Recurrent Pancreatic Adenocarcinoma Research Articles

A phase II open-label study of enfortumab vedotin in patients with previously treated locally advanced, recurrent, or metastatic pancreatic adenocarcinoma (EPIC).

TPS719 Background: Nectin-4 is a type I transmembrane protein member of the nectin family involved in the formation and maintenance of adherens junctions. In contrast to its limited expression in normal tissues, aberrant overexpression of nectin-4 has been identified in various solid tumors, including in pancreatic adenocarcinoma. About 71% of human PDAC specimens stain positive and 13% stain strongly positive for nectin-4. Mechanistically, nectin-4 has been associated with various pro-oncogenic cellular processes, including the promotion of tumor cell proliferation and metastasis via WNT- βcatenin pathway activation. It interacts with ERBB2/HER2 and activates Rac1 (small G protein) to ultimately upregulate PI3K-AKT pathway signaling, leading to cell survival and proliferation. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) to cells expressing Nectin-4. EV is FDA approved as a single agent for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy based on the EV-301 Trial which demonstrated overall survival benefit. Taken together, the above data and the efficacy of EV seen in bladder cancer warrants the evaluation of EV in advanced pancreatic adenocarcinoma. Methods: Design: Open-label, phase II single-arm trial of EV (n=28) in previously treated locally advanced, recurrent, or metastatic pancreatic adenocarcinoma. Treatment schedule: EV 1.25 mg/kg administered IV on D1, D8, D15 every 28 days until disease progression or unacceptable toxicity. Imaging assessment will be done every 8 weeks. A biopsy prior to therapy and a biopsy on treatment (between days 15-21 of cycle 1) is required. Eligibility: Patients with previously treated, locally advanced, recurrent, or metastatic pancreatic adenocarcinoma. Inclusion criteria also include ECOG PS 0-1 and at least 1 line of prior therapy. Objectives: The primary objective is to determine anti-tumor activity by overall response rate using RECIST 1.1. Secondary objectives include safety, duration of response, disease control rate, progression-free survival and overall survival. Exploratory objectives include Nectin-4 expression (H-score) in tumor tissue and the relationship between the mutational profile of the tumor and response. Statistical Plan: A Simon’s two-stage Minimax design will be used. In the first stage, 18 pts will be accrued. If there is less than 1 response in these 18 pts, the study will be stopped for futility. Otherwise, 10 additional pts will be accrued for a total of 28 pts. The null hypothesis will be rejected if 3 or more responses are observed in 28 pts. Enrollment is currently ongoing. Clinical trial information: NCT05915351 .

Detection and treatment of recurrent pancreatic ductal adenocarcinoma – a european prospective, snapshot study

Detection and treatment of recurrent pancreatic ductal adenocarcinoma – a european prospective, snapshot study

Early Outcomes of MR-Guided SBRT for Patients with Recurrent Pancreatic Adenocarcinoma

Local treatment options for patients with locally recurrent pancreatic adenocarcinoma (L-PAC) are limited, with expected median survival time (MST) of 8-11 months (mo) following recurrence. MRI-guided radiation therapy (MRgRT) provides the ability to dose escalate while sparing normal tissue. The literature for MR-guided Stereotactic Body Radiotherapy (MRgSBRT) for L-PAC is sparse. Here we report on the early outcomes of MRgSBRT in patients with L-PAC. Patients with prior resection of pancreatic adenocarcinoma with post-operative chemotherapy as indicated followed by local recurrence of disease at prior surgical site and treated with MRgSBRT at a single tertiary referral center from 5-2021 to 8-2022 for L-PAC were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Descriptive analysis of the patient, disease, and treatment characteristics were performed. Endpoints included local control, defined as absence of tumor progression per RECIST criteria, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events (CTCAE), version 5. Eleven patients with L-PAC were identified with median follow-up of 10.7 mo (3.2 - 22.3). Ten of those underwent surgical resection at the treating radiation facility and one patient underwent preoperative radiation for 50.4 Gy in 28 fractions followed by surgical resection at an outside hospital. MRgRT was delivered a median of 18.8 mo (3.5 - 48.0) following resection. There were 5 females and 6 males, with a median age of 72 years (52-83) and median KPS of 80 (60-100). OS rates following initial diagnosis at 12, 18 and 24 mo were 100%, 82%, and 61%, respectively, with an MST of 25.3 mo (12.4-53.1). OS rates following recurrence at 6 and 12 mo were 82% and 52%, respectively, with an MST of 10.7 mo (3.2 - 21.9). One patient experienced local failure at 7.8 mo, and 9 patients experienced distant failure at a median of 3.4 mo (0.3 - 21.9) following MRgSBRT. Five patients experienced distant failure less than 3 mo following radiation. Grade 1 or 2 acute GI toxicity was noted in 45% of patients and chronic GI toxicity, in 18% of patients. No Grade≥3 AEs were noted. MRgSBRT for recurrent pancreatic adenocarcinoma demonstrates good local control with acceptable acute and chronic toxicity as well as reasonable overall survival. Distant failure remains a substantial problem with a significant number of patients demonstrating metastases immediately following radiation, suggesting the presence of micro-metastatic disease prior to local therapy. Adequate patient selection for MRgSBRT, and proper integration of systemic therapy in this patient population remains a topic of discussion that requires further exploration.

