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Keywords:

  • cancer;
  • gemcitabine;
  • meta-analysis;
  • thromboembolic events

Abstract

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References

Aims

Gemcitabine has been associated with an increased risk of arterial and venous thromboembolic events (ATEs and VTEs), although the overall risk remains unclear. As indications for its use in oncology are expanding, a comprehensive characterization of these complications becomes imperative.

Methods

Pubmed was searched for articles published from 1 January 1990 to 31 December 2012. Eligible studies included prospective randomized controlled phase II and III trials evaluating gemcitabine based vs. non-gemcitabine based chemotherapy in patients with solid tumours. Data on VTEs and ATEs were extracted. Overall incidence rates, odds ratio (OR), and 95% confidence intervals (CIs) were calculated employing fixed or random effects models depending on the heterogeneity of included trials.

Results

A total of 4845 patients from 19 trials were included. Among patients treated with gemcitabine based chemotherapy, the overall incidence of VTEs (13 studies comprising 3823 patients) and ATEs (eight studies consisting of 2431 patients) was 2.1% (95% CI 1.2%, 3.8%) and 2.2% (95% CI 1.4%, 3.2%). The associated ORs of VTEs and ATEs were 1.56 (95% CI 0.86, 2.83, P = 0.15) and 1.82 (95% CI 0.89, 3.75, P = 0.10) compared with non-gemcitabine based therapy. A tendency to increase the risk of ATE and VTEs was also detected in any prespecified subgroup.

Conclusion

The use of gemcitabine does not significantly increase the risk of VTEs and ATEs in patients with solid tumours when compared with non-gemcitabine based chemotherapy.


What is Already Known about this Subject

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References
  • Gemcitabine has been associated with an increased risk of arterial and venous thromboembolic events (ATEs and VTEs), but the overall incidence and risk of developing thromboembolic events is still unknown.

What this Study Adds

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References
  • Our study for the first time demonstrates that the use of gemcitabine has a tendency to increase the risk of VTEs and ATEs in patients with solid tumours when compared with non-gemcitabine based chemotherapy.

Introduction

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References

Venous and arterial thromboembolic events (VTEs and ATEs) are a major source of morbidity and mortality for cancer patients [1-3]. The importance of cancer-associated thrombosis comes from the fact that it is exceedingly common in cancer patients. It is reported that appropriately one fifth of all VTEs occur in cancer patients and the ones who develop thromboembolic events have a worse prognosis and an increased risk of death [1, 4]. Several clinical characteristics have been associated with increased risk of developing thromboembolic events in patients with cancer, including more advanced disease, systematic chemotherapy, anti-angiogenic therapy, multiple comorbidities and concomitant medications [5-9].

Among chemotherapeutic agents, gemcitabine based regimens particularly have been associated with a wide range of thromboembolic complications [10]. However, this association is mostly based on case reports, single arm prospective studies and retrospective analyses [11-17]. For example, in one prospective study of 108 patients with advanced non-small-cell lung cancer (NSCLC) who underwent chemotherapy with gemcitabine and cisplatin, 22 thromboembolic events occurred in 19 patients (17.6%, 95% CI 10.3, 24.8%), including 10 ATEs (two myocardial infarctions, seven lower limb arterial thrombosis and one ischaemic stroke) and 12 VTEs (three catheter-related upper limb venous thromboembolic events, six venous thrombosis of the lower limb and three pulmonary embolic episodes) [13]. As gemcitabine represents an important contemporary chemotherapeutic agent and the indications for its use in oncology have been expanding, a comprehensive characterization of these complications becomes imperative. Therefore, we performed a systematic review and meta-analysis of randomized controlled trials to evaluate the incidence and odds ratio (OR) of VTEs and ATEs in cancer patients receiving gemcitabine based vs. non-gemcitabine based chemotherapy.

Methods

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References

Data source

The selection and systematic review of trials was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [18]. Trials were selected from those published in PubMed between 1 January 1990, and 31 December 2012, with ‘gemcitabine,’ ‘cancer,’ ‘carcinoma’ and ‘randomized clinical trial’ as keywords. Only trials published in peer-reviewed publications in full manuscript form in English were eligible. Only the most recent publication was included when duplicates were identified. We also reviewed the reference lists of the original and review articles to identify relevant studies.

