Neoadjuvant radioimmunotherapy in pancreatic cancer enhances effector T cell infiltration and shortens their distances to tumor cells.

Radiotherapy is hypothesized to have an immune-modulating effect on the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) to sensitize it to anti-PD-1 antibody (a-PD-1) treatment. We collected paired pre- and posttreatment specimens from a clinical trial evaluating combination treatment with GVAX vaccine, a-PD-1, and stereotactic body radiation (SBRT) following chemotherapy for locally advanced PDACs (LAPC). With resected PDACs following different neoadjuvant therapies as comparisons, effector cells in PDACs were found to skew toward a more exhausted status in LAPCs following chemotherapy. The combination of GVAX/a-PD-1/SBRT drives TME to favor antitumor immune response including increased densities of GZMB+CD8+ T cells, TH1, and TH17, which are associated with longer survival, however increases immunosuppressive M2-like tumor-associated macrophages (TAMs). Adding SBRT to GVAX/a-PD-1 shortens the distances from PD-1+CD8+ T cells to tumor cells and to PD-L1+ myeloid cells, which portends prolonged survival. These findings have guided the design of next radioimmunotherapy studies by targeting M2-like TAM in PDACs.

Surgical and local control outcomes after sequential short-course radiation therapy and chemotherapy for rectal cancer.

Background: Total neoadjuvant therapy (TNT) is an accepted approach for the management of locally advanced rectal cancer (LARC) and is associated with a decreased risk of development of metastatic disease compared to standard neoadjuvant therapy. However, questions remain regarding surgical outcomes and local control in patients who proceed to surgery, particularly when radiation is given first in the neoadjuvant sequence. We report on our institution's experience with patients who underwent short-course radiation therapy, consolidation chemotherapy, and surgery. Methods: We retrospectively reviewed surgical specimen outcomes, postoperative complications, and local/pelvic control in a large cohort of patients with LARC who underwent neoadjuvant therapy incorporating upfront short-course radiation therapy followed by consolidation chemotherapy. Results: In our cohort of 83 patients who proceeded to surgery, a complete/near-complete mesorectal specimen was achieved in 90 % of patients. This outcome was not associated with the time interval from completion of radiation to surgery. Postoperative complications were acceptably low. Local control at two years was 93.4 % for all patients- 97.6 % for those with low-risk disease and 90.4 % for high-risk disease. Conclusion: Upfront short-course radiation therapy and consolidation chemotherapy is an effective treatment course. Extended interval from completion of short-course radiation therapy did not impact surgical specimen quality.

Circulating Tumor DNA to Predict Radiographic and Pathologic Response to Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer.

Despite advances in treatment and response assessment in locally advanced rectal cancer (LARC), it is unclear which patients should undergo nonoperative management (NOM). We performed a single-center, retrospective study to evaluate post-total neoadjuvant therapy (TNT) circulating tumor DNA (ctDNA) in predicting treatment response. We found that post-TNT ctDNA had a sensitivity of 23% and specificity of 100% for predicting residual disease upon resection, with a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 47%. For predicting poor tumor regression on MRI, ctDNA had a sensitivity of 16% and specificity of 96%, with a PPV of 75% and NPV of 60%. A commercially available ctDNA assay was insufficient to predict residual disease after TNT and should not be used alone to select patients for NOM in LARC.

A Multi-Institutional Safety and Feasibility Study Exploring the Use of Hydrogel to Create Spatial Separation between the Pancreas and Duodenum in Patients with Pancreatic Cancer.

