Post-neoadjuvant treatment pancreatic cancer resectability and outcome prediction using CT, 18F-FDG PET/MRI and CA 19–9

Patient characteristics

Of the 120 patients (mean age ± standard deviation [SD], 66.7 ± 8.4 years), 65 were women (Table 1). Baseline CT resectability category determined at the multidisciplinary team (MDT) conference was resectable (14.2% [17/120]), borderline resectable (59.2% [71/120]), and locally advanced (26.7% [32/120]). Among 120 patients, 98 (81.7% [98/120]) underwent surgery (curative-intent surgery [n = 93], palliative due to local unresectability [n = 3], and palliative due to peritoneal seeding [n = 2]), whereas the remaining 22 (18.3% [22/120]) did not undergo surgery due to local unresectability determined at MDT conferences (n = 17), percutaneous biopsy-confirmed hepatic (n = 2) and pulmonary metastasis (n = 1), clinically confirmed peritoneal seeding (n = 1), and both local unresectability and clinically confirmed peritoneal seeding (n = 1). Of the 93 patients who underwent curative-intent surgery, 69 (74.2% [69/93]) achieved R0 resection.

Table 1 Baseline characteristics of the study populationResectability status categorization in consensus on post-NAT CT according to NCCN guidelines and R0 resection rate of each category

According to the consensus review, 26 patients had locally advanced tumors, 34 borderline resectable tumors, 54 resectable tumors, and 6 metastatic diseases on post-NAT CT, according to the NCCN guidelines. The R0 resection rate of each category was 18.8% (6/26), 64.7% (22/34), 75.9% (41/54), and 0%, respectively.

Changes in resectability confidence score after review of PET/MRI and CA 19–9

Resectability scores in consensus among the reviewers on post-NAT CECT were distributed as: score 1 (20.8% [25/120]), 2 (6.7%, [8/120]), 3 (19.2% [23/120]), 4 (35.0%, [42/120]), and 5 (18.3% [22/120]) (Fig. 2A), and the R0 resectability of each score was 12.0% (3/25), 37.5% (3/8), 69.6% (16/23), 76.2% (32/42), and 68.2% (15/22), respectively. After addition of PET/MRI, resectability confidence scores were 1 (15.8% [19/120]), 2 (5.8% [7/120]), 3 (6.7% [8/120]), 4 (40.8% [49/120]), and 5 (30.8% [37/120]) (Fig. 2A), and the R0 resectability of each score was 0% (0/19), 28.6% (2/7), 12.5% (1/8), 79.6% (39/49), and 73.0% (27/37), respectively. Additional review of PET imaging and CA 19–9 changed the resectability confidence scores of CECT to 1 (16.7% [20/120]), 2 (9.2% [11/120]), 3 (5.8% [7/120]), 4 (39.2% [47/120]), and 5 (29.2% [35/120]) (Fig. 2B), with R0 resectability of each score being 5.0% (1/20), 27.3% (3/11), 28.6% (2/7), 78.7% (37/47), and 74.3% (26/35), respectively.

Fig. 2figure 2

Flow diagram showing changes in CT resectability scores. Flow diagram shows changes in CT resectability scores of the three reviewers in consensus after review of post-neoadjuvant therapy PET/MRI (A) and PET imaging plus carbohydrate antigen 19–9 (B) and R0 resection rate of each score. Score 1, definitely unresectable; score 2, probably unresectable; score 3, indeterminate; score 4, probably resectable; score 5, definitely resectable. NAT, neoadjuvant therapy; PDAC, pancreatic ductal adenocarcinoma; PET, positron emission tomography; CA 19–9, carbohydrate antigen 19–9

Additional review of PET/MRI led to reclassification of 24 cases with CECT scores 1, 2, or 3 towards resectability (score 4 or 5). Reclassification was most frequently observed in cases with CECT score 3 to CECT plus PET/MRI score 4 (75.0%, [18/24]) (Table 2). After addition of PET plus CA 19–9, 20 cases with CECT score 1, 2, or 3 were reclassified towards resectability, and changes in CECT score 3 to CECT plus PET plus CA 19–9 score 4 were most frequent (85.0%, [17/20]).

