Locally Advanced Pancreatic Cancer Patients Research Articles

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

This study aims to evaluate short- and long-term outcomes following pancreatectomy in patients with LAPC compared to (B)RPC patients. 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). 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). 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). 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.

[Short-term outcomes of the TRIANGLE operation after neoadjuvant chemotherapy in locally advanced pancreatic cancer].

Objective: To investigate the safety and efficacy of the TRIANGLE operation after neoadjuvant chemotherapy in locally advanced pancreatic cancer(LAPC). Methods: This study is a retrospective case series analysis. Between January 2020 and December 2022, a total of 103 patients were diagnosed as LAPC who underwent neoadjuvant chemotherapy at the Pancreas Center, the First Affiliated Hospital of Nanjing Medical University. Among them, 26 patients (25.2%) underwent the TRIANGLE operation. There were 15 males and 11 females,with a age of (59±7) years (range: 49 to 74 years). The pre-treatment serum CA19-9(M(IQR)) was 248.8(391.6)U/ml (range: 0 to 1 428 U/ml),and the serum carcinoembryonic antigen was 4.1(3.8)μg/L(range: 1.4 to 13.4 μg/L). The neoadjuvant chemotherapy regimens included: mFOLFIRINOX regimen in 6 cases(23.1%), GnP regimen in 14 cases(53.8%), and mFOLFIRINOX+GnP regimen in 6 cases(23.1%). The follow-up duration extended until June 2023 or until the occurrence of the patient's death or loss to follow-up. The Kaplan-Meier method was employed to estimate the 1-year and 3-year overall survival rates. Results: After neoadjuvant chemotherapy,CA19-9 levels decreased by 92.3(40.1)%(range:2.1% to 97.7%). Evaluation of the response to treatment revealed 13 cases(50.0%) of stable disease,11 cases(42.3%) of partial response,and 2 cases(7.7%) of complete response. The surgical operation consisted of 12 cases(46.2%) of pancreaticoduodenectomy,12 cases(46.2%) of distal pancreatectomy,and 2 cases(7.7%) of total pancreatectomy. Margin determination was based on the "standardised pathology protocol" and the "1 mm" principle. No R2 and R1(direct) resections were observed,while the R0 resection rate was 61.5%(16/26), and the R1(1 mm) resection rate was 38.5%(10/26).The R1(1 mm) resection rates for the anterior margin,posterior margin,transected margin,portal vein groove margin,and uncinate margin were 23.1%(6/26),19.2%(5/26),12.5%(3/24),2/14, and 1/12, respectively. The overall postoperative complication rate was 57.8%(15/26),with major complications including grade B/C pancreatic fistula 25.0%(6/24,excluding 2 cases of total pancreatectomy),delayed gastric emptying in 23.1%(6/26),wound complications 11.5%(3/26),postoperative hemorrhage 7.7%(2/26), chylous fistula 7.7%(2/26) and bile fistula 3.8%(1/26). No reoperation was performed during the perioperative period(<90 days). One patient died on the 32nd day postoperatively due to a ruptured pseudoaneurysm. A total of 25 patients were followed up,with a follow-up time of 21(24)months(range: 8 to 42 months). During the follow-up period,8 cases(32.0%) died due to tumor recurrence and metastasis,while 17 patients(68.0%) remained alive,including 11 cases of disease-free survival,5 cases of distant metastasis,and 1 case of local recurrence. The overall survival rates at 1- and 3-year after the initiation of neoadjuvant chemotherapy were 95.8% and 58.9%, respectively. The overall survival rates at 1- and 3-year after surgery were 77.7% and 57.8%, respectively. Conclusion: Performing pancreatoduodenectomy according to the Heidelberg triangle protocol in LAPC patients after neoadjuvant chemotherapy might increase the R0 resection rate without increasing perioperative mortality or the incidence of major postoperative complications.

Abstract A005: A multi-institutional randomized phase III trial of chemotherapy alone versus chemotherapy and ablative 5-fraction MRI-guided adaptive radiation therapy for locally advanced pancreatic cancer (LAP-ABLATE)

