Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer

Pancreatic cancer is the fourth or fifth leading cause of solid tumour deaths in Western industrialized countries. Due to its predominantly late diagnosis, most patients are diagnosed with advanced or metastatic disease at first presentation [1, 2]. Without effective treatment, a median survival of only 3 to 4 months is expected in metastatic disease.

Single-agent gemcitabine has evolved as a standard of care for treatment of locally advanced and metastatic pancreatic cancer. However, treatment effects remain moderate with median overall survival (OS) times in the range of 5 to 8 months and 1-year survival rates in the range of 17–25%.

To improve therapeutic efficacy numerous randomized trials have investigated gemcitabine-based combination regimens adding a second cytotoxic agent such as a platinum analog [3‐7], a fluoropyrimidine [8‐13], a multitarget antifolate [14] or topoisomerase inhibitors [15‐17]. While some studies showed an improvement of objective response rates (ORR) and progression-free survival (PFS) with combination chemotherapy, most trials lacked statistical power and failed to demonstrate a statistically significant prolongation of survival. So far, only the preliminary results of one randomized study showed a significant survival benefit in favour of combination chemotherapy [13].

The present analysis tries to overcome the statistical limitations of the individual trials and investigates the treatment effects in total and in various combination groups. Three groups characterized by the combination partner were formed prospectively: in the first group, gemcitabine was combined with a platinum analog like oxaliplatin or cisplatin. The second group included fluoropyrimidines like 5-fluorouracil (5-FU) or capecitabine as combination partners; the third group comprised all other cytotoxic agents such as pemetrexed, irinotecan, and exatecan.

The meta-analysis was performed according to a prospectively written protocol and analysis plan.

Pancreatic cancer is a highly malignant disease, and survival is expected to be short in advanced disease. Once treatment has been initiated, response evaluation by imaging is difficult and tumor response is not regarded as a reliable parameter of treatment efficacy. It therefore appears that OS should be evaluated as a primary endpoint when different treatment options and therapeutic regimens are compared. In view of the rather short course of the disease first-line therapy is expected to have the greatest impact on OS. Accordingly, the present meta-analysis chose to evaluate 15 randomized trials based on the available survival data only.

The starting point of this analysis has been the perception that single-agent gemcitabine as the present standard of care is only moderately active in metastatic pancreatic cancer and allows a median OS of only 5–8 months in randomized trials. In view of the manifold trials investigating gemcitabine-based combination therapies only two studies stand out which reported a significant improvement of survival in favour of the combination therapy [13, 23]. In both trials patient numbers exceeded 500, and the hazard ratios achieved in favour of the combination were nearly identical: HR = 0.80 (p = 0.026) for gemcitabine plus capecitabine [13], and HR = 0.81 (p = 0.025) for gemcitabine plus erlotinib [18].

This meta-analysis evaluated the 15 available trials comparing gemcitabine versus gemcitabine plus one other chemotherapy drug excluding combined therapy with targeted agents. When all 15 trials (4465 patients) are taken together a highly significant (p = 0.004) advantage of survival is obtained in favour of combination therapy. However, the gain in survival time is slim (HR = 0.91; 95% CI 0.85 – 0.97) and clinical relevance remains moderate.

In a subsequent step, trials were grouped according to the combination partner and separate analyses were performed for combinations with either platinum analogs, fluoropyrimidines or "other" agents (Table 10). This analysis indicated that the combination of gemcitabine plus a platinum analog (cisplatin or oxaliplatin) was significantly superior to gemcitabine alone inducing a HR of 0.85 (p = 0.01) with a low heterogeneity of results (p = 0.97). However, one must keep in mind that the study of Louvet and colleagues as well as the E 6201 study by Poplin and co-workers used a FDR gemcitabine application [3, 4] in the combination arm (i.e., gemcitabine in the GemOx arm was not given as a standard 30-minute infusion [5‐7], but at a FDR infusion of 10 mg/m²/min). Also the combination of gemcitabine with a fluoropyrimidine induced a significant survival benefit (HR = 0.90, p = 0.03). The somewhat heterogeneous result (p = 0.42) in this group of trials was essentially due to the more inconsistent survival data obtained by the trials using 5-FU as a combination partner. By contrast, when only the three trials using capecitabine as a combination partner were analysed together, a HR of 0.83 (p = 0.01) was obtained.