Study selection

Our primary objective was to evaluate the association between treatment with gemcitabine based therapy and risk of VTEs and ATEs in patients with cancer. Clinical trials meeting the following criteria were included in the meta-analysis: 1) prospective randomized controlled phase II or III trial of cancer patients, 2) random assignment of participants to treatment with gemcitabine or non-gemcitabine containing therapy and 3) available data on all grade VTEs or ATEs. The quality of reports of clinical trials was assessed and calculated using the five item Jadad scale including randomization, double-blinding and withdrawals as previously described [19].

Data extraction and clinical end point

Data extraction was conducted independently by two investigators (WXQ and ZS) and any discrepancy between the reviewers was resolved by consensus. For each study, the following information was extracted: author, publication year, trial phase, treatment arms, number of patients enrolled, number evaluable for toxicity, underlying malignancy, median age, median treatment duration, median progression free survival, adverse outcomes of interest (VTEs and ATEs), gemcitabine dosage (mg m−2) and schedules used. The following adverse outcomes were considered as VTEs/ATEs and included in the main analysis: thrombosis/thrombus/embolism (excluded vascular access related-thrombosis if reported separately), arterial thrombosis, cerebral infarct, cerebral ischaemia, cerebrovascular accident, myocardial infarction and myocardial ischaemia. Phlebitis (including superficial thrombosis) was initially included and subsequently extracted from analysis to observe if it led to different results of the main comparisons. We assessed and recorded adverse events according to the National Cancer Institute's common toxicity criteria (version 2 or 3), which has been adopted widely in cancer clinical trials [20].

Statistical analysis

All analyses were performed using Stata version 12.0 software (Stata Corporation, College Station, TX, USA) and Open Meta-Analyst software version 4.16.12 (Tufts University). For the calculation of incidence, the number of patients with ATEs/VTEs and the number of patients receiving gemcitabine were extracted from the selected clinical trials. The proportion of patients with ATEs/VTEs and 95% confidence interval (CI) were derived for each study. For the calculation of the OR, patients assigned to gemcitabine based therapy were compared only with those assigned to control treatment in the same trial. We used the Peto method to calculate ORs and 95% CIs because this method provides the best confidence interval coverage and is more powerful and relatively less biased than the fixed or random effects analysis when dealing with low event rates [21]. Between study heterogeneity was estimated using the χ2-based Q test and I2 statistic [22]. Heterogeneity was considered statistically significant when Pheterogeneity < 0.1 or I2 > 50%. If heterogeneity existed, data were analyzed using a random effects model (DerSimonian Larid method). In the absence of heterogeneity, a fixed effects model was used. A two-sided P value less than 0.05 was considered significant. Prespecified subgroup analyses were performed according to tumour type, phase of trials, publication year or ethnicity. The presence of publication bias was evaluated by using the Begg and Egger tests [23, 24]. The trim and fill method was also used to explore potential biases.

Results

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References

Our search yielded 1457 publications describing the use of gemcitabine, and 19 RCTs were finally included in the meta-analysis. The selection process is summarized in Figure 1. In total, 4845 patients were investigated in these trials and they had a variety of cancers: NSCLC (13 trials) [25-37], breast cancer (three trials) [38-40], pancreatic cancer (two trials) [41, 42] and head and neck cancer (one trial) [43]. Sample sizes were in the range of 52 to 620 patients, with five trials including >400 patients each. According to the inclusion criteria of each trial, patients were required to have adequate renal, hepatic and haematologic function. The median age of study participants was in the range of 54–77 years (some studies only reported the mean age). The quality of 19 included trials was moderate and the median Jadad score was 2 (range = 2–3). None of the included trials was a double-blind randomized placebo controlled trial. Six trials did not mention the blinding of allocation clearly in the randomization process and thus had Jadad scores of 3. Thirteen trials did not mention the blinding of allocation clearly in the randomization process, and did not mention the concealment of allocation and thus had Jadad scores of 2. Table 1 reports the study and patient characteristics for the included trials.

figure

Figure 1. Selection process for randomized controlled trials included in the meta-analysis