Prognostic factor in patient with recurrent pancreatic adenocarcinoma.

To elucidate prognostic factors for post-recurrence survival in patients with pancreatic ductal adenocarcinoma (PDAC). Patients who underwent curative-intent surgery for PDAC between January 2014 and May 2020 were identified. Among them, patients who had postoperative recurrences and received chemotherapy were retrospectively investigated. Independent prognostic factors for survival after recurrence were investigated using multivariate analyses. Eligible patients were divided into two groups according to the presence or absence of the identified prognostic factors, and survival times after recurrence were compared. Eighty-four patients with recurrent PDAC were included. Multivariate analysis showed that red blood cell (RBC) transfusion (HR, 2.80; p = 0.0051), low albumin level (HR, 1.84; p = 0.0402), and high carbohydrate antigen 19-9 (CA19-9) level at recurrence (HR, 2.11; p = 0.0258) were significant predictors of shorter survival after recurrence. The median survival times after recurrence in the transfusion and non-transfusion groups were 5.5 vs. 18.1months (p < 0.0001), respectively; those in the low and normal albumin groups were 10.1 vs. 18.7months (p = 0.0049), and those in the high and normal CA19-9 groups were 11.5 vs. 22.6months (p = 0.0023), respectively. RBC transfusion, low albumin, and high CA19-9 levels at recurrence negatively affected survival after recurrence in patients with PDAC.

Comment On: Prospective Phase II Trials Validate the Effect of Neoadjuvant Chemotherapy on Pattern of Recurrence in Pancreatic Adenocarcinoma.

We read with great interest the article by Dr. Chawla et al.1 They investigated the pattern of recurrence from a retrospective cohort of patients treated with neoadjuvant chemotherapy (NAC) followed by chemoradiation and then surgery or surgery first followed by adjuvant chemotherapy and 2 prospective cohorts of patients derived from 2 phase II clinical trials assessing patients treated with NAC in borderline-resectable and locally advanced pancreatic adenocarcinoma (PDAC). They found that the site of recurrence in PDAC is mostly distant metastasis (DM) rather than locoregional, regardless of the use of NAC and margin status. After reading their article, we have some questions that we hope to communicate with the authors. First, the authors consider that the surgical margin distance less than 1 mm of the resection is R1 resection, which can be agreed upon by most surgeons in the resectable or borderline-resectable cohort. However, in the locally advanced cohort, for PDCA with vascular invasion, how did the authors determine the status of the surgical margin because the tumor was removed along the vessels? In theory, for PDCA with vascular invasion, the surgical margin distance is always less than 1 mm. Then, according to the authors’ definition of surgical margin, PDCA with vascular invasion would have no way to achieve an R0 resection. Second, in the locally advanced cohort, the DM rate was only 67%. Patients in the locally advanced cohort had the highest tumor stage but the lowest DM rate compared to other cohorts. Different from the treatment of other cohorts (surgery + adjuvant therapy), losartan is added to the treatment in the locally advanced cohort. Is the decrease in DM associated with the use of losartan? To observe recurrence patterns consistent with the rest of the cohort, we think that treatment in the locally advanced cohort should be substantially consistent with the rest of the cohort. We raise these questions not to challenge Chawla et al.’s1 research but to have a friendly academic exchange with them. And, we acknowledge Chawla et al.1 for their contribution to the discovery of recurrence patterns in PDCA. Meanwhile, we are also very grateful to Annals of Surgery Open for giving us a platform to communicate.

The Prognostic Utility of a Geriatric Assessment for Patients with Pancreatic Cancer Receiving Gemcitabine-based Chemotherapy: A Prospective Observational Study.

