The point at which a potential surrogate endpoint could be theoretically validated has been seriously discussed [41]. The correlation approach has been widely adopted to validate the efficiency of a surrogate endpoint in locally advanced lung cancer [25], gastric cancer [26, 42] and colorectal cancer [27]. In the present study, we included a total of 20 high quality adjuvant randomized controlled trials to evaluate the surrogacy of DFS for OS in pancreatic cancer. Our finding demonstrated that the correlation between DFS and OS was strong (0.80 to 0.82), irrespective of the applied weighting strategies. Sensitivity analyses that were restricted to phase 3 trials, large trials, trials with mature follow-up periods, and trials with adjuvant therapy versus adjuvant therapy also yielded strong or very strong correlations (0.80 to 0.93) between DFS and OS. Therefore, we proposed the use of DFS as the surrogate endpoint for OS in adjuvant trials of pancreatic cancer.
Although the recent advance in adjuvant chemotherapy have translated into substantial survival benefit for pancreatic cancer, a large number of these treated patients still suffered from relapse or metastasis; thus, new therapeutic strategies are urgently needed. Clinicians are now evaluating the therapeutic effect of more intensive adjuvant chemotherapy, adjuvant targeted therapy and immunotherapy in pancreatic cancer after curative resection. It is well recognized that OS is the standard endpoint for clinical trials; however, using the endpoint of OS to perform the phase 3 trials is time consuming, thus postponing the new therapy strategies in clinical application. Therefore, we urgently need reliable surrogate endpoints for OS in adjuvant trials of pancreatic cancer, among which DFS is the most reasonable surrogate endpoint, and it has been set as the primary endpoint in several phase 3 trials [7, 17-19, 23, 37]. A previous meta-analysis reported that the correlation between DFS and OS was not strong enough to support the DFS as the reliable surrogate endpoint for OS in adjuvant trials of pancreatic cancer [28]; nonetheless, they only included a total of 12 trials, among which one trial was adjuvant setting for periampullary cancer rather than pancreatic cancer [29]. Therefore, in the present meta-analysis, we applied more rigorous criteria through three weighting strategies to address this urgent issue. Our findings revealed that the degree of association between DFS and OS was strong, which was further verified through extensive sensitivity analyses and a leave-one-out analysis validation approach. We believe that the robust correlation between DFS and OS in adjuvant therapy of pancreatic cancer is mainly attributable to the fact that pancreatic cancer is an aggressive tumor and that the subsequent lines of therapy are limited if patients develop relapse or metastasis.
Given the fact that adjuvant chemotherapy has showed superior survival outcome to observation for pancreatic cancer, adjuvant chemotherapy including gemcitabine-based or S-1-based regimens rather than observation would be set as the control arm in adjuvant trials. Interesting, we found that the correlation between DFS and OS was not strong (0.68 to 0.73) with restriction to trials with adjuvant therapy versus observation; nonetheless, we noted a very strong correlation between DFS and OS when we restricted the analysis to trials with adjuvant therapy versus adjuvant therapy (0.89 to 0.93). Therefore, in future adjuvant trials of pancreatic cancer, DFS could be served as the robust surrogate endpoint for OS.
STE is an alternative measure for surrogate endpoint validation [32]. Using a surrogate endpoint with STE closer to 1, it would be easier to predict an OS benefit. In the present meta-analysis, our finding showed that the STE was 0.96 for DFS, indicating that an adjuvant trial in pancreatic cancer producing a hazard reduction of at least 4% for disease recurrence or death could be expected to promise a statistically significant reduction in OS.
There are several limitations that should be noted. First, the data for our analysis were extracted from trial level rather than an individual patient; therefore, a potential published bias cannot be excluded. Second, the included trials spanned nearly three decades, and the ascertainment of DFS was mainly influenced by the image examination and surveillance interval, thus may have changed considerably over time and among trials. Third, long-term follow-up was not available from all trials included in our analysis. Pancreatic cancer is a relatively aggressive malignancy with severe heterogeneity; thus, the short follow-up in adjuvant trials will result in fairly wide confidence intervals of HR about the treatment effects. In the sensitivity analysis, the correlation between DFS and OS remained strong (R2 = 0.75) when we included trials with median follow-up > 24 months. Third, the included trials at our analysis comprised a wide range of therapeutic strategies, which included trials of adjuvant chemotherapy, radiation therapy, chemoradiotherapy, chemoimmunotherapy and targeted treatment. Although we performed sensitivity analysis to eliminate the potential effect of these treatment heterogeneities, the results of our analysis should be interpreted with caution. Therefore, we strongly recommended authors of individual trials to share their data to further verify the results of our analysis through individual-patient data.