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Purpose: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC)., Methods: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures., Results: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy ( P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS., Conclusion: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

Background: Postoperative adverse events (AEs) in patients with borderline resectable pancreatic ductal adenocarcinoma (BR-PC) treated with neoadjuvant therapy and pancreatectomy in the national cooperative group setting have not been previously characterized. We conducted a preplanned secondary analysis of patients enrolled on the Alliance A021501 clinical trial to quantify perioperative AE rates., Methods: The A021501 phase 2 trial randomized patients with BR-PC to receive 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX and hypofractionated radiotherapy (Arm 2), followed by pancreatectomy (December 31, 2016 to May 31, 2019). Adverse events were assessed 90 days after pancreatectomy., Results: Of 126 enrolled patients, 51 (40%) underwent pancreatectomy (n = 32, Arm 1; n = 19, Arm 2) at 28 institutions. Five (10%) patients required reoperation within 90 days; 56% of patients (n = 27/48) experienced at least one grade 3 or higher AE (50% vs. 67%, p = 0.37). Ninety-day mortality was 2.0%. Readmission was less frequent in Arm 1 (16% vs. 42%, p = 0.05), but there were no differences between study arms in rates of reoperation (13% vs. 5%), pancreatic fistula or intra-abdominal abscess requiring drainage (9% vs. 16%), or wound infection (6% vs. 16%). Pancreatic fistula or intra-abdominal abscess requiring drainage was associated with receipt of adjuvant therapy (p = 0.012). No difference in overall survival was observed based on occurrence of postoperative AEs (hazard ratio = 1.1; 95% confidence interval 0.5-2.6)., Conclusions: In this multicenter study, rates of postoperative AEs were consistent with those previously reported. Multimodality trials of preoperative therapy for BR-PC may be performed in the cooperative group setting with careful quality assurance and safety monitoring., Trial Registration: Clinicaltrials.gov identifier: NCT02839343., (© 2024. Society of Surgical Oncology.)

Background: Surgery in selected patients with locally advanced pancreatic cancer after induction chemotherapy may have drawbacks related to surgical risks and breaks or delays in oncological treatment, in particular when curative intent resection is not possible (that is non-therapeutic laparotomy). The aim of this study was to assess the incidence and oncological impact of a non-therapeutic laparotomy in patients with locally advanced pancreatic cancer treated with induction (m)FOLFIRINOX chemotherapy., Methods: This was a retrospective international multicentre study including patients diagnosed with pathology-proven locally advanced pancreatic cancer treated with at least one cycle of (m)FOLFIRINOX (2012-2019). Patients undergoing a non-therapeutic laparotomy (group A) were compared with those not undergoing surgery (group B) and those undergoing resection (group C)., Results: Overall, 663 patients with locally advanced pancreatic cancer were included (67 patients (10.1%) in group A, 425 patients (64.1%) in group B, and 171 patients (25.8%) in group C). A non-therapeutic laparotomy occurred in 28.2% of all explorations (67 of 238), with occult metastases in 30 patients (30 of 67, 44.8%) and a 90-day mortality rate of 3.0% (2 of 67). Administration of palliative therapy (65.9% versus 73.1%; P = 0.307) and median overall survival (20.4 [95% c.i. 15.9 to 27.3] versus 20.2 [95% c.i. 19.1 to 22.7] months; P = 0.752) did not differ between group A and group B respectively. The median overall survival in group C was 36.1 (95% c.i. 30.5 to 41.2) months. The 5-year overall survival rates were 11.4%, 8.7%, and 24.7% in group A, group B, and group C, respectively. Compared with group B, non-therapeutic laparotomy (group A) was not associated with reduced overall survival (HR = 0.88 [95% c.i. 0.61 to 1.27])., Conclusion: More than a quarter of surgically explored patients with locally advanced pancreatic cancer after induction (m)FOLFIRINOX did not undergo a resection. Such non-therapeutic laparotomy does not appear to substantially impact oncological outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain., Methods: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012-2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0-20 vs 21-40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1-4 vs 5-8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis., Results: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score-matched. After matching, median OS was 26.2 months (95% CI, 24.0-38.4) with RT versus 32.8 months (95% CI, 25.3-42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92)., Conclusions: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.