PURPOSE: The administration of dose-escalated radiation for pancreatic adenocarcinoma remains challenging because of the proximity of dose-limiting stomach and bowel, particularly the duodenum for pancreatic head tumors. We explore whether endoscopic injection of a temporary, absorbable hydrogel into the pancreatico-duodenal (PD) groove is safe and feasible for the purpose of increasing spatial separation between pancreatic head tumors and the duodenum. METHODS AND MATERIALS: Six patients with localized pancreatic adenocarcinoma underwent endoscopic injection of hydrogel into the PD groove. Safety was assessed based on the incidence of procedure-related adverse events resulting in a delay of radiation therapy initiation. Feasibility was defined as the ability to create spatial separation between the pancreas and duodenum, as assessed on simulation CT. RESULTS: All 6 patients were able to undergo endoscopic injection of hydrogel into the PD groove. No device-related events were experienced at any point in follow-up. Presence of hydrogel in the PD groove was apparent on simulation CT in all 6 patients. Mean space created by the hydrogel was 7.7 mm +/- 2.4 mm. In 3 patients who underwent Whipple resection, presence of hydrogel in the PD groove was pathologically confirmed with no evidence of damage to the duodenum. CONCLUSIONS: Endoscopic injection of hydrogel into the PD groove is safe and feasible. Characterization of the dosimetric benefit that this technique may offer in the setting of dose-escalated radiation should also be pursued, as should the ability of such dosimetric benefit to translate into clinically improved tumor control.

Challenges and opportunities in stereotactic body proton radiotherapy of liver malignancies.

Stereotactic body proton radiotherapy (SBPT) has the potential to be an effective tool for treating liver malignancies. While proton therapy enables near-zero exit dose and could improve normal tissue sparing, including liver and other surrounding structures, there are challenges in implementing the SBPT technique for proton therapy, including respiratory motion, range uncertainties, dose regimen, treatment planning, and image guidance. This article summarizes the technical and clinical challenges facing SBPT, along with the potential benefits of SBPT for liver malignancies. The clinical implementation of the technique is also described for the first six patients treated at the Johns Hopkins Proton Therapy Center using liver SBPT.

Inter-Breath-Hold Geometric and Dosimetric Variations in Organs at Risk during Pancreatic Stereotactic Body Radiotherapy: Implications for Adaptive Radiation Therapy.

Pancreatic cancer is the fourth leading cause of cancer-related death, with nearly 60,000 cases each year and less than a 10% 5-year overall survival rate. Radiation therapy (RT) is highly beneficial as a local-regional anticancer treatment. As anatomical variation is of great concern, motion management techniques, such as DIBH, are commonly used to minimize OARs toxicities; however, the variability between DIBHs has not been well studied. Here, we present an unprecedented systematic analysis of patients' anatomical reproducibility over multiple DIBH motion-management technique uses for pancreatic cancer RT. We used data from 20 patients; four DIBH scans were available for each patient to design 80 SBRT plans. Our results demonstrated that (i) there is considerable variation in OAR geometry and dose between same-subject DIBH scans; (ii) the RT plan designed for one scan may not be directly applicable to another scan; (iii) the RT treatment designed using a DIBH simulation CT results in different dosimetry in the DIBH treatment delivery; and (iv) this confirms the importance of adaptive radiation therapy (ART), such as MR-Linacs, for pancreatic RT delivery. The ART treatment delivery technique can account for anatomical variation between referenced and scheduled plans, and thus avoid toxicities of OARs because of anatomical variations between DIBH patient setups.

Comparative In Silico Analysis of Ultra-Hypofractionated Intensity-Modulated Photon Radiotherapy (IMRT) Versus Intensity-Modulated Proton Therapy (IMPT) in the Pre-Operative Treatment of Retroperitoneal Sarcoma.

BACKGROUND: While pre-operative radiation did not improve abdominal recurrence-free survival for retroperitoneal sarcoma (RPS) in the randomized STRASS trial, it did reduce rates of local recurrence. However, the risk of toxicity was substantial and the time to surgery was prolonged. A combination of hypofractionation and proton therapy may reduce delays from the initiation of radiation to surgery and limit the dose to surrounding organs at risk (OARs). We conducted a dosimetric comparison of the pre-operative ultra-hypofractionated intensity-modulated photon (IMRT) and proton radiotherapy (IMPT). METHODS: Pre-operative IMRT and IMPT plans were generated on 10 RPS patients. The prescription was 25 Gy radiobiological equivalents (GyEs) (radiobiological effective dose of 1.1) to the clinical target volume and 30 GyEs to the margin at risk, all in five fractions. Comparisons were made using student T-tests. RESULTS: The following endpoints were significantly lower with IMPT than with IMRT: mean doses to liver, bone, and all genitourinary and gastrointestinal OARs; bowel, kidney, and bone V5-V20; stomach V15; liver V5; maximum doses to stomach, spinal canal, and body; and whole-body integral dose. CONCLUSIONS: IMPT maintained target coverage while significantly reducing the dose to adjacent OARs and integral dose compared to IMRT. A prospective trial treating RPS with pre-operative ultra-hypofractionated IMPT at our institution is currently being pursued.

Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma.

A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.

Effectiveness of the nutrition referral system in a multidisciplinary pancreatic cancer clinic.

PURPOSE: Proactive nutrition screening and intervention is associated with improved outcomes for patients with pancreatic adenocarcinoma (PDAC). To better optimize nutrition amongst our PDAC population, we implemented systematic malnutrition screening in the Johns Hopkins pancreas multidisciplinary clinic (PMDC) and assessed the effectiveness of our nutrition referral system. METHODS: This was a single institution prospective study of patients seen in the PMDC, screened for malnutrition using the Malnutrition Screening Tool (MST) (score range=0 to 5, score > 2 indicates risk of malnutrition), and offered referrals to the oncology dietitian. Patients that requested a referral but did not attend a nutrition appointment were contacted by phone to assess barriers to seeing the dietitian. Univariate (UVA) and multivariable (MVA) analyses were carried out to identify predictors of referral status and appointment completion status. RESULTS: A total of 97 patients were included in the study, of which 72 (74.2%) requested a referral and 25 (25.8%) declined. Of the 72 patients who requested a referral, 31 (43.1%) attended an appointment with the oncology dietitian. Data on information session attendance was available for 35 patients, of which 8 (22.9%) attended a pre-clinic information session in which the importance of optimal nutrition was highlighted. On MVA, information session attendance was significantly associated with requesting a referral (OR: 11.1, 95% CI 1.12-1.0E3, p=0.037) and successfully meeting with the oncology dietitian (OR: 5.88, 95% CI 1.00-33.3, p=0.049). CONCLUSION: PMDC teams should institute educational initiatives on the importance of optimal nutrition in order to increase patient engagement with nutrition services.

Advances in Radiotherapy for Rectal Cancer.

The current preferred standard of care management for patients with locally advanced rectal cancer is total neoadjuvant therapy, in which all chemotherapy and radiotherapy is delivered before surgery. Within this approach, developed in response to persistently high distant failure rates despite excellent local control with preoperative chemoradiotherapy, there remains questions regarding the optimal radiotherapy regimen (short course vs long course) and sequencing of chemotherapy (induction vs consolidation).

The Timing of Surgery Following Stereotactic Body Radiation Therapy Impacts Local Control for Borderline Resectable or Locally Advanced Pancreatic Cancer.

We aimed to evaluate the impact of time from stereotactic body radiation therapy (SBRT) to surgery on treatment outcomes and post-operative complications in patients with borderline resectable or locally advanced pancreatic cancer (BRPC/LAPC). We conducted a single-institutional retrospective analysis of patients with BRPC/LAPC treated from 2016 to 2021 with neoadjuvant chemotherapy followed by SBRT and surgical resection. Covariates were stratified by time from SBRT to surgery. A Cox regression model was used to identify variables associated with survival outcomes. In 171 patients with BRPC/LAPC, the median time from SBRT to surgery was 6.4 (range: 2.7-25.3) weeks. Hence, patients were stratified by the timing of surgery: ≥6 and <6 weeks after SBRT. In univariable Cox regression, surgery ≥6 weeks was associated with improved local control (LC, HR 0.55, 95% CI 0.30-0.98; p = 0.042), pathologic node positivity, elevated baseline CA19-9, and inferior LC if of the male sex. In multivariable analysis, surgery ≥6 weeks (p = 0.013; HR 0.46, 95%CI 0.25-0.85), node positivity (p = 0.019; HR 2.09, 95% CI 1.13-3.88), and baseline elevated CA19-9 (p = 0.002; HR 2.73, 95% CI 1.44-5.18) remained independently associated with LC. Clavien-Dindo Grade ≥3B complications occurred in 4/63 (6.3%) vs. 5/99 (5.5%) patients undergoing surgery <6 weeks and ≥6 weeks after SBRT (p = 0.7). In summary, the timing of surgery ≥6 weeks after SBRT was associated with improved local control and low post-operative complication rates, irrespective of the surgical timing. Further investigation of the influence of surgical timing following radiotherapy is warranted.

