The yield of chest computed tomography in patients with locally advanced pancreatic cancer

Abstract Objective To evaluate the incidence of pulmonary metastases on chest computed tomography (CT) in patients with locally advanced pancreatic cancer (LAPC). Methods All patients diagnosed with LAPC in a single tertiary center (Erasmus MC) between October 2011 and December 2017 were reviewed. The staging chest CT scan and follow‐up chest CT scans were evaluated. Pulmonary nodules were divided into three categories: apparent benign, too small to characterize, and apparent malignant. Results In 124 consecutive patients diagnosed with LAPC, 119 (96%) patients underwent a staging chest CT scan at the initial presentation. In 88 (74%) patients no pulmonary nodules were found; in 16 (13%) patients an apparent benign pulmonary nodule was found, and in 15 (13%) patients a pulmonary nodule too small to characterize was found. Follow‐up chest CT scan(s) were performed in 111 (93%) patients. In one patient with either no pulmonary nodule or an apparent benign pulmonary nodule at initial staging, an apparent malignant pulmonary nodule was found on a follow‐up chest CT scan. However, a biopsy of the nodule was inconclusive. Of 15 patients in whom a pulmonary nodule too small to characterize was found at staging, 12 (80%) patients underwent a follow‐up CT scan; in 4 (33%) of these patients, an apparent malignant pulmonary nodule was found. Conclusion In patients with LAPC in whom at diagnosis a chest CT scan revealed either no pulmonary nodules or apparent benign pulmonary nodules, routine follow‐up chest CT scans is not recommended. Patients with pulmonary nodules too small to characterize are at risk to develop apparent malignant pulmonary nodules during follow‐up.

and portal vein. 3 Moreover, imaging should demonstrate no evidence of metastatic disease.
A chest computed tomography (CT) scan is more sensitive and specific in detecting pulmonary metastases than a conventional chest X-ray. 4 In patients with pancreatic cancer, the National Comprehensive Center Network (NCCN) guidelines recommend routine chest CT scans. 5 Chest CT scan in (borderline) resectable pancreatic cancer, nonetheless, was found to be of no influence on survival. [6][7][8] Chest CT scans frequently reveal subcentimeter pulmonary nodules that are often said to be too small to characterize. They impose a clinical dilemma, as these nodules of uncertain nature induce uncertainty with regard to their nature and as such carry a huge emotional burden to patients. These findings often lead to additional invasive diagnostic tests, which delays the start of treatment and can impose additional risks to the patients. For example, diagnostic transthoracic lung biopsies harbor a considerable risk of pneumothorax or intrathoracic bleeding and frequently are found to be nondiagnostic. 9 Moreover, the clinical value of a chest CT scan in LAPC could be questioned, because systemic chemotherapy is the first-line treatment for both LAPC and metastatic disease. 10 Detection of metastatic disease in LAPC patients is particularly relevant in the era of several locoregional treatments for pancreatic cancer, including radiofrequency ablation, irreversible electroporation, and stereotactic body radiotherapy (SBRT). 11 While the benefit of these treatments has not been shown definitively, even their strongest proponents agree that they are unlikely to benefit patients with metastatic disease. The aim of this study is to evaluate the yield of routine chest CT scans in patients with LAPC at initial staging and during follow-up.

| METHODS
We retrospectively reviewed all consecutive patients diagnosed with LAPC between October 2011 to December 2017 seen at Erasmus MC, The Netherlands. The database used for this study was approved by the Institutional Review Board, and informed consent was waived.
A diagnostic CT scan of the chest and abdomen was performed at diagnosis and during follow-up. The CT scan was done on a 128 slice CT scanner with three phases (unenhanced, late arterial [35 seconds], and portal venous [70 seconds]) of the upper abdomen after intravenous injection of contrast medium. In addition, the lower abdomen and chest were scanned in the last phase. The majority of the staging CT scans were performed in our institute; however, some patients already underwent a staging CT scan in the hospital of referral. If the quality of these CT scans was up to the standard and scan were performed less than 4 weeks before therapy, these scans were added in our imaging archive and formally reassessed. Otherwise, the patient underwent a new CT scan in our institute following the guidelines as described above. Diagnosis of LAPC was according to the Dutch guidelines. 12 All patients with LAPC were offered a treatment consisting of eight cycles of FOLFIRINOX followed by either conventional or stereotactic body radiotherapy when no disease progression was observed on follow-up scanning. If FOLFIRINOX was not feasible, other chemotherapy regimens or best supportive care were discussed with the patient. Usually, follow-up CT scans were performed after four and eight cycles of FOLFIRINOX, and 3 months after radiotherapy. In the case of SBRT, an additional CT scan was per-  Pulmonary nodules observed during initial and follow-up CT scans were divided into three categories: apparent benign, too small to characterize, and apparent malignant, whereby an apparent benign nodule was defined as a lesion with homogenous calcification.
A nodule was considered too small to characterize was a noncalcified nodule under 1 cm, or pleural effusion ( Figure 1). 8 Comparisons of patient's characteristics between patients without pulmonary nodule or benign nodules versus patients with nodules too small to characterize were analyzed using Fisher exact test for categorical variables, and a nonparametric median test for continuous variables. Overall survival (OS) was calculated from the date of first staging CT scan until the death of any cause. The survival outcome is presented using Kaplan-Maier and compared logrank in SPSS (version 21). A P value less than .05 was considered statistically significant.

| RESULTS
In total 124 consecutive patients diagnosed with LAPC between  Table 1.
In 31 (26%) patients a pulmonary nodule was found on the initial staging CT scan. In 15 (13%) patients the nodules were classified as too small to characterize, whereas in 16 (13%) patients the nodules were classified as apparent benign. The baseline characteristics gender, age, tumor diameter, tumor location, smoking history, and baseline serum CA19-9 and CEA were not associated with the presence of nodules too small to characterize on staging chest CT scan (Table 2) [10][11][12][13][14][15] in patients without these nodules (P = .88) (Figure 3).

| DISCUSSION
Staging and restaging chest CT scans are routinely performed in patients with LAPC. To our knowledge, this is the first study to,   there was no difference in initial treatment management between patients with and without pulmonary nodules.
The main limitation of our study is its retrospective design, which implicates that patients who were deemed as metastasized pancreatic cancer due to pulmonary metastasis are missed in this study.
Moreover, the definitions used for resectability before and after induction therapy are more conservative than used by NCCN guidelines, which could influence the generality of our findings.
Furthermore, the data is obtained from only one institute. Nonetheless, our institute is the biggest academic hospital in the Netherlands where most of the patients are referred from nonacademic hospitals. However, more studies are needed to confirm our findings.
In conclusion, follow-up chest CT scans added information on pulmonary metastasis only in 4% of the patients. However, these nodules were first seen as too small to characterize on staging chest CT scans. The management and survival of patients with nodules too small to characterize on staging CT scan did not significantly differ from patients without these nodules. Routinely follow-up chest CT should be questioned, unless undefined pulmonary nodules are found on staging chest CT scan.

DATA AVAILABILITY STATEMENT
Data available on request due to privacy/ethical restrictions.