Background and Objectives: The impact of perioperative blood transfusion (PBT) on outcomes for pancreatic ductal adenocarcinoma (PDAC) patients given multimodality therapy (MMT) remains undefined. We sought to evaluate the association of PBT with survival after PDAC resection., Methods: Pancreatectomy patients (July 2011-December 2017) who received MMT were abstracted from a prospective database. Overall survival (OS) was compared by PBT within 30 days, 24 h (24HR-BT), or 24 h until 30 days (Postop-BT)., Results: Most (76.6%) of 312 MMT patients underwent neoadjuvant therapy (NT). Eighty-nine patients (28.5%) received PBT; 58 (18.6%) 24HR-BT, and 31 (9.9%) Postop-BT. Compared with surgery-first, NT patients received more 24HR-BTs (22.2% vs. 6.8%, p = 0.003) and PBTs overall (32.6% vs. 15.1%, p = 0.004). Overall median OS was 45 months. The association of PBT with shorter median OS appeared limited to first 24-h transfusions (34 months 24HR-BT vs. 48 months Postop-BT vs. 53 months no-PBT, p = 0.009) and was dose-dependent, with a median OS of 52 months for 0 units 24HR-BT, 35 months for 1 unit, and 25 months for ≥2 units (p = 0.004). Independent predictors of OS included node-positivity (hazard ratio [HR]: 1.93, p < 0.001), perineural invasion (HR: 1.64, p = 0.050), postoperative pancreatic fistula (HR: 1.94, p = 0.018), and 24HR-BT (HR: 1.75, p = 0.001)., Conclusions: Transfusions given within 24 h are associated with dose-dependent decreases in survival after pancreatectomy for PDAC., (© 2021 Wiley Periodicals LLC.)

Importance: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (GA) are first-line chemotherapy regimens for pancreatic cancer. Their relative efficacy in the setting of localized disease is unknown., Objective: To evaluate radiographic and serologic measures of responses associated with first-line chemotherapy with FOLFIRINOX or GA, and to determine the association between these drug regimens, putative measures of response, and survival., Design, Setting, and Participants: This case series assessed 485 consecutive patients who were diagnosed as having previously untreated localized pancreatic ductal adenocarcinoma at The University of Texas MD Anderson Cancer Center between January 1, 2010, and December 31, 2017, and who received at least 3 cycles of first-line chemotherapy with FOLFIRINOX or GA. The median (range) follow-up duration was 33 (2-28) months., Exposures: Administration of FOLFIRINOX (285 patients [59%]) or GA (200 patients [41%]) as first-line chemotherapy., Main Outcomes and Measures: Resection rate, radiographic metrics (Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, and change in tumor volume or anatomic staging), a serologic metric (serum cancer antigen 19-9 level), and overall survival after administration of first-line chemotherapy., Results: In total, 485 patients (266 [55%] male) were included in the analysis. Patients treated with FOLFIRINOX were generally younger (median [range] age at diagnosis: 61 [30-81] vs 71 [36-89] years; P = .001) and had better performance status as indicated by the Eastern Cooperative Oncology Group scale (range 0-4, with lower numbers representing better performance) score of 2 or lower (274 patients [96%] vs 165 patients [82%] P = .001) but more invasive tumors than patients who received GA (91 [32%] vs 90 [45%] resectable tumors; P = .01). After propensity score matching to control for these biases, many objective serologic and radiographic metrics of response associated with administration of FOLFIRINOX or GA-including low rates of local tumor downstaging-did not differ. However, RECIST partial response was more common among patients treated with FOLFIRINOX (27 of 140 patients [19%]) than with GA (8 of 140 patients [6%]; P = .001). Moreover, (chemo)radiation (50% vs 34%; P = .001) was more commonly administered to and pancreatectomy (27% vs 16%; P = .01) was subsequently performed more frequently for patients initially treated with FOLFIRINOX. The overall survival duration of patients treated with either regimen was similar (hazard ratio, 1.48; 95% CI, 0.97-2.26; P = .07)., Conclusions and Relevance: In this cohort of patients with localized pancreatic adenocarcinoma who received FOLFIRINOX or GA as their first line of therapy, FOLFIRINOX was associated with higher rates of RECIST partial response and subsequent pancreatectomy than GA, but the overall survival associated with these regimens was similar.

