2 Department of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
3 Department of General Surgery, Yiwu Central Hospital, Yiwu 322000, China
|Date of Web Publication||7-Oct-2016|
Department of General Surgery, Yiwu Central Hospital, Yiwu 322000
Source of Support: None, Conflict of Interest: None
Purpose: The aim of this study is to assess the efficacy and safety of combination chemotherapy with gemcitabine (GEM) and cisplatin (CIS) compared with GEM alone in patients with pancreatic cancer.
Methods: A computerized search through electronic databases, including PubMed (until February 2016), was performed to obtain eligible randomized controlled trials that compared effectiveness of GEM and CIS combination chemotherapy with GEM alone in patients with pancreatic cancer. The indicators we used were overall response rate, stable disease rate, progressive disease rate, and 1-year overall survival. Relative risk and 95% confidence interval were calculated and pooled using a fixed effects model.
Results: Compared with GEM alone, combination chemotherapy has significant advantage in the overall response rate (odds ratio [OR] =0.52, P = 0.004), stable disease (OR = 0.68, P = 0.05), and progressive disease (OR = 2.11, P = 0.0002). However, the control group and experimental group have no significant difference in 1-year survival (OR = 1.07, P = 0.75). The combination chemotherapy with GEM and CIS group had higher hematological toxicities including neutropenia (OR = 0.39, P = 0.0003), thrombocytopenia (OR = 0.3, P < 0.0001), and anemia (OR = 0.41, P = 0.004).
Conclusions: Overall response rate, stable disease, and progressive disease, as well as 1-year survival rate in patients who received GEM + CIS, were superior to those treated with GEM alone. Combination chemotherapy with GEM and CIS may offer greater benefits in the treatment of pancreatic cancer than that of GEM alone although the combination group had higher hematological toxicities.
Keywords: Chemotherapy, cisplatin, gemcitabine, meta-analysis, pancreatic cancer
|How to cite this article:|
Huang D, Fang J, Luo G. Meta-analysis of gemcitabine and cisplatin combination chemotherapy versus gemcitabine alone for pancreatic cancer. J Can Res Ther 2016;12, Suppl S1:104-8
|How to cite this URL:|
Huang D, Fang J, Luo G. Meta-analysis of gemcitabine and cisplatin combination chemotherapy versus gemcitabine alone for pancreatic cancer. J Can Res Ther [serial online] 2016 [cited 2019 Feb 20];12:104-8. Available from: http://www.cancerjournal.net/text.asp?2016/12/5/104/191616
| > Introduction|| |
Pancreatic cancer has become one of the most fatal diseases over the past years. The 5-year survival rate is 4%, which is the lowest for all types of cancer. Among a majority of patients present with locally advanced or metastatic disease, the median life expectancy is 3–6 months for metastatic disease and 6–10 months for nonmetastatic disease. Some patients are eligible for surgery at diagnosis, but the effect of advanced pancreatic cancer remains unsatisfactory. Therefore, the development of more effective therapy is essential to improve the patient survival. Although gemcitabine (GEM) has been accepted as a standard first-line treatment for patients with advanced pancreatic cancer  in recent years, patients who receive this therapy have a median overall survival (OS) of only 5.65 months. As a valid inducer of apoptosis in pancreatic cancer cells, cisplatin (CIS) is among the most effective and widely used chemotherapeutic agents. A combination of GEM and CIS was synergistic so that it worsened DNA damage.,
However, it is not fully clear that whether overall response rate, stable disease rate (SDR), progress disease rate, and 1-year survival rate using combination chemotherapy with GEM and CIS are superior to that using GEM alone. Therefore, we conducted a meta-analysis to assess the efficacy and safety of combination therapy in patients with pancreatic cancer.
| > Methods|| |
Studies were searched among PubMed using the terms: “Gemcitabine,” “cisplatin,” and “pancreatic cancer,” in title and abstract. The databases were searched for studies published from May 2007 to February 2016. Only trails published in English were involved. Reference lists of related articles were manually checked to search for additional eligible publications. All references of relevant articles were scanned, and all additional studies of potential interest were retrieved for further analysis.
Eligible trails have to meet the following criteria: Patients involved were diagnosed with pancreatic cancer through cytological diagnosis or pathological diagnosis; randomized controlled trials (RCTs) using GEM individually or in combination with CIS to treat pancreatic cancer, without surgery or other treatment; trails with patients who previously had received cancer immunotherapy or other molecular targeted therapy were excluded.
