Javed, Ammar A.

Abstract Background Some centres advocate preoperative radiotherapy in patients with pancreatic cancer and arterial involvement despite a lack of Level 1 evidence on survival benefit. Although it has been suggested that preoperative radiotherapy may increase the risk of postpancreatectomy haemorrhage (PPH) and morbidity, evidence is again lacking. This study investigated the association between preoperative radiotherapy and both PPH and major morbidity following arterial divestment/resection during pancreatic adenocarcinoma resection after chemotherapy. Methods Consecutive patients diagnosed with pancreatic adenocarcinoma and > 180° arterial involvement who were treated with preoperative chemotherapy with or without radiotherapy followed by pancreatic resection with arterial divestment/resection were included in the study. Logistic regression analyses including propensity score-based overlap weighting were performed to investigate associations between radiotherapy and in-hospital PPH grade B/C and major morbidity, expressed as adjusted risk differences (aRDs). Results Overall, 246 patients undergoing pancreatic resection with arterial resection (169, 69%) or divestment (77, 31%) were included. Radiotherapy was not associated with PPH (aRD 6%; 95% confidence interval (c.i.) −3 to 14), regardless of arterial divestment (aRD 3%; 95% c.i. −5 to 11) or arterial resection (aRD 12%; 95% c.i. 1 to 23; Pinteraction = 0.189). Radiotherapy was associated with a 14% (95% c.i. 2 to 25) higher risk of major morbidity, especially after arterial resection (aRD 27%; 95% c.i. 11 to 43) compared with arterial divestment (aRD −12%; 95% c.i. −35 to 11; Pinteraction = 0.006) and after external beam radiotherapy (aRD 21%; 95% c.i. 8 to 32) compared with stereotactic body radiotherapy (aRD −12%; 95% c.i. −27 to 6; Pinteraction = 0.0001). Ninety-day mortality was increased, albeit not significantly, after preoperative radiotherapy (10 (8%) versus 3 (3%) deaths with versus without preoperative radiotherapy, respectively; P = 0.067). Conclusions Radiotherapy before resection of pancreatic cancer with > 180° arterial involvement was associated with an increased risk of postoperative major morbidity when arterial resection, but not arterial divestment, was performed. This risk should be taken into account when considering preoperative radiotherapy in patients who may require arterial resection.

Abstract Background The increased use of superior mesenteric artery (SMA) divestment has been a driver behind the increased resection rate for locally advanced pancreatic cancer following preoperative therapy. This has also resulted in an increase in the rate of postoperative neurogenic diarrhoea, but knowledge about postoperative neurogenic diarrhoea is lacking. The aims of this study were to determine the incidence, risk factors, management, and outcomes of neurogenic diarrhoea after SMA divestment/resection for pancreatic adenocarcinoma. Methods This multicentre retrospective study included consecutive patients undergoing pancreatic adenocarcinoma resection, including SMA divestment/resection, after preoperative chemotherapy with or without radiotherapy between 2016 and 2022. Primary endpoints were the incidence of postoperative neurogenic diarrhoea, associated factors, treatment strategies, and outcomes. Secondary endpoints were the rate of adjuvant chemotherapy and the impact of neurogenic diarrhoea on overall survival (OS). Results Overall, 291 patients who underwent pancreatic resection with concomitant SMA divestment (240, 82%) or resection (51, 18%) were included in the study. Postoperative neurogenic diarrhoea was diagnosed in 193 patients. The adjusted risk of developing neurogenic diarrhoea was 59% (95% confidence interval (c.i.) 46 to 73) after ≤ 180° SMA divestment, 80% (95% c.i. 67 to 93) after > 180° SMA divestment, and 77% (95% c.i. 66 to 88) after SMA resection. Postoperative neurogenic diarrhoea was treated with non-opioid drugs (29, 15%), non-opium opioids (140, 73%), opium tincture (69, 36%), and/or octreotide (49, 25%), and normalized in 51% of patients. After adjusting for confounders, neurogenic diarrhoea was not significantly associated with OS (hazard ratio 0.83; 95% c.i. 0.55 to 1.25). Conclusion Neurogenic diarrhoea occurred in two-thirds of patients following resection of pancreatic adenocarcinoma with concomitant SMA divestment/resection, particularly after > 180° SMA divestment or SMA resection. Although challenging to manage, neurogenic diarrhoea is not associated with impaired OS. Evidence-based treatment strategies are needed for adequate management.

