Annals of Oncology Advance Access originally published online on July 28, 2007
Annals of Oncology 2007 18(10):1652-1659; doi:10.1093/annonc/mdm283
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© 2007 European Society for Medical Oncology
gastrointestinal tumors |
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
1 Medical Clinic III, Klinikum Grosshadern, Munich, Germany
2 Ospedali Riuniti, Bergamo, Italy
3 Wissenschaftlicher Service Pharma, Langenfeld, Germany
4 Service d'Oncologie, Médecine Interne, Hôpital St. Antoine, Paris, France
* Correspondence to: Dr V. Heinemann, Medical Clinic III, Klinikum Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany. Tel: +49-89-7095-0, Fax: +49-89-7095-5257; E-mail: Volker.Heinemann{at}med.uni-muenchen.de
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Abstract |
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Background: The aim was to evaluate the efficacy of gemcitabine combined with a platinum agent compared to single-agent gemcitabine in a pooled analysis of two randomized trials.
Methods: The French Multidisciplinary Clinical Research Group (GERCOR)/Italian Group for the Study of Gastrointestinal Tract Cancer (GISCAD) intergroup study comparing gemcitabine plus oxaliplatin to gemcitabine and a German multicenter trial comparing gemcitabine plus cisplatin versus gemcitabine were included in a pooled analysis based on individual patient data.
Results: Among 503 evaluable patients, 252 received gemcitabine plus a platinum analog (GP), while 251 patients were treated with gemcitabine alone. For progression-free survival (PFS), the pooled univariate analysis indicated a hazard ratio (HR) of 0.75 (P = 0.0030) in favour of the GP combination. The benefit from the GP combination was greatest in the subgroup of patients with performance status (PS) = 0 (HR = 0.64; P = 0.013). Also overall survival was significantly superior in patients receiving the GP combination (HR = 0.81; P = 0.031). Again, patients with PS = 0 appeared to have a greater benefit from treatment intensification (HR = 0.72; P = 0.063).
Conclusion: The pooled analysis of the GERCOR/GISCAD intergroup study and the German multicenter study indicates that the combination of gemcitabine with a platinum analog such as oxaliplatin or cisplatin significantly improves progression-free survival and overall survival as compared to single-agent gemcitabine in advanced pancreatic cancer. The benefit seems to prevail in patients with a good performance status.
Key words: cisplatin, combination therapy, gemcitabine, oxaliplatin, pancreatic cancer, prognostic factors
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introduction |
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The prognosis of pancreatic cancer remains dismal for most patients. Due to its predominantly late diagnosis, most patients are diagnosed with metastatic disease at first presentation [1, 2]. Without effective treatment, these patients have a median survival of only 3 to 4 months, while locally advanced, non-metastatic disease is associated with a median survival of 6 to 10 months. Systemic chemotherapy with single-agent gemcitabine at present is regarded as a standard of care for treatment of locally advanced and metastatic pancreatic cancer and consequently serves as a reference treatment in randomized trials [3–5].
To improve therapeutic efficacy, several randomized trials have investigated gemcitabine-based combination regimens. While some studies showed an improvement of response rates and progression-free survival, a significant prolongation of survival has not been achieved when gemcitabine was combined with platinum analogs [6–10], antimetabolites [11–14] or topoisomerase inhibitors [15–17]. So far, only two randomized studies show a significant survival benefit in favour of combination chemotherapy [18, 19].
The combination of gemcitabine with platinum analogs is based on preclinical data indicating that gemcitabine not only increases cisplatin-induced DNA cross-links, but also effectively inhibits their repair. It has also been shown that cisplatin enhances the incorporation of gemcitabine triphosphates into DNA and thereby induces apoptosis of tumor cells [20, 21]. The synergistic cytotoxicity observed in vitro clearly relates to the multiple mechanisms of drug interaction [22, 23]. Phase II and III studies suggest that the combination of gemcitabine and cisplatin (GemCis) is active in pancreatic cancer. First-line treatment of advanced pancreatic cancer with GemCis induced response rates ranging from 9% to 26%, median times to tumor progression of 3.6 to 5.4 months and median survival times of 5.6 to 8.2 months [6, 7, 9, 24–26].
