Unresectable Locally Advanced Pancreatic Cancer Research Articles

Survival benefits of radiotherapy in locally advanced unresectable and metastatic pancreatic cancer: a single-institution cohort and SEER database analysis

BackgroundChemotherapy (CT) remains the primary treatment for locally advanced unresectable pancreatic cancer (LAUPC) and metastatic pancreatic cancer (MPC). The role of radiotherapy (RT) in these conditions remains unclear. This study compares the outcomes of CT alone versus CT combined with RT (combined-modality therapy [CMT]) in LAUPC and MPC patients.Materials and methodsWe conducted a retrospective analysis of LAUPC and MPC patients treated with either CT or CMT from a single institution and Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier curves and Cox hazards models evaluated the association between treatment modalities and overall survival (OS). Propensity score matching (PSM) ensured balanced comparisons. Landmark analysis addressed immortal time bias. Subgroup analyses were based on clinical characteristics. eXtreme Gradient Boosting (XGBoost) and Shapley Additive Explanations (SHAP) assessed outcome prediction and influence of significant predictors.ResultsThe study included 102 patients receiving CMT and 155 receiving CT at single institution, along with 1733 CMT and 9310 CT patients from the SEER dataset. In the single-institution cohort, CMT showed superior survival compared to CT both before (median OS: 20.5 vs. 11.5 months, hazard ratio [HR]: 0.47, 95% CI: 0.34-0.65, P=0.001) and after PSM (median OS: 22.2 vs. 11.8 months, HR: 0.49, 95% CI: 0.30-0.79, P=0.003). Multivariate analyses confirmed that CMT was independently associated with improved OS both before (HR: 0.54, 95% CI: 0.38-0.77, P=0.001) and after PSM (HR: 0.45, 95% CI: 0.27-0.73, P=0.001). Landmark analysis indicated better OS for patients receiving CMT compared to CT alone. Subgroup analysis revealed an OS benefit for CMT across most subgroups. SHAP value analysis indicated that CMT was the most significant contributor to survival outcomes. SEER database validation confirmed these findings.ConclusionsThis study demonstrates that CMT significantly improves OS in LAUPC and MPC patients compared to CT alone. Integrating RT with CT could be beneficial for treating LAUPC and MPC.

Impact of Preoperative Osteosarcopenia and Postoperative Administration of Pancrelipase on the Prognosis of Borderline Resectable and Unresectable Locally Advanced Pancreatic Cancer.

This study aimed to identify postoperative recurrence and prognostic factors, including osteosarcopenia for borderline resectable (BR) and unresectable locally advanced (UR-LA) pancreatic cancer and to examine the impact of postoperative pancreatic enzyme replacement therapy (PERT). We retrospectively examined 32 resected patients with BR and UR-LA pancreatic cancer. We investigated independent factors in the disease-free survival and overall survival. The relation of osteosarcopenia with the clinicopathological factors was investigated. Additionally, the association of the administration of a standard dose of pancrelipase, the amount of lipase required for patients with pancreatic exocrine insufficiency, for ≥6months postoperatively with improvement of sarcopenia, osteopenia, and osteosarcopenia and completion rate of adjuvant chemotherapy was investigated. Multivariate analyses identified osteosarcopenia (P = 0.049) and lymph node metastasis (P = 0.01) as independent recurrence predictors, and osteosarcopenia (P = 0.002), maximum tumor diameter ≥40mm (P = 0.006), and no adjuvant therapy (P = 0.01) as independent prognostic predictors. In the osteosarcopenia group, serum CA19-9 levels were higher (P = 0.03). The administration of a standard dose of pancrelipase for ≥6months postoperatively was none in the osteosarcopenia group (0% vs 42.9%, P = 0.01), while significantly improved postoperative sarcopenia (33% vs 0%, P = 0.004), increased number of cycles of adjuvant chemotherapy (n = 6 vs n = 3, P = 0.03), and the completion rate of adjuvant chemotherapy in excluding cases interrupted because of recurrence (86% vs 25%, P = 0.007). Osteosarcopenia was an independent recurrent and prognostic factor in patients after pancreatectomy for locally advanced pancreatic cancer. Appropriate postoperative PERT may contribute to a better prognosis by improving sarcopenia and increasing the completion rate of adjuvant chemotherapy.

