Main

Advanced pancreatic cancer has a poor prognosis, with a median survival of 2–6 months for metastatic disease and 6–11 months for locally advanced disease (Cancer Research, 2006). Chemotherapy with fluoropyrimidines, gemcitabine, either alone or in combination with other agents (Rocha Lima and Flores, 2006), and chemoradiation are all used in the palliative setting (Mancuso et al, 2006). Overall survival meta-analyses, using relative risk (Yip et al, 2006) or the hazard ratio (HR) (Fung et al, 2003; Sultana et al, 2007), have established a role for chemotherapy over best supportive care. Questions have arisen as to the cost at which this survival advantage is gained, in particular, the toxicity profile. Following from our previous survival meta-analysis (Sultana et al, 2007), we present the results of the secondary outcome measures meta-analysis.

There has only been one fully published meta-analysis evaluating secondary outcome measures, with no pooling of the results of these end points (Yip et al, 2006). Other published reports have assessed this only for the comparison of gemcitabine combinations vs gemcitabine. (Liang, 2005; Milella et al, 2006; Heinemann et al, 2006a; Xie et al, 2006a, 2006b; Bria et al, 2007; Heinemann et al, 2007). To fully evaluate the risks vs the benefits of treatment, a comprehensive evaluation including assessment of several composite end points is required.

Methods

Detailed description of the methodology of the systematic review has already been described (Sultana et al, 2007).

The secondary outcome measures evaluated were progression-free survival (PFS – time from randomisation to progression or death) or time to progression (TTP – time from randomisation to disease progression), overall response rate (ORR – number of partial and complete responses) and toxicity (as published by the trialists, was recorded, with the most frequently reported events analysed).

Individual trial level time to event data (PFS/TTP) were summarised by the log HR and its variance was approximated using previously reported methods (Parmar et al, 1998; Williamson et al, 2002). Trial level log HRs and their variances were pooled using an inverse variance, weighted average and results presented as a HR and 95% confidence interval.

Dichotomous data (ORR and toxicity) were summarised using relative risks and 95% confidence intervals and pooled using the Mantel–Haenszel method for combining trials (Deeks et al, 2001). Heterogeneity was assessed by visual inspection of the Forrest plot, the Cochran's χ2 test (using a 10% significance level, in view of the low power of tests for heterogeneity (Paul and Donner, 1992)) and interpretation of the I2 statistic (percentage of variation due to heterogeneity with higher values indicating a greater degree of heterogeneity) (Deeks et al, 2004). A fixed effect approach was adopted unless there was evidence of significant unexplained heterogeneity in which case a random effects approach was used.

Results

Results are presented for the comparisons with adequate data to assess the secondary outcome measures.

5FU vs 5FU combination chemotherapy

There were five studies (Supplementary Table 1) (Kovach et al, 1974; Cullinan et al, 1985, 1990; Ducreux et al, 2002; Maisey et al, 2002) (n=700) included in this comparison. A HR of <1 indicates a survival advantage for 5FU combination chemotherapy.

Two trials assessed TTP (Figure 1) and found no significant advantage for 5FU combinations over 5FU alone (HR=1.02; 95% CI=0.85–1.23). For PFS, 5FU combination appeared better than 5FU alone (two trials; 416 patients; HR=0.67; 95% CI=0.46–0.98). The ORR (Figure 2) was superior (five trials; 700 patients; RR=0.43; 95% CI=0.25–0.74) in the 5FU combination arm. Grade 3 or 4 vomiting was significantly greater in the 5FU combination chemotherapy arm (two trials; 320 patients; RR=3.76; 95% CI=1.67–8.44). There was a higher occurrence of diarrhoea (two trials 406 patients; RR=1.49; 95% CI=0.58–3.84), stomatitis (three trials; 529 patients; RR=1.29; 95% CI=0.75–2.22) and thrombocytopenia (two trials; 332 patients; RR=2.15; 95% CI=0.83–5.53) in the combination chemotherapy arm (Figure 3). Data for leucopenia, neutropenia, anaemia and nausea are displayed in Figure 3. There was significant between trial heterogeneity in the PFS analysis, unlike for the TTP and response rate analyses.

Figure 1
figure 1

5FU single agent vs 5FU-based combination chemotherapy – PFS/TTP analyses.

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Figure 2
figure 2

5FU single agent vs 5FU-based combination chemotherapy – response rate analyses.

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Figure 3
figure 3

5FU single agent vs 5FU-based combination chemotherapy – toxicity analyses.

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Gemcitabine vs 5FU

Two randomised controlled trials involving 197 patients were assessed (Burris et al, 1997; Cantore et al, 2004), including unpublished individual patient data (Cantore et al, 2004). A HR of <1 indicates a survival advantage for gemcitabine. Gemcitabine resulted in survival advantage on TTP analysis, (HR=0.46; 95% CI=0.31–0.70), but not for PFS analysis (HR=0.94; 95% CI=0.58–1.53).

Overall response rate appeared better in the gemcitabine arm; however, the wide confidence interval suggests a benefit for either gemcitabine or 5FU (one trial; 126 patients; RR=0.14; 95% CI=0.01–2.66). In the Burris trial (Burris et al, 1997), haematological toxicity was seen more frequently following gemcitabine therapy (grades 3 and 4 neutropenia in 25% of gemcitabine and 4.9% of 5FU patients; P<0.001).