Abstract Background: Prospective studies demonstrate that chemotherapy and non-ablative radiation therapy (RT) achieve superior locoregional control (LRC) although have not improved overall survival (OS) relative to chemotherapy alone for patients with locally advanced pancreatic cancer (LAPC). Emerging data suggest that significant radiation dose escalation may further enhance LRC, and it has been hypothesized that in a subset of patients this may improve OS. However, delivering ablative radiation dose in 5 or fewer fractions with computerized tomography (CT) guidance is associated with unacceptable rates of grade 3-5 toxicity. Safe dose escalation can be facilitated by radiation delivery systems that utilize magnetic resonance image (MRI) guidance and on-table adaptive replanning. A growing body of literature describes promising efficacy and safety of ablative 5-fraction stereotactic MRI-guided adaptive radiation therapy (SMART) for LAPC compared to historical non-ablative outcomes. Based on these encouraging results, the LAP-ABLATE trial has been designed to test the hypothesis that ablative SMART improves OS. Methods: The LAP-ABLATE trial is a multi-institutional group sequential randomized phase III study for patients with LAPC. Patients are eligible after first receiving 4-6 months of (modified)FOLFIRINOX or gemcitabine/nab-paclitaxel with either stable or responding disease. Other key eligibility criteria include CA 19-9 &amp;lt;180 U/mL and no contraindication to undergoing MRI scans. Patients are randomized (1:2) to receiving no ablative SMART (arm A) versus ablative SMART (arm B), with subsequent systemic therapy or surgery being optional in both arms. Ablative SMART will be delivered using the MRIdian Linac, a 0.35 Tesla MRI-guided linear accelerator. The prescribed dose is 50 Gy to gross disease and 33 Gy to elective regions in 5 fractions using a simultaneous integrated boost (SIB). The primary objective is to compare 2-year OS with secondary objectives including assessment of LRC, distant metastasis free survival (DMFS), progression-free survival (PFS), quality of life (QOL), and toxicity. Randomization will be stratified by participating center, baseline CA 19-9 level and induction chemotherapy regimen. Target accrual is 267 patients (arm A: 89, arm B: 178). Discussion: The LAP-ABLATE trial is the first prospective randomized phase III study designed to compare OS in LAPC patients following induction systemic therapy randomized to with or without ablative 5-fraction RT. Citation Format: Michael D. Chuong, Jessica M. Frakes, Kathryn E. Mittauer, James Good, Josh Kim, Daniel Chang, Dae Won Kim, Stefanie Corradini, Luca Boldrini, Mokenge Malafa, Eileen O'Reilly. A multi-institutional randomized phase III trial of chemotherapy alone versus chemotherapy and ablative 5-fraction MRI-guided adaptive radiation therapy for locally advanced pancreatic cancer (LAP-ABLATE) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A005.

Analysis of the cost-effectiveness of proton beam therapy for unresectable pancreatic cancer in Japan.

Proton beam therapy (PBT) has recently been included in Japan's social health insurance benefits package. This study aimed to determine the cost-effectiveness of PBT for unresectable, locally advanced pancreatic cancer (LAPC) as a replacement for conventional photon radiotherapy (RT). We estimated the incremental cost-effectiveness ratio (ICER) of PBT as a replacement for three-dimensional conformal RT (3DCRT), a conventional photon RT, using clinical evidence in the literature and expense complemented by expert opinions. We used a decision tree and an economic and Markov model to illustrate the disease courses followed by LAPC patients. Effectiveness was estimated as quality-adjusted life years (QALY) using utility weights for the health state. Social insurance fees were calculated as the costs. The stability of the ICER against the assumptions made was appraised using sensitivity analyses. The effectiveness of PBT and 3DCRT was 1.67610615 and 0.97181271 QALY, respectively. The ICER was estimated to be ¥5,376,915 (US$46,756) per QALY. According to the suggested threshold for anti-cancer therapy from the Japanese authority of ¥7,500,000 (US$65,217) per QALY gain, such a replacement would be considered cost-effective. The one-way and probabilistic sensitivity analyses demonstrated stability of the base-case ICER. PBT, as a replacement for conventional photon radiotherapy, is cost-effective and justifiable as an efficient use of finite healthcare resources. Making it a standard treatment option and available to every patient in Japan is socially acceptable from the perspective of health economics.

Ablative 5-Fraction CT vs. MR-Guided Pancreatic SBRT: Evaluation of Interfraction Anatomic Changes on Dosimetric Constraints.

CT-guided SBRT for locally advanced pancreatic cancer (LAPC) is usually non-ablative (BED < 100 Gy10) to minimize grade 3+ toxicity risks given the concern of interfraction anatomic changes (IACs) in GI anatomy and imaging quality associated with kV-CBCT. Emerging data demonstrate that MR guidance facilitates 5-fraction (fx) dose escalation due to superior soft tissue contrast, continuous intrafraction imaging, automatic beam gating, and on-table adaptive replanning capability. Treatment outcomes for ablative 5-fx CT- vs. MR-guided SBRT are not well characterized, nor are differences in predicted GI OAR doses when accounting for IACs. Weevaluated 40 plans (20 CT, 20 MR) for 20 LAPC patients (pts) previously treated in breath hold (BH) on a 0.35 T MR-Linac. Prescribed dose was 50 Gy (gross disease) and 33 Gy (elective) in 5 fx using a simultaneous integrated boost technique. CT plans were retrospectively created using 2-3 VMAT arcs with the same prescription dose, target volumes (assuming BH), and constraints (prioritizing OARs over target coverage) as the MR IMRT plans (∼20-40 fields). CT planners were blinded to MR plans. We compared predicted GI OAR dose of CT vs. MR plans across each of the 5 fx for all 20 patients to evaluate the dosimetric impact of IACs by coregistering CT plans to the anatomy of the day based on 0.35T MR scans acquired for GI OAR segmentation and treatment delivery. MedianV100% of the GTV, CTV, PTV50, and PTV33 across the original CT vs. MR plans were 97.5% vs. 91.3% (p = 0.017), 99.9% vs. 98.2% (p<0.01), 86.2% vs. 79.3% (p = 0.39), and 97.2% vs. 93.0% (p<0.01), respectively. GI OAR constraints were met for all original CT/MR plans although it was predicted that 1+ GI OAR constraint would be violated (most commonly duodenum) for 88/100 CT vs. 85/100 MR fractions. Across the 88 violated CT fractions, the median predicted GI OAR doses were duodenum V35: 3.3 cc (range: 0.16-18.0cc), duodenum V40: 1.2 cc (range: 0.01-11.9cc), small bowel V35: 1.2 cc (range: 0.4-10.9cc), small bowel V40: 0.2 cc (range: 0.04-7.0cc), stomach V35: 1.5 cc (range: 0.52-6.8cc), stomach V40: 0.3 cc (range: 0.05-2.8cc). GI OAR doses across the 85 violated MR fractions were similar. Median fxs per pt with 1+ predicted GI OAR violation was 5 (range: 1-5) for both CT and MR plans. This isthe first evaluation of IAC effects on predicted GI OAR dose for 5-fx CT- vs. MR-guided SBRT. Although VMAT arcs facilitated higher target coverage in the initial CT plans, GI OAR constraint violations were observed in 85-88% of CT/MR plans. Although on-table adaptive replanning is routine on MR-guided Linacs it is not commonly available on CT-guided Linacs. As such, ablative 5-fx SBRT delivered with CT guidance is expected to result in significant toxicity due to exceeding GI OAR constraints for most delivered fractions.