Objective To evaluate the effect of a pretreatment geriatric assessment on the clinical outcomes in older patients with unresectable or recurrent pancreatic ductal adenocarcinoma (PDAC) scheduled to receive gemcitabine (GEM)/GEM+nab-paclitaxel (GnP). Patients Older patients with unresectable PDAC scheduled to receive GEM/GnP who visited Kyorin University Hospital and cooperating institutions were enrolled and followed from April 2015 to March 2020. The maximum observation period was two years. All patients underwent a cancer-specific geriatric assessment (CSGA) and optional geriatric assessment (GA) before treatment initiation and two months after the start of treatment. The patients' background characteristics, tumor progression, tumor site, and regimen (GEM/GnP) were examined in a Cox proportional hazards model. The relationship between the overall survival (OS) and GA score was also determined. Eligible patients (age ≥70 years old with histopathologically confirmed unresectable or recurrent PDAC) were scheduled to receive first-line chemotherapy. Results The performance status (PS) and activities of daily living (ADL)/instrumental ADL (IADL) scores at baseline correlated with the OS. Furthermore, even in cases with normal baseline values, lower Frontal Assessment Battery scores and higher Geriatric Depression Scale-Short Form scores after treatment initiation were significantly correlated with OS. Conclusion The baseline PS, ADL, and IADL may be prognostic factors in older PDAC patients. In addition, a normal frontal lobe function and depression scores prior to treatment initiation that rapidly worsened during treatment were independently associated with a reduced OS. Selecting appropriate interventions and improving the therapeutic environment may prolong the OS in such patients.

Utility of endoscopic ultrasound for assessment of locoregional recurrence of pancreatic adenocarcinoma after surgical resection

Background and study aims Up to 80 % of patients with pancreatic adenocarcinoma develop locoregional recurrence after primary resection. However, the detection of recurrent pancreatic ductal adenocarcinoma (RPDAC) after pancreatic surgery can be challenging because of difficulty distinguishing locoregional recurrence from normal postoperative or post-radiation changes. We sought to evaluate the utility of endoscopic ultrasound (EUS), in detecting pancreatic adenocarcinoma recurrence after surgical resection and its impact on the clinical management of patients. Patients and methods This was a retrospective study of all pancreatic cancer patients who underwent EUS post-resection at two tertiary care centers between January 2004 and June 2019. Results Sixty-seven patients were identified. Of these, 57 (85 %) were diagnosed with RPDAC, resulting in change in clinical management of 46 (72 %) patients. EUS identified masses not seen on computed tomography, magnetic resonance imaging, or positron emission tomography in seven (14 %). Conclusions EUS is useful in detecting RPDAC after pancreatic surgery and can lead to significant impact on clinical management.

Landscape of CTDNA DNA in patients with metastatic/locally recurrent pancreatic adenocarcinoma

Background: Pancreatic adenocarcinoma often presents with advanced, unresectable or metastatic disease leading to a poor prognosis. Liquid biopsy by circulating tumor DNA (ctDNA) is becoming an important noninvasive diagnostic tool for patients with pancreatic cancer. The purpose of our study was to characterize mutational status of patients with metastatic or recurrent pancreatic adenocarcinoma and investigate the feasibility of obtaining ctDNA routinely for patients in the clinical setting.

Stereotactic Body Radiation Therapy is Safe and Feasible for the Treatment of Locally Recurrent Pancreatic Adenocarcinoma after Curative Resection

<h3>Purpose/Objective(s)</h3> Locoregional relapse rates following surgical resection of pancreatic cancer can be as high as 45-50%. The majority of these patients are not candidates for re-resection due to co-morbidities and/or technically unresectable disease, highlighting the role of non-invasive options such as radiation therapy. The purpose of this study was to report on a cohort of radiation-naïve patients who developed isolated local recurrence following surgical resection and were subsequently treated with stereotactic body radiation therapy (SBRT). <h3>Materials/Methods</h3> Patients who were treated with SBRT for locally recurrent pancreatic cancer after initial curative resection were retrospectively reviewed. Clinical outcomes were calculated from completion of SBRT and included overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS). Univariate and multivariate analyses were performed to identify variables associated with clinical outcomes. Kaplan-Meier analysis was performed for survival outcomes. Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0. <h3>Results</h3> From September 2012 to November 2018, a total of 19 patients were treated with SBRT for locally recurrent pancreatic cancer after initial surgical resection. No patients had prior radiation. The most common SBRT dose/fractionation was 33 Gy in 5 fractions (12/19, 63.1 %), followed by 25 Gy in 5 fractions (4/19, 21.0%), 28 Gy in 5 fractions (1/19, 5.3%), 27 Gy in 4 fractions (1/19, 5.3%), and 26.4 Gy in 4 fractions (1/19, 5.3%). Peri-SBRT chemotherapy was administered to 10 patients, in the pre-SBRT (3/19, 15.7%) and/or post-SBRT (8/19, 42.1%) setting. Median OS was 17.1 months, with 6-month and 1-year OS rates of 94.4% and 69.6%, respectively. A total of 9 patients (47.4%) developed local failure after SBRT. Pattern of first failure after SBRT was distant in 7 patients (46.7%), local in 5 patients (33.3%), and synchronous distant and local in 3 patients (20.0%). One patient developed local failure after developing distant disease first. Of the 9 local failures, 3 (33.3%) were out-of-field, involving the porta hepatis (n=1), pancreaticojejunostomy (n=1), and pancreatic remnant (n=1). Median LPFS was 22.2 months, with 6-month and 1-year LPFS rates of 86.9% and 63.2%, respectively. A biologically effective dose (BED₁₀) < 54.8 Gy was associated with inferior LPFS (1-year LPFS, 25.0% vs 80.2%, p<0.009). Median DMFS and PFS were 15.6 months. There was 1 case (5.3 %) of grade 3 gastric perforation. There were no cases of grade 4-5 toxicity events. <h3>Conclusion</h3> Stereotactic body radiation therapy for local recurrence after initial curative resection is safe and feasible. A BED₁₀ < 54.8 Gy was significantly associated with inferior local control, and one-third of local failures were out-of-field. Further studies investigating dose escalation and optimal treatment volumes in the locally recurrent setting are warranted.