Postoperative surveillance of pancreatic ductal adenocarcinoma (PDAC) recurrence: practice pattern on standardized imaging and reporting from the society of abdominal radiology disease focus panel on PDAC.

PURPOSE: Surgical resection is the only potential curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC), but unfortunately most patients recur within 5 years of surgery. This article aims to assess the practice patterns across major academic institutions and develop consensus recommendations for postoperative imaging and interpretation in patients with PDAC. METHODS: The consensus recommendations for postoperative imaging surveillance following PDAC resection were developed using the Delphi method. Members of the Society of Abdominal Radiology (SAR) PDAC Disease Focused Panel (DFP) underwent three rounds of surveys followed by live webinar group discussions to develop consensus recommendations. RESULTS: Significant variations currently exist in the postoperative surveillance of PDAC, even among academic institutions. Differentiating common postoperative inflammatory and fibrotic changes from tumor recurrence remains a diagnostic challenge, and there is no reliable size threshold or growth rate of imaging findings that can provide differentiation. A new liver lesion or peritoneal nodule should be considered suspicious for tumor recurrence, and the imaging features should be interpreted in the appropriate clinical context (e.g., CA 19-9, clinical presentation, pathologic staging). CONCLUSION: Postoperative imaging following PDAC resection is challenging to interpret due to the presence of confounding postoperative inflammatory changes. A standardized reporting template for locoregional findings and report impression may improve communication of relaying risk of recurrence with referring providers, which merits validation in future studies.

Patterns and kinetics of hepatocellular carcinoma relapse post-liver transplantation: oligorecurrence and role of local therapies.

Background: Amongst patients with recurrent hepatocellular carcinoma (HCC) post-liver transplantation, systemic therapy options may be limited by immunosuppression or poor performance status. Thus, we aimed to assess the impact of metastasis-directed therapy to all sites of disease (MDT-All) in HCC patients with limited disease recurrence [i.e., oligorecurrence (oligoM1)] post-transplantation and characterize pre-transplant characteristics associated with oligoM1. Methods: In this retrospective cohort study, patients at a single institution with recurrent HCC post-liver transplantation were identified. OligoM1 disease was defined as ≤3 lesions at recurrence, while polyrecurrent (polyM1) disease was defined as >3 lesions. Outcomes were compared in patients with oligoM1 disease by receipt of MDT-All. Regression analyses were used to identify predictors of polyM1 disease and characteristics associated with post-recurrence outcomes. Results: Forty-three patients with recurrent HCC post-liver transplantation from 2005-2022 were identified. Twenty-seven (63%) patients had oligoM1. Microvascular invasion was independently associated with polyM1 [odds ratio (OR): 14.64; 95% confidence interval (CI): 1.48-144.77; P=0.022]. Elevated alpha-fetoprotein (AFP) ≥400 ng/mL [hazard ratio (HR): 2.44; 95% CI: 1.08, 5.52; P=0.033] at recurrence was independently associated with inferior overall survival (OS), while oligoM1 (HR: 0.42; 95% CI: 0.21, 0.87; P=0.018) was independently associated with favorable OS. Amongst patients with oligoM1 who received MDT-All (n=15) median OS was 38.4 vs. 16.1 months for those who did not receive MDT-All (log-rank P=0.021). There was a non-significant improvement in polyprogression-free survival (polyPFS) (median 14.0 vs. 10.7 months, P=0.1) amongst oligoM1 patients who received MDT-All compared to those who did not. Conclusions: Receipt of MDT-All was associated with improved OS amongst patients with limited HCC disease recurrence following liver transplantation.