Background: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated., Methods: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method., Results: We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III-IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX., Conclusions: This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Neoadjuvant therapy (NT) is used for advanced pancreatic ductal adenocarcinoma (PDAC). No clear guidelines exist for switching therapies when patients do not respond to initial NT. We sought to characterize patients who underwent early switch from FOLFIRINOX to gemcitabine/nab-paclitaxel (GA) as NT for PDAC., Methods: We identified patients at a single institution switched from FOLFIRINOX to GA within the first 4 months of NT for PDAC during 2012-2017. We compared clinicopathologic data and oncologic outcomes., Results: Of 25 patients who met the criteria, 21 showed a serologic or radiographic response to GA; 11 (52%) reached resection. Responders had decreased carbohydrate antigen (CA) 19-9 levels from pretreatment to post-GA (P = 0.036). Resected responders had significantly decreased CA 19-9 comparing preswitch to post-GA (P = 0.048). The only predictor of GA response was prechemotherapy CA 19-9 of less than1000 U/mL (P = 0.021). Predictors of reaching resection were head/uncinate tumor (P = 0.010) and presenting stage lower than locally advanced (P = 0.041)., Conclusions: When patients do not respond to neoadjuvant FOLFIRINOX, early switch to GA should be considered. Future efforts should be directed toward identifying markers that will allow correct choice of initial therapy rather than attempting to rescue patients who respond poorly to first-line therapy.

Background: Preoperative chemotherapy provides early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy for localized pancreatic ductal adenocarcinoma (PDAC). For locally advanced (LA) PDAC, induction chemotherapy is the standard of care. This study evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy for localized PDAC., Methods: Clinicopathologic features, treatment, and outcomes were evaluated for 99 patients with localized PDAC. The patients were staged using previously published criteria as follows: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR-C (comorbidities requiring medical optimization), and LA., Results: The 99 patients (PR/BR/LA: 45/14/40) were treated with Gem/nab-P. Clinical staging showed that 20 patients had PR or BR-A disease, whereas 39 patients had BR-B or BR-C disease. The BR-B+C cases included one or more of the following: age of 80 years or older (13%), Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more (13%), moderate to severe comorbidities (55%), CA19-9 of 1000 or higher (28%), and suspicion for metastases (21%). The majority of the patients received biweekly Gem/nab-P dosing, which was well tolerated. Pancreatectomy was performed for 12 (60%) of 20 patients with PR+BR-A, 2 (5%) of 39 patients with BR-B+C, and 1 (3%) of 40 patients with LA disease. During a median follow-up period of 26 months, the median overall survival (OS) period was 18 months (95% confidence interval [CI], 15.6-20.5 months) for all the patients, 17 months (95% CI, 14.6-19.5 months) for the unresected patients, and not reached for the resected patients (p = 0.028 for resected vs unresected patients)., Conclusions: A significant number of patients with radiographically resectable PDAC albeit aggressive biology (BR-B), medically inoperable conditions (BR-C), or both received biweekly first-line Gem/nab-P. The resection rates were lower for the BR-B/BR-C patients than for the PR/BR-A patients (hazard ratio [HR], 0.43; 95% CI, 0.19-1.00; p = 0.05).

Introduction: While preoperative chemotherapy is frequently utilized before resection of non-neuroendocrine liver metastases, patients with resectable neuroendocrine liver metastases typically undergo surgery first. FAS is a cytotoxic chemotherapy regimen that is associated with substantial response rates in locally advanced and metastatic pancreatic neuroendocrine tumors., Methods: All patients who underwent R0/R1 resection of pancreatic neuroendocrine liver metastases at a single institution between 1998 and 2015 were included. The outcomes of patients treated with preoperative FAS were compared with those of patients who were not., Results: Of the 67 patients included, 27 (40.3%) received preoperative FAS, whereas 40 (59.7%) did not. Despite being associated with higher rates of synchronous disease, lymph node metastases, and larger tumor size, patients who received preoperative FAS had similar overall survival [overall survival (OS), 108.2 months (95% confidence interval (CI) 78.0-136.0) vs. 107.0 months (95% CI 78.0-136.0), p = 0.64] and recurrence-free survival [RFS, 25.1 months (95% CI 23.2-27.0) vs. 18.0 months (95% CI 13.8-22.2), p = 0.16] as patients who did not. Among patients who presented with synchronous liver metastases (n = 46), the median OS [97.3 months (95% CI 65.9-128.6) vs. 65.0 months (95% CI 28.1-101.9), p = 0.001] and RFS [24.8 months (95% CI 22.6-26.9) vs. 12.1 months (2.2-22.0), p = 0.003] were significantly greater among patients who received preoperative FAS compared with those who did not., Conclusions: The use of FAS before liver resection is associated with improved OS compared with surgery alone among patients with advanced synchronous pancreatic neuroendocrine liver metastases.