Clinical Outcomes of Proton Beam Therapy for Unresectable Locally Advanced Pancreatic Cancer: A Single-Center Retrospective Study

PurposeWe retrospectively researched the treatment outcome of proton beam therapy (PBT) and assessed its efficacy for inoperable locally advanced pancreatic cancer (LAPC) at our institution. Materials and MethodsFifty-four patients (28 males and 26 females, median age 67 years of ranges from 40 to 88 years were diagnosed with unresectable stage III LAPC and administered PBT from April 2009 to March 2020. Either patients who could not complete PBT, or had new distant metastases during the treatment, or did not have enough follow-up time were excluded from this study. All patients were clinically staged based on the International Union of Cancer TNM staging system (UICC 8th edition) using CT, MRI, and PET, and were diagnosed as stage III (histologic type: eighteen adenocarcinoma patients, thirty-six clinically diagnosed patients). PBT was performed using the passive method, with a median total dose of 67.5 GyE (range: 50-77 GyE/25-35 fractions). Chemotherapy was used in combination during PBT in forty-six patients (85.2%). Overall survival (OS), local progression-free survival (LPFS), progression-free survival (PFS), and median overall survival time (MST) were analyzed by Kaplan-Meier and log-rank tests. Univariate and multivariate analyses were performed for the following factors: maximum standardized uptake value (SUVmax), ECOG-performance status (PS), tumor site, total irradiation dose, concurrent chemotherapy, and primary tumor site. Cutoff values for SUVmax and tumor diameter were estimated using receiver operating characteristic (ROC) curves and area under the curve (AUC) based on OS. Multivariate analysis was evaluated using the Cox proportional hazards models. Adverse events were evaluated using CTCAE ver. 5.0. ResultsThe median observation period was 17.4 months of ranges from 4.0 to 89.7 months. The median tumor diameter was 36.5 mm of ranges from 15 to 90 mm, the median SUVmax was 5.85 (range: 2.1-27.6), and their cutoff values were estimated to 37 mm and 4.8 mm, respectively. 1-, 2-year OS were 77.8%, 35.2% with MST 18.2 months, respectively and only one patient survived more than 5 years. 12 patients (22.2%) developed local recurrence, and 1-, 2-year LPFS rate were 89.7% and 74.5%, respectively; PFS at 1-year was 58.8%. PS score, Tumor site and irradiation dose were the prognostic factor related to OS that showed a significant difference. On the other hand, there was a significant difference in factors involved in LPFS, 96.7%/77.9% in the first year and 86.6%/54.4% in the second year in the groups with tumor dose ≥67.5 GyE and <67.5 GyE, respectively (p = 0.015). Treatment-related acute toxicities were neutropenia (Grade1/2/3:3.7%/11.1%/31.5%), leukopenia (Grade 1/2/3:1.8%/7.4%/20.4%), and thrombocytopenia (Grade 1/2:1.8%/7.4%), while the late effects including peptic ulcer were captured only grade2+. The late adverse events of Grade 3 or higher were not observed. ConclusionsPBT achieving 67.5 Gy combined with standard chemotherapy showed the excellent local control for unresectable LAPC. Total irradiation dose, Tumor site and PS score at an initial diagnosis could be important prognostic factors. In this study, the dose-effect relationship was found so an increase in dose should be considered to improve prognosis.

Experience of seven Spanish centres with echoendoscopically implanted 32P microparticles associated with chemotherapy in locally advanced pancreatic adenocarcinoma.

e16358 Background: 32P brachytherapy delivered by echoendoscopy (EUS) represents an innovative therapy in locally advanced pancreatic cancer (LAPC). The device to implant it is approved in unresectable LAPC in combination with gemcitabine-based chemotherapy. Our aim is to present the preliminary efficacy and safety results of a series that brings together the experience of seven centres in Spain. Methods: After being assessed by a multidisciplinary committee and meeting eligibility criteria (Table 1), patients signed consent to receive intratumoural 32P by EUS within the international observational registry OSPREY (March 2022-February 2024). Complications associated with intratumoural 32P injection via EUS, associated adverse events (AEs) and preliminary efficacy results (progression-free survival [PFS], distant and locoregional, and overall survival [OS]) were analysed. Results: Thirteen patients (7 females; age 65 years [range 48, 79]; 10 ECOG 1) with unresectable LAPC (7 in head, 3 in uncinate and 3 in body; tumour size 36.8 mm [range 25, 60]) were included. The median time from tumour diagnosis to procedure was 5 months [1.4, 28.9]. Only 4 patients (30 %) had received a previous line of treatment. Eleven patients (85%) received gemcitabine-based chemotherapy concomitant with intratumoural 32P (8 gemcitabine plus nabpaclitaxel; 3 gemcitabine monotherapy). There were no complications or AEs related to 32P injection or EUS. A total of 7 patients (54%) had chemotherapy-related AEs, with 2 cases of G3 neutropenia; 6 had G1-2 toxicities: neutropenia (1), thrombopenia (2), anaemia (1), nausea (1), asthenia (1), diarrhoea (1) and constipation (1). Two patients underwent surgery after intratumoural treatment. With a median follow-up of 17.3 months after injection, 8 patients (61.5 %) have progressed, all of them distantly, and three also locoregionally. The median PFS since 32P injection is 8.4 months (95% CI 2.7, NR). Six patients are alive at the end of follow-up (46.2 %) with a median OS since 32P injection of 13.8 months 95% CI [10, NR]. At data cut-off, five patients remain on-treatment. Conclusions: Our initial experience suggests that intratumoural 32P associated with gemcitabine-based chemotherapy is safe. Patients after 32P injection achieve long overall survival. Our ongoing prospective registry will allow evaluation of the oncological outcomes of this therapy at longer follow-up times. [Table: see text]

Irreversible electroporation to bring initially unresectable locally advanced pancreatic adenocarcinoma to surgery: the IRECAP phase II study.

