The aim of this meta-analysis and review of the literature was to investigate the potential role for neoadjuvant treatment in patients with pancreatic adenocarcinoma. Neoadjuvant therapy has been shown to have significant impact in several GI malignancies, and has many theoretical advantages over adjuvant treatment in patients with pancreatic adenocarcinoma. Preoperative treatment has been proposed to have greater benefits on well-oxygenated, non-devascularized tissue, with improved delivery of chemotherapeutic agents. 9
Secondly, preoperative treatment may be better tolerated, allowing for higher completion rates. Neoadjuvant treatment may also reduce any delay in therapy, and could potentially downstage unresectable tumors. 23
Of those patients with resectable pancreatic adenocarcinoma, 65.8% underwent curative resection. This finding is similar to the rate of resection reported in patients with resectable disease who did not receive neoadjuvant treatment. 24
Not surprisingly, 85.1% of the patients in this group had RO resections (). Patients with resectable tumors were also found to have significantly more stable disease than those patients with more advanced disease, 73.9% versus 40.9%, respectively (). The longest estimated median survival (23.0 months, range 11.7–34 months) was observed in Group A patients. Therefore, patients with resectable disease have similar outcomes, regardless of neoadjuvant treatment.
Nearly one-third of tumors initially deemed borderline/unresectable were ultimately suitable for surgical resection after treatment. Group B patients also demonstrated a significantly higher partial response (31.8%) when compared to those patients with resectable disease. This finding is likely explained by the larger overall size of tumors found in Group B patients. This patient population, by definition, had larger, more advanced tumors that were considered borderline or unresectable masses. Those patients with increased tumor burden were able to demonstrate a higher partial response when compared to patients with smaller tumors. The overall median survival for patients with locally advanced disease was 11.2 months (range 9–19.4 months). In this same group of patients, the estimated survival time increased to 22.3 months after resection. From this data we conclude that patients with borderline/unresectable disease have increased partial response rates and a survival time similar to patients with resectable disease after receiving neoadjuvant treatment plus resection.
There were inherent limitations to our meta-analysis. The power of our study was low and the insignificant differences in subgroup comparisons are probably due to lack of statistical power, especially when compared to others that included all study types in their analysis. Given that there is no data from phase III trials, we limited our scope to prospective, phase II trials to obtain the best data available. Despite this, our findings are consistent with similar, larger studies.21
Although trials included in this analysis were from 1993 to 2010, actual treatment dates spanned from 1986 to 2006 (Table S1
). Most trials were 2–4 years in length, with three trials lasting 5–6 years. During this 20 year period, there have been major changes in the treatment of pancreatic cancer, including chemotherapy, radiotherapy, and surgical management. This aspect introduces great variability in patient treatment between trials. The definition for resectability varied widely between studies. Studies included in this analysis spanned seven years and had a wide range of resection criteria, some of which were not clearly stated altogether. This finding is most evident in patients with locally advanced disease, especially those with “borderline tumors”. As a result of this variation, our analysis grouped patients with borderline disease and those patients with unresectable disease together into one group. Despite this limitation, our analysis reflects the best data available on this particular topic.
Another limitation of our study is the deficiency of margin status data. It is widely accepted that margin status in pancreatic resection is a crucial factor when determining patient outcomes. However, margins were not clearly defined in these trials, and no analysis could be performed to relate margin status and patient outcomes after receiving neoadjuvant treatment.
Publication bias is one of the major concerns of meta-analysis. The estimates could be inflated when the results are mainly based on published studies. We used funnel plots as a visual aid to investigate potential publication bias. However, due to the limited number of studies in our meta-analyses, it might be difficult to identify all publication bias from the funnel plot, since a funnel plot with a small number of studies may appear asymmetric simply by chance. It is well known that the techniques we have for correcting for publication bias are sometimes poor. Thus, we might not able to remove the potential publication bias completely. The likelihood of potential publication bias could be further reduced if unpublished studies that meet the inclusion criteria were available.
The problem of heterogeneity found in all meta-analysis studies was partially handled using the random effects model. The Cochran Q test was used to detect heterogeneity of the meta-analysis. We used a p-value of less than 0.10 to indicate heterogeneity rather than the conventional cutpoint of 0.05 because the Cochran Q test has low statistical power at detecting heterogeneity when there are few studies. Approximately 2/3 of our meta-analyses show significant evidence of heterogeneity. Random-effects models were used to take into account the between-study variation. Causes of heterogeneity were investigated by using a general linear model. However, no significant source of heterogeneity was detected.
In conclusion, the data compiled from this meta-analysis highlights the importance of preoperative staging. Despite the limitations of this study, the data suggest that patients with borderline or unresectable disease may see the most benefit from neoadjuvant treatment. Like other GI malignancies, treating patients with borderline resectable pancreatic cancer before surgery may ultimately allow for resection in a significant number of these patients, and provides a period of time to select those patients with better tumor biology that will benefit from resection. In contrast, preoperative therapy in those patients with resectable tumors has minimal benefit and may delay a potentially curative operation. With the advent of more effective chemotherapeutic or targeted treatments, a neoadjuvant approach may evolve into a more effective option. However, there is a great need to establish and adhere to a set of standardized resection criteria for patient stratification to enable the pursuit of larger, more comprehensive trials in the future.