Background: Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and 64% of operations achieved an R0 resection. However, the individual contributions of preoperative chemotherapy and radiation therapy to therapeutic outcome remain poorly defined., Methods: In Alliance for Clinical Oncology Trial A021501, a recently activated randomized phase II trial, patients (N = 134) with a CT or MRI showing a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed anatomic criteria for borderline resectable disease will be randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 and infusional 5-fluorouracil 2400 mg/m 2 over 2 days for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33-40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy will undergo pancreatectomy and will subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , bolus 5-fluorouracil 400 mg/m 2 , and infusional 5-fluorouracil 2400 mg/m 2 over 2 days for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The primary analysis will compare the 18-month overall survival rate of each arm to a historical control rate of 50%. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site., Discussion: This study will help define standard preoperative treatment regimens for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials., Trial Registration: ClinicalTrials.gov : NCT02839343 , registered July 14, 2016.

Purpose To update the Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline published on May 31, 2016. The October 2016 update focuses solely on new evidence that pertains to clinical question 4 of the guideline: What is the appropriate adjuvant regimen for patients with pancreatic cancer who have undergone an R0 or R1 resection of their primary tumor? Methods The recently published results of a randomized phase III study prompted an update of this guideline. The high quality of the reported evidence and the potential for its clinical impact prompted the Expert Panel to revise one of the guideline recommendations. Results The ESPAC-4 study, a multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy compared gemcitabine and capecitabine with gemcitabine monotherapy in 730 evaluable patients with resected pancreatic ductal adenocarcinoma. Median overall survival was improved in the doublet arm to 28.0 months (95% CI, 23.5 to 31.5 months) versus 25.5 months (95% CI, 22.7 to 27.9 months) for gemcitabine alone (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = .032). Grade 3 and 4 adverse events were similar in both arms, although higher rates of hand-foot syndrome and diarrhea occurred in patients randomly assigned to the doublet arm. Recommendations All patients with resected pancreatic cancer who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy in the absence of medical or surgical contraindications. The doublet regimen of gemcitabine and capecitabine is preferred in the absence of concerns for toxicity or tolerance; alternatively, monotherapy with gemcitabine or fluorouracil plus folinic acid can be offered. Adjuvant treatment should be initiated within 8 weeks of surgical resection, assuming complete recovery. The remaining recommendations from the original 2016 ASCO guideline are unchanged.

Background: BRCA1/BRCA2 germ line (GL) mutation carriers with pancreatic adenocarcinoma (PDAC) may have distinct outcomes. We recently described an apparent more favourable prognosis of surgically resected BRCA-associated PDAC patients in a single-arm, uncontrolled, retrospective study. However, the prognostic impact of GL BRCA1/2 mutations in surgically resected PDAC has not been compared with a matched control population., Methods: A larger multi-centre, case-control retrospective analysis was performed. Cases were patients with surgically resected, BRCA1/2-associated PDAC from 2004 to 2013. Controls included surgically resected PDAC cases treated during the same time period that were either BRCA non-carriers, or had no family history of breast, ovarian or pancreatic cancers. Cases and controls were matched by: age at diagnosis (within ±5-year period) and institution. Demographics, clinical history, overall survival (OS) and disease-free survival (DFS) were abstracted from patient records. Statistical comparisons were assessed using χ 2 - and Fisher's exact test, and median DFS/OS using Kaplan-Meier method and log-rank testing., Results: Twenty-five patients with BRCA1-(n=4) or BRCA2 (N=21)-associated resectable PDAC were identified. Mean age was 55.7 years (range, 34-78 years), 48% (n=12) were females and 76% (n=19) were Jewish. Cases were compared (1 : 2) with 49 resectable PDAC controls, and were balanced for age, ethnicity and other relevant clinical and pathological features. BRCA-associated PDAC patients received neoadjuvant, or adjuvant platinum-based treatment more frequently than controls (7 out of 8 vs 6 out of 14) and (7 out of 21 vs 3 out of 44), respectively. No significant difference in median OS (37.06 vs 38.77 months, P=0.838) and in DFS (14.3 vs 12.0 months, P=0.303) could be demonstrated between cases and controls. A trend to increased DFS was observed among BRCA-positive cases treated with neoadjuvant/adjuvant platinum-containing regimens (n=10) compared with similarly treated controls (n=7) (39.1 vs 12.4 months, P=0.255)., Conclusions: In this retrospective analysis, the prognosis of surgically resectable BRCA-associated PDAC is no different than that of sporadic PDAC from the same institution. The role of platinum-based adjuvant therapy in this setting requires prospective investigation.

