Evaluation of Short- and Long-Term Outcomes After Resection in Patients with Locally Advanced versus (Borderline) Resectable Pancreatic Cancer.

OBJECTIVE: This study aims to evaluate short- and long-term outcomes following pancreatectomy in patients with LAPC compared to (B)RPC patients. SUMMARY BACKGROUND DATA: Selected patients diagnosed with locally advanced pancreatic cancer (LAPC) are increasingly undergoing resection following induction chemotherapy. To evaluate the benefit of this treatment approach, it is helpful to compare outcomes in resected patients with primary LAPC to outcomes in resected patients with primary (borderline) resectable pancreatic cancer ((B)RPC). METHODS: Two prospectively maintained nationwide databases were used for this study. Patients with (B)RPC undergoing upfront tumor resection and patients with resected LAPC after induction therapy were included. Outcomes were postoperative pancreas-specific complications, 90-day mortality, pathological outcomes, disease-free interval (DFI), and overall survival (OS). RESULTS: Overall, 879 patients were included; 103 with LAPC (12%) and 776 with (B)RPC (88%). LAPC patients had a lower WHO performance score and CACI. Postoperative pancreas-specific complications were comparable between groups, except delayed gastric emptying grade C, which occurred more often in LAPC patients (9% vs. 3%, P=0.03). Ninety-day mortality was comparable. About half of the patients in both groups (54% in LAPC vs. 48% in (B)RPC), P=0.21) had a radical resection (R0). DFI was 13 months in both groups (P=0.12) and OS from date of diagnosis was 24 months in LAPC patients and 19 months in (B)RPC patients (P=0.34). CONCLUSIONS: In our nationwide prospective databases, pancreas-specific complications, mortality and survival in patients with LAPC following pancreatectomy are comparable with those undergoing resection for (B)RPC. These outcomes suggest that postoperative morbidity and mortality after tumor resection in carefully selected patients with LAPC are acceptable.

Minimum and Optimal CA19-9 Response After Two Months Induction Chemotherapy in Patients With Locally Advanced Pancreatic Cancer: A Nationwide Multicenter Study.

OBJECTIVE: This nationwide multicenter study aimed to define clinically relevant thresholds of relative serum CA19-9 response after 2 months of induction chemotherapy in patients with locally advanced pancreatic cancer (LAPC). BACKGROUND: CA19-9 is seen as leading biomarker for response evaluation in patients with LAPC, but early clinically useful cut-offs are lacking. METHODS: All consecutive patients with LAPC after 4 cycles (m)FOLFIRINOX or 2 cycles gemcitabine-nab-paclitaxel induction chemotherapy (±radiotherapy) with CA19-9 ≥5 U/mL at baseline were analyzed (2015-2019). The association of CA19-9 response with median OS (mOS) was evaluated for different CA19-9 cut-off points. Minimum and optimal CA19-9 response were established via log-rank test. Predictors for OS were analyzed using COX regression analysis. RESULTS: Overall, 212 patients were included, of whom 42 (19.8%) underwent resection. Minimum CA19-9 response demonstrating a clinically significant median OS difference (12.7 vs. 19.6 months) was seen at ≥40% CA19-9 decrease. The optimal cutoff for CA19-9 response was ≥60% decrease (21.7 vs. 14.0 mo, P =0.021). Only for patients with elevated CA19-9 levels at baseline (n=184), CA19-9 decrease ≥60% [hazard ratio (HR)=0.59, 95% CI, 0.36-0.98, P =0.042] was independently associated with prolonged OS, as were SBRT (HR=0.42, 95% CI, 0.25-0.70; P =0.001), and resection (HR=0.25, 95% CI, 0.14-0.46, P <0.001), and duration of chemotherapy (HR=0.75, 95% CI, 0.69-0.82, P <0.001). CONCLUSIONS: CA19-9 decrease of ≥60% following induction chemotherapy as optimal response cut-off in patients with LAPC is an independent predictor for OS when CA19-9 is increased at baseline. Furthermore, ≥40% is the minimum cut-off demonstrating survival benefit. These cut-offs may be used when discussing treatment strategies during early response evaluation.