The aim of the IRECAP study was to evaluate the rate of locally advanced pancreas cancer patients (LAPC) who could undergo R0 or R1 surgery after irreversible electroporation (IRE). IRECAP study is a phase II, single-center, open-label, prospective, non-randomized trial registered at clinicaltrials.gov (NCT03105921). Patients with LAPC were first treated by 3-month neo-adjuvant chemotherapy in order to avoid inclusion of either patients with LAPC having become resectable after chemotherapy or patients with rapid disease progression. In cases of stable disease, IRE was performed percutaneously under CT guidance. Surgery was planned between 28 and 90days after IRE. Tumor specimens were studied to evaluate the resection margins (R0/R1/R2). Six men and 11 women were included (median age 61years, range 37-77years). No IRE-related death was observed. Ten patients (58%, 10/17) experienced 25 serious adverse events related to IRE. Four patients progressed between IRE and surgery and were excluded from surgery. Thirteen patients were finally operated, six withheld for pancreas resection, three for diffuse peritoneal carcinosis, two for massive vascular entrapment, and one for hepato-cellular carcinoma not diagnosed before surgery. Rate of R1-R0 was 35% (n = 6/17). Median overall survival was 31months (95% CI; 4-undefined) for the six patients with R0/R1 resection and 21months (95% CI; 4-25) for the 11 patients without resection or R2 resection (logrank p = 0.044). After neoadjuvant chemotherapy, IRE could provide R0 or R1 resection in 35% of LAPC, which seems to be associated with higher OS. After induction chemotherapy, stable locally advanced pancreatic cancers can be treated by irreversible electroporation, which could lead to a secondary 35% rate of R0 or R1 surgical resection which may be associated with a significantly higher overall survival. • In cases of unresectable LAPC (locally advanced pancreatic cancer), percutaneous irreversible electroporation (pIRE) is feasible (100% success rate of the procedure), but is associated with a 58% rate of grade 3-4 adverse events. • In patients with unresectable LAPC, pIRE could lead 35% of patients to R0-R1 surgical resection. • From IRE, median overall survival was 31months (95% CI; 4-undefined) for the patients with R0/R1 resection and 21months (95% CI; 4-25) for the patients without resection or R2 resection (logrank p = 0.044).

Multisite Is Superior to Single-Site Intratumoral Chemotherapy to Retard the Outcomes of Pancreatic Ductal Adenocarcinoma in a Murine Model.

Locally advanced unresectable pancreatic cancer (LAPC) has a dismal prognosis, with intratumoral therapies showing limited benefits. We assume that the dense stroma within these tumors hampers drug dispersion. This study explores the efficacy of multisite intratumoral injections in improving a drug's distribution while minimizing its side effects. In mice with orthotopic LAPC tumors, weekly intratumoral injections of oxaliplatin at four separate sites reduced the tumor growth by 46% compared with saline (p < 0.003). Oxaliplatin exhibited the greatest impact on the tumor microenvironment relative to gemcitabine, Abraxane, or their combination, with increased necrosis, apoptosis, fibroblasts, inflammation, and infiltrating lymphocytes (p < 0.008). When combined with intravenous FOLFIRINOX (FFX), multisite intratumoral oxaliplatin reduced the tumor weight by 35% compared with single-site injection (p = 0.007). No additional visible toxicity was observed even at a 10-fold occurrence of intratumoral treatment. This co-modality treatment significantly improved survival compared with other groups (p = 0.007). Multisite intratumoral therapy in tandem with systemic treatment holds promise for reducing the tumor size and enhancing the overall survival in LAPC.

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.

Preoperative Therapy for Unresectable Locally Advanced Pancreatic Cancer for ≥6 Months Improves Prognosis After Pancreatectomy.