Study of a Geometric Score to Identify the Increased Risk of Local Failure after SBRT for Locally Advanced Pancreatic Cancer (LAPC)

A previous analysis on an institutional cohort of LAPC patients, treated with intensive induction chemotherapy followed by SBRT, proved that local failures (LFs) predominantly occurred within the RT field. This suggests a specific efficacy of a complete covering of the macroscopic (GTV) aggressive disease with high doses (i.e., simultaneous boost [SIB] doses). Still, this is often not feasible due to the proximity of extremely radiosensitive organs at risk (OARs), which forces the use of "Simultaneous Integrated Protection" (SIP), limiting the dose to safe values in a portion of the GTV. This analysis aimed to quantitatively assess the role of GTV size and incomplete GTV covering with SIB in increasing the risk of LF. We included 51 consecutive LAPC pts treated with SBRT (Nov 2016 - Nov 2019): 30 Gy in 5 fractions to the tumor PTV, 50 Gy SIB to the region of vessel abutment/encasement, 25 Gy SIP to the overlap between tumor PTV, and the Planning OAR volumes. We used univariate/multivariable survival analysis (UVA/MVA, Cox regression, Kaplan-Meier Curves, Log-Rank test) to assess the association of LF with the GTV size and the amount of the GTV which the SIB did not cover. Specifically, we defined a set of incomplete GTV-covering levels: GTV75 (= yes if less than 75% of the GTV was included in the 50 Gy SIB isodose), GTV70, GTV50 and GTV30. Variables with p≤0.2 at UVA were included for MVA assessment. MVA models were considered relevant if their likelihood was significantly higher when compared to UVA. With a median follow-up of 17 months (range 1.4-47) 12 pts experienced LF. The GTV size (p = 0.007, risk factor for LF, Hazard Ratio [HR] 1.04 for 1 cc increase in GTV size) and GTV70 (p = 0.2, risk factor, HR = 3.73 for GTV70 = yes) were selected at UVA and included in MVA. To build a simple decision tool, we dichotomized the GTV size as below/above 25 cc (selected from Youden Index on the ROC curve): HR = 9.3 if GTV>25 cc. We used dichotomized GTV size and GTV70 to build a 3-level Geometric Score for the prediction of the risk of LF: [Low Risk (LR)] if "GTV<25cc AND GTV70 = no"; [Intermediate Risk (IR)] if "GTV>25cc OR GTV70 = yes"; [High Risk (HiR)] if "GTV>25cc AND GTV70 = yes". Pts classified at HiR had a significantly higher probability of LF: HR = 6.9 (95% CI 1.5-32.9) compared to LR, and HR = 13.2 (95% CI 3.6-48.4) when compared to IR. 10/12 LFs are in the HiR group. A large GTV size, coupled with an incomplete (<70%) covering of GTV from the SIB, highly increases the risk of LF: 62% actuarial probability in the HiR group vs 7% in the LR/IR groups. Full coverage of the GTV with SIB would be of clinical relevance for pts with large macroscopic tumors. The Geometric Score could be used to select pts that would effectively benefit from online tumor tracking (e.g., with an MRI-Linac), allowing a reduction of the SIP volume and a consequent decrease in the amount of GTV left uncovered by the SIB.

The impact of intensified staging and combined therapies in locally advanced pancreatic cancer: a secondary analysis of prospective studies.