Like cisplatin, oxaliplatin acts as an alkylating agent on DNA, inducing cytotoxic lesions by the formation of intrastrand cross-links [27]. While both agents share a common mechanism of action, they differ with respect to their mechanisms of resistance. In contrast to cisplatin, the activity of oxaliplatin is maintained in mismatch-repair–deficient tumor cells. The rationale for the combined use of gemcitabine and oxaliplatin is based on preclinical data indicating synergistic drug interaction in human cancer cell lines [28]. The combination of gemcitabine with oxaliplatin (GemOx) was shown to be active in a Phase II trial where a progression-free survival of 5.3 months and an overall survival of 9.2 months was reported [29]. These data were essentially confirmed by a subsequent Phase III trial demonstrating that the GemOx combination was superior to single-agent gemcitabine, increasing progression-free survival from 3.7 months to 5.8 months and overall survival from 7.1 months to 9.0 months [8]. The lack of a statistically significant difference in survival may at least in part be explained by the comparably long survival time in the control arm, which may have been influenced by second-line therapy applied in 55% of patients.
Several randomized trials are now available that consistently report the favourable impact of gemcitabine in combination with platinum analogs on the survival of patients with advanced pancreatic cancer [6–9]. Among the largest studies were the French Multidisciplinary Clinical Research Group (GERCOR)/Italian Group for the Study of Gastrointestinal Tract Cancer (GISCAD) intergroup study, comparing GemOx to gemcitabine alone [8], and a German multicenter study comparing GemCis to single-agent gemcitabine [7]. None of these studies had sufficient statistical power to demonstrate a significant survival advantage. This is explained by recent experience that the incremental prolongation of overall survival achieved by combination regimens as compared to single-agent therapy is of only moderate size and—at best—remains in the range of 20%–30%. In view of these limited gains in survival it becomes evident that large patient numbers are necessary to provide an adequate statistical basis. To reach this goal, we therefore combined individual patient data from the GERCOR/GISCAD and the German multicenter trials and performed a pooled analysis.
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methods |
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trials included in the pooled analysis
A pooled analysis using single-patient data was performed. The two largest European trials investigating combinations of gemcitabine with platinum analogs were included in the analysis. The GERCOR/GISCAD intergroup study compared GemOx to gemcitabine and included 326 patients. The German multicenter study compared GemCis to gemcitabine and included 195 patients. Both trials investigated patients with histologically proven, unresectable, locally advanced or metastatic pancreatic cancer. The inclusion and exclusion criteria were comparable and both trials investigated overall survival as a primary end point. In the GERCOR/GISCAD trial, more than 50% of patients received second-line treatment at the time of disease progression. Among these, the majority (74%) of patients in the gemcitabine arm made a crossover to a platinum-based regimen. In the German trial, only 16% of patients received second-line therapy and only 2% of patients crossed to the combination of gemcitabine and cisplatin.
Two additional randomized trials were candidates for an extension of the present pooled analysis to a meta-analysis, but were not included since single-patient data could not be obtained [6, 9]. At the time the analysis was performed, the data from the Eastern Cooperative Oncology Group (ECOG) 6201 trial [10] had not yet been presented and therefore were not included. Since the totality of evidence could not be utilized, the results of the present analysis must be regarded as hypothesis-generating.
statistical design of the pooled analysis
The present report is based on individual patient data. Standard methods for meta-analysis were used in this investigation [30], i.e. applying stratified versions of the contingency table tests for response data and of the log rank test for time-to-event data according to the Mantel–Haenszel technique [31, 32]. The log rank tests were stratified for study group in order to ensure that only patients being randomized against each other were statistically compared. Because of the limited number of trials included, only the fixed-effect model methodology was applied. Prognostic factor analyses were performed as crude comparisons without stratification. All reported P values result from two-sided versions of the respective tests.
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results |
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patient disposition and baseline characteristics
The French/Italian GERCOR/GISCAD trial recruited 326 patients, of whom 313 were eligible for analysis. Reasons for ineligibility were neuroendocrine tumor (two patients), death before treatment initiation (two patients), high bilirubin level at baseline (eight patients) and withdrawal of consent before first cycle (one patient). The German multicenter study included 195 patients, with 190 evaluable patients. Five patients did not receive treatment as per protocol and further follow-up was omitted. This leads to a total number of 503 analysable patients. The distribution of age, gender, performance status (PS) and stage of disease was comparable between the combination and the single-agent groups (Table 1).
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pooled univariate analyses of tumor response rates
In the univariate analysis of the pooled trial results, overall response rates were significantly improved by platinum-based combination therapy as compared to single-agent gemcitabine (22% vs 14%). In the stratified test the odds ratio reached a level of 1.69 (95% CI; 1.06–2.70; P = 0.028). There was a trend towards better tumor response in younger patients and females, while performance status, stage of disease and tumor grading did not have a major effect on response rates (Table 2).