Introduction: 5-Fluorouracil, doxorubicin, and streptozocin (FAS) leads to a 39 % response rate in advanced pancreatic neuroendocrine tumors (pNETs). We sought to validate our hypothesis that preoperative FAS may facilitate resection of locoregionally advanced pNETs by reducing the anatomic extent of the primary tumor., Patients: All patients who received FAS between 2000 and 2012 as initial therapy for a localized pNET were reviewed. Tumor size and vascular relationships were compared on pretreatment and posttreatment imaging studies to quantify treatment response., Results: Twenty-nine patients received a median 4 cycles of FAS (range 2-15). Rates of RECIST progressive disease (PD), stable disease (SD), and partial response (PR) were 3, 90, and 7 %, respectively. An interface was observed between the tumor and a major mesenteric artery and/or vein in 19 (66 %) and 24 (83 %) patients, respectively; after therapy with FAS, 17 (59 %) and 22 (76 %) had persistent interface with artery and/or vein. Fourteen (48 %) patients underwent pancreatectomy, 7 (50 %) required vascular management, and 9 (64 %) operations were R0. The median overall survival of unresected and resected patients was 41 months (95 % CI, 16-66) and 112 months (95 % CI, 104-120) (P = 0.04)., Conclusions: Although patients receiving FAS for locoregionally advanced pNETs are unlikely to progress during systemic therapy, significant "downstaging" appears uncommon.

Background: Previous studies have suggested that preoperative chemoradiation (CRT) is associated with an improved margin-negative resection rate among patients who undergo pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, the optimal preoperative regimen has not been established., Methods: All patients with PDAC who received chemotherapy and/or CRT followed by PD between 1999 and 2014 were retrospectively reviewed. The effects of 2 external-beam radiation regimens-a standard course of 50.4 Gy in 28 fractions and a hypofractionated course of 30 Gy in 10 fractions-were compared. Differences in clinicopathologic characteristics, locoregional recurrence (LR), and overall survival (OS) were assessed., Results: Among 472 patients who received preoperative therapy, 224 (47.5%) received 30 Gy, 221 (46.8%) received 50.4 Gy, and 27 (5.7%) received chemotherapy alone. Patients who received 50.4 Gy were more likely to have advanced-stage disease and to have received induction and postoperative chemotherapy, but there was no difference in the R1 margin status, treatment effect, LR, or OS between the 2 radiation groups (all P values > .05). Patients who received preoperative CRT had a lower rate of LR than patients who received preoperative chemotherapy alone (P < .01). In a multivariate Cox proportional hazards analysis, 50.4 Gy was associated with OS and LR similar to those associated with 30 Gy, whereas the absence of preoperative radiation was associated with a higher rate of LR (odds ratio, 2.21; 95% confidence interval, 1.04-4.70) and similar OS., Conclusions: Preoperative hypofractionated CRT was associated with similar local control and OS in comparison with standard CRT in patients undergoing PD for PDAC. The use of chemotherapy alone without CRT was associated with poorer local control but similar survival. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2671-2679. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Importance: Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported., Objective: To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting., Design, Setting, and Participants: A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014., Interventions: Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy., Main Outcomes and Measures: Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate., Results: The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration., Conclusions and Relevance: The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients., Trial Registration: clinicaltrials.gov Identifier: NCT01821612., Competing Interests: Disclosures: None reported.