To investigate the use of comprehensive pre-treatment staging with multiple diagnostic modalities, including functional imaging and minimally invasive surgical procedures, in locally advanced pancreatic cancer (LAPC) patients. The primary objective was to detect occult metastatic disease using staging laparoscopy and 18FFDG-PET/CT scan. The study also evaluated treatment efficacy and outcomes in LAPC patients treated with combined therapies. This study was a secondary analysis of three prospective studies of chemoradiotherapy (CRT) with or without induction chemotherapy (IC). The inclusion period was from December 2009 until February 2023. An intensified pretreatment staging was conducted for all LAPC patients. Patients without distant disease at initial staging, with borderline resectable or unresectable LAPC, were enrolled in chemoradiotherapy combination protocols (CRT with or without IC). IC regimens included GemOx or FOLFIRINOX for four cycles, followed by concurrent CRT with gemcitabine. The primary endpoint was the detection of occult metastatic disease, and secondary objectives included resection rate, treatment toxicity, overall survival (OS), progression-free survival (PFS), local control (LC), and metastasis-free survival (MFS). Out of the 134 LAPC patients, 33.5% were identified with metastatic disease. Of these, 23.1% had a positive exploratory laparoscopy. Additionally, 13.4% were identified as having distant metastases by 18-FDG PET/CT. The median PFS for all patients who completed CRT was 14.3 months, and the median OS was 17.2 months. Resected patients after the combined therapies demonstrated significantly improved outcomes compared to non-resected patients (median PFS, 22.5mo vs. 9.5mo, P<0.001; median OS, 38.2mo vs. 13mo, P<0.001). Moreover, patients treated with IC followed by CRT showed significantly better outcomes compared to upfront CRT group (median PFS, 19mo vs. 9.9mo, P<0.001; median OS, 19.3mo vs. 14.6mo, P<0.001). At univariate logistic regression analysis, the adding of IC was the only predictor for resection rate (95% CI 0.12-1.02, P=0.05), and this data was confirmed at multivariate analysis (95% CI 0.09-0.98, P=0.04). Haematological and gastrointestinal toxicities were observed during treatment, with manageable adverse events. The use of comprehensive pre-treatment staging, including laparoscopy and 18F-FDG-PET/CT scan, is an effective approach in identifying occult metastatic disease in LAPC patients. Our findings offer valuable insights into accurate staging and treatment efficacy, providing evidence-based support for optimal management strategies in LAPC patients.

Assessment of the level III of Inoue by preoperative endoscopic ultrasound and elastography: a novel approach to predict a periarterial divestment technique in borderline resectable (BR) or locally advanced (LA) pancreatic adenocarcinoma—How I do it

BackgroundPeriarterial divestment is a surgical technique to approach borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) with arterial involvement. There are no reports in the literature regarding the role of endoscopic ultrasound and elastography (EUS-EG) in exploring the integrity of Inoue’s level III and its correlation with the periarterial divestment technique feasibility. Our research is aimed at exploring the role of EUS-EG in this scenario.MethodsWe describe our approach to Inoue’s level II by EUS-EG in patients with BR and LA pancreatic cancer patients after neoadjuvant chemotherapy.ResultsBetween June 2019 and December 2020, four patients out of 25 were eligible to perform a preoperative EUS-EG. In all cases, Inoue’s level III integrity was corroborated by EUS-EG and confirmed posteriorly in the surgical scenario where a periarterial divestment technique was feasible. Vein resections were necessary in all cases, with no need for arterial resection. An R0 (> 1 mm) margin was achieved in all patients, and the histopathological assessment showed the presence of neurovascular tissue at the peripheral arterial margin.ConclusionPreoperatively, EUS-EG is a novel approach to explore the integrity of Inoue’s level III and could be helpful to preclude a periarterial divestment technique in borderline resectable or locally advanced pancreatic adenocarcinoma with arterial involvement.

Irreversible electroporation combined with chemotherapy and PD-1/PD-L1 blockade enhanced antitumor immunity for locally advanced pancreatic cancer.

Irreversible electroporation (IRE) is a novel local tumor ablation approach with the potential to stimulate an antitumor immune response. However, it is not effective in preventing distant metastasis in isolation. This study aimed to compare the potential of augmenting the antitumor immune response in patients with locally advanced pancreatic cancer (LAPC) who underwent IRE combined with chemotherapy and PD-1/PD-L1 blockade with those who underwent IRE combined with chemotherapy. A retrospective review was conducted on LAPC patients treated either with IRE in combination with chemotherapy and PD-1/PD-L1 blockade (group A) or with IRE with chemotherapy alone (group B) from July 2015 to June 2021. The primary outcomes were overall survival (OS) and progression-free survival (PFS), with immune responses and adverse events serving as secondary endpoints. Risk factors for OS and PFS were identified using univariate and multivariate analyses. A total of 103 patients were included in the final analysis, comprising 25 in group A and 78 in group B. The median duration of follow-up was 18.2 months (3.0-38.6 months). Group A patients demonstrated improved survival compared to group B (median OS: 23.6 vs. 19.4 months, p = 0.001; median PFS: 18.2 vs. 14.7 months, p = 0.022). The data suggest a robust immune response in group A, while adverse events related to the treatment were similar in both groups. The multivariate analysis identified the combination of IRE, chemotherapy, and PD-1/PD-L1 blockade as an independent prognostic factor for OS and PFS. The addition of PD-1/PD-L1 blockade to the regimen of IRE combined with chemotherapy enhanced antitumor immunity and extended survival in LAPC patients.