Multiagent Chemotherapy Followed by Stereotactic Body Radiotherapy Versus Conventional Radiotherapy for Resected Pancreas Cancer.

BACKGROUND AND PURPOSE: Chemotherapy followed by margin-negative resection (R0) is the treatment of choice for patients with localized pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant multiagent chemotherapy (MAC) or MAC then radiotherapy (RT) may optimize surgical candidacy. The purpose of this study was to compare pathologic outcomes of MAC followed by conventionally fractionated radiotherapy (CRT) versus stereotactic body radiotherapy (SBRT) for patients with resected PDAC. METHODS: Patients diagnosed with nonmetastatic PDAC between 2012 and 2017 and who received preoperative MAC or MAC+RT were identified in the National Cancer Database. Variables associated with R0 and overall survival were identified with logistic regression and Cox analysis (P<0.05). RESULTS: A total of 5273 patients were identified (MAC: 3900, MAC+CRT: 955, MAC+SBRT: 418). The median RT dose/fraction (fx) in the MAC+CRT and MAC+SBRT cohorts was 50.4 Gy/28 fx and 33 Gy/5 fx. Patients receiving MAC+CRT versus MAC+SBRT had similar rates of ypT3-T4 disease (54% vs. 58%, P=0.187), R0 (87% vs. 84%, P=0.168), and pathologic complete response (pathologic complete response; 6% vs. 4%, P=0.052), however, MAC+CRT was associated with less regional lymphatic disease (ypN+: 28% vs. 41%, P<0.001). The median overall survival of patients receiving MAC+CRT versus MAC+SBRT was 24.6 versus 29.5 months (P=0.045). CONCLUSIONS: For patients with resected PDAC, MAC+CRT, and MAC+SBRT had similar rates of R0 and pathologic complete response, although MAC+CRT was associated with lower ypN+. Prospective evaluation of neoadjuvant RT regimens with attention to radiation therapy design is warranted.

Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy.

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teff). We prospectively collected and applied multi-omic analyses to paired pre- and post-treatment PDAC specimens collected in a platform neoadjuvant study of granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDAC vaccine (GVAX) vaccine ± nivolumab (anti-programmed cell death protein 1 [PD-1]) to uncover sensitivity and resistance mechanisms. We show that GVAX-induced tertiary lymphoid aggregates become immune-regulatory sites in response to GVAX + nivolumab. Higher densities of tumor-associated neutrophils (TANs) following GVAX + nivolumab portend poorer overall survival (OS). Increased T cells expressing CD137 associated with cytotoxic Teff signatures and correlated with increased OS. Bulk and single-cell RNA sequencing found that nivolumab alters CD4+ T cell chemotaxis signaling in association with CD11b+ neutrophil degranulation, and CD8+ T cell expression of CD137 was required for optimal T cell activation. These findings provide insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include TAN regulators and T cell activators.

A safety study of intraoperative radiation therapy following stereotactic body radiation therapy and multi-agent chemotherapy in the treatment of localized pancreatic adenocarcinoma: study protocol of a phase I trial.