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Table 1. Characteristics of 19 randomized controlled clinical trials included in the meta-analysis
Author/yearPhaseUnderlying malignanciesPatients enrolledTreatment armMedian age (years)Median treatment duration (months/cycles)Median PFS/TTF (months)Number of patients for analysisNumber of VTEsNumber of ATEsJadad score
  1. ATE, arterial thromboembolic event; BEV, bevacizumab; CBP, carboplatin; CDDP, cisplatin; CPT-11, irinotecan; DOC, docetaxel; GEM, gemcitabine; IFO, ifosfamide; L-OHP, oxaliplatin; MBC; metastatic breast cancer; NR, not reported; NSCLC, non-small-cell lung cancer; NVB, vinorelbine; PEM, pemetrexed; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PTX, paclitaxel; q.4.w., every 4 weeks; q.3.w., every 3 weeks; qd, every day; SOR, sorafenib; TTF, time-to-treatment failure; VTE, venous thromboembolic event.

Sandler et al. 2000 [25]IIINSCLC522GEM 1000 mg m−2 + CDDP q.4.w.624 cycles5.6260NR42
CDDP q.4.w.634 cycles3.7262NR1
Scagliotti et al. 2002 [26]IIINSCLC620GEM 1000 mg m−2 + CDDP q.4.w.639.44.6197142
PTX+CBP q.4.w.628.74.619421
NVB+CDDP q.4.w.638.23.819821
Sculier et al. 2002 [24]IIINSCLC284GEM 1000 mg m−2 + CDDP+CBP q.4.w.NRNR86 days92NR42
IFO+GEM q.4.w.NRNR84 days94NR0
CDDP+IFO+CBP q.4.w.NRNR84 days94NR3
Comella et al. 2004 [28]IINSCLC264GEM 1200 mg m−2 q.4.w.753 cycles3.368NR23
PTX q.4.w.723 cycles3.763NR3
GEM 1000 mg m−2 + NVB q.3.w.723 cycles4.168NR1
GEM+PTX q.3.w.733 cycles4.565NR3
Georgoulias et al. 2005 [29]IIINSCLC413GEM 1000 mg m−2 + DOC q.3.w.634 cyclesNR197NR12
NVB+DDP q.3.w.644 cyclesNR192NR0
Lutz et al. 2005 [41]IIPancreatic cancer96GEM 800 mg m−2 + DOC q.3.w.584 cycles3.9451NR2
TXT+DDP q.3.w.594 cycles2.8440NR
Tan et al. 2005 [30]IIINSCLC316GEM 1000 mg m−2 + NVB q.3.w.594 cycles3.91545NR2
NVB+CBP q.3.w.604 cycles4.41551NR
Fountzilas et al. 2006 [43]IIHead and neck cancer166GEM 1000 mg m−2 + PTX q.3.w.63NR4.485NR32
PTX+PLD q.3.w.65NR6.081NR1
Leong et al. 2007 [31]IINSCLC135GEM 800 mg m−2 q.4.w.722 cycles3.42431NR2
NVB q.4.w.732 cycles2.99450NR
TXT q.4.w.722 cycles2.78461NR
Martin et al. 2007 [38]IIIMBC252GEM 1200 mg m−2 + NVB q.3.w.586 cycles6.01231NR3
NVB q.3.w.574 cycles4.01252NR
Ohe et al. 2007 [32]IIINSCLC602GEM 1000 mg m−2 + CDDP q.3.w.61NR3.21510NR2
PTX+CBP q.3.w.63NR3.21480NR
CPT-11 + CDDP q.4.w.62NR3.31470NR
NVB+CDDP q.3.w.61NR3.01461NR
Brufsky et al. 2011 [39]IIMBC191GEM 1500 mg m−2 + PTX+BEV q.4.w.55.26 cycles11.3935NR3
PTX+BEV q.4.w.57.56 cycles8.8943NR
Kosmidis et al. 2011 [33]IIINSCLC398GEM 1000 mg m−2 + PTX q.3.w.594 cycles5.01851NR3
PTX+NVB q.4.w.623 cycles4.41851NR
Seidman et al. 2011 [40]IIIMBC475GEM 1000 mg m−2 + DOC q.3.w.576 cycles6.72374NR2
CAP+DOC q.3.w.546 cycles5.12261NR
Weissman et al. 2011 [34]IIINSCLC383GEM 1000 mg m−2 + L-OHP q.3.w.634 cycles4.441840NR3
CBP+PTX q.3.w.644 cycles4.671871NR 
EI-Khoueiry et al. 2012 [42]IIPancreatic cancer52GEM 1000 mg m−2 + SOR q.4.w.652 cycles2.3373NR2
SOR qd.662 cycles2.9150NR
Han et al. 2012 [35]IIINSCLC313GEM 1250 mg m−2 + DDP q.3.w.56.56 cycles6.41501NR3
Gefitinib qd.57163 days5.81590NR 
Spigel et al. 2012 [37]IINSCLC110GEM 1500 mg m−2 + PEM+BEV q.4.w.762.5 cycles4.755412
PEM+CBP+BEV q.3.w.776 cycles10.25540
Price et al. 2012 [36]IINSCLC111GEM 100 mg m−2 + Radiotherapy74NRNR55NR12
Radiotherapy75NRNR56NR0