Nationwide Use and Outcome of Surgery for Locally Advanced Pancreatic Cancer Following Induction Chemotherapy.

BACKGROUND: Several international high-volume centers have reported good outcomes after resection of locally advanced pancreatic cancer (LAPC) following chemo(radio)therapy, but it is unclear how this translates to nationwide clinical practice and outcome. This study aims to assess the nationwide use and outcome of resection of LAPC following induction chemo(radio)therapy. PATIENTS AND METHODS: A multicenter retrospective study including all patients who underwent resection for LAPC following chemo(radio)therapy in all 16 Dutch pancreatic surgery centers (2014-2020), registered in the mandatory Dutch Pancreatic Cancer Audit. LAPC is defined as arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion. RESULTS: Overall, 142 patients underwent resection for LAPC, of whom 34.5% met the 2022 National Comprehensive Cancer Network criteria. FOLFIRINOX was the most commonly (93.7%) used chemotherapy [median 5 cycles (IQR 4-8)]. Venous and arterial resections were performed in 51.4% and 14.8% of patients. Most resections (73.9%) were performed in high-volume centers (i.e., ≥ 60 pancreatoduodenectomies/year). Overall median volume of LAPC resections/center was 4 (IQR 1-7). In-hospital/30-day major morbidity was 37.3% and 90-day mortality was 4.2%. Median OS from diagnosis was 26 months (95% CI 23-28) and 5-year OS 18%. Surgery in high-volume centers [HR = 0.542 (95% CI 0.318-0.923)], ypN1-2 [HR = 3.141 (95% CI 1.886-5.234)], and major morbidity [HR = 2.031 (95% CI 1.272-3.244)] were associated with OS. CONCLUSIONS: Resection of LAPC following chemo(radio)therapy is infrequently performed in the Netherlands, albeit with acceptable morbidity, mortality, and OS. Given these findings, a structured nationwide approach involving international centers of excellence would be needed to improve selection of patients with LAPC for surgical resection following induction therapy.

Measurement of metabolite levels and treatment-induced changes in hepatic metastases of gastro-esophageal cancer using 7-T phosphorus magnetic resonance spectroscopic imaging.

Methods for early treatment response evaluation to systemic therapy of liver metastases are lacking. Tumor tissue often exhibits an increased ratio of phosphomonoesters to phosphodiesters (PME/PDE), which can be noninvasively measured by phosphorus magnetic resonance spectroscopy (31P MRS), and may be a marker for early therapy response assessment in liver metastases. However, with commonly used 31P surface coils for liver 31P MRS, the liver is not fully covered, and metastases may be missed. The objective of this study was to demonstrate the feasibility of 31P MRS imaging (31P MRSI) with full liver coverage to assess 31P metabolite levels and chemotherapy-induced changes in liver metastases of gastro-esophageal cancer, using a 31P whole-body birdcage transmit coil in combination with a 31P body receive array at 7 T. 3D 31P MRSI data were acquired in two patients with hepatic metastases of esophageal cancer, before the start of chemotherapy and after 2 (and 9 in patient 2) weeks of chemotherapy. 3D 31P MRSI acquisitions were performed using an integrated 31P whole-body transmit coil in combination with a 16-channel body receive array at 7 T, with a field of view covering the full abdomen and a nominal voxel size of 20-mm isotropic. From the 31P MRSI data, 12 31P metabolite signals were quantified. Prior to chemotherapy initiation, both PMEs, that is, phosphocholine (PC) and phosphoethanolamine (PE), were significantly higher in all metastases compared with the levels previously determined in the liver of healthy volunteers. After 2 weeks of chemotherapy, PC and PE levels remained high or even increased further, resulting in increased PME/PDE ratios compared with healthy liver tissue, in correspondence with the clinical assessment of progressive disease after 2 months of chemotherapy. The suggested approach may present a viable tool for early therapy (non)response assessment of tumor metabolism in patients with liver metastases.