BACKGROUND: Localized pancreatic adenocarcinoma carries a poor prognosis even after aggressive therapy. Up to 40% of patients may develop locoregional disease as the first site of failure. As such, there may be a role for intensification of local therapy such as radiation therapy. Radiation dose escalation for pancreatic cancer is limited by proximity of the tumor to the duodenum. However, the duodenum is removed during Whipple procedure, allowing the opportunity to dose escalate with intraoperative radiation therapy (IORT). Although prior studies have shown potential benefit of IORT in pancreatic cancer, these studies did not utilize ablative doses (biologically effective dose [BED10] > 100 Gy). Furthermore, the optimal radiation target volume in this setting is unclear. There has been increased interest in a "Triangle Volume" (TV), bordered by the celiac axis, superior mesenteric artery, common hepatic artery, portal vein, and superior mesenteric vein. Dissection of this area, has been advocated for by surgeons from Heidelberg as it contains extra-pancreatic perineural and lymphatic tracts, which may harbor microscopic disease at risk of mediating local failure. Interestingly, a recent analysis from our institution indicated that nearly all local failures occur in the TV. Therefore, the purpose of this protocol is to evaluate the safety of delivering an ablative radiation dose to the TV with IORT following neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT). METHODS: Patients with non-metastatic pancreatic adenocarcinoma centered in the head or neck of the pancreas will be enrolled. Following treatment with multi-agent neoadjuvant chemotherapy, patients will undergo SBRT (40 Gy/5 fractions) followed by IORT (15 Gy/1 fraction) to the TV during the Whipple procedure. The primary objective is acute (< 90 days) toxicity after IORT measured by Clavien-Dindo classification. Secondary objectives include late (> 90 days) toxicity after IORT measured by Clavien-Dindo classification, overall survival, local progression-free survival, distant metastasis-free survival, and progression-free survival. DISCUSSION: If the results show that delivering an ablative radiation dose to the TV with IORT after neoadjuvant chemotherapy and SBRT is safe and feasible, it warrants further investigation in a phase II trial to evaluate efficacy of this approach. Trial Registration This study was registered at ClinicalTrials.gov on 12/2/2021 (NCT05141513). https://clinicaltrials.gov/ct2/show/NCT05141513.

Risk of Pancreatic Cancer in the Long-Term Prospective Follow-Up of Familial Pancreatic Cancer Kindreds.

BACKGROUND: A family history of pancreatic cancer is associated with increased pancreatic cancer risk. However, risk estimates for individuals in kindreds with an aggregation of pancreatic cancer (>1 relative) are imprecise because of small samples sizes or potentially impacted by biases inherent in retrospective data. OBJECTIVE: The objective of this study is to determine the age-specific pancreatic cancer risk as a function of family history using prospective data. METHODS: We compared pancreatic cancer incidence (n = 167) in 21 141 individuals from 4433 families enrolled in the National Familial Pancreatic Cancer Registry with that expected based on Surveillance Epidemiology and End Results data and estimated the cumulative probability of pancreatic cancer using competing risk regression. RESULTS: Familial pancreatic kindred members (kindreds with pancreatic cancer in 2 first-degree relatives [FDRs] or a pathogenic variant) had a standardized incidence ratio of 4.86 (95% confidence interval [CI] = 4.01 to 5.90), and sporadic kindred members (kindreds not meeting familial criteria) had a standardized incidence ratio of 2.55 (95% CI = 1.95 to 3.34). Risk in familial pancreatic cancer kindreds increased with an increasing number of FDRs with pancreatic cancer, with a standardized incidence ratio of 3.46 (95% CI = 2.52 to 4.76), 5.44 (95% CI = 4.07 to 7.26), and 10.78 (95% CI = 6.87 to 16.89) for 1, 2, and 3 or more FDRs with pancreatic cancer, respectively. Risk was also higher among individuals with a family history of young-onset (aged younger than 50 years) pancreatic cancer. CONCLUSION: Pancreatic cancer risk is strongly dependent on family history, including both the degree of relationship(s) and age of onset of pancreatic cancer in relatives. These risk estimates will help inform the design of early detection studies and the risk and benefit analysis of screening trials.

Post-radiation neutrophil-to-lymphocyte ratio is a prognostic marker in patients with localized pancreatic adenocarcinoma treated with anti-PD-1 antibody and stereotactic body radiation therapy.