This leads to the conclusion that the combination of gemcitabine with either a platinum analog or capecitabine may allow a clinically relevant prolongation of survival supported by hazard ratios in the range of 0.83 – 0.85. Compared to these positive results, combinations of gemcitabine with either pemetrexed or topoisomerase I inhibitors (irinotecan or exatecan) did not have any effect on survival (HR = 0.99) and consequently have no place in clinical practice.

To date, five meta-analyses evaluating radiotherapy and chemotherapy in advanced, non-resectable pancreatic cancer have been published [24‐28]. These analyses showed that chemotherapy is able to prolong survival (compared to best supportive care only) in patients with advanced pancreatic cancer [24, 26], and there is also evidence that gemcitabine-based combination chemotherapy may be superior to single-agent gemcitabine regarding overall survival [25, 26, 28]. In accordance to our data, the most promising survival advantage was observed when gemcitabine was combined with either a platinum compound or capecitabine: Sultana and colleagues in their meta-analysis for example reported a HR of 0.85 (95% CI 0.74 – 0.96, p = 0.01) for the addition of cisplatin or oxaliplatin to standard gemcitabine and a HR of 0.83 (95% CI 0.72 – 0.96, p = 0.01) for the addition of capecitabine to single-agent gemcitabine, respectively [26]. Further meta-analytic data on treatment efficacy (e. g. time-to-progression, progression-free survival, response rate) and toxicity variables have also been reported [25, 27], however such an analysis was not the intent of our investigations.

In a further step of our meta-analysis, those trials were identified and evaluated in which survival data were reported in patient subgroups with a defined performance status. Data from 1682 patients only were available for this pre-defined subgroup analysis, representing about 38% of all patients (4465) from this meta-analysis. Thus, these results should be regarded carefully as a possible outcome reporting bias can not be excluded. Storniolo and coworkers had previously demonstrated that single-agent treatment with gemcitabine induced a median survival of 5.5 months in patients with a KPS ≥ 70%, while patients with a KPS < 70% did not appear to profit from therapy (median OS = 2.4 months) [29]. Likewise, single randomized studies have indicated that a benefit from combination chemotherapy can only be expected in patients with a good performance status [30]. The present meta-analysis of five trials indicates that combination chemotherapy induces its greatest benefit in patients with a good performance status [3, 5, 9, 12, 13]. In these patients (ECOG 0–1 or KPS = 90–100%), a combination of gemcitabine with platinum analogs or fluoropyrimidines induced a statistically significant and also clinically relevant HR of 0.76 (p < 0.0001). By contrast, patients with a poor KPS of 60–80% rather seem to have no survival advantage from the more intensive combination chemotherapy (HR = 1.08).

In conclusion, the subgroup analysis of five large randomized trials provides a possible rationale in favour of combination chemotherapy when applied in good performance status patients who can tolerate prolonged intensive therapy. However, post-hoc subgroup analyses from single randomized trials can only be regarded as hypothesis-generating, and even if there is increasing evidence for an important prognostic role of performance status, a prospective evaluation of this (clinically relevant) issue is strongly recommended for future clinical trials in advanced pancreatic cancer. A re-evaluation of performance status data from all the 15 trials included in this meta-analysis – even perhaps based on individual patient data – would be another promising approach to overcome the limitations of a possible outcome reporting bias.

This meta-analysis was focused on gemcitabine-based chemotherapy combinations and excluded combinations with targeted agents. The results therefore pertain only to the referred chemotherapy doublets. Randomized trials comparing gemcitabine versus gemcitabine plus metalloproteinase inhibitors, tipifarnib or bevacizumab did not show a significant survival benefit [31‐34]. More promising results were obtained from inhibition of the epidermal growth factor receptor (EGFR) by the oral tyrosinekinase inhibitor erlotinib. The combination of gemcitabine with erlotinib induced a significant improvement of PFS and OS when compared to gemcitabine alone [23]. However, preliminary data from a randomized trial investigating the EGFR-directed antibody cetuximab as a combination partner (SWOG S0205) did not show a significant survival benefit for gemcitabine plus cetuximab compared to gemcitabine monotherapy [35].

The question needs to be asked if the results of this meta-analysis have an impact on the design of future trials performed in pancreatic cancer. In conclusion, the following statements can be made:

1. One might consider separate treatment strategies for patients with good and poor performance status in future clinical trials.

2. It has become clear that combination chemotherapy may be a valuable tool to improve treatment efficacy in patients with a good performance status. Further prospective exploration of intensive treatment is needed specifically in this patient group.

3. Patients with a poor performance status possibly have no further benefit from combination chemotherapy and thus should perhaps rather receive single-agent gemcitabine. They also should be candidates for new investigational treatment approaches.