Incidence of VTEs and ATEs

A total of 3823 patients (13 trials) were considered for the incidence analysis of VTEs. In the gemcitabine group, 27 patients experienced VTEs compared with 19 patients in the non-gemcitabine group. The highest incidence (8.1%; 95% CI 2.6%, 22.3%) was observed in a phase II pancreatic cancer trial [42] and the lowest incidence was observed in two trials in which no VTEs occurred [32, 34]. Using a random effects model (heterogeneity test: Q = 25.164, P = 0.014, I2 = 52%), the summary incidence of VTEs in patients receiving gemcitabine based therapy was 2.1% (95% CI 1.2%, 3.8%, Figure 2).

figure

Figure 2. Incidence of venous thromboembolic events associated with gemcitabine

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A total of 2431 patients (eight trials) were considered for the incidence analysis of ATEs. 24 patients experienced ATEs compared with 19 patients in the non-gemcitabine group. The highest incidence (3.5%; 95% CI, 1.1%–10.4%) was observed in a phase II head and neck cancer trial [43], and the lowest incidence (0.5%; 95%CI: 0.1%–3.5%) was observed in a phase III NSCLC trial [29]. Using a fixed-effects model (heterogeneity test: Q = 4.062; P = 0.773; I2 = 0%), the summary incidence of ATEs in patients receiving gemcitabine based therapy was 2.2% (95% CI, 1.4%–3.2%, Figure 3).

figure

Figure 3. Incidence of arterial thromboembolic events associated with gemcitabine

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Odds ratio of VTEs and ATEs

To investigate the specific contribution of gemcitabine to the development of ATEs/VTEs and exclude the influence of confounding factors such as underlying malignancy, and other therapeutic interventions, we determined the OR of gemcitabine associated VTEs and ATEs. The combined results demonstrated that the use of gemcitabine did not significantly increase the risk of developing VTEs (Peto OR 1.56, 95% CI 0.86, 2.83, P = 0.15, Figure 4) using a fixed effect model (I2 = 0%, P = 0.91). Similar results in the risk of VTEs were also detected in subgroup analysis according to tumour type, phase of trials, publication year or ethnicity. In addition, the highest OR of VTEs was observed in pancreatic cancer patients with OR of 5.03 (95% CI 0.59, 42.62, P = 0.138), but the differences among tumour types were not statistically significant (Table 2).

figure

Figure 4. Relative risk of venous thromboembolic events associated with gemcitabine based vs. non-gemcitabine based therapy

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Table 2. Odds ratio of VTEs based on prespecified subgroups
GroupSubgroupNumber of trialsVTEs, Number/total numberI2(%)Odds ratio (95% CI)P for odds ratioP for group difference
GemcitabineNon-gemcitabine
  1. MBC, metastatic breast cancer; NA, not available; NSCLC, non-small-cell lung cancer.