This study aimed to identify the optimal duration of pretreatment for unresectable locally advanced (UR-LA) pancreatic cancer and analyze its effect on the prognosis. This retrospective study included 39 patients with UR-LA pancreatic cancer after pancreatectomy. The cutoff period of preoperative therapy was determined using a receiver operating characteristic curve. We investigated the relationship between preoperative and intraoperative clinical variables and overall survival (OS) in univariate and multivariate analyses. The relationship between the preoperative therapy duration and the clinicopathological variables was investigated. OS was compared according to preoperative therapy duration and the presence or absence of adjuvant surgery. After pretreatment, 15 patients underwent adjuvant surgery and 24 patients continued on chemotherapy without surgery. The multivariate analysis demonstrated preoperative therapy duration ≥6 months was an independent prognostic factor [hazard ratio (HR)=0.10, p=0.04]. No significant difference in the clinicopathological variables was observed between the two groups according to preoperative therapy duration. The OS was significantly better in patients who underwent adjuvant surgery after preoperative therapy duration ≥6 months than in those after preoperative therapy duration <6 months and in those without adjuvant surgery (5-year OS rates: 80% vs. 0%; p=0.01 and 5-year OS rates: 80% vs. 0%; p=0.004, respectively). The OS was not significantly better in patients with adjuvant surgery after preoperative therapy duration <6 months than in those without adjuvant surgery (2-year OS rates: 45.7% vs. 38.1%; p=0.98). Preoperative therapy for UR-LA pancreatic cancer for ≥6 months is necessary to improve prognosis after adjuvant surgery.

Clinical impact of multimodal treatment including chemoradiotherapy, conversion surgery and postoperative chemotherapy for borderline resectable and unresectable locally advanced pancreatic cancer without disease progression after gemcitabine plus nab-paclitaxel

BackgroundThe purpose of this study was to investigate treatment outcomes of chemoradiotherapy (CRT) using S-1 with or without conversion surgery after gemcitabine plus nab-paclitaxel (GnP) for borderline resectable (BR) and unresectable locally advanced (UR-LA) pancreatic cancer. MethodsFrom 2016 to 2020, patients without disease progression after GnP for BR or UR-LA pancreatic cancer underwent CRT with S-1. If distant metastasis was not detected after CRT, conversion surgery and oral administration of S-1 as postoperative adjuvant chemotherapy for at least 6 months was performed. ResultsForty patients were included in the present study. The median number of cycles of GnP was 6. Surgery was performed after CRT in 25 patients. The median progression-free survival (PFS) and overall survival (OS) periods from the start of radiotherapy were 24.6 and 27.4 months, respectively. The OS periods from the start of radiotherapy in patients who underwent conversion surgery and those who did not undergo conversion surgery were 41.3 and 16.8 months, respectively. The PFS periods from the start of radiotherapy in patients who underwent surgery and those who did not undergo surgery were 28.3 and 8.6 months, respectively. Patients who were able to receive S-1 after conversion surgery for more than 6 months had better OS than those who were not (p = 0.039), although there was no significant difference of PFS (p = 0.365). ConclusionsIn BR/UR-LA pancreatic cancer without disease progression after GnP, multimodal treatment including CRT, conversion surgery and the scheduled postoperative chemotherapy may be effective.

Significance of multiple tumor markers measurements in conversion surgery for unresectable locally advanced pancreatic cancer

BackgroundThis study aimed to evaluate the significance of multiple tumor markers (TMs) measurements in determining the indications for conversion surgery (CS) in the management of unresectable locally advanced pancreatic cancer (UR-LAPC). MethodsA total of 103 patients with UR-LAPC, treated between 2008 and June 2021, were enrolled in this study. Three TMs, including carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and Duke pancreatic monoclonal antigen type 2 (DUPAN-2), were measured. ResultsTwenty-five patients (24%) underwent CS. The median preoperative treatment period was 9.5 months. The median survival time (MST) from the initial treatment for patients with CS was significantly longer than that for patients without surgery (34.6 vs. 18.9 months, P < 0.001). The number of elevated TMs before CS was one in five patients and two in five patients, while 15 patients had normal levels of all three TMs. Notably, the MST from the initial treatment for patients with all three preoperative normal TMs levels was favorable for 70.5 months. In contrast, patients with one or two preoperatively elevated TMs levels had a significantly worse prognosis (25.4 and 21.0 months, respectively, P < 0.001). Furthermore, the relapse-free survival of patients with three preoperative normal TMs levels was significantly longer than those with one or two elevated TMs levels (21.9 vs. 11.3 or 3.0 months, respectively, P < 0.001). Non-normal values of all TMs before CS were identified as independent poor prognostic factors. ConclusionsSimultaneous measurement and assessment of the three TMs levels may help determine the surgical indications for UR-LAPC after systemic anticancer treatment.

Optimizing patient selection for stereotactic ablative radiotherapy in patients with locally advanced pancreatic cancer after initial chemotherapy -a single center prospective cohort.

The role of stereotactic ablative radiation therapy (SABR) as local treatment option after chemotherapy for locally advanced pancreatic cancer (LAPC) is evolving. However adequate patient selection criteria for SABR in patients with LAPC are lacking. A prospective institutional database collected data of patients with LAPC treated with chemotherapy, mainly FOLFIRINOX, followed by SABR, which was delivered using magnetic resonance guided radiotherapy, 40 Gy in 5 fractions within two weeks. Primary endpoint was overall survival (OS). Cox regression analyses were performed to identify predictors for OS. Overall, 74 patients were included, median age 66 years, 45.9% had a KPS score of ≥90. Median OS was 19.6 months from diagnosis and 12.1 months from start of SABR. Local control was 90% at one year. Multivariable Cox regression analyses identified KPS ≥90, age <70, and absence of pain prior to SABR as independent favorable predictors for OS. The rate of grade ≥3 fatigue and late gastro-intestinal toxicity was 2.7%. SABR is a well-tolerated treatment in patients with unresectable LAPC following chemotherapy, with better outcomes when applied in patients with higher performance score, age <70 years and absence of pain. Future randomized trials will have to confirm these findings.