Salvage ablative radiation therapy for loco-regionally recurrent pancreatic ductal adenocarcinoma following surgical resection.

552 Background: Dose escalated radiation therapy for localized pancreatic ductal adenocarcinoma (PDAC) is associated with improved outcomes (Reyngold, JAMA Onc, 2021). Overall survival (OS) and loco-regional failure (LRF) rates with ablative radiation therapy (A-RT) in unresectable PDAC approach those of surgery. Herein, we report outcomes of A-RT as loco-regional salvage after resection. Methods: A prospective database (2016 onward) has been maintained of all patients receiving A-RT at for PDAC. A-RT is defined as a biologically effective dose (BED) ≥96 Gy (α/β = 10). We analyzed consecutive patients from June 2016 through January 2021 who received A-RT for isolated loco-regional recurrences after resection. Survival was calculated using the Kaplan-Meier method. Results: Sixty-nine patients (40 men, 29 women) with median age of 67 received A-RT for loco-regionally recurrent PDAC. At diagnosis of recurrence, median disease-free interval from time of initial resection was 15.6 months (range 6.2–82.7) and median CA 19-9 was 65 U/mL (range &lt; 1–1087). Twenty-one patients (30%) received neoadjuvant chemotherapy prior to surgery: pancreaticoduodenectomy (57 patients, 83%) or distal pancreatectomy (12 patients, 17%). There was a negative resection margin in 55 patients (80%). Most had T1/T2 (61 patients, 88%) and node-positive disease (44 patients, 64%). Radiation fractionation ranged from 5-25 fractions (median 25) to a total dose of 50-75 Gy (median 75). Median follow up was 16.2 months from RT. Median OS was 26.5 months from diagnosis of recurrence and 20.7 months from time of salvage A-RT. Twelve- and 24-month OS were 78.5% (95% CI 66.3–86.7) and 40.3% (25.8–54.3), respectively. In-field local failure was 8.5% (0.3–36.0) at 12 months and 27.5% (5.2–57.0) at 24 months. Respective disease-free survival at 12 and 24 months were 32.9% (21.7–44.1) and 12.3% (5.7–21.6). Grade 3 or greater gastrointestinal bleeding (GIB) occurred in 7 patients (10%), including one grade 4 event while on anticoagulation and one grade 5 event in a patient with portal hypertension. Conclusions: A-RT achieves favorable OS and LRF outcomes in patients with PDAC and an isolated loco-regional recurrence after surgical resection.

Efficacy and Safety of Reirradiation with Stereotactic Body Radiation Therapy for Locally Recurrent Pancreatic Adenocarcinoma

AimsThe purpose of this study was to report on outcomes of a cohort of patients who were treated with reirradiation with stereotactic body radiation therapy (SBRT) for locally recurrent pancreatic adenocarcinoma. Materials and methodsPatients treated with SBRT reirradiation for locally recurrent pancreatic adenocarcinoma from December 2009 to April 2020 were included in the study. Descriptive statistics were used to record patient demographics, tumour and treatment characteristics. Kaplan–Meier analysis was used to evaluate overall survival, local progression-free survival (LPFS), distant metastasis-free survival and progression-free survival (PFS). ResultsIn total, 27 patients were included in the study. The median follow-up time from local recurrence was 19.7 months (range 4.2–43.1 months). Most patients received five-fraction SBRT (26/27, 96%). The median overall survival after local recurrence treatment was 18.3 months (range 3.0–42.6 months), with 6-month, 1-year and 2-year overall survival rates of 88.5%, 73.1% and 33.6%. The median LPFS after local recurrence treatment was 16.2 months (range 2.3–33.6 months), with 6-month, 1-year and 2-year LPFS rates of 95.8%, 62.9% and 27.2%. Peri-SBRT chemotherapy improved LPFS (median 17.5 versus 8.5 months; P = 0.010) and overall survival (median 19.3 versus 5.5 months; P = 0.049). Tumours ≤ 3 cm in the greatest dimension showed better local control (median LPFS 19.2 versus 10.2 months; P = 0.130). There was one case (4%) of acute grade 3 pain and one case (4%) of late grade 3 gastrointestinal toxicity. ConclusionsReirradiation with five-fraction SBRT is safe, but local control remains suboptimal. Patients with smaller tumours experienced improved outcomes, as did patients whose treatment plan included the administration of peri-SBRT chemotherapy.