PURPOSE: To investigate the role of pre- and post-stereotactic body radiation therapy (SBRT) neutrophil-to-lymphocyte ratio (NLR) in patients with localized pancreatic cancer treated with anti-PD-1 (programmed cell death protein-1) antibody and SBRT. MATERIALS AND METHODS: This was a retrospective review of 68 patients with borderline resectable or locally advanced pancreatic cancer treated with anti-PD-1 antibody and SBRT after multi-agent chemotherapy. Immunotherapy was administered with 5-fraction SBRT in the neoadjuvant, concurrent, or adjuvant/maintenance setting. Clinical outcomes included overall survival (OS), local progression-free survival, distant metastasis-free survival, and progression-free survival. Median pre- and post-SBRT peripheral blood markers were compared with the Mann-Whitney U test. Univariate and multivariable analyses (UVA and MVA) were performed to identify variables associated with clinical outcomes. Linear regression was performed to determine correlations between variables and peripheral blood markers. RESULTS: A total of 68 patients were included in the study. The percent change between median pre- and post-SBRT absolute lymphocyte count (ALC), absolute neutrophil count, and NLR were -36.0% (p < 0.001), -5.6% (p = 0.190), and +35.7% (p = 0.003), respectively. Median OS after SBRT was 22.4 months. On UVA, pre-SBRT CA19-9 (hazard ratio [HR] = 1.001; 95% confidence interval [CI], 1.000-1.001; p = 0.031), post-SBRT ALC (HR = 0.33; 95% CI, 0.11-0.91; p = 0.031), and post-SBRT NLR (HR = 1.13; 95% CI, 1.04-1.22; p = 0.009) were associated with OS. On MVA, induction chemotherapy duration (HR = 0.75; 95% CI, 0.57-0.99; p = 0.048) and post-SBRT NLR (HR = 1.14; 95% CI, 1.04-1.23; p = 0.002) predicted for OS. Patients with post-SBRT NLR ≥3.2 had a median OS of 15.6 months versus 27.6 months in patients with post-SBRT NLR <3.2 (p = 0.009). On MVA linear regression, log10CTV had a negative correlation with post-SBRT ALC (regression coefficient = -0.314; 95% CI, -0.626 to -0.003; p = 0.048). CONCLUSION: Elevated NLR after SBRT is primarily due to depletion of lymphocytes and associated with worse survival outcomes in localized pancreatic cancer treated with anti-PD-1 antibody. Larger CTVs were associated with decreased post-SBRT ALC.

Postoperative Chemotherapy is Associated with Improved Survival in Patients with Node-Positive Pancreatic Ductal Adenocarcinoma After Neoadjuvant Therapy.

BACKGROUND: Postoperative chemotherapy following pancreatic cancer resection is the standard of care. The utility of postoperative chemotherapy for patients who receive neoadjuvant therapy (NAT) is unclear. METHODS: Patients who underwent pancreatectomy after NAT with FOLFIRINOX or gemcitabine-based chemotherapy for non-metastatic pancreatic adenocarcinoma (2015-2019) were identified. Patients who received less than 2 months of neoadjuvant chemotherapy or died within 90 days from surgery were excluded. RESULTS: A total of 427 patients (resectable, 22.2%; borderline resectable, 37.9%; locally advanced, 39.8%) were identified with the majority (69.3%) receiving neoadjuvant FOLFIRINOX. Median duration of NAT was 4.1 months. Following resection, postoperative chemotherapy was associated with an improved median overall survival (OS) (28.7 vs. 20.4 months, P = 0.006). Risk-adjusted multivariable modeling showed negative nodal status (N0), favorable pathologic response (College of American Pathologists score 0 & 1), and receipt of postoperative chemotherapy to be independent predictors of improved OS. Regimen, duration, and number of cycles of NAT were not significant predictors. Thirty-four percent (60/176) of node-positive and 50.1% (126/251) of node-negative patients did not receive postoperative chemotherapy due to poor functional status, postoperative complications, and patient preference. Among patients with node-positive disease, postoperative chemotherapy was associated with improved median OS (27.2 vs. 10.5 months, P < 0.001). Among node-negative patients, postoperative chemotherapy was not associated with a survival benefit (median OS, 30.9 vs. 36.9 months; P = 0.406). CONCLUSION: Although there is no standard NAT regimen for patients with pancreatic cancer, postoperative chemotherapy following NAT and resection appears to be associated with improved OS for patients with node-positive disease.