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pooled univariate analyses of progression-free survival
The median progression-free survival (PFS) in the total group of 503 patients amounted to 18 weeks. PFS was slightly longer in the French/Italian trial compared to the German trial (18 vs 16 weeks), which may correspond to the slightly more favourable profile of most prognostic factors. Remarkably, the risk difference between the treatment arms was identical in both study groups (hazard ratio [HR] = 0.75). The borderline significance level between combination and single-agent therapy observed in the individual trials was improved up to a statistically more convincing level of evidence (24 vs 15 weeks; P = 0.0030) in the pooled stratified test (Figure 1). In the prognostic factor analyses, performance status and stage of disease were predominant predictors for PFS, while age, gender and pathological tumor grading did not have major impact (Table 3).
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progression-free survival: subgroups and adjusted comparisons
The effect of treatment on PFS was associated with at least borderline significance in most of the prognostic subgroups defined by age, gender, performance status, extent of disease and tumor grade (Table 4). Corresponding to the excellent balancing of the baseline characteristics, the P values in parentheses show that the test results adjusted for the respective covariates are very similar to the significance level shown above. However, the treatment effect varies considerably from subgroup to subgroup: while the effect of platinum-based combination chemotherapy was considerably greater in the group with locally advanced disease only (35 vs 21 weeks; P = 0.051), the most important interaction was observed with regard to performance status, indicating a clearly greater benefit from combination chemotherapy in patients with a good performance status (33 vs 14 weeks; P = 0.013).
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pooled univariate analysis of overall survival
Median overall survival (OS) of the combined group of 503 patients was 33 weeks (Table 5). Again the French/Italian trial showed a slightly better prognosis corresponding to the more favourable baseline profile. As for PFS, OS also exhibited a high degree of homogeneity between the French/Italian and the German study groups (HR 0.82 and 0.80, respectively). In contrast to the non-significant P values in the individual trials, the pooled stratified test clearly reached the conventional level of significance (HR = 0.81; P = 0.031) (Figure 2). In the prognostic factor analysis neither age nor gender were identified as predictive for OS. Tumor grading had a moderate prognostic impact demonstrating that the more undifferentiated tumors were associated with a trend towards shorter survival. As for PFS, the most important predictors of prognosis were stage of disease (P < 0.0001) and performance status (P < 0.0001).
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overall survival: subgroup comparisons
The conventional significance level was not reached in most of the comparisons due to the loss of power in the subgroups (Table 6). However, the hazard ratios indicate some important differences. While the effect was comparable in both age groups, the present analysis points to a considerably greater effect of treatment intensification in the female population. This may be an artefact, as the HR estimate in males was still within the confidence interval for females. Whereas the treatment effect was rather homogeneous across the subgroups defined by tumor stage and tumor grading, a distinct dissimilarity was seen in the performance status subgroups. The superiority of the combination arm was rather pronounced (and of borderline significance despite the low sample size) in patients with good performance status (ECOG = 0) (OS 52 versus 36 weeks; P = 0.063), while it was of marginal size in patients with an impaired performance status (ECOG = 1 or 2) (OS 28 versus 28 weeks). In summary, there was strong evidence for the existence of an unfavourable subgroup, defined as patients with ECOG performance status of 1–2 who do not benefit from the more aggressive combination chemotherapy.
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discussion |
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The focus of this analysis was to evaluate the therapeutic efficacy of a combined treatment with gemcitabine plus a platinum analog such as cisplatin or oxaliplatin in locally advanced or metastatic pancreatic cancer. Several randomized trials had indicated a consistent superiority of gemcitabine–platinum combinations over gemcitabine alone, but no trial was adequately powered to demonstrate a statistically significant survival benefit of moderate size. The present analysis included individual patient data from the French/Italian GERCOR/GISCAD trial and a German multicenter trial. It clearly indicates the superior efficacy of the gemcitabine–platinum combination. Compared to single-agent gemcitabine, this combination not only induced a significant improvement in progression-free survival (HR = 0.75; P = 0.0030), but also caused a significant prolongation of overall survival (HR = 0.81; P = 0.031). These results are further supported by a meta-analysis of published trial data, which again indicates the significant superiority of gemcitabine–platinum combinations over gemcitabine alone [33].