Table 2 Results of reclassification of CECT score after additional review of PET/MRI and CA 19–9Comparison of diagnostic performance among CECT, CECT plus PET/MRI, and CECT plus PET plus CA19-9 in determining R0 resectability

Significant differences were observed in pooled AUC of CECT, CECT plus PET/MRI, and CECT plus PET plus CA 19–9 regarding R0 resectability (0.853 vs. 0.873 vs 0.874, p = 0.026) (Table 3). Pairwise comparison showed that CECT plus PET plus CA 19–9 showed significantly higher pooled AUC compared to CECT (adjusted p = 0.047). In addition, there were significant differences in pooled sensitivity of three image sets (66.2% vs. 86.0% vs. 84.5%, p < 0.001). Pairwise comparison showed that sensitivities of CECT plus PET/MRI and CECT plus PET plus CA 19–9 were significantly higher than that of CECT alone (adjusted p < 0.001).

Table 3 Comparison of diagnostic performance among CECT, CECT plus PET/MRI, and CECT plus PET plus CA 19–9 and post-hoc pairwise comparison

Significant differences were found in pooled specificity of three image sets (67.3% vs. 58.8% vs. 60.1%, p = 0.048) (Table 3). Specificity of CECT plus PET/MRI was marginally lower than that of CECT alone (adjusted p = 0.042), but there was no significant difference in specificity between CECT alone and CECT plus PET plus CA 19–9 (adjusted p = 0.081). Representative cases are shown in Figs. 3 and 4.

Fig. 3figure 3

A 70-year-old man with pancreatic cancer. Axial portal venous phase image of baseline contrast-enhanced computed tomography (CECT) scan (A) shows a 5 cm-sized pancreatic cancer in the uncinate process, contacting > 180 degree with superior mesenteric artery (arrow) and causing contour irregularity of superior mesenteric vein (arrowhead). On arterial phase image of post-neoadjuvant therapy (NAT) CECT scan (B), pancreatic cancer showed decrease in size to 3 cm and ≤ 180 degree contact with superior mesenteric artery (arrow), and contour irregularity of superior mesenteric vein was resolved. CECT resectability score was 3 (indeterminate resectability) according to the three reviewers in consensus. Since there was no diffusion restriction on diffusion-weighted imaging (DWI) (C) and no fluorodexyglucose (FDG) avidity on. 18F-FDG-positron emission tomography (PET) (D) at tumor-vessel contact of post-NAT PET/MRI, and carbohydrate antigen level (CA) 19–9 was 3284 U/mL at initial diagnosis which reduced to 4 U/mL after NAT, the reviewers modified the resectability score to 4 (probably resectable) on both CT plus PET/MRI set and CT plus PET plus CA 19–9. The patient underwent Whipple’s surgery, and pathologic analysis showed no residual tumor with ypT0N0

Fig. 4figure 4

A 54-year-old woman with pancreatic cancer. Axial portal venous phase image of the baseline contrast-enhanced computed tomography (CECT) scan (A) demonstrates a 3 cm-sized pancreatic head cancer, contacting the superior mesenteric vein with vein contour irregularity (arrow). On arterial phase image of post-neoadjuvant therapy (NAT) CT scan (B), the size of pancreatic cancer decreased to 1.7 cm, but contour irregularity of the superior mesenteric vein was still noted (arrow). CECT resectability score was 3 (indeterminate resectability) according to the three reviewers in consensus. Diffusion restriction was seen at the tumor-vessel contact on diffusion-weighted imaging (DWI) (arrow) (C) and fluorodexyglucose (FDG) avidity at tumor-vessel contact was not seen on. 18F-fluorodexyglucose (FDG)-positron emission tomography (PET) (D) of PET/MRI. Carbohydrate antigen level (CA) 19–9 was 245U/mL at initial diagnosis, which reduced to 30 U/mL after NAT. The reviewers assigned resectability score 3 on CT plus PET/MRI set and score 4 on CT plus PET plus CA 19–9. The patient underwent Whipple’s surgery, and pathologic analysis showed College of American Pathologists grade 2 (moderate response) with ypT0N0