Summary of Background Data: Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer is typically managed like pancreatic intraepithelial neoplasia (PanIN)-derived pancreatic cancer. However, in IPMN-derived pancreatic cancer, the role of chemotherapy remains controversial, particularly in the neoadjuvant setting (NAT). Objective: To evaluate the role of neoadjuvant chemotherapy in IPMN-derived pancreatic cancer. Methods: Patients with IPMN-derived pancreatic cancer treated with either upfront surgery (US) or NAT were identified from eight international centers (2000-2023). Clinicopathologic data were compared. Date of first treatment was used for Kaplan-Meier and log-rank tests to compare overall (OS) and recurrence free survival (RFS). Multivariable Cox-regression was performed in patients that underwent NAT. Results: In 1,019 patients, 76 (7%) underwent NAT. Patients who received NAT had higher baseline CA19-9 levels (P<0.001). Of these 76 patients, 27 (36%), 20 (26%), and 29 (38%) had resectable, borderline resectable, or locally advanced pancreatic cancer at diagnosis, respectively. Advanced resectability stage was significantly more common in the NAT patients as compared to those who underwent US (P<0.001). OS for US patients was 38.0 months (95%CI: 33.7.1-44.3), which was not statistically different than those that received NAT [27.5 mo (95%CI: 23.1-46.7), P=0.121]. This was also valid for patients with resectable disease [US: 38.1 mo vs. NAT: 35.6 mo, P=0.920)]. Complete or marked pathological treatment response (P=0.046) and serological CA19-9 normalization after NAT (P=0.017) were associated with improved survival. On Cox-regression for OS, N2 disease [HR: 4.15 (95%CI: 1.71-10.10)], elevated CA19-9 [HR: 2.02 (95%CI:1.06-3.85)] and R1 margin [HR: 2.36 (95%CI:1.20-4.61)] was independently associated with OS after NAT, while resectability status was not. Conclusion: After NAT and resection, advanced resectability stage was not associated with worse OS indicating the value of this approach for borderline resectable and locally advanced IPMN-derived pancreatic cancer. The benefit of NAT in resectable disease is unclear and may require an individualized approach. Biological treatment effect can be assessed with CA19-9 and confirmed by pathologic response.

SEEK and you may find cancer earlier Many cancers can be cured by surgery and/or systemic therapies when detected before they have metastasized. This clinical reality, coupled with the growing appreciation that cancer's rapid genetic evolution limits its response to drugs, have fueled interest in methodologies for earlier detection of the disease. Cohen et al. developed a noninvasive blood test, called CancerSEEK that can detect eight common human cancer types (see the Perspective by Kalinich and Haber). The test assesses eight circulating protein biomarkers and tumor-specific mutations in circulating DNA. In a study of 1000 patients previously diagnosed with cancer and 850 healthy control individuals, CancerSEEK detected cancer with a sensitivity of 69 to 98% (depending on cancer type) and 99% specificity. Science , this issue p. 926 ; see also p. 866

Significance Few patients with pancreatic cancer survive longer than 5 y, in part because most patients are identified only after their disease has progressed to an advanced stage. In this study, we show how combining mutations in circulating tumor DNA (ctDNA) with protein markers can result in a screening test with improved sensitivity while retaining specificity. The combination of the ctDNA and protein markers was superior to any single marker. Moreover, the combination detected nearly two-thirds of pancreatic cancers that had no evidence of distant metastasis at the time of surgical resection. The strategy may represent an approach to detect cancers of many types at an earlier stage.