Abstract 5397: Prediction of conversion surgery completion following neoadjuvant modified FOLFIRINOX in borderline resectable and locally advanced pancreatic adenocarcinoma: machine learning algorithm analysis

Abstract Background: Neoadjuvant modified (m) FOLFIRINOX is a standard therapy for medically fit patients with borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). Completion of conversion surgery following mFOLFIRINOX is an important prognostic factor. In this study, we evaluated multiple machine learning models to predict completion of conversion surgery following neoadjuvant mFOLFIRINOX in BRPC and LAPC. Methods: Between January 2017 and December 2020, a total of 647 patients with BRPC and LAPC treated with neoadjuvant mFOLFIRINOX at Asan Medical Center, Seoul, South Korea were enrolled. All demographic and clinicopathological data were retrospectively collected; age, ECOG performance status, BMI, resectability as per the NCCN guidelines, tumor location, tumor size, maximum standardized uptake value assessed by 18F-FDG PET/CT, number of cycles of mFOLFIRINOX, tumor response to mFOLFIRINOX, and serum CA 19-9. Several machine learning models, such as logistic regression and random forest classifier, were trained to predict curative-intent resection and were then internally validated. The relative importance of each variable was analyzed using both Gini importance and permutation importance. Results: Among 647 patients, 173 (26.7%) underwent curative-intent conversion surgery (R0 or R1) following mFOLFIRINOX. The patients who underwent surgery showed significantly better overall survival (median 42.1 vs 17.2 months, P&amp;lt;0.0001) than those who did not. In multivariable analysis using logistic regression, age, resectability as per the NCCN guidelines, tumor size, number of cycles of mFOLFIRINOX, tumor response to mFOLFIRINOX, and CA 19-9 change rate (percentage change in CA 19-9 after mFOLFIRINOX) were significantly correlated to tumor removal with curative-intent conversion surgery. Random forest classifier showed the best predictive capability with AUC at 0.832. The most important feature was the CA 19-9 change rate. Conclusions: In this large cohort-based analysis, completion of conversion surgery could be predicted successfully in BRPC and LAPC patients treated with neoadjuvant mFOLFIRINOX using machine learning models. Further external validation is necessary for generalization. Citation Format: Hyunseok Yoon, Kyu-Pyo Kim, Inkeun Park, Jae Ho Jeong, Heung-Moon Chang, Baek-Yeol Ryoo, Changhoon Yoo. Prediction of conversion surgery completion following neoadjuvant modified FOLFIRINOX in borderline resectable and locally advanced pancreatic adenocarcinoma: machine learning algorithm analysis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5397.

Abstract 983: Design and methodology of LAPIS, an ongoing, phase III trial of neoadjuvant pamrevlumab (pam) with chemotherapy (CT) in patients (pts) with unresectable, locally advanced pancreatic cancer (LAPC)