Surgical Resection or Ablation for Recurrent Pancreatic Ductal Adenocarcinoma: An Analysis of Oncologic Outcomes According to the Recurrence Type.

To evaluate the survival benefits of curative-intent treatment (CIT, including surgery or ablation) for recurrent pancreatic ductal adenocarcinoma (PDAC) depending on the recurrence type and compared the survival outcomes with other treatment modalities. The treatment for recurrent PDAC is mostly chemotherapy or best supportive care (BSC). Still, the role of CIT for recurrent PDAC is not well established. PDAC patients who underwent pancreatectomy between 2004 and 2019 were included. Recurrences were categorized as locoregional (LR), distant, or disseminated. Recurrent PDAC management was classified as CIT, chemotherapy ± radiation therapy (CTX ± RTX), or BSC. The survival after recurrence (SAR) rate was measured from the first day of recurrence to the date of death or last follow-up. Two hundred eighteen patients had recurrent PDAC and were analyzed (27 CIT, 128 CTX ± RTX, 63 BSC). The 1-, 3-, and 5-year SAR rates were 65.4%, 11.5%, and 11.5% for CIT, 42.1%, 4.0%, and 0% for CTX ± RTX, and 15.9%, 1.6%, and 0% for BSC, respectively. Subgroup analysis indicated the SAR rate was significantly better in the CIT group than in the CTX ± RTX and BSC groups in LR type (P = 0.027) and distant type (P < 0.001). In multivariate analysis, the albumin level at recurrence (hazard ratio, 2.14; 95% confidence interval, 1.15-18.3, P = 0.038) and operation time of the second operation (hazard ratio, 0.98; 95% confidence interval, 0.97-0.99, P = 0.021) were associated with a favorable prognosis of SAR in the CIT group. CIT should be considered in recurrent PDAC for LR and distant metastases in selected patients.

Longstanding postoperative fluid collection influences recurrence of pancreatic malignancy

Background/AimsPostoperative abdominal fluid collection (PAFC) is a frequent complication of pancreatobiliary cancer surgery. The effects of the existence and duration of PAFC are not well known. This study aimed to assess the effects of PAFC on patient prognosis after surgery for pancreatobiliary adenocarcinoma and the association of longstanding PAFC with the recurrence of pancreatic cancer.MethodsWe retrospectively analyzed the data of 194 consecutive patients with pancreatobiliary adenocarcinoma who underwent curative operations from August 2005 to December 2019. The presence of PAFC was assessed using computed tomography within a week of surgery; PAFC lasting > 4 weeks was defined as longstanding PAFC.ResultsAmong 194 patients, PAFC occurred in 165 (85.1%), and 74 of these had longstanding PAFC. The recurrence rate of pancreatobiliary adenocarcinoma was significantly higher in patients with longstanding PAFC than in patients with non-longstanding PAFC (p = 0.025). Recurrence was also significantly associated with high T stage (T3, T4; p = 0.040), lymph node involvement (p < 0.001), perineural invasion (p < 0.006), and non-receipt of adjuvant chemotherapy (p = 0.025). Longstanding PAFC was significantly associated with the recurrence of pancreatic adenocarcinoma (p = 0.016). However, cancer-specific survival was related to neither the presence nor the duration of PAFC.ConclusionsThe presence of longstanding PAFC was associated with the recurrence of pancreatic adenocarcinoma. However, a larger prospective study is necessary to confirm the findings.

Long-term outcomes of a prospective single institution study with multiagent chemotherapy and stereotactic body radiation therapy in locally advanced or recurrent pancreatic adenocarcinoma.