Comparative Effectiveness of Chemotherapy Alone Versus Radiotherapy-Based Regimens in Locally Advanced Pancreatic Cancer: A Real-World Multicenter Analysis (PAULA-1)

Different options for locally advanced pancreatic cancer (LAPC) are available based on international guidelines: chemotherapy (CHT), chemoradiation (CRT), and stereotactic body radiotherapy (SBRT). However, the role of radiotherapy is debated in LAPC. We retrospectively compared CHT, CRT, and SBRT ± CHT in a real-world setting in terms of overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS). LAPC patients from a multicentric retrospective database were included (2005–2018). Survival curves were calculated using the Kaplan–Meier method. Multivariable Cox analysis was performed to identify predictors of LC, OS, and DMFS. Of the 419 patients included, 71.1% were treated with CRT, 15.5% with CHT, and 13.4% with SBRT. Multivariable analysis showed higher LC rates for CRT (HR: 0.56, 95%CI 0.34–0.92, p = 0.022) or SBRT (HR: 0.27, 95%CI 0.13–0.54, p &lt; 0.001), compared to CHT. CRT (HR: 0.44, 95%CI 0.28–0.70, p &lt; 0.001) and SBRT (HR: 0.40, 95%CI 0.22–0.74, p = 0.003) were predictors of prolonged OS with respect to CHT. No significant differences were recorded in terms of DMFS. In selected patients, the addition of radiotherapy to CHT is still an option to be considered. In patients referred for radiotherapy, CRT can be replaced by SBRT considering its duration, higher LC rate, and OS rate, which are at least comparable to that of CRT.

“Conversion surgery” for locally advanced pancreatic cancer: A position paper by the study group at the joint meeting of the International Association of Pancreatology (IAP) & Japan Pancreas Society (JPS) 2022

Locally advanced pancreatic cancer (LAPC), which progresses locally and surrounds major vessels, has historically been deemed unresectable. Surgery alone failed to provide curative resection and improve overall survival. With the advancements in treatment, reports have shown favorable results in LAPC after undergoing successful chemotherapy therapy or chemoradiation therapy followed by surgical resection, so-called “conversion surgery”, at experienced high-volume centers. However, recognizing significant regional and institutional disparities in the management of LAPC, an international consensus meeting on conversion surgery for LAPC was held during the Joint Congress of the 26th Meeting of the International Association of Pancreatology (IAP) and the 53rd Annual Meeting of Japan Pancreas Society (JPS) in Kyoto in July 2022. During the meeting, presenters reported the current best multidisciplinary practices for LAPC, including preoperative modalities, best systemic treatment regimens and durations, procedures of conversion surgery with or without vascular resections, biomarkers, and genetic studies. It was unanimously agreed among the experts in this meeting that “cancer biology is surpassing locoregional anatomical resectability” in the era of effective multiagent treatment. The biology of pancreatic cancer has yet to be further elucidated, and we believe it is essential to improve the treatment outcomes of LAPC patients through continued efforts from each institution and more international collaboration. This article summarizes the agreement during the discussion amongst the experts in the meeting. We hope that this will serve as a foundation for future international collaboration and recommendations for future guidelines.

Combined CT and serum CA19-9 for stratifying risk for progression in patients with locally advanced pancreatic cancer receiving intraoperative radiotherapy.

The aim of this study was to evaluate the significance of baseline computed tomography (CT) imaging features and carbohydrate antigen 19-9 (CA19-9) in predicting prognosis of locally advanced pancreatic cancer (LAPC) receiving intraoperative radiotherapy (IORT) and to establish a progression risk nomogram that helps to identify the potential beneficiary of IORT. A total of 88 LAPC patients with IORT as their initial treatment were enrolled retrospectively. Clinical data and CT imaging features were analyzed. Cox regression analyses were performed to identify the independent risk factors for progression-free survival (PFS) and to establish a nomogram. A risk-score was calculated by the coefficients of the regression model to stratify the risk of progression. Multivariate analyses revealed that relative enhanced value in portal-venous phase (REV-PVP), peripancreatic fat infiltration, necrosis, and CA19-9 were significantly associated with PFS (all p < 0.05). The nomogram was constructed according to the above variables and showed a good performance in predicting the risk of progression with a concordance index (C-index) of 0.779. Our nomogram stratified patients with LAPC into low- and high-risk groups with distinct differences in progression after IORT (p < 0.001). The integrated nomogram would help clinicians to identify appropriate patients who might benefit from IORT before treatment and to adapt an individualized treatment strategy.

Abstract CT084: Targeted intra-arterial gemcitabine vs. continuation of IV gemcitabine plus nab-paclitaxel following Induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for unresectable locally advanced pancreatic cancer (TIGeR-PaC) - phase III trial interim analysis