For each candidate trial, two reviewers independently recorded the characteristics of the studies, including the first author, publication year, number of patients, intervention group, control group, and age of the patients. Discrepancies were handled through group discussion. Analytical data that would be included in our meta-analysis but were missing from the original published studies were requested from their authors.
Our study followed the preferred reporting items for systematic reviews and meta-analyses statement. Significant differences between studies were reported in terms of odds ratio (OR), with a 95% confidence interval (CI) for dichotomous outcomes. Heterogeneity of the results of the trials was assessed with the I2 statistic using the Chi-square test at a = 0.1. Primary assessment was done with a fixed model. When P ≥ 0.05 and I2 ≤ 50%, it was considered that the trials are without heterogeneity and a fixed effect model was used to perform meta-analysis. When P < 0.05 and I2 > 50%, it was considered that the trials are with significant heterogeneity. The source of the heterogeneity was further analyzed. P ≤0.05 was considered statistically significant. If there was no significant clinical heterogeneity, the secondary confirmatory analysis was done with a random effects model. Otherwise, descriptive analysis was performed. If necessary, sensitivity analyses were performed to test the stability of identified outcomes. All data and statistical analyses, except for publication bias, were combined and performed using RevMan 5.3.0 (The Cochrane Collaboration, Copenhagen, Denmark).
| > Results|| |
A total of 4 RCTs ,,, from 443 potential articles were selected for our meta-analysis [Figure 1].
The principal characteristics of the selected articles are listed in [Table 1]. The four trials, with a total of 922 patients, were published in English between 2007 and 2016. The trials are all randomized, controlled, and Phase II or III trails.
Objective response rate
The overall response rate was defined as the proportion of patients who had a complete response or partial response. Two-hundred five patients received GEM alone and 297 received the GEM + CIS combination. Meta-analysis of the pooled data shows that the overall response rate was significantly different for the GS and GEM alone chemotherapies (OR = 0.52, 95% CI: 0.33–0.82, P = 0.004 [Figure 2]). This suggested that GEM + CIS can greatly improve overall response rate compared with GEM alone in pancreatic cancer
|Figure 2: Results for combination chemotherapy with gemcitabine and cisplatin versus gemcitabine – Overall response rate|
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Stable disease rate
Meta-analysis of the pooled data demonstrated that the overall response rate was significantly different for the GS and GEM alone chemotherapies (OR = 0.68, 95% CI: 0.46–1.00, P = 0.05 [Figure 3]). This suggested that GEM + CIS can improve SDR compared with GEM alone in pancreatic cancer.
|Figure 3: Results for combination chemotherapy with gemcitabine and cisplatin versus gemcitabine – Stable disease|
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Progressive disease rate
Meta-analysis of the pooled data demonstrated that the overall response rate was significantly different for the GS and GEM alone chemotherapies (OR = 2.11, 95% CI: 1.43–3.11, P = 0.0002 [Figure 4]). This suggested that GEM + CIS can reduce progressive disease rate (PDR) compared with GEM alone in pancreatic cancer.
|Figure 4: Results for combination chemotherapy with gemcitabine and cisplatin versus gemcitabine – Progressive disease|
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One-year survival rate
We use 1-year survival rate to evaluate survival rate of patients. GEM + CIS group and GEM alone group have no significant difference in 1-year survival (OR = 1.07, 95% CI: 0.72–1.52, P = 0.75 [Figure 5]).
|Figure 5: Results for combination chemotherapy with gemcitabine and cisplatin versus gemcitabine – 1-year survival rate|
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The major Grade 3–4 adverse events with regard to hematological toxicities are compared in [Figure 6],[Figure 7],[Figure 8]. These results suggested that GEM + CIS group has higher hematological toxicities including neutropenia (OR = 0.39, 95% CI: 0.23–0.65, P = 0.0003 [Figure 6]), thrombocytopenia (OR = 0.3, 95% CI: 0.17–0.52, P < 0.0001, [Figure 7]), and anemia (OR = 0.41, 95% CI: 0.22-0.76, P = 0.004 [Figure 8]). Although the frequency of Grade 3–4 adverse events in the GEM + CIS group was higher than that in the GEM group involving hematological toxicities, the toxicities were predictable and controllable.