440 Background: We previously reported a multi-center study in which gemcitabine and stereotactic body radiation therapy (SBRT) were shown to be safe with outcomes comparable to chemoradiation in locally advanced pancreatic cancer (LAPC). This prospective clinical trial was developed to evaluate the efficacy of adding SBRT to multi-agent chemotherapy in LAPC. Herein, we report on the long-term survival outcomes. Methods: From 2012 to 2015, 48 patients (pts) were prospectively enrolled after multidisciplinary evaluation at a single high-volume pancreatic center. Pts received multi-agent chemotherapy (CTX) with modified mFOLFIRINOX (mFFX) or gemcitabine/abraxane followed by 5 fractions of SBRT (median 33 Gy; range, 25-33 Gy). At the time of fiducial placement, biopsies were obtained and DNA extracted for targeted sequencing using MSK-IMPACT. Kaplan-Meier curves were generated to compare survival outcomes by sub-group. Multivariate analysis (MVA) was performed to identify factors prognostic for survival. Results: 44 pts (91.7%) had LAPC disease and 4 (8.3%) had locally recurrent disease. The median follow-up interval was 21.5 months (mo) from diagnosis. CTX consisted of mFFX in 25 pts (52.1%) with 24 pts (50.0%) receiving therapy for a duration ≥4 mo. Of 44 pts with LAPC, 15 (34.1%) were surgically explored, and 11 (73.3%) achieved a margin-negative resection. From diagnosis and after completion of SBRT, respectively, the median overall survival (OS) was 21.6 (95% CI 16-29.7 mo) and 14.6 mo (95% CI: 11.6-23.0 mo); median progression free survival (PFS) was 13.2 (95% CI 11.9-18.1mo) and 6.4 mo (95% CI: 5-12.7 mo); median local PFS (LPFS) was 23.9 (95% CI 18.9-56.9 mo) and 15.8 mo (95% CI: 12.9-27.6 mo); and median distant metastasis free survival (DMFS) was 18.4 (95% CI 12.6-29.3 mo) and 8.5 mo (95% CI: 6.3-17.2 mo). Resected pts experienced better DMFS at 1-year (78% vs. 34%, p= 0.004) with an improved trend for 1-year OS (73% vs. 52%, p= 0.331). If CTX duration was ≥4 mo, 1-year OS (75% vs. 42%, p= 0.018), PFS (50% vs. 21%, p= 0.022), and DMFS (72% vs. 29%, p= 0.031) were significantly improved. In 44 LAPC pts, MVA confirmed ≥4 mo duration of CTX was associated with OS, PFS, and DMFS. Surgical resection was associated with improved DMFS, and CA19-9 level prior to SBRT was associated with PFS and LPFS. The most common mutations detected from biopsy specimens were KRAS (64.3%) , TP53 (50%), and SMAD4 (16.7%). Conclusions: In a prospective trial of pts with LAPC receiving multiagent CTX and SBRT, clinical outcomes were improved with longer durations of CT ( &gt; 4 mo). A high proportion of LAPC pts underwent margin negative resection with favorable outcomes. Future studies should focus on which pts are most likely to benefit from SBRT and surgery following multiagent CTX. In pts who cannot undergo resection, escalated doses of SBRT may be indicated. Clinical trial information: NCT01781728.

Real-world outcomes in recurrent versus de novo metastatic pancreatic adenocarcinoma.

387 Background: Optimal management of patients with recurrent pancreatic ductal adenocarcinoma (PDAC) is unknown. In the clinical trials that established a survival benefit with combination chemotherapy compared to single agent gemcitabine, patients with recurrent PDAC were either excluded (PRODIGE-4) or severely underrepresented (MPACT). In this study, we evaluated clinical outcomes of recurrent PDAC patients who receive systemic therapy and compared outcomes to patients with de novo advanced PDAC. Methods: Patients diagnosed with advanced PDAC between 2014 and October of 2019 were included using the nationwide Flatiron Health EHR-derived de-identified database. Patients without a clinic visit or initiation of treatment within 90 days of diagnosis were excluded. Patients were characterized as either de novo or recurrent PDAC based on stage at diagnosis and history of surgery. Patients with recurrent PDAC were further stratified based on time to recurrent disease. Overall survival (OS) was summarized within groups via Kaplan-Meier survival estimates, and compared between groups in the context of univariable and multivariable Cox proportional hazards models. The covariates adjusted for were gender, age, race, ECOG, smoking status, primary site, CA199, albumin, lymphocytes, neutrophils and monocytes. Results: We included 5170 patients with advanced PDAC, of which 1101 (21.3%) met criteria for recurrent disease. Patients with recurrent PDAC were more likely to have tumors in the head of the pancreas (71% vs 40%, p &lt; 0.001) and had lower median CA19-9 (92.8 vs 617, p &lt; 0.001), compared to the de novo PDAC patients. Median OS for the recurrent group was 10.8 m (95% CI = 9.9-11.7) vs. 7.3 m (95% CI = 7.0-7.7) in the de novo group (p &lt; 0.001, both univariate and multivariable adjusted analyses). The most common first line palliative chemotherapy in patients with recurrent disease was Nab-paclitaxel plus gemcitabine (41%) or FOLFIRINOX (21%). Patients who recurred within six months of surgery (28%) had an OS of 10.0 m (95% CI = 8.7 -11) vs. 11.6 m (95% CI 10-12, p = 0.256) in those who recurred greater than six months from surgery. Conclusions: Our data suggest that patients with recurrent disease have significantly better survival outcomes compared to patients with de novo metastatic disease. We did not observe a significant difference in survival of patients who recurred within 6 months of resection compared to those who recurred greater than six months after surgery. These data support the inclusion of patients with recurrent PDAC in clinical trials, including those who develop recurrent disease within 6 months of surgery, with appropriate stratification for these variables.