Overall 1327/165419/216901.56 (0.86, 2.83)0.145NA
Tumour typeNSCLC813/111913/166501.27 (0.57–2.82)0.5540.895
Pancreas24/820/5905.03 (0.59, 42.62)0.138 
MBC310/4536/44501.66 (0.62, 4.47)0.318 
Phase of trialsPhase II514/2738/29901.72 (0.72, 4.10)0.2240.790
Phase III813/138111/187001.43 (0.63, 3.24)0.392 
Publication year2000–200537/3965/59101.91 (0.60, 6.12)0.2760.761
2006–20121020/125814/157801.45 (0.72, 2.90)0.295 
EthnicsAsian36/4552/75503.27 (0.79, 13.48)0.1010.553
Non-Asian1021/119917/141401.33 (0.69, 2.56)0.398 

Eight randomized trials were available to calculate the OR of ATEs. The meta-analysis showed that the summary OR of ATEs in gemcitabine based vs. non-gemcitabine based therapy was a non-significant 1.82 (95% CI 0.89, 3.75, P = 0.10, Figure 5). The test for heterogeneity was not significant (I2 = 0%, P = 0.59). Additionally, a tendency to increase the risk of ATE was also detected in prespecified subgroups according to tumour type, phase of trials or publication year (Table 3).

figure

Figure 5. Relative risk of arterial thromboembolic events associated with gemcitabine based vs. non-gemcitabine based therapy

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Table 3. Odds ratio of ATEs based on prespecified subgroups
GroupSubgroupNumber of trialsATEs, Number/total numberI2(%)Odds ratio (95% CI)P for odds ratioP for group difference
GemcitabineNon-gemcitabine
  1. ATE, arterial thrombosis events; NA, not available; NSCLC, non-small-cell lung cancer.

Overall 824/123610/119501.82 (0.89, 3.75)0.102NA
Tumour typeNSCLC721/11519/111401.72 (0.80, 3.73)0.1680.868
Head and neck cancer13/851/8102.93 (0.30, 28.73)0.326 
Phase of trialsPhase II411/3964/25501.43 (0.47, 4.39)0.5280.640
Phase III413/8406/94052.16 (0.84, 5.54)0.108 
Publication year2000–2005519/10419/1003211.52 (0.68, 3.41)0.3060.631
2006–201235/1951/19203.75 (0.75, 18.75)0.108 

Sensitivity analysis

Sensitivity analyses using an empirical continuity correction [21] (fixed Mantel-Haenszel OR for VTEs: 1.62, 95% CI 0.94, 2.78; OR for ATEs: 1.60, 95% CI 0.83, 3.08), with a continuity of 0.5 correction (fixed Mantel-Haenszel OR for VTEs: 1.50, 95% CI 0.84, 2.69; OR for ATEs: 1.67, 95% CI 0.84, 3.35), or without a continuity correction (fixed Mantel-Haenszel OR of VTEs: 1.59, 95% CI 0.86, 2.95; OR for ATEs: 1.77, 95% CI 0.85, 3.68) showed results similar to those of the primary analysis (Table 4).

Table 4. Sensitivity analyses for the outcome of VTEs and ATEs
FactorsSensitivity analysisStatistical modelOR (95% CI)
  1. ATEs, arterial thrombosis events; CI, confidence interval; MH, Mantel-Haenszel test; VTEs, venous thrombosis events.

VTEsEmpirical continuity correctionFixed (MH)1.62 (0.94, 2.78)
No continuity correctionFixed (MH)1.59 (0.86, 2.95)
A continuity correction of 0.5Fixed (MH)1.50 (0.84, 2.69)
ATEsEmpirical continuity correctionFixed (MH)1.60 (0.83, 3.08)
No continuity correctionFixed (MH)1.77 (0.85, 3.68)
A continuity correction of 0.5Fixed (MH)1.67 (0.84, 3.35)

Publication bias

No evidence of publication bias was detected for the OR of VTEs and ATEs in this study by either Begg or Egger's test (OR of VTEs: Begg's test P = 0.542; Egger's test P = 0.568; OR of ATEs: Begg's test P = 0.142; Egger's test P = 0.256). Analogously, the trim and fill analysis did not show a publication bias for VTE and ATE events.

Discussion

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References

Our meta-analysis is the first, to the best of our knowledge, to explore the risk of thromboembolic events associated with gemcitabine. The combined analysis of data from randomized controlled trials shows that the use of gemcitabine has a tendency to increase the risk of VTEs and ATEs in cancer patients when compared with non-gemcitabine based therapy. Additionally, the overall incidence of gemcitabine associated VTEs and ATEs is 2.1% (95% CI 1.2%, 3.8%) and 2.2% (95% CI 1.4%, 3.2%), respectively. A tendency to increase the risk of ATE and VTEs was also detected in any prespecified subgroup.