Abstract Background: Treatment of locally advanced pancreatic cancer (LAPC) remains a clinical challenge with a median survival of 16-18 months1. Control of local disease, beyond systemic therapy, is part of the treatment paradigm being investigated in this patient population. Double balloon mediated local delivery of intra-arterial gemcitabine (IAG) into the tumor has been demonstrated to be safe in this patient population2. TIGeR-PaC is an ongoing Phase III clinical trial comparing the efficacy of this approach compared to standard of care IV gemcitabine/nab-paclitaxel (GN) for patients with LAPC. Methods: The trial is designed with an induction phase for all patients of upfront systemic chemotherapy and radiation prior to randomization to IAG or continuation of GN. ECOG 0-1 LAPC patients receive 3 cycles of GN and 1 cycle of radiation (SBRT, 33 Gy in 5 fractions). Following induction, patients with non-progressive disease are randomized to receive IAG (8 treatments bi-weekly for 16 weeks) or continuation of GN for 4 cycles over 16 weeks. After the 16 weeks of randomized therapy, patients with non-progressive disease receive continuation systemic therapy of GN or low-dose oral capecitabine, per investigator’s preference until disease progression and are followed for survival only. The primary endpoint is the overall survival (OS), and the study is powered at an 80% power to detect a hazard ratio of 0.6 between the two arms. It is assumed that the hazard functions are proportional only during the randomized treatment period, after which the two hazard functions become approximately identical during the continuing treatment period. The primary endpoint of OS for the two treatment arms will be compared using a 2-sided Wilcoxon test. The first interim analysis of the trial for the ITT population is performed after the 26th out of an expected 86 events have occurred in the trial (30%). Clinical Endpoint Analysis: The first interim analysis of the primary endpoint of OS was conducted on Feb 2nd, 2023. This was based on a data lock on survival status of all patients after the sponsor became aware that the 26th event in the trial occurred on Dec. 21st, 2022. As of that date, 45 patients had been randomized in the trial and the survival status of all 45 subjects was used as of the date for analysis. Of the 45 patients randomized, 23 were randomized to IAG and 22 to continuation of IV GN. There were equal number of primary events, 13, in each arm. The median survival in the control arm is 10 months, versus 16 months in the IAG arm. The p-values based on Wilcoxson non-proportional hazard ratio is 0.051 between the 2 arms. The study continues to accrue patients with a second interim analysis (after 52 events) expected at end of 2024. 1. Hammel P, Huguet F, van Laethem JL, et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib. JAMA. 2016;315(17):1844. 2. Rosemurgy AS, Ross SB, Vitulli PL, et al. Safety Study of Targeted and Localized Intra-Arterial Delivery of Gemcitabine in Patients with Locally Advanced Pancreatic Adenocarcinoma. J Pancreat Cancer. 2017;3(1):58-65. Citation Format: Michael Pishvaian, Amer Zureikat, Charles Lopez, Kenneth Meredith, Emmanuel Zervos, Hassan Hatoum, Ki Chung, Daniel J. Berg, Antonio Ucar, Ripal Gandhi, Reza Nazemzadeh, Parikh Nainesh, Paula Novelli, Brian Kouri, Christopher Laing, Brian Boone, Thor Johnson, Susan Bates, Karyn Goodman, Ramtin Agah. Targeted intra-arterial gemcitabine vs. continuation of IV gemcitabine plus nab-paclitaxel following Induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for unresectable locally advanced pancreatic cancer (TIGeR-PaC) - phase III trial interim analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT084.

Response of Locally Advanced Pancreatic Cancer to Intratumoral Injection of Large Surface Area Microparticle Paclitaxel: Initial Report of Safety and Clinical Outcome.

Large surface area microparticle paclitaxel (LSAM-PTX) provides an intratumoral (IT) chemotherapeutic depot. Safety, tolerability, and tumor response to IT LSAM-PTX delivered by endoscopic ultrasound-fine needle injection were evaluated in subjects with unresectable locally advanced pancreatic cancer (LAPC). Ten subjects treated in a dose escalation phase and 22 additional subjects receiving 2 injections, 4 weeks apart, of 15 mg/mL LSAM-PTX were followed for 12 months. Paclitaxel pharmacokinetics were evaluated, imaging at 3 and 6 months determined tumor response, and multiplex immunofluorescence was conducted to characterize local immune response. Most treatment-emergent adverse events were attributed to LAPC. Plasma paclitaxel levels were negligible. Eight subjects' tumors became resectable after IT LSAM-PTX, and 5 of 6 (83%) were resected with R0. Multiplex immunofluorescence of resected tumors demonstrated increased T cells, natural killer cells, and macrophages and decreased myeloid-derived suppressor cells. Six-month disease control rate was 94%, and median overall survival was 19.7 months in the 2-injection subjects. For nonresected and resected groups, overall survival times were 18.9 and 35.2 months, respectively. Neoadjuvant IT LSAM-PTX, in combination with SOC, was well tolerated and may provide benefits to LAPC patients, evidenced by enhanced immune response, improved disease control rate, restaging leading to surgery, and extended survival.

Feasibility, safety, and efficacy of stereotactic body radiotherapy combined with intradermal heat-killed mycobacterium obuense (IMM-101) vaccination for non-progressive locally advanced pancreatic cancer, after induction chemotherapy with (modified)FOLFIRINOX – The LAPC-2 trial

Background and purposeIn this phase I/II trial, non-progressive locally advanced pancreatic cancer (LAPC) patients after (modified)FOLFIRINOX therapy were treated with stereotactic body radiotherapy (SBRT) combined with heat-killed mycobacterium (IMM-101) vaccinations. We aimed to assess safety, feasibility, and efficacy of this treatment approach. Materials and methodsOn five consecutive days, patients received a total of 40 Gray (Gy) of SBRT with a dose of 8 Gy per fraction. Starting two weeks prior to SBRT, they in addition received six bi-weekly intradermal vaccinations with one milligram of IMM-101. The primary outcomes were the number of grade 4 or higher adverse events and the one-year progression free-survival (PFS) rate. ResultsThirty-eight patients were included and started study treatment. Median follow-up was 28.4 months (95 %CI 24.3 – 32.6). We observed one grade 5, no grade 4 and thirteen grade 3 adverse events, none related to IMM-101. The one-year PFS rate was 47 %, the median PFS was 11.7 months (95 %CI 11.0 – 12.5) and the median overall survival was 19.0 months (95 %CI 16.2 – 21.9). Eight (21 %) tumors were resected, of which 6 (75 %) were R0 resections. Outcomes were comparable with the outcomes of the patients from the previous LAPC-1 trial, in which LAPC patients were treated with SBRT, without IMM-101. ConclusionCombination treatment with IMM-101 and SBRT was safe and feasible for non-progressive locally advanced pancreatic cancer patients after (modified)FOLFIRINOX. No improvement in the progression-free survival could be demonstrated by adding IMM-101 to SBRT.