Background: Preoperative/neoadjuvant therapy (NT) is increasingly utilized for the treatment of pancreatic ductal adenocarcinoma (PDAC). However, little data exist regarding information on the use of additional postoperative therapy following NT. The lymph node ratio (LNR) is a prognostic marker of oncologic outcomes after NT and resection. In this study, we evaluated the effectiveness of postoperative therapy following NT, stratified by LNR., Methods: A prospective tumor registry database was queried to identify patients with PDAC who underwent resection following NT from 1990 to 2008. Clinicopathologic factors were compared to identify associations with overall survival (OS) and time to recurrence (TTR) based on postoperative chemotherapy status., Results: Thirty-six (14 %) of the 263 patients received additional postoperative therapy. No differences were observed in the pathologic characteristics between patients who received postoperative chemotherapy and those who did not. The median LNR was 0.12 for patients with N + disease. Following NT, the administration of postoperative therapy was associated with improved median OS (72 vs. 33 months; p = 0.008) for patients with an LNR < 0.15. There was no association between postoperative chemotherapy and OS for patients with LNR ≥ 0.15. Multivariate analysis demonstrated that the administration of postoperative systemic therapy in patients with a low LNR was associated with a reduced risk of death (hazard ratio 0.49; p = 0.02)., Conclusion: Postoperative chemotherapy after NT in patients with low LNR is associated with improved oncologic outcomes.

Background: Little is known about changes in body composition that may occur during neoadjuvant therapy for pancreatic cancer. This study was designed to characterize these changes and their potential relationships with therapeutic outcomes., Methods: The study population consisted of patients with potentially resectable pancreatic cancer treated on a phase II trial of neoadjuvant chemotherapy and chemoradiation. Skeletal muscle and adipose tissue compartments were measured before and after administration of neoadjuvant therapy using SliceOMatic software (TomoVision, 2012) and protocol-mandated CT scans. Sarcopenia was defined using gender-adjusted norms., Results: Among 89 eligible patients, 46 (52 %) patients met anthropometric criteria for sarcopenia prior to the initiation of neoadjuvant therapy. Further depletion of skeletal muscle, visceral adipose tissue, and subcutaneous adipose tissue occurred during neoadjuvant therapy, but these losses did not preclude the performance of potentially curative surgery. Degree of skeletal muscle loss correlated with disease-free survival while visceral adipose loss was associated with overall and progression-free survival. However, completion of all therapy, including pancreatectomy, was the only independently significant predictor of outcome in a multivariate analysis of overall survival., Discussion: These data suggest that body composition analysis of standard CT images may provide clinically relevant information for patients with potentially resectable pancreatic cancer who receive neoadjuvant therapy. Anthropometric changes must be considered in the design of preoperative therapy regimens, and further efforts should focus on maintenance of muscle and visceral adipose tissue in the preoperative setting.

Background: The use of neoadjuvant therapy (NAC) for the treatment of potentially resectable pancreatic cancer remains controversial. In this study, we sought to evaluate cancer-specific endpoints in patients undergoing a NAC versus a surgery-first (SF) approach with specific emphasis on lymph node metastases., Methods: A total of 222 patients who underwent NAC and 85 patients who underwent SF were identified from 1990 to 2008 and compared for cancer-related endpoints. Peripancreatic lymph nodes from 135 neoadjuvant therapy patients were evaluated for histologic tumor regression., Results: Patients who underwent NAC followed by surgery had improved overall survival and time to local recurrence compared with the SF approach. NAC patients were less likely to have lymph node metastases (p = 0.001), lymphovascular invasion (LVI), and had smaller tumors. On multivariate analysis, lymph node positivity was associated with SF, tumor size, and the presence of LVI. NAC patients with N0 disease had equivalent outcomes to patients with a low-LNR (0.01-0.15), whereas patients with a LNR >0.15 had reduced survival, and time to local and distant recurrence. Ten of 135 (7.4 %) NAC patients had evidence of tumor regression in at least one lymph node., Conclusions: Patients with potentially resectable PDAC selected to undergo NAC had improved survival and longer time to recurrence. Although some of these differences may be related to improvements in multimodality therapy completion rates, tumor regression in lymph node metastases exists and may demonstrate a biologic benefit of NAC compared with a SF approach.