31 P MR Spectroscopy in the Pancreas: Repeatability, Comparison With Liver, and Pilot Pancreatic Cancer Data.

BACKGROUND: Non-invasive evaluation of phosphomonoesters (PMEs) and phosphodiesters (PDEs) by 31-phosphorus MR spectroscopy (31 P MRS) may have potential for early therapy (non-)response assessment in cancer. However, 31 P MRS has not yet been applied to investigate the human pancreas in vivo. PURPOSE: To assess the technical feasibility and repeatability of 31 P MR spectroscopic imaging (MRSI) of the pancreas, compare 31 P metabolite levels between pancreas and liver, and determine the feasibility of 31 P MRSI in pancreatic cancer. STUDY TYPE: Prospective cohort study. POPULATION: 10 healthy subjects (age 34 ± 12 years, four females) and one patient (73-year-old female) with pancreatic ductal adenocarcinoma. FIELD STRENGTH/SEQUENCE: 7-T, 31 P FID-MRSI, 1 H gradient-echo MRI. ASSESSMENT: 31 P FID-MRSI of the abdomen (including the pancreas and liver) was performed with a nominal voxel size of 20 mm (isotropic). For repeatability measurements, healthy subjects were scanned twice on the same day. The patient was only scanned once. Test-retest 31 P MRSI data of pancreas and liver voxels (segmented on 1 H MRI) of healthy subjects were quantified by fitting in the time domain and signal amplitudes were normalized to γ-adenosine triphosphate. In addition, the PME/PDE ratio was calculated. Metabolite levels were averaged over all voxels within the pancreas, right liver lobe and left liver lobe, respectively. STATISTICAL TESTS: Repeatability of test-retest data from healthy pancreas was assessed by paired t-tests, Bland-Altman analyses, and calculation of the intrasubject coefficients of variation (CoVs). Significant differences between healthy pancreas and right and left liver lobes were assessed with a two-way analysis of variance (ANOVA) for repeated measures. A P-value <0.05 was considered statistically significant. RESULTS: The intrasubject CoVs for PME, PDE, and PME/PDE in healthy pancreas were below 20%. Furthermore, PME and PME/PDE were significantly higher in pancreas compared to liver. In the patient with pancreatic cancer, qualitatively, elevated relative PME signals were observed in comparison with healthy pancreas. DATA CONCLUSION: In vivo 31 P MRSI of the human healthy pancreas and in pancreatic cancer may be feasible at 7 T. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Early Recurrence After Resection of Locally Advanced Pancreatic Cancer Following Induction Therapy: An International Multicenter Study.

OBJECTIVE: To establish an evidence-based cutoff and predictors for early recurrence in patients with resected locally advanced pancreatic cancer (LAPC). BACKGROUND: It is unclear how many and which patients develop early recurrence after LAPC resection. Surgery in these patients is probably of little benefit. METHODS: We analyzed all consecutive patients undergoing resection of LAPC after induction chemotherapy who were included in prospective databases in The Netherlands (2015-2019) and the Johns Hopkins Hospital (2016-2018). The optimal definition for "early recurrence" was determined by the post-recurrence survival (PRS). Patients were compared for overall survival (OS). Predictors for early recurrence were evaluated using logistic regression analysis. RESULTS: Overall, 168 patients were included. After a median follow-up of 28 months, recurrence was observed in 118 patients (70.2%). The optimal cutoff for recurrence-free survival to differentiate between early (n=52) and late recurrence (n=66) was 6 months ( P <0.001). OS was 8.4 months [95% confidence interval (CI): 7.3-9.6] in the early recurrence group (n=52) versus 31.1 months (95% CI: 25.7-36.4) in the late/no recurrence group (n=116) ( P <0.001). A preoperative predictor for early recurrence was postinduction therapy carbohydrate antigen (CA) 19-9≥100 U/mL [odds ratio (OR)=4.15, 95% CI: 1.75-9.84, P =0.001]. Postoperative predictors were poor tumor differentiation (OR=4.67, 95% CI: 1.83-11.90, P =0.001) and no adjuvant chemotherapy (OR=6.04, 95% CI: 2.43-16.55, P <0.001). CONCLUSIONS: Early recurrence was observed in one third of patients after LAPC resection and was associated with poor survival. Patients with post-induction therapy CA 19-9 ≥100 U/mL, poor tumor differentiation and no adjuvant therapy were especially at risk. This information is valuable for patient counseling before and after resection of LAPC.