The GemOx combination induced a significantly greater objective response rate than single-agent gemcitabine (28% vs 17%; P = 0.029) [8]. In the trial evaluating GemCis, a significant difference in response rates was not observed (11% vs 9%; P = 0.80). The GemCis combination was, however, superior to gemcitabine alone when disease control rate accounting for overall response rate plus stable disease rate was analysed (70.4% vs 48.5%; P < 0.001) [7]. It should, however, be taken into account that data arising from analyses of objective response rates appear to be less stringent than those regarding progression-free and overall survival, especially in the case of pancreatic cancer, with limited validity of lesion measurement in a large fraction of the patient population.
The results obtained in the pooled analysis need to be seen in the context of a growing number of randomized trials combining gemcitabine with other cytotoxic agents. So far, only one trial, with 533 patients, showed that a combination of gemcitabine with capecitabine induced a significantly longer survival compared to gemcitabine alone (7.4 vs 6.0 months; P = 0.026) [18]. A further trial (n = 319) comparing a modified regimen of the gemcitabine–capecitabine combination with gemcitabine alone failed, however, to reach the level of significance (8.4 vs 7.3 months; P = 0.34) [14]. Among the randomized trials investigating targeted agents, so far only one study demonstrated a significant survival benefit (HR = 0.81; P = 0.025) when gemcitabine plus erlotinib was tested against gemcitabine alone in 530 patients with advanced pancreatic cancer [19].
In view of the poor prognosis of pancreatic cancer, the definition of reliable predictive and prognostic factors gains clinical importance. In patients receiving single-agent gemcitabine, the correlation of efficacy parameters to baseline factors indicated that performance status, stage of disease and pretreatment were important prognostic factors for survival, while age, gender and ethnic origin had no significant effect [34].
In the analysis of the pooled trial results 503 patients were evaluated for prognostic factors. Apart from the treatment arm, only performance status and stage of disease were highly significantly related to both progression-free and overall survival. The choice of an adequate treatment may be based on optimal patient selection according to prognostic factors. This analysis indicates that the greatest benefit from gemcitabine–platinum combination therapy was obtained by patients with good performance status (ECOG PS = 0). In these patients the combination induced a significant prolongation of PFS (HR = 0.64; P = 0.013) and a strong trend towards an improved OS (HR = 0.72; P = 0.063). By contrast, combination therapy failed to cause a significant improvement in patients with a more unfavourable performance status (ECOG 1–2). It may be concluded that patients with good performance status should be candidates for the more intensive combination therapy, while patients with a compromised performance status should rather be offered cytotoxic treatment with gemcitabine alone.
The common theme of the two trials pooled together in this analysis was the combined use of gemcitabine with a platinum agent and its comparison to single-agent gemcitabine. Other trials potentially qualifying for this analysis did not provide single-patient data and therefore could not be included. However, the present analysis also has clear limitations. Cisplatin and oxaliplatin are both alkylating agents and therefore share common mechanisms of action, but they are characterized by different mechanisms of resistance. Furthermore, the French/Italian trial applied gemcitabine as a fixed-dose rate (FDR) infusion, while in the German multicenter trial gemcitabine was given as a 30-minute infusion. Pharmacological data suggested that gemcitabine applied at a fixed-dose rate may have greater antitumor activity than the standard regimen [35]. However, the two randomized trials performed in pancreatic cancer could not show a significant superiority of fixed-dose rate compared to standard infusion with regard to the preset primary end points of these trials [10, 35].
It might be argued that the apparent differences between the French/Italian and the German trials may confound the joined analysis. This report shows, however, a strong degree of homogeneity of trial results when the effect of combination therapy on progression-free and overall survival was analysed. Based on comparable treatment effects the pooled evaluation increases the strength of analysis and at least partly overcomes the statistical limitations of the individual trials.
First results are now available of the ECOG 6201 trial comparing standard-dose gemcitabine to FDR gemcitabine and in a third arm to the GemOx regimen [10]. In general, survival times observed in this trial are lower than in previous randomized studies, indicating, in the light of our results, a suboptimal patient selection for cytotoxic treatment intensification. Neither FDR gemcitabine nor GemOx proved to induce a statistically significantly better overall survival than standard gemcitabine. A more detailed analysis of the data, including data on mature response and PFS, is needed to integrate the results into a perspective of pancreatic cancer therapy.
In conclusion, this pooled analysis of two randomized trials indicates that the combination of gemcitabine with a platinum analog such as oxaliplatin or cisplatin significantly improves progression-free and overall survival when compared to gemcitabine alone. The benefit from combination therapy is predominantly detected in patients with a good performance status.
Received for publication February 2, 2007. Revision received May 11, 2007. Accepted for publication May 14, 2007.
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