Comparison of diagnostic performance of CECT and CECT plus PET/MRI in detection of distant metastasis

Seven patients had distant metastasis (peritoneum [n = 4], liver [n = 2], and lung [n = 1]). No significant differences were found between pooled AUC, sensitivity, and specificity of CECT and those of CECT plus PET/MRI to detect distant metastasis (pooled AUC, 0.877 vs. 0.983, p = 0.314; pooled sensitivity, 38.1% [8/21] vs. 52.4% [11/21], p = 0.375; pooled specificity, 97.9% [332/339] vs. 99.4% [333/339], p = 0.125).

Predictive factors for RFS in patients who achieved R0 resection

Among 69 patients who achieved R0 resection, 28 (40.6% [28/69]) experienced tumor recurrence during the mean follow-up period of 18.0 ± 11.7 months (range, 0–52), which was clinically confirmed at MDT conferences (n = 22) or pathologically diagnosed through biopsy (n = 6). Tumor recurrence sites were liver (n = 13), local recurrence (n = 8), peritoneum (n = 5), lymph node (n = 3), both liver and peritoneum (n = 2), pleura (n = 1), abdominal wall (n = 1), both liver and lung (n = 1), and liver, lymph node, and peritoneum (n = 1). The estimated one-, three-, and five-year RFS rates were 74.6%, 44.2%, and 23.6%, respectively. FDG avidity at tumor-vessel contact on post-NAT PET (hazard ration [HR] = 2.99, 95% confidence interval [CI] = 1.36–6.55, p = 0.011) was significantly related to RFS, along with sex (HR = 0.46, 95% CI = 0.21–1.00), pathologic T stage (HR = 1.53, 95% CI = 1.06–2.22, p = 0.024), pathologic N stage (HR = 2.16, 95% CI = 1.08–4.32, p = 0.034), lymphatic invasion (HR = 4.08, 95% CI = 1.64–10.17, p = 0.006), vascular invasion (HR = 2.97, 95% CI = 1.38–6.39, p = 0.008), perineural invasion (HR = 2.72, 95% CI = 1.15–6.43, p = 0.015), tumor grade (HR = 1.59, 95% CI = 1.00–2.52, p = 0.048), and tumor regression grade (HR = 1.57, 95% CI = 1.01–2.43, p = 0.037) in univariate analyses (Table 4). Multivariate analyses showed that FDG avidity at tumor-vessel contact on post-NAT PET of PET/MRI (HR = 4.37, 95% CI = 1.13–16.92, p = 0.033) and vascular invasion on pathology (HR = 5.36, 95% CI = 1.73–16.59, p = 0.004) were independent predictors of RFS.

Table 4 Predictive factors for recurrence-free survival in patients who underwent R0 resectionInterobserver agreement of CECT, CECT plus PET/MRI, and CECT plus PET plus CA 19–9 for resectability

Interobserver agreement of CECT, CECT plus PET/MRI, and CECT plus PET plus CA 19–9 for resectability was moderate with ICC of 0.700 (95% CI, 0.621–0.770), 0.667 (95% CI, 0.582–0.743), and 0.703 (95% CI, 0.624–0.772), respectively.

Interobserver agreement for FDG avidity and diffusion restriction at tumor-vessel contact was moderate with ICC of 0.698 (95% CI, 0.622–0.771) and 0.572 (95% CI, 0.473–0.663), respectively.

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