Abstract Background: LAPC is associated with a median overall survival (OS) of 15-18 mos in contemporary clinical trials. CT is typically the initial treatment, and subsequent surgical resection with curative intent is rare. Pam is a fully human monoclonal antibody that inhibits the effects of connective tissue growth factor. Phase I and II trials (NCT01181245 and NCT02210559) of CT+pam provided the rationale for a Phase III study of pts with LAPC. CT plus pam/placebo (PBO) is being evaluated in the Phase III LAPIS trial (NCT03941093). Objective: LAPIS is evaluating the efficacy and safety of CT+pam/PBO as first-line/neoadjuvant therapy in unresectable LAPC. Methods: LAPIS is a global, Phase III, PBO-controlled trial with six cycles of CT+pam/PBO therapy given in a first-line/neoadjuvant setting, surgical eligibility using protocol-specific response criteria, surgery, and follow-up periods, including long-term follow-up for OS. Major eligibility criteria include adults (≥18 yrs of age); ECOG PS of 0-1; histologic/cytologic confirmation of pancreatic cancer; LAPC diagnosis considered unresectable by standard criteria (NCCN v2.2018 and reviewed by central radiology); measurable disease by RECIST v1.1; and treatment-naïve status. Pts were randomized 1:1 to pam+investigator’s choice CT (gemcitabine 1,000 mg/m2+nab-paclitaxel 125 mg/m2; or either FOLFIRINOX [5-fluoruracil 400 mg/m2+folinic acid/leucovorin 400 mg/m2; 5-fluoruracil 2,400 mg/m2; irinotecan 180 mg/m2; oxaliplatin 85 mg/m2; or mFOLFIRINOX [folinic acid/leucovorin 400 mg/m2; 5-fluoruracil 2,400 mg/m2; irinotecan 180 mg/m2; oxaliplatin 85 mg/m2]), or CT+PBO, then stratified by unreconstructable disease (yes/no) and geographic region. Pts received six cycles (24 wks) of first-line therapy prior to surgical eligibility decision. Surgical eligibility was defined per protocol for pts with ≥1 of the following: decline in carbohydrate antigen 19-9 ≥50%; FDG-PET value decrease by ≥30%; radiographic downstage to resectable/borderline resectable criteria per NCCN. Surgical recommendation (resect or not) is provided by the central surgical board. Final decisions on surgery remain with site surgeons. Primary endpoint is OS. Key secondary endpoints include event-free survival [EFS, defined as time to “treatment failure” based on earliest occurrence of 1) failure to achieve local disease-free status at end of treatment and/or after surgery; 2) local or distant recurrence; or 3) death], progression-free survival (PFS), and objective response rate (ORR; complete or partial response) by RECIST v 1.1. Safety (including treatment-emergent adverse events) is evaluated throughout the study, Days 28 and 60 after last CT dose, and Day 90 post-surgery. LAPIS enrollment is complete (N=284). Study completion is estimated for early 2024. Citation Format: Vincent J. Picozzi, Syed Raza, Jack Li, Ewa Carrier. Design and methodology of LAPIS, an ongoing, phase III trial of neoadjuvant pamrevlumab (pam) with chemotherapy (CT) in patients (pts) with unresectable, locally advanced pancreatic cancer (LAPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 983.

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.

Multi-Institutional Comparison of Ablative Radiation Therapy in 5 Versus 15-25 Fractions for Locally Advanced Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> Ablative RT doses ∼100Gy BED₁₀ are associated with improved overall survival (OS) in patients with locally advanced unresectable pancreatic cancer (LAPC), but the optimal fractionation scheme remains unknown. <h3>Materials/Methods</h3> We performed a retrospective analysis of consecutive LAPC patients treated at 2 high-volume institutions with either 50 Gy in 5 fractions using a 0.35T MR Linac and online adaptive replanning between 2018-2021 or 67.5-75 Gy in 15-25 fractions using CBCT guidance and selective offline adaptive replanning between 2016-2019. All were treated with breath hold or gating. Elective nodal coverage was used in 94%. Clinical characteristics between the groups were compared using Fisher's exact test. Freedom from local progression (FFLP) by RECIST and OS were estimated from time of RT with the Kaplan-Meier method. Log-rank test and Cox proportional hazards regression model were used for univariate (UVA) and multivariate (MVA) analyses. <h3>Results</h3> 183 patients were evaluated including 62 (34%) treated with 50 Gy in 5 fractions, 23 (123%) treated with 67.5 Gy in 15 fractions, and 98 (54%) treated with 75 Gy in 25 fractions. Median age was 67 years (range 35 to 91), 53% were male, 72% had a head tumor location, 81% were T3/4 with a median tumor size of 3.8 cm (range 1.4-7.4 cm) and 38% were lymph node positive. Patients receiving 5 fractions were more likely to be N0 than patients receiving 15-25 fractions (69.3% vs 44.6%, p=0.0219), and there were no other clinical differences between the groups. 98% received induction chemotherapy for a median of 3.9 months (FOLFIRINOX 61%, Gemcitabine/Nab-paclitaxel 29%, other 10%). Median follow-up was 38 months. Median FFLP and OS were 31 and 18 months, with 2-yr FFLP and 2-yr OS of 62.9% (95%CI 47.9 – 69.3%) and 36.2% (26.0 – 40.9%), respectively. There were no significant differences in FFLP (HR= 1.493, 95%CI 0.8030 – 2.775, p=0.1598) or OS (HR=1.321, 95%CI 0.8835 – 1.974, p=0.1580) between patients receiving 5 vs 15-25 fractions, respectively, on UVA. Likewise, after adjusting for T stage, nodal status, tumor size, chemotherapy type and duration, there were no significant differences in OS between the groups on MVA (HR=1.234, 95%CI 0.8151 – 1.833, p=0.3070). The rate of grade 3+ GI bleeding was 4.8% and 8% (p=0.5476) in patients receiving 5 vs 15-25 fractions, respectively. <h3>Conclusion</h3> In appropriately selected LAPC patients, ablative RT (BED₁₀ ∼100 Gy) in 5 fractions delivered with MR guidance and online adaptive replanning or 15-25 fractions delivered with CT guidance and selective offline adaptive replanning both appear to achieve excellent efficacy and minimal severe toxicity. Choice of fractionation scheme should be based on anatomical considerations and available technology.

