Added value of digital FDG-PET/CT in disease staging and restaging in patients with resectable or borderline resectable pancreatic cancer

The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is extremely poor. Upon diagnosis, only 20% of patients can undergo resection with curative intent, whereas 40% present with locally advanced pancreatic cancer (LAPC), and 40% with metastatic disease. Neoadjuvant therapy (NAT) is playing an increasing role. Emerging evidence is showing clear benefits of NAT for borderline resectable (BR) and locally advanced pancreatic cancer (LAPC), which is driving a shift from up-front surgery to treatment with NAT, even in resectable pancreatic cancer [1,2]. The purpose of NAT is not only to decrease tumor size to facilitate margin-negative resection and to optimally select surgical candidates, but also to increase the relative proportion of patients who are able to receive chemotherapy (as compared to the adjuvant setting).

To carefully select surgical candidates after neo-adjuvant treatment, accurate assessment of response is crucial in re-staging and determining resectability [[3], [4], [5], [6], [7]]. However, traditional cross-sectional imaging modalities for this purpose such as contrast enhanced CT (ceCT) and/or MRI, poorly predict response, rendering NAT radiologic evaluations relatively ineffective [[7], [8], [9], [10]]. The main response parameter in these modalities is based on tumor size [11], which is unreliable due to the inability to differentiate treatment-related necrosis, therapy-induced fibrosis and tumor-associated pancreatitis from residual vital tumor tissue [3,5,12]. The same holds true for a CT-based observed change in tumor attenuation. Cassinotto et al. [13] showed that the diagnostic performance of ceCT to predict resectability decreased after neo-adjuvant treatment (58% vs. 83%). Similarly, Ferrone et al. [14] showed that ceCT after FOLFIRINOX treatment no longer adequately predicted resectability of the tumor. This underlines the critical need for improved methods to objectively determine the adequacy of response to NAT.

Besides cross-sectional imaging, the serum CA19-9 level is commonly used as a biochemical marker for (re)staging for PDAC. It has added value for monitoring response to systemic therapy and correlates with overall survival [15]. Adding a 30% decrease in CA19-9 levels to RECIST-assessment of LAPC following neo-adjuvant chemotherapy was shown to improve the diagnostic accuracy for predicting resectability, especially in patients with RECIST-stable disease [16]. However, the utility of CA 19.9 also has limitations, since 10% of patients are upfront non-secretors and up to one-third have normal levels at presentation (normo-secretors). Also, variability exists regarding what constitutes an appropriate NAT response (ie, stability, partial stability, or normalization) [17,18]. In addition, patients with cholangitis or pancreatitis may show increased CA19-9 causing false positives [19].

FDG-PET/CT has been evaluated for monitoring the (neo)adjuvant treatment response in various malignancies, including pancreatic cancer [[20], [21], [22]]. It provides insight into tumor viability during NAT, and reveal metabolic changes earlier than changes in radiologic tumor size [23]. Studies using analog PET-CT have demonstrated improved visualization of local tumor response to neo-adjuvant therapy when compared to ceCT as well as improved sensitivity for detecting distant metastatic disease, especially in the liver [[19], [20], [21],[24], [25], [26], [27], [28], [29], [30], [31], [32], [33]]. The PET-PANC study showed that in patients with primary suspected pancreatic malignancies non-therapeutic laparotomy was avoided in 21% of patients [25]. Based on this study, PET-CT was added to the staging recommendations in the UK NICE guidelines [34].

A recent meta-analysis revealed that metabolic parameters derived from PET/CT can be useful as prognostic markers in pancreatic ductal adenocarcinoma [17]. Two recent studies showed that FDG-PET/CT response correlates with survival in borderline resectable and locally advanced pancreatic cancer [19,32]. Importantly, the study of Abdelrahman et al. [19] showed that PET/CT could also predict the surgical specimen histological response, which is the most direct evidence of NAT effect, and this was superior to CA 19–9 response alone. Given these results, FDG-PET/CT may be the optimal modality for preoperative assessment of NAT response, allowing improved stratification of patients into specific downstream options (i.e., proceed to surgery, continue with current NAT, or switch chemotherapy).

Despite these encouraging results, PET/CT still remains controversial in standard practice for pancreatic cancer in many institutions. International consensus guidelines outside the UK recommend that FDG-PET/CT may be used in suspected pancreatic cancer patients per institutional preference in high risk patients, but is not a substitute for high-quality contrast-enhanced CT (ce-CT) [2,35]. This is most likely due to the inherently variable FDG-uptake of pancreatic adenocarcinoma and the well-known low specificity for differentiation between malignant and inflammatory tissue, combined with the relatively low spatial resolution of conventional analog PET/CT [29].

Recently, a new generation of digital PET/CT scanners was introduced by several vendors, that provide improved image quality, diagnostic confidence, and accuracy as compared to analog PET/CT as shown in a number of studies [[36], [37], [38], [39]]), but this has not yet been shown in pancreatic cancer. The aim of this study was to evaluate the added value of digital PET/CT compared to the standard work-up with ceCT and CA19-9 alone, as a staging and restaging imaging modality in patients with resectable or borderline resectable pancreatic cancer, who were treated with neo-adjuvant therapy. Primary endpoints were the evaluation of primary tumor response compared to standard ceCT and CA19.9, as well as the ability to detect distant metastatic disease.

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