Irreversible electroporation as treatment option within a multidisciplinary approach for locally advanced pancreatic cancer.

727 Background: The treatment plan for patients diagnosed with locally advanced pancreatic cancer (LAPC) is developed by a multidisciplinary team by which systemic chemotherapy is employed followed by surgical resection. Strategies that provide local control in LAPC patients who demonstrate stability/regression without metastasis have gained increasing attention. Irreversible electroporation (IRE) is a non-thermal ablative approach that employs short, high-voltage electrical pulses to create permanent nano-defects in the tumor cell membrane resulting in lethal disruption of tumor cell homeostasis while preserving the integrity of the underlying vascular architecture. This study sought to review IRE outcomes at a high-volume, single institution hepato-pancreato-biliary surgical center. Methods: After obtaining institutional review board approval, data for patients treated with IRE was retrieved from the electronic medical record from 2013-2022. IRE in situ is defined as non-thermal ablation to a tumor without resection. Margin enhancement IRE is defined as non-thermal ablation to residual tumor that could not be resected in its entirety within the adventitial plane. IRE assisted resection is defined as non-thermal ablation to a tumor encasing surrounding structures to allow for complete resection. Results: A total of 101 IREs have been performed at our institution from 2013-2022. Demographics for our cohort include 48 (47.5%) female patients, an average age of 63 years (range 43 – 84), and an average BMI of 26.4 kg/m2 (range 17 – 47). Of these IRE operations, 27 (26.7%) were in-situ, 35 (34.7%) were margin enhancement, and 50 (49.5%) were assisted resections. 2.0% and 11.9% died within 30 and 90 days of the operation, respectively. Median disease-free survival for our patient cohort was 15 months (range 0 to 74). 1-year, 3-year, 5-year, and overall survival for the three cohorts are shown. Conclusions: Using IRE in patients presenting with LAPC provides additional treatment options to the standard treatment pathway. Further classifying IRE use to in situ, margin enhancement, and assisted resection and incorporating these procedures into a multidisciplinary treatment approach has the potential to improve survival rates for appropriately selected LAPC patients. [Table: see text]

Depth of response in patients with locally advanced pancreatic cancer treated with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel combination therapy: An exploratory subgroup analysis of JCOG1407.

746 Background: Depth of response (DpR; max% reduction from baseline in sum of target lesion diameters), has been reported to be associated with improved prognosis in several malignancies. However, there have been few reports regarding DpR in patients with locally advanced pancreatic cancer (LAPC). Thus, we investigated the association between DpR and overall survival (OS), and whether there were any differences in treatment efficacy on DpR between modified FOLFIRINOX (mFFX) versus gemcitabine plus nab-paclitaxel (GnP) as 1st-line chemotherapy for LAPC, using the results from JCOG1407 which was a randomized phase II trial comparing these regimens. Methods: Of the 126 patients enrolled in JCOG1407, patients were eligible except for the followings; patients who never had an imaging study or had only non-target lesions. The association between DpR and OS was investigated by dividing DpR into 3 groups at the tertile point (T1, T2 and T3 from largest to smallest), and whether DpR contributes to OS was examined by multivariable analysis. The differences in treatment efficacy between both regimens were investigated byevaluating DpR, time to DpR, and duration of response (DoR). Results: A total of 109 patients were eligible for this study (n = 53/56 in mFFX/GnP). The number of patients in T1, T2, and T3 were 37, 36, and 36, respectively. The median OS of T1, T2, and T3 were 29.3 (95% CI, 21.0-NE), 20.6 (95% CI, 15.8-24.5), and 19.0 months (95% CI, 12.7-22.4), respectively ( P= 0.0237). Multivariable analysis identified DpR as an independent prognostic factor for OS (HR 1.883, 95% CI 1.030-3.442, P= 0.040 for T2 vs. T1, and HR 2.523, 95% CI 1.342-4.744, P= 0.004 for T3 vs. T1). The median DpR in GnP was better than that in mFFX (28.9 vs. 22.7%; P= 0.041). The median DoR in mFFX tended to be longer compared to that in GnP (8.2 vs. 5.3 months; P= 0.132). No differences in mean time to DpR were observed between the two regimens. Conclusions: In LAPC patients receiving 1st-line chemotherapy, larger DpR contributed to OS. Although OS and PFS between mFFX and GnP were similar, the treatment efficacy on DpR and DoR might be different between the two regimens. Clinical trial information: UMIN000023143 .

Stomach and duodenum dose-volume constraints for locally advanced pancreatic cancer patients treated in 15 fractions in combination with chemotherapy.