Retrospective Clinical Outcomes of Proton Beam Therapy for Unresectable Locally Advanced Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> We retrospectively researched on the treatment outcomes and assessed the efficacy of proton beam therapy (PBT) for unresectable locally advanced pancreatic cancer (LAPC). <h3>Materials/Methods</h3> Fifty-four patients who were diagnosed unresectable LAPC and administered PBT between April 2009 to March 2020 at our institution. Patients who could not completed PBT, had new distant metastases during treatment, and did not have enough follow-up time were excluded in this study. Statistical analyses were performed by calculating overall survival rate (OS) and local control rate (LC). Median survival time (MST) was analyzed by several following factors; maximum standardized uptake values (SUV_max) of FDG-PET evaluation, performance status (PS), tumor site, total irradiation dose, and combination use of chemotherapy. Treatment toxicities were evaluated by Common Terminology Criteria for Adverse Events (CTCAE ver.5.0). OS, MST, and LC were analyzed using the Kaplan-Meier method and log-rank test. The cut-off values for SUV_max and tumor diameter were estimated using the receiver operating characteristic (ROC) curve and area under the curve (AUC) based on MST. <h3>Results</h3> This study included 28 men and 26 women whose median age was 67.5 years (range, 40 to 88 years). All patients were clinical stage III LAPC according to the Union for International Cancer Control (UICC) TNM staging system (8th edition). Median follow-up time was 17.4 months (range, 4.0 to 89.7 months). The median total dose was 67.5GyE (range, 50-77 GyE/25-35 fractions). The median tumor diameter was 36.5mm (range, 15 to 90 mm). The median SUV_max was 5.85 (range, 2.1 to 27.6). Chemotherapy regimens during PBT were following; 24 patients were gemcitabine alone, 5 were tegafur-gimeracil-oteracil (TS-1) alone, 17 were paclitaxel and TS-1. Eight patients did not receive chemotherapy because of their poor general condition. The One-year, 2-year, 3-year OS were 74.1%, 33.3%, 10.8%, respectively. The One-year, 2-year, 3-year LC were 89.0%, 84.6%, 84.6%, respectively. The MST was 17.1 months. Only one patient survived longer than 5 years. The cut-off values were estimated for SUV_max: 4.8 and tumor diameter: 37mm. Two-year OS based on PS-score group were following; PS 0/1/2: 26.1/ 13.4/8.0 months, respectively with significant differences (each group P<0.01). Treatment related acute toxicities were neutropenia (Grade1/2/3: 2/6/17 patients), leukopenia (Grade1/2/3: 1/4/11 patients), thrombocytopenia (Grade1/2: 1/4 patients), respectively. Late toxicity was gastrointestinal ulcer (Grade1/2: 2/2 patients). No Grade 3 or higher late adverse events were observed. <h3>Conclusion</h3> PBT combined standard chemotherapy achieved excellent local control. However, it did not control systematic tumor progression. PS score at first visit could be important prognostic factor.

SO-2 Comparison of resected vs non-resected patients with unresectable locally advanced pancreatic cancer (LAPC) receiving P-32 microparticles with gemcitabine/nab-paclitaxel or FOLFIRINOX chemotherapy in the PanCO study

Unresectable LAPC has a poor prognosis. Current standard-of-care (SoC) is limited to chemotherapy or chemo-radiotherapy. Brachytherapy using a device containing beta-radiation-emitting Phosphorous-32 (P-32) microparticles is implanted directly into pancreatic tumours via endoscopic-ultrasound (EUS) guidance. We report a post-hoc analysis of resected vs. non-resected cohorts in PanCO, a single-arm, multi-centre, pilot study of P-32 microparticles with SoC chemotherapy in patients with unresectable LAPC.

Comparing concurrent chemoradiotherapy, 125 I seed implantation combined with chemotherapy, and chemotherapy alone efficacy in treating unresectable locally advanced pancreatic cancer

Background The prognosis for unresectable locally advanced pancreatic cancer (LAPC) is still poor, and the best therapeutic option is still unknown. The common treatments for LAPC, concurrent chemoradiotherapy (CCRT), 125I seed implantation combined with chemotherapy (125IC), and chemotherapy alone (CA), were studied. In addition, we looked into the impact of radiation dose on the survival of patients receiving chemoradiotherapy. Methods This study included 202 patients with unresectable LAPC who were separated into three groups based on treatment methods: CCRT, 125IC, and CA. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier and Cox regression methods. The differences between groups were analyzed using the chi-square test and the Fisher exact test. All three groups were compared at the same time and then in pairs. To investigate the impact of radiation dose on survival, patients with CCRT were divided into groups based on radiation dose (<54.9 Gy/≥54.9 Gy) or biological effective dose (BED) of radiotherapy (<65.32 Gy/≥65.32 Gy). Univariate and multivariate analyses were also performed to explore the factors associated with prognosis. Results Patients who received CCRT had a superior OS rate than those who received 125IC or CA (p = 0.009). Multivariate analyses showed that ECOG score 2 (p<0.001) and 125IC (p=0.012) treatment method were substantially associated with poor OS, while being male (p=0.005) and ECOG score 2 (p<0.001) were significantly associated with poor PFS. When comparing the effects of radiation dose on survival, concurrent chemotherapy with high-dose radiotherapy (CCHRT) was found to have a better OS rate (p=0.003) than concurrent chemotherapy with low-dose irradiation (CCLRT). PFS, on the other hand, did not differ statistically in any of the groups (p>0.05). Multivariate analyses showed that age ≥ 64.5 years (p=0.038), ECOG score 2(p=0.001), and CCLRT (p=0.001) were significantly associated with poor OS, while being male (p=0.023) was associated with poor PFS. Conclusions Patients who received CCRT for unresectable LAPC had a greater OS rate than those who received 125IC or CA. Within permitted bounds, CCHRT outperformed CCLRT in terms of OS.