|Figure 6: Results for combination chemotherapy with gemcitabine and cisplatin versus gemcitabine – Grade 3–4 adverse events: neutropenia|
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|Figure 7: Results for combination chemotherapy with gemcitabine and cisplatin versus gemcitabine – Grade 3–4 adverse events: thrombocytopenia|
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|Figure 8: Results for combination chemotherapy with gemcitabine and cisplatin versus gemcitabine – Grade 3–4 adverse events: anemia|
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| > Discussion|| |
This meta-analysis intended to identify the therapeutic effect, associated with hematological toxicities, including neutropenia, thrombocytopenia, and anemia of pancreatic cancer. The study demonstrates that GEM combination with CIS is more effective in objective response rate, SDR, and PDR compared with GEM alone. The result suggests that most significant advantage of GEM combination with CIS compared with GEM alone is their effectiveness in preventing tumor progression. However, GEM + CIS group and GEM alone group have no significant difference in 1-year survival. In addition, the combination chemotherapy with GEM and CIS group had higher hematological toxicities including neutropenia, thrombocytopenia, and anemia.
Although great progress has been achieved in understanding of molecular mechanism of pancreatic cancer and development of targeting drugs in recent years, prognosis is still far from satisfactory. Combined administration is clearly a treatment option to be considered for patients with pancreatic cancer, which can offer additive or synergistic effects to blockade aberrant signaling.
According to the published meta-analysis, GEM-based combination therapy significantly improved OS. However, the advantage was limited due to a higher toxicity. It was suggested that the prescription of GEM-based combination regimens should be recommended. Another meta-analysis revealed that polychemotherapy significantly improved OS, PFS, and response rate compared with GEM alone.
GEM in combination with CIS has advantage in preventing tumor progression; the severe hematological toxicities, such as neutropenia, thrombocytopenia, and anemia still cannot be ignored. In clinical practice, the balance between therapeutic effect and associated adverse events should be carefully evaluated before the final selection.
Some limitations of the present meta-analysis should be acknowledged. First, we excluded non-English language studies but mitigated the risk by searching more databases. Second, the existence of selection bias, lead-time bias, and length-time bias was limitation in our included studies. These reduced the credibility of this meta-analysis. Third, this meta-analysis found no difference in 1-year survival. This may be caused by fewer studies. Therefore, more studies with large sample size are required to identify the root reason of this phenomenon.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Welsch T, Kleeff J, Seitz HK, Büchler P, Friess H, Büchler MW. Update on pancreatic cancer and alcohol-associated risk. J Gastroenterol Hepatol 2006;21 Suppl 3:S69-75.
Hawes RH, Xiong Q, Waxman I, Chang KJ, Evans DB, Abbruzzese JL. A multispecialty approach to the diagnosis and management of pancreatic cancer. Am J Gastroenterol 2000;95:17-31.
Kulke MH. Recent developments in the pharmacological treatment of advanced pancreatic cancer. Expert Opin Investig Drugs 2003;12:983-92.
Chen B, Xu M, Zhang H, Wang JX, Zheng P, Gong L, et al.
Cisplatin-induced non-apoptotic death of pancreatic cancer cells requires mitochondrial cyclophilin-D-p53 signaling. Biochem Biophys Res Commun 2013;437:526-31.
Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Peters GJ. Synergistic interaction between cisplatin and gemcitabine in vitro
. Clin Cancer Res 1996;2:521-30.
Peters GJ, Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Braakhuis BJ. Interaction between cisplatin and gemcitabine in vitro
and in vivo
. Semin Oncol 1995;22 4 Suppl 11:72-9.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009;339:b2700.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
Chao Y, Wu CY, Wang JP, Lee RC, Lee WP, Li CP. A randomized controlled trial of gemcitabine plus cisplatin versus gemcitabine alone in the treatment of metastatic pancreatic cancer. Cancer Chemother Pharmacol 2013;72:637-42.
Inal A, Kos FT, Algin E, Yildiz R, Dikiltas M, Unek IT, et al.
Gemcitabine alone versus combination of gemcitabine and cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: A retrospective analysis of multicenter study. Neoplasma 2012;59:297-301.
Colucci G, Labianca R, Di Costanzo F, Gebbia V, Cartenì G, Massidda B, 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;28:1645-51.
Palmer DH, Stocken DD, Hewitt H, Markham CE, Hassan AB, Johnson PJ, et al.
A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: Gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol 2007;14:2088-96.
Ciliberto D, Botta C, Correale P, Rossi M, Caraglia M, Tassone 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.
Petrelli F, Coinu A, Borgonovo K, Cabiddu M, Ghilardi M, Barni S. Polychemotherapy or gemcitabine in advanced pancreatic cancer: A meta-analysis. Dig Liver Dis 2014;46:452-9.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]