Background and Objectives: Patient-derived orthotopic xenograft (PDOX) nude-mouse models replicate the behavior of clinical cancer, including metastasis. The objective of the study was to determine the efficacy of zoledronic acid (ZA) on metastasis of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of pancreatic cancer., Methods: In the present study, we examined the efficacy of ZA on pancreatic cancer growth and metastasis in a PDOX nude-mouse model., Results: ZA monotherapy did not significantly suppress primary tumor growth. However, the primary tumor weight of gemcitabine (GEM) and combination GEM + ZA-treated mice was significantly decreased compared to the control group (GEM: P = 0.003; GEM + ZA: P = 0.002). The primary tumor weight of GEM + ZA-treated mice was significantly decreased compared to GEM-treated mice (P = 0.016). The metastasis weight decreased in ZA- or GEM-treated mice compared to the control group (ZA: P = 0.009; GEM: P = 0.007. No metastasis was detected in combination GEM + ZA-treated mice compared to the control group (GEM + ZA; P = 0.005)., Conclusions: The results of the present study indicate that ZA can selectively target metastasis in a pancreatic cancer PDOX model and that the combination of ZA and GEM should be evaluated clinically in the near future for this highly treatment-resistant disease., (© 2014 Wiley Periodicals, Inc.)

Background: A well-defined treatment strategy for elderly patients with resectable pancreatic cancer is lacking. Multiple reports have described highly selected older cancer patients who have successfully undergone pancreatectomy. However, multimodality therapy is essential for long-term survival, and elderly patients are at high risk for not receiving adjuvant therapy postoperatively. We sought to describe the treatment patterns and outcomes of a series of elderly patients with pancreatic cancer who were treated with a multimodality strategy that liberally used neoadjuvant therapy., Study Design: We retrospectively reviewed treatment plans, short-term outcomes, and overall survival of all patients 70 years old and older, presenting to our institution over a 9-year period, who were treated for potentially resectable or borderline resectable pancreatic cancer., Results: There were 179 (76%) of 236 patients treated with curative intent. Of these patients, 153 (85%) initiated neoadjuvant therapy: 74 (48%) subsequently underwent pancreatectomy and 79 did not due to disease progression (n = 46), insufficient performance status (n = 23), or other reasons (n = 10). Eleven (42%) of 26 patients who underwent surgery first received postoperative therapy. Among patients treated with curative intent, the median overall survival of all patients initiating neoadjuvant therapy (16.6 months [range 2.1 to 142.7 months]) was similar to that of patients undergoing resection primarily (15.1 months [range 5.4 to 100.8 months]), p = 0.53. After pancreatectomy, patients had a 2% in-hospital mortality rate and 91% were discharged home., Conclusions: Eighty-five percent of all patients 70 years old and older, who underwent pancreatectomy for potentially resectable or borderline resectable pancreatic cancer, received multimodality therapy. More than 90% were discharged home. These data demonstrate a potential role for neoadjuvant therapy in selecting elderly patients for surgery, and support further studies to refine individualized treatment protocols for this high-risk population., (Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Barriers to multimodality therapy (MMT) completion among patients with resectable pancreatic adenocarcinoma include early cancer progression and postoperative major complications (PMC). We sought to evaluate the influence of these factors on MMT completion rates of patients treated with neoadjuvant therapy (NT) and surgery-first (SF) approaches. We evaluated all operable patients treated for clinically resectable pancreatic head adenocarcinoma at our institution from 2002 to 2007. Rates of MMT completion, 90-day PMC, and overall survival (OS) were evaluated. Ninety-five of 115 (83 %) NT and 29/50 (58 %) SF patients completed MMT. Patients who completed MMT lived longer than those who did not (36 vs. 11 months, p < 0.001). The most common reason that NT (11 %) and SF (26 %) patients failed to complete MMT was early disease progression. The rates of PMC among NT and SF patients were similar. Among SF patients, 69 % with no PMC completed MMT versus 29 % after PMC (p = 0.040). PMC were associated with decreased OS in SF patients but not in NT patients. The impact of early cancer progression and PMC upon completion of MMT is reduced by delivery of nonoperative therapies prior to pancreaticoduodenectomy. NT sequencing is a practical treatment strategy, particularly for patients at high biological or perioperative risk.