Competing Risk Analysis of Outcomes of Unresectable Pancreatic Cancer Patients Undergoing Definitive Radiotherapy.

PurposeWe investigated potential factors, including clinicopathological features, treatment modalities, neutrophil-to-lymphocyte ratio (NLR), carbohydrate antigen (CA) 19-9 level, tumor responses correlating with overall survival (OS), local progression (LP), and distant metastases (DMs), in patients with locally advanced pancreatic cancer (LAPC) who received definitive radiotherapy (RT).MethodsWe retrospectively analyzed demographic characteristics; biologically effective doses (BED10, calculated with an α/β of 10) of RT; and clinical outcomes of 57 unresectable LAPC (all pancreatic adenocarcinoma) patients receiving definitive RT using modern techniques with and without systemic therapy between January 2009 and March 2019 at our institution. We used Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 to evaluate the radiographic tumor response after RT. The association between prognostic factors and OS was assessed using the Kaplan–Meier analysis and a Cox regression model, whereas baseline characteristics and treatment details were collected for competing-risk regression of the association with LP and DM using the Fine–Gray model.ResultsA median BED10 of 67.1 Gy resulted in a disease control rate of 87.7%, and the median OS was 11.8 months after a median follow-up of 32.1 months. The 1-year OS rate, cumulative incidences of LP, and DM were 49.2%, 38.5%, and 62.9%, respectively. Multivariate analyses showed that pre-RT NLR ≥3.5 (adjusted hazard ratio [HR] = 8.245, p < 0.001), CA19-9 reduction rate ≥50% (adjusted HR = 0.261, p = 0.005), RT without concurrent chemoradiotherapy (adjusted HR = 5.903, p = 0.004), and administration of chemotherapy after RT (adjusted HR = 0.207, p = 0.03) were independent prognostic factors for OS. Positive lymph nodal metastases (adjusted subdistribution HR [sHR] = 3.712, p = 0.003) and higher tumor reduction after RT (adjusted sHR = 0.922, p < 0.001) were significant prognostic factors for LP, whereas BED10 ≥ 67.1 Gy (adjusted sHR = 0.297, p = 0.002), CA19-9 reduction rate ≥50% (adjusted sHR = 0.334, p = 0.023), and RT alone (adjusted sHR = 2.633, p = 0.047) were significant prognostic factors for DM.ConclusionOur results indicate that pre-RT NLR and post-RT monitoring of CA19-9 and tumor size reduction can help identify whether patients belong to the good or poor prognostic group of LAPC. The incorporation of new systemic treatments during and after a higher BED10 RT dose for LAPC patients is warranted.

CA19-9 Reduction After 4 Months of Treatment Is a Prognostic Factor for Locally Advanced Pancreatic Cancer.

Carbohydrate antigen 19-9 (CA19-9) levels may aid in the determination of subsequent treatment in patients with unresectable locally-advanced pancreatic cancer (LAPC) treated with chemotherapy. However, the relationship between the timing and magnitude of CA19-9 changes and clinical outcomes remains unclear. This study was conducted to identify the timing and magnitude of CA19-9 changes, which are most strongly associated with outcomes in LAPC patients. We retrospectively analyzed consecutive LAPC patients treated with gemcitabine plus nab-paclitaxel (GnP) or modified FOLFIRINOX (mFFX) as the first-line chemotherapy between March 2014 and December 2018 in our hospital. Multivariate analyses were performed to identify prognostic factors of chemotherapy in LAPC. Ninety-four patients were included (GnP/mFFX: 72/22). The median overall survival was 20.3 months, and the median progression-free survival was 8.8 months. CA19-9 values before treatment did not affect prognosis. However, CA19-9 <100 U/ml or more than a 70% reduction in CA19-9 four months after commencing treatment was associated with a good prognosis (hazard ratio=0.17; 95% confidence interval=0.09-0.33; p<0.01). CA19-9 values 4 months after commencing treatment are a significant prognostic factor in LAPC patients undergoing chemotherapy.