To assess dosimetry predictors of gastric and duodenal toxicities for locally advanced pancreatic cancer (LAPC) patients treated with chemo-radiotherapy in 15 fractions. Data from 204 LAPC patients treated with induction+concurrent chemotherapy and radiotherapy (44.25 Gy in 15 fractions) were available. Forty-three patients received a simultaneous integrated boost of 48-58 Gy. Gastric/duodenal Common Terminology Criteria for Adverse Events v. 5 (CTCAEv5) Grade ≥2 toxicities were analyzed. Absolute/% duodenal and stomach dose-volume histograms (DVHs) of patients with/without toxicities were compared: the most predictive DVH points were identified, and their association with toxicity was tested in univariate and multivariate logistic regressions together with near-maximum dose (D0.03) and selected clinical variables. Toxicity occurred in 18 patients: 3 duodenal (ulcer and duodenitis) and 10 gastric (ulcer and stomatitis); 5/18 experienced both. At univariate analysis, V44cc (duodenum: p = 0.02, OR = 1.07; stomach: p = 0.01, OR = 1.12) and D0.03 (p = 0.07, OR = 1.19; p = 0.008, OR = 1.12) were found to be the most predictive parameters. Stomach/duodenum V44Gy and stomach D0.03 were confirmed at multivariate analysis and found to be sufficiently robust at internal, bootstrap-based validation; the results regarding duodenum D0.03 were less robust. No clinical variables or %DVH was significantly associated with toxicity. The best duodenum cutoff values were V44Gy < 9.1 cc (and D0.03 < 47.6 Gy); concerning the stomach, they were V44Gy < 2 cc and D0.03 < 45 Gy. The identified predictors showed a high negative predictive value (>94%). In a large cohort treated with hypofractionated radiotherapy for LAPC, the risk of duodenal/gastric toxicities was associated with duodenum/stomach DVH. Constraining duodenum V44Gy < 9.1 cc, stomach V44Gy < 2 cc, and stomach D0.03 < 45 Gy should keep the toxicity rate at approximately or below 5%. The association with duodenum D0.03 was not sufficiently robust due to the limited number of events, although results suggest that a limit of 45-46 Gy should be safe.

High Intensity Focused Ultrasound Ablation for Patients With Locally Advanced Pancreatic Adenocarcinoma: A Propensity Score-Matching Analysis.

This retrospective study was conducted to assess the efficacy and safety of high intensity focused ultrasound (HIFU) in combination with chemotherapy compared with chemotherapy alone in treating patients with unresectable locally advanced pancreatic cancer (LAPC). The data of unresectable LAPC patients who received chemotherapy with or without HIFU ablation were retrieved retrospectively. The overall survival (OS), objective response rate (ORR), cancer antigen 19-9 response rate, and safety were compared between these two groups before and after propensity score matching (PSM). Overall, 254 patients with LAPC were included, of whom 92 underwent HIFU ablation. After PSM to control for potential biases, HIFU was associated with improved OS (12.8 versus 12.2 months, log-rank P=.046), as compared to patients without HIFU ablation. Patients with numeric rating scale (NRS) less than 4, and receiving HIFU ablation were significantly associated with improved OS (adjusted hazard ratio [aHR]=0.365 [95% confidence interval (CI)=0.148-0.655], P=.002; aHR=0.490 [95% CI=0.250-0.961], P=.038; respectively) by multivariate analyses with the adjustment of age, NRS, and tumor size. ORR was also observed to be higher in HIFU group of 30.0% than in the chemotherapy group of 13.3% (P=.039). No severe adverse events of special interest or HIFU-caused deaths were observed. Patients with unresectable LAPC who received gemcitabine-based chemotherapy might benefit from additional HIFU ablation.

Normalization of tumor markers and a clear resection margin affect progression-free survival of patients with unresectable pancreatic cancer who have undergone conversion surgery

BackgroundWith the advent of intensive combination regimens, an increasing number of patients with unresectable pancreatic cancer (UPC) have regained the opportunity for surgery. We investigated the clinical benefits and prognostic factors of conversion surgery (CS) in UPC patients.MethodsWe retrospectively enrolled patients with UPC who had received CS following first-line systemic treatment in our center between 2014 to 2022. Treatment response, safety of the surgical procedure and clinicopathological data were collected. We analyzed the prognostic factors for postoperative survival among UPC patients who had CS.ResultsSixty-seven patients with UPC were enrolled (53 with locally advanced pancreatic cancer (LAPC) and 14 with metastatic pancreatic cancer (MPC)). The duration of preoperative systemic treatment was 4.17 months for LAPC patients and 6.52 months for MPC patients. All patients experienced a partial response (PR) or had stable disease (SD) preoperatively according to imaging. Tumor resection was unsuccessful in four patients and, finally, R0 resection was obtained in 81% of cases. Downstaging was determined pathologically in 87% of cases; four patients achieved a complete pathological response. Median postoperative-progression-free survival (PO-PFS) was 9.77 months and postoperative overall survival (PO-OS) was 31.2 months. Multivariate logistic regression analyses revealed that the resection margin and postoperative changes in levels of tumor markers were significant prognostic factors for PO-PFS. No factors were associated significantly with PO-OS according to multivariate analyses.ConclusionsCS is a promising strategy for improving the prognosis of UPC patients. The resection margin and postoperative change in levels of tumor markers are the most important prognostic factors for prolonged PFS. Multidisciplinary treatment in high-volume centers is strongly recommended. Prospective studies must be undertaken to resolve the various problems regarding optimal regimens, the duration of treatment, and detailed criteria for CS.