In vivo phosphorus magnetic resonance spectroscopic imaging of the whole human liver at 7 T using a phosphorus whole-body transmit coil and 16-channel receive array: Repeatability and effects of principal component analysis-based denoising.

Quantitative three-dimensional (3D) imaging of phosphorus (31 P) metabolites is potentially a promising technique with which to assess the progression of liver disease and monitor therapy response. However, 31 P magnetic resonance spectroscopy has a low sensitivity and commonly used 31 P surface coils do not provide full coverage of the liver. This study aimed to overcome these limitations by using a 31 P whole-body transmit coil in combination with a 16-channel 31 P receive array at 7 T. Using this setup, we determined the repeatability of whole-liver 31 P magnetic resonance spectroscopic imaging (31 P MRSI) in healthy subjects and assessed the effects of principal component analysis (PCA)-based denoising on the repeatability parameters. In addition, spatial variations of 31 P metabolites within the liver were analyzed. 3D 31 P MRSI data of the liver were acquired with a nominal voxel size of 20 mm isotropic in 10 healthy volunteers twice on the same day. Data were reconstructed without denoising, and with PCA-based denoising before or after channel combination. From the test-retest data, repeatability parameters for metabolite level quantification were determined for 12 31 P metabolite signals. On average, 31 P MR spectra from 100 ± 25 voxels in the liver were analyzed. Only voxels with contamination from skeletal muscle or the gall bladder were excluded and no voxels were discarded based on (low) signal-to-noise ratio (SNR). Repeatability for most quantified 31 P metabolite levels in the liver was good to excellent, with an intrasubject variability below 10%. PCA-based denoising increased the SNR ~ 3-fold, but did not improve the repeatability for mean liver 31 P metabolite quantification with the fitting constraints used. Significant spatial heterogeneity of various 31 P metabolite levels within the liver was observed, with marked differences for the phosphomonoester and phosphodiester metabolites between the left and right lobe. In conclusion, using a 31 P whole-body transmit coil in combination with a 16-channel 31 P receive array at 7 T allowed 31 P MRSI acquisitions with full liver coverage and good to excellent repeatability.

Prospective of 31 P MR Spectroscopy in Hepatopancreatobiliary Cancer: A Systematic Review of the Literature.

BACKGROUND: The incidence of liver and pancreatic cancer is rising. Patients benefit from current treatments, but there are limitations in the evaluation of (early) response to treatment. Tumor metabolic alterations can be measured noninvasively with phosphorus (31 P) magnetic resonance spectroscopy (MRS). PURPOSE: To conduct a quantitative analysis of the available literature on 31 P MRS performed in hepatopancreatobiliary cancer and to provide insight into its current and potential for therapy (non-) response assessment. POPULATION: Patients with hepatopancreatobiliary cancer. FIELD STRENGTH/SEQUENCE: 31 P MRS. ASSESSMENT: The PubMed, EMBASE, and Cochrane library databases were systematically searched for studies published to 17 March 17, 2022. All 31 P MRS studies in hepatopancreatobiliary cancer reporting 31 P metabolite levels were included. STATISTICAL TESTS: Relative differences in 31 P metabolite levels/ratios between patients before therapy and healthy controls, and the relative changes in 31 P metabolite levels/ratios in patients before and after therapy were determined. RESULTS: The search yielded 10 studies, comprising 301 subjects, of whom 132 (44%) healthy volunteers and 169 (56%) patients with liver cancer of various etiology. To date, 31 P MRS has not been applied in pancreatic cancer. In liver cancer, alterations in levels of 31 P metabolites involved in cell proliferation (phosphomonoesters [PMEs] and phosphodiesters [PDEs]) and energy metabolism (ATP and inorganic phosphate [Pi]) were observed. In particular, liver tumors were associated with elevations of PME/PDE and PME/Pi compared to healthy liver tissue, although there was a broad variety among studies (elevations of 2%-267% and 21%-233%, respectively). Changes in PME/PDE in liver tumors upon therapy were substantial, yet very heterogeneous and both decreases and increases were observed, whereas PME/Pi was consistently decreased after therapy in all studies (-13% to -76%). DATA CONCLUSION: 31 P MRS has great potential for treatment monitoring in oncology. Future studies are needed to correlate the changes in 31 P metabolite levels in hepatopancreatobiliary tumors with treatment response. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Yield of Screening for COVID-19 in Asymptomatic Patients Before Elective or Emergency Surgery Using Chest CT and RT-PCR (SCOUT): Multicenter Study.