One possible explanation for this finding is the under-reporting of VTEs and ATEs. Because clinical trials with gemcitabine are usually not designed specifically to address toxic events, the number of cancer trials reporting these vascular events is very low. In our search, 88.4% of prospective clinical trials were excluded because data on thromboembolic events was unavailable. In addition, thromboembolic events are usually under-diagnosed because they are asymptomatic at presentation and therefore, often diagnosed incidentally. Another possible explanation for this finding is that a relatively small number of patients were included in our study and thus there is lack of statistical power to demonstrate a significant difference. As a result, more high quality randomized controlled trials are still needed to investigate whether gemcitabine is associated with VTEs and ATEs.

The pathogenesis of gemcitabine-induced thrombogenicity remains unclear, although several studies have suggested potential mechanisms. Gemcitabine-induced thrombocytopenia and thrombocytosis may be directly related to the increased risk of thromboembolic events, because either one of these adverse events may be important in overwhelming the regulatory mechanisms and overturning the balance towards thrombophilia [10]. Gemcitabine may also be capable of coagulation cascade activation and possibly endothelial damage [17]. However, the precise mechanism by which gemcitabine induces a shift towards the procoagulant state remains to be clarified.

Currently, the international guidelines do not recommend routine VTE prophylaxis during chemotherapy in outpatient settings [44]. Some recent data suggest that low molecular weight heparin prophylaxis can reduce the risk of VTE in patients with certain types of cancer [45]. Our data of a non-significantly increased risk of VTEs with gemcitabine used in solid tumours could be used as the basis for testing thromboprophylaxis in an appropriate clinical trial setting.

Our meta-analysis has several limitations. First, this meta-analysis is not based on individual patient data and meta-analyses based on published data tend to overestimate treatment effects compared with individual patient data analyses. In addition, it precludes a more comprehensive analysis such as adjusting for baseline factors and other differences that exist between the trials from which the data are pooled. Secondly, there are potentially important differences among the included studies, including differing dosage, administration schedule and infusion duration of gemcitabine, periods of study conduct and study investigators. All of these could possibly impact on gemcitabine-related thrombosis events and increase the clinical heterogeneity among included trials. Additionally, our study includes a mixed population of patients treated with a gemcitabine based combination (including platinum, capecitabine, paclitaxel, docetaxel, irinotecan, bevacizumab, pemetrexed and vinorebline) therapy or gemcitabine alone, It is possible that the concomitant administration of other drugs (such as the combination with bevacizumab or platinum) in a few of the trials may have contributed to a higher risk of VTEs and ATEs. Indeed, previous meta-analyses have demonstrated that the use of bevacizumab or platinum in cancer patients is associated with an increased risk of thrombotic events [9, 46]. Therefore, all of these would increase the heterogeneity and make the interpretation of the results more problematic. Thirdly, these studies were conducted at various international institutions by different investigators and may have potential bias in reporting the types of adverse events. In particular, the frequency of VTEs is under-reported in clinical trials. Trials which reported zero VTEs and ATEs in one or both arms were also included for analysis. In this setting, using fixed effects models and continuity corrections would bias the results towards null. However we feel that including trials reporting zero VTEs and ATEs would provide the most conservative estimate. Finally, the included studies were conducted at major academic institutions among patients with adequate major organ function and may not reflect the general patient population in the community or patients with organ dysfunction. It could be that thrombosis is more frequent in a ‘real-life’ setting, as a retrospective cohort analysis showed [47].

Conclusion

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References

In conclusion, with the present evidence, the use of gemcitabine does not increase the risk of VTEs and ATEs in patients with solid tumours when compared with non-gemcitabine based chemotherapy.

Competing Interests

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

References

  1. Top of page
  2. Abstract
  3. What is Already Known about this Subject
  4. What this Study Adds
  5. Introduction
  6. Methods
  7. Results
  8. Discussion
  9. Conclusion
  10. Competing Interests
  11. References
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