Phase II randomized, double-blind study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients (HCRN GI14-198).

413 Background: Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR)-mediated signaling and angiogenesis contribute to the pathogenesis and progression of pancreatic adenocarcinoma (PCA).VEGF is expressed in all PCA tumors. VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of PCA cells. The pVEGFR-2 is significantly associated with invasion of the anterior capsule of pancreas and arteries. In preclinical studies, the anti-tumor activity of fluoropyrimidines, but not that of gemcitabine, caused the release of bone marrow derived circulating endothelial progenitor cells (CEPs) and Tie-2 expressing monocytes (TEMs) as well as the induction of pro-angiogenic growth factors. Methods: This phase II randomized, multi-center, and double-blinded trial was designed to compare the efficacy and safety of mFOLFIRINOX/ramucirumab (Arm A) versus mFOLFIRINOX/ placebo (Arm B) as front-line therapy in recurrent or metastatic PCA patients. The primary endpoint was progression free survival (PFS) at 9 months, and the secondary endpoints included overall survival (OS) and response rate. Results: A total of 86 subjects were enrolled, 82 were eligible (42 in Arm A v. 40 in Arm B). The mean age of the subjects in the two arms were comparable (61.7 v. 63.0, respectively); 43 male, 69 Caucasian. On the univariate analysis, there was no difference in distribution between the 2 arms for age, gender, race and ethnicity. The median PFS was 5.6 in Arm A compared to 6.7 months in Arm B (one-sided log-rank, p = 0.322). At 9 months, the progression free rates were 25.1% v. 35% for Arms A and B, respectively. The mFOLFIRINOX/ramucirumab combination was well tolerated. Patients in Arm A reported a slightly higher number of adverse events (AEs) encounters, most commonly diarrhea (29 vs 28), fatigue (25 v. 25), vomiting (24 v. 14), weight loss (23 v. 17), and abdominal pain (20 v. 15). Arm A had more SAEs than Arm B (43 v. 25), with sepsis most commonly reported in both arms (3 in each), vomiting (3 v. 2), diarrhea (3 v.1) and duodenal obstruction (3 v. 0). Arm B had a slightly higher response rate (22.58%) compared to Arm A (17.65%) that was not statistically significant. The median OS in Arm A was 10.3 compared to 9.7 months for Arm B (one-sided log-rank, p = 0.094). Conclusions: In this randomized phase 2 study, the addition of ramucirumab to mFOLFIRINOX did not improve PFS, response rate, or OS as initial therapy for metastatic pancreatic cancer. FOLFIRINOX/Ramucirumab combination was well tolerated in the treatment of PCA. Clinical trial information: NCT02581215.

Negative prognostic implications of splenomegaly in nivolumab-treated advanced or recurrent pancreatic adenocarcinoma

ABSTRACT Immune checkpoint inhibitors have limited efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). We investigated prognostic markers for nivolumab-based therapy in advanced or recurrent PDAC. Consecutive patients receiving nivolumab-based therapy at our institution between 2015 and 2020 were evaluated. Overall survival (OS) was analyzed through univariate and multivariate analyses. Spleen volume was estimated from the width, thickness, and length of the spleen. A total of 45 patients were identified. Biweekly nivolumab was administered as monotherapy (n = 5) or in combination with chemotherapy or targeted therapy (n = 40). Among 31 evaluable patients, the response and disease control rates were 7% and 36%, respectively. The baseline median spleen volume was 267 (110–674) mL. Patients with spleens ≥267 mL had significantly shorter median OS (1.9 months, 95% confidence interval [CI], 1.0–2.7) than did those with smaller spleens (8.2 months, 95% CI, 5.6–10.8; P = .003). In the multivariate analysis, spleen volume of <267 mL, ≤2 lines of prior chemotherapy, ECOG performance status of 0–2, add-on nivolumab with stable disease after prior therapy, concomitant or sequential cell therapy, high lymphocyte count, and total bilirubin <1 mg/dL were independent favorable prognostic factors for OS. In the control groups of patients receiving gemcitabine-based chemotherapy (n = 142) or FOLFIRINOX regimen (n = 24), spleen volume exhibited no prognostic significance. In heavily pretreated PDAC, a large spleen may predict poor OS following nivolumab-based immunotherapy. Studies with larger cohorts should confirm the prognostic value of spleen volume.