OBJECTIVE: To determine the yield of preoperative screening for COVID-19 with chest CT and RT-PCR in patients without COVID-19 symptoms. SUMMARY OF BACKGROUND DATA: Many centers are currently screening surgical patients for COVID-19 using either chest CT, RT-PCR or both, due to the risk for worsened surgical outcomes and nosocomial spread. The optimal design and yield of such a strategy are currently unknown. METHODS: This multicenter study included consecutive adult patients without COVID-19 symptoms who underwent preoperative screening using chest CT and RT-PCR before elective or emergency surgery under general anesthesia. RESULTS: A total of 2093 patients without COVID-19 symptoms were included in 14 participating centers; 1224 were screened by CT and RT-PCR and 869 by chest CT only. The positive yield of screening using a combination of chest CT and RT-PCR was 1.5% [95% confidence interval (CI): 0.8-2.1]. Individual yields were 0.7% (95% CI: 0.2-1.1) for chest CT and 1.1% (95% CI: 0.6-1.7) for RT-PCR; the incremental yield of chest CT was 0.4%. In relation to COVID-19 community prevalence, up to ∼6% positive RT-PCR was found for a daily hospital admission rate >1.5 per 100,000 inhabitants, and around 1.0% for lower prevalence. CONCLUSIONS: One in every 100 patients without COVID-19 symptoms tested positive for SARS-CoV-2 with RT-PCR; this yield increased in conjunction with community prevalence. The added value of chest CT was limited. Preoperative screening allowed us to take adequate precautions for SARS-CoV-2 positive patients in a surgical population, whereas negative patients needed only routine procedures.

Preoperative chemotherapy, radiotherapy and surgical decision-making in patients with borderline resectable and locally advanced pancreatic cancer.

Surgical resection combined with systemic chemotherapy is the cornerstone of treatment for patients with localized pancreatic cancer. Upfront surgery is considered suboptimal in cases with extensive vascular involvement, which can be classified as either borderline resectable pancreatic cancer or locally advanced pancreatic cancer. In these patients, FOLFIRINOX or gemcitabine plus nab-paclitaxel chemotherapy is currently used as preoperative chemotherapy and is eventually combined with radiotherapy. Thus, more patients might reach 5-year overall survival. Patient selection for chemotherapy, radiotherapy and subsequent surgery is based on anatomical, biological and conditional parameters. Current guidelines and clinical practices vary considerably regarding preoperative chemotherapy and radiotherapy, response evaluation, and indications for surgery. In this Review, we provide an overview of the clinical evidence regarding disease staging, preoperative therapy, response evaluation and surgery in patients with borderline resectable pancreatic cancer or locally advanced pancreatic cancer. In addition, a clinical work-up is proposed based on the available evidence and guidelines. We identify knowledge gaps and outline a proposed research agenda.

[Resection of locally advanced pancreatic cancer: careful selection and shared decision making]. / Resectie van het lokaal gevorderd pancreascarcinoom.

The landscape regarding the treatment possibilities for patients with locally advanced pancreatic cancer (LAPC) has changed over the last decade. The introduction of modern multi-agent chemotherapeutic regimens (i.e., FOLFIRINOX and gemcitabine/nab-paclitaxel) has improved outcomes. A minority, but still a substantial group of patients, nowadays undergo surgical resection after induction chemotherapy, providing a chance of long-term overall survival comparable to (borderline) resectable pancreatic cancer. However, selecting appropriate candidates for surgery after induction chemotherapy remains challenging, as surgery includes substantial risks which should not outweigh the potential survival benefit. Shared decision making is crucial as patients usually overestimate the value of resection. Here, we present two patients with LAPC who underwent surgical resection, but both with various work-up strategies, leading to different outcomes. These patients highlight the importance of a multidisciplinary approach to select appropriate candidates for the best treatment option, avoiding futile surgery.