Gemcitabine vs gemcitabine-based combination chemotherapy

Nineteen studies involving 4697 patients were included (Supplementary Table 2) (Berlin et al, 2002; Colucci et al, 2002; Wang et al, 2002; Heinemann et al, 2003; Scheithauer et al, 2003; Li and Chao, 2004; Ohkawa, 2004; Rocha Lima et al, 2004; Viret et al, 2004; Cunningham et al, 2005; Di Costanzo et al, 2005; Hermann et al, 2005; Louvet et al, 2005; Oettle et al, 2005; Reiss et al, 2005; Reni et al, 2005; Stathopoulos et al, 2005; Abou-Alfa et al, 2006; Poplin et al, 2006). Data from four of the included studies (Abou-Alfa et al, 2006; Heinemann et al, 2006b; Stathopoulos et al, 2006; Herrmann et al, 2007) were based on abstracts and extra data provided by the authors (Hermann et al, 2005; Stathopoulos et al, 2005). A HR of <1 indicates a survival advantage for gemcitabine-based combination chemotherapy.

Progression-free survival (four trials; 864 patients; HR=0.78; 95% CI=0.70–0.88), TTP (3 trials; 559 patients; HR=0.85; 95% CI=0.72–0.99) (Figure 4) and ORR (Figure 5) (17 trials; 3577 patients; RR=0.56; 95% CI=0.46–0.68) were significantly better in the gemcitabine combination chemotherapy arm. Haematological toxicity was greater in the gemcitabine combination chemotherapy arm (Figure 6), including thrombocytopenia (18 trials; 4564 patients; RR=1.94; 95% CI=1.32–2.84), leucopenia (eight trials; 1606 patients; RR=1.46; 95% CI=1.15–1.86), neutropenia (15 trials; 3818 patients; RR=1.48; 95% CI=1.07–2.05) and anaemia (15 trials; 3745 patients; RR=1.14; 95% CI=0.82–1.59). Gastrointestinal side effects (Figure 7) of nausea (nine trials; 3055 patients; RR=1.77; 95% CI=1.37–2.29), vomiting (10 trials; 3471 patients; RR=1.64; 95% CI=1.24–2.16) and diarrhoea (14 trials; 3531 patients; RR=2.73; 95% CI=1.87–3.98) were significantly increased, with a trend towards increased stomatitis (7 trials; 2007 patients; RR=1.84; 95% CI=0.86–3.92) in the gemcitabine combination chemotherapy arm. There was no significant inter-trial heterogeneity for the end points of PFS, TTP and ORR.

Figure 4
figure 4

Results for gemcitabine vs gemcitabine-based combination chemotherapy – TTP/PFS.

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Figure 5
figure 5

Results for gemcitabine vs gemcitabine-based combination chemotherapy – response rate.

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Figure 6
figure 6

Results for gemcitabine vs gemcitabine-based combination chemotherapy – haematological toxicity.

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Figure 7
figure 7

Results for gemcitabine vs gemcitabine-based combination chemotherapy – gastrointestinal toxicity.

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Examination of the funnel plots revealed evidence of bias, possibly publication bias, but this is difficult to interpret in view of the small number of studies within each comparison.

Discussion

5FU combinations did not prolong TTP over 5FU alone, despite significantly better response rate with the former. The study of Yip et al (2006) assessed the parameters described in our analyses, but did not pool the results unlike our approach. In the two trials that had assessed PFS, the overall summary estimate favoured 5FU combination chemotherapy, but there was significant inter-trial heterogeneity. This may be due to the differences in dosing. The dose of 5FU administered was lower in the Maisey et al (2002) study (300 mg m−2 day−1 in both arms) compared to the Ducreux et al (2002) study (500 mg m−2 day−1 used in the single-agent arm and 1000 mg m−2 used in the combination arm).

As overall survival is a better indicator of efficacy than response rate (Maisey et al, 2002), the evidence from these end points, interpreted alongside the overall survival result (Sultana et al, 2007), do not support the use of 5FU combinations over 5FU single agent.

Meta-analyses of the secondary end points were not possible in the gemcitabine vs 5FU comparison, as these results were only available for one randomised trial.

Previous meta-analyses of secondary end points evaluating gemcitabine-based combinations vs gemcitabine employed differing survival analyses methodology (Liang, 2005; Heinemann et al, 2006a; Milella et al, 2006; Xie et al, 2006a). In contrast to these reports, our survival analyses were conducted using the HR, which is the ideal measure for time-to-event analyses, as it accounts for both censoring of data and the time it takes for the event (such as death or progression) to occur (Parmar et al, 1998).

For gemcitabine-based chemotherapy vs gemcitabine alone, our findings of improved PFS/TTP are in agreement with the meta-analyses of Xie et al (2006b). Better ORR with the combination regimens was in keeping with the studies of Xie et al and Milella et al (Xie et al, 2006b), while increased toxicity profile was noted by Xie et al (2006b). The meta-analyses that examined gemcitabine plus a platinum agent vs gemcitabine alone found better PFS/TTP in the combination arm (Xie et al, 2006a; Heinemann et al, 2007), significant improvement in ORR (Heinemann et al, 2007) and greater toxicity (Xie et al, 2006a).

We have done our utmost to cover most reported end points in the randomised controlled trials. We could not address quality of life due to the different methods used for reporting quality of life. Although we have pooled the response rate and adverse events data across studies to permit a clinically relevant analysis, reporting of these parameters varied. Response rates were reported using clinical parameters, the WHO and RECIST criteria, whereas the CTC, WHO and ECOG scales were used for toxicity data.

To conclude, there is insufficient evidence to suggest a TTP, response rate and toxicity advantage in administering 5FU in combination with other chemotherapy agents over 5FU alone. There is a small but significant TTP/PFS advantage, as well as improved response rate, with gemcitabine-based combinations, and this provides a justification for the use of these agents, despite their greater toxicity. An area for further randomised controlled trials to assess is which gemcitabine-based combination chemotherapy regimens are least toxic, while retaining all the other advantages of the combination approach.