Background: We previously introduced a classification system for patients with localized pancreatic adenocarcinoma that integrates assessments of tumor anatomy, cancer biology, and patient physiology. By means of this system, we sought to analyze outcomes of patients with resectable anatomy but heterogeneous biology and physiology who were treated with neoadjuvant therapy., Methods: We evaluated consecutive patients (2002-2007) with anatomically potentially resectable cancers treated with chemotherapy or chemoradiation before potential pancreatectomy. We compared clinical factors and outcomes of patients classified as having disease that was clinically resectable (CR; no extrapancreatic disease, preserved performance status); suspicion for extrapancreatic disease (BR-B); or marginal performance status or significant comorbidity (BR-C). Patients with borderline resectable anatomy (BR-A) were excluded., Results: Resection rates for 138 CR, 41 BR-B, and 38 BR-C patients were 75, 46, and 37%, respectively (P < 0.001). Metastases, detected during treatment in 23% of patients, were the most common contraindication to resection among CR (15%) and BR-B (46%) patients. Performance status rarely precluded surgery except among BR-C (32%) patients. Factors associated with selection against surgery were older age, poor performance status, pain, and therapeutic complications (P < 0.05). The median overall survival of all patients was 21 months. Resected and unresected BR-B and BR-C patients had median overall survival durations similar to those of resected and unresected CR patients, respectively (P > 0.22)., Conclusions: This system describes discrete clinical subgroups of patients with pancreatic cancer who have similar, potentially resectable tumor anatomy but heterogeneous physiology and cancer biology. It may be used with neoadjuvant therapy to predict outcomes, individualize treatment algorithms, and optimize survival.

Purpose: We conducted a phase II trial to assess the survival duration and quality of life of patients who received adjuvant interferon-based chemoradiation for pancreatic adenocarcinoma after pancreaticoduodenectomy., Methods: Patients with a performance status of 0 or 1 were enrolled to receive interferon-alfa-2b (3 million units MWF), cisplatin (30 mg/m(2), 6 doses) and 5-fluorouracil (5-FU; 175 mg/m(2)/day), concurrent with external-beam radiation (50.4 Gy) and followed by 2 courses of systemic 5-FU. The protocol was modified to include an optional 9 day break in the middle of chemoradiation. Quality of life was assessed by use of validated instruments., Results: Twenty-eight patients were eligible for analysis. The operation of 15 (54%) patients was performed at other institutions. All patients had T3 tumors, 22 (79%) had positive lymph nodes and 4 (14%) had positive (R1) margins. 24 (86%) patients completed therapy. In all, 25 (89%) patients experienced grade 3 toxicity and 3 (11%) patients were hospitalized. The most common grade 3 events were leukopenia (15, 54%) and neutropenia (12, 43%). No grade 4 toxicity occurred. Overall quality of life decreased during chemoradiation but returned to baseline thereafter and was stable throughout surveillance. 19 patients have died; the median follow-up of the 9 survivors is 62 months. The median OS duration of treated patients was 42.3 (95% confidence interval 30.5-54.2) months., Conclusions: Adjuvant interferon-based chemoradiation can be delivered safely and tolerably-though with substantial reversible toxicity-to patients of good performance status at an experienced cancer center. Therapy may be associated with an improvement in overall survival.

Metronomic chemotherapy suppresses growth of primary tumors and established metastases. However, its effect on metastatic progression is essentially unknown. We report the treatment of a metastatically competent model of pancreatic cancer with metronomic gemcitabine and sunitinib. Mice with orthotopic, red fluorescent protein-expressing, pancreatic cancer tumorgrafts were treated with gemcitabine on a metronomic (1 mg/kg daily, METG) or maximum tolerated dose (150 mg/kg twice weekly, MTDG) schedule with or without sunitinib (SU). Rates of primary tumor growth, metastasis, ascites, and survival were calculated. Gemcitabine at a daily dose of 2 mg or greater led to toxicity within 1 month in mice without tumors but METG at 1 mg/kg/d was well tolerated. Mice with pancreatic cancer tumorgrafts died with metastatic disease at a median of 25 days. METG/SU significantly prolonged median overall survival (44 days) compared with control or either regimen alone (P < 0.05). Primary tumor growth was inhibited by METG/SU (P = 0.03) but neither METG nor sunitinib alone. In contrast, treatment with METG suppressed metastasis at multiple sites, an effect enhanced by sunitinib. MTDG with or without sunitinib had the most favorable effect on primary tumor growth and survival, but its antimetastatic efficacy was similar to that of METG/SU. von Willebrand factor expression was inhibited by METG. Antimetastatic activity approaching that of MTDG is achieved with a total dose reduced 42 times using METG and is further enhanced by sunitinib. Our results suggest the potential of this therapeutic paradigm against pancreatic cancer in the adjuvant and maintenance settings., ((c)2010 AACR.)