Robotic completion pancreatectomy for recurrent pancreatic duct adenocarcinoma four years after open pancreatoduodenectomy

Presenter: Karolin Ginting MD | The Jewish Hospital Background: Second primary tumor in remnant pancreas is rare given poor prognosis with pancreatic ductal adenocarcinoma (PDAC). We are seeing long term survivors given recent advances in surgical technique and chemotherapy. Previous studies have shown the potential benefit of competition total pancreatectomy in improving survival rate in patients with isolated cancer in remnant pancreas. However, this poses technical challenges due to adhesions and complex anatomy. Robotic techniques offer potential technical advantage in oncologic resection of remnant pancreas. Methods: We described an isolated recurrence of pancreatic ductal adenocarcinoma in a 60-year-old female who underwent pancreaticoduodenectomy (PD) four years ago for pancreatic ductal adenocarcinoma. Interestingly, this patient also had synchronous hepatic cholangiocarcinoma that was resected at the time of initial PD. Results: Robotic en-bloc resection of the pancreatic remnant with splenectomy and left adrenalectomy was completed without complication and was discharged on post-operative day 4. Final pathology showed ductal adenocarcinoma with 1 of 15 positive lymph nodes. She completed adjuvant gemcitabine and capecitabine post operatively. Surveillance CT scan of the chest, abdomen and pelvis a year later was negative for recurrence. Conclusion: Robotic en-bloc resection and completion pancreatectomy in a patient with isolated recurrent PDAC is feasible and safe. In addition, minimally invasive surgery in this case allowed the patient to recovered more expeditiously and with less pain compared to her initial surgery.

A phase II study of gemcitabine, erlotinib and S-1 in patients with advanced pancreatic cancer.

Background: We evaluated the efficacy and safety of gemcitabine in combination with erlotinib and S-1 for the treatment of advanced pancreatic cancer.Methods: Chemotherapy-naïve patients with pathologically-proven locally advanced, recurrent, or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine was administered at 1,000 mg/m2 intravenously on days 1 and 8, erlotinib was administered at 100 mg/day on days 1-21, and S-1 was administered at 60 mg/m2 on days 1-14 every 21 days and continued to a maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2 was permitted from the second cycle for pre-defined tolerable patients.Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1-8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The confirmed overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and the disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively.Conclusion: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer.

Recurrence, survival, and therapy-free interval after irreversible electroporation for pancreatic adenocarcinoma

Presenter: Wooil Kwon MD, PhD | Columbia University Background: Locally advanced pancreatic cancer (LAPC) is particularly challenging to treat. Systemic therapy may prolong survival but cannot offer a cure. Patients do not qualify for resection according to international guidelines, but accumulating experience from high volume centers in the modern era of chemotherapy suggest survival benefit in select patients undergoing resection. Recent efforts have focused on expanding surgical options. Irreversible electroporation (IRE) can be used to primarily control tumors in situ or to extend resection margins. This study provides valuable insight on survival, recurrence, and complications from a center that has integrated IRE into its treatment protocols. Methods: Data were collected for patients with T4 pancreatic ductal adenocarcinoma treated with IRE at a single tertiary center from 2012-2020. Those undergoing second IRE or IRE for other diagnoses were excluded. Primary end points included patterns of adjuvant and palliative therapy, overall survival (OS), recurrence free survival (RFS) and Clavien-Dindo complications. Therapy-free interval was defined as time from last neoadjuvant chemotherapy or radiation to the initiation of adjuvant or palliative therapy for recurrence. OS and RFS were evaluated by Kaplan Meier analysis and compared via log-rank test. Potential predictive factors were evaluated by Cox proportional hazard regression. Results: Of 110 patients, 46 underwent in situ IRE and 64 for margin extension. Eight (7.27%) were treated for recurrent pancreatic adenocarcinoma. Patients were similar in baseline characteristics, tumor location, and receipt of neoadjuvant chemotherapy. Median overall tumor size of 3.4 (2.8-4.0) on preoperative imaging was not different between IRE approach (p= 0.2810), Median OS from diagnosis (28.18 months, IQR 15.94-51.91) was similar for in situ vs. resection with margin extension (30.03 vs. 24.59 months, p=0.3298). There was no difference in local/distant RFS (respectively 7.26 vs. 10.59 months, p=0.7543). Both groups were similar with regard to Grades 3-5 90-day complications (28.3% vs. 25.0%, p=0.7018). Univariate Cox regression found no individual predictors of survival or recurrence to be significant. Adjuvant chemotherapy was given to 25.53% of patients who survived beyond 90 days. Thirty-two (34.04%) were not initially treated with adjuvant therapy, but later received treatment for recurrence. This group benefitted from a median therapy-free interval of 12.08 months (9.14-27.59) from last neoadjuvant chemotherapy or radiation, while maintaining similar overall survival (21.09 months vs. 20.96 months for planned adjuvant therapy, p=0.454). Conclusion: Many patients in this series would not have been candidates for traditional surgical resection. Compared to historical controls and studies of systemic therapy alone, this study demonstrates the favorable survival outcomes of IRE. By demonstrating a median one year treatment-free interval from neoadjuvant chemotherapy or radiation, this study highlights the potential for IRE to improve quality of life by limiting the inconveniences and toxicities of systemic therapy and raises questions about the role of adjuvant therapy after maximal neoadjuvant therapy for these selected patients.