Description of the condition
Pancreatic cancer is the 10th most common cancer in the UK and USA in terms of incidence (Jemal 2010; ONS 2010), but is among the fourth or fifth leading causes of cancer death (Jemal 2010; ONS 2010b). The only treatment with potential for cure is resection (surgical removal), but even in specialised centres just 10% to 15% of diagnosed patients have resectable disease (Stathis 2010). Of the remainder, 30% to 35% have locally advanced disease and 50% have metastatic disease (Stathis 2010).
Description of the intervention
In patients with resectable disease, adjuvant chemotherapy has improved overall survival (Neoptolemos 2010) or disease-free survival (Oettle 2007), and more than doubled the five-year survival rates from 10% to nearly 25% (Van Laethem 2012).
The majority of patients will require palliative treatment (chemotherapy or chemoradiotherapy with or without follow-on chemotherapy), with a median survival of 6 to 11 months in patients with locally advanced pancreatic cancer and two to six months in those with metastatic disease (Stathis 2010). The role of chemotherapy in advanced pancreatic cancer, and in particular for gemcitabine-based combinations over single-agent gemcitabine (overall survival advantage), has been established both in randomised controlled trials and subsequent aggregate data meta-analyses of these (Sultana 2007).
How the intervention might work
Pancreatectomy with standard lymphadenectomy is advocated for resectable disease, but patients tend to succumb to recurrence either loco-regionally or in the liver (Abrams 2001; Hishinuma 2006; Koshy 2005; Sperti 1997). Adjuvant treatment following curative resection acts by targeting micro-metastatic disease (Chua 2005), thereby improving outcomes. The attractiveness of neoadjuvant therapy lies in the fact that nearly 20% to 30% of resected patients fail to receive adjuvant therapy on the grounds of delayed recovery from major surgery, co-morbidities, patient choice and early recurrence (Yeo 1995). Palliative chemotherapy provides an overall survival benefit and improves symptom control/quality of life compared to best supportive care (Burris 1997; Sultana 2007; Yip 2006). Chemoradiotherapy/combination therapy has been administered in locally advanced pancreatic cancer patients with the intention of down-staging the disease.
Why it is important to do this review
In an individual patient data (IPD) meta-analysis, adjuvant chemotherapy resulted in a 25% reduction in the risk of death (hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.64 to 0.90) compared to no chemotherapy. In contrast, there was no significant difference between chemoradiation versus no chemoradiation (HR 1.09, 95% CI 0.89 to 1.32) (Stocken 2005).
A subsequent aggregate data meta-analysis of adjuvant treatment concluded that chemotherapy improved median survival by three months (95% CI 0.3 to 5.7 months; P = 0.03), but did not impact on five-year survival rates, possibly due to the low numbers at risk at this time point (Boeck 2007). It included two further randomised controlled trials (RCTs) on chemotherapy versus best supportive care (Kosuge 2006; Oettle 2007), compared to the previously published individual patient data meta-analyses. A criticism of this study was the methodology of the meta-analysis, utilising median survival and rates at different time points. These have been shown to not be the ideal surrogate measures for meta-analyses of survival data (Michiels 2005).
Aggregate data meta-analyses of randomised controlled trials of chemotherapy (Heinemann 2008; Hu 2011; Sultana 2007; Xie 2010; Yip 2006) in advanced pancreatic cancer patients have suggested a survival advantage for gemcitabine combination chemotherapy. The role of chemoradiotherapy, with or without follow-on chemotherapy, is controversial in the management of advanced pancreatic cancer. The only level 1a evidence in this area found a significant survival benefit for chemoradiotherapy over radiotherapy, but not for chemoradiotherapy with follow-on chemotherapy compared to chemotherapy alone (Sultana 2007b). However, the heterogeneity in the trials included, combined with the fact that both staging and radiotherapy techniques had progressed since the inception of the majority of the trials, limited the conclusions that could be drawn.
The role of neoadjuvant/preoperative therapy in pancreatic cancer is less clear cut. Most studies have been retrospective or prospective cohort/phase I/II trials. A comprehensive systematic review by Gillen et al of 111 prospective (n = 78) (including phase I/II studies) and retrospective (n = 33) studies found that the median survival for resectable patients who received neoadjuvant chemotherapy and went on to have a resection was 23.3 months (95% CI 12 to 54 months) (Gillen 2010). Another meta-analysis evaluated gemcitabine given alone or in combination with radiotherapy prior to surgery in localised and locally advanced pancreatic cancer (Andriulli 2011). In the 707 patients analysed, they found little support for neoadjuvant therapy in resectable patients, and only marginal benefit in locally advanced disease (39% were resectable on restaging, of whom 68% could undergo resection). A limitation of this study was the inability to assess survival data. Another meta-analysis of both prospective and retrospective cohort studies found a higher risk of perioperative death in patients receiving preoperative chemoradiotherapy, though there was no difference in overall complications (Laurence 2011). Meta-analysis of prospective phase II studies recommended preoperative treatment only in the context of locally advanced disease (Assifi 2011).
Updated aggregate data meta-analyses incorporating recent and ongoing RCTs, and using the most appropriate methods for survival analyses, are warranted.