Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Surgical resection is the most reliable chance for cure, but high rates of positive margins and local failure persist. Neoadjuvant therapies (NAT), including chemotherapy and radiation therapy (RT), are being explored to improve surgical outcomes, particularly in borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). This review aims to summarize the current landscape and future directions for neoadjuvant RT (NART) in PDAC.

The review includes a detailed analysis of past and ongoing clinical trials investigating various NART approaches in PDAC, with an emphasis on different RT techniques, fractionation schemes, and their integration into multimodal treatment strategies.

Early evidence suggests that NART can improve resection margins and local control. However, recent trials, including the Alliance A021501 and LAP-07 trials, have failed to demonstrate significant survival benefits with the addition of RT to NAT. Nevertheless, nuances in trial design and execution continue to keep the question of NART open. Newer approaches, such as stereotactic magnetic resonance-guided adaptive radiation therapy (SMART), show promise in improving local control and survival, but further phase 3 trials are needed.

While NART has shown potential in improving local control in PDAC, its impact on overall survival remains unclear. Ongoing trials, particularly those utilizing advanced techniques like SMART, are critical in defining the role of RT in the neoadjuvant setting for PDAC. Collaboration across multidisciplinary teams is essential to optimize treatment strategies and trial outcomes.

The use of radiation therapy (RT) for pancreatic cancer continues to be controversial, despite recent technical advances. Improvements in systemic control have created an evolving role for RT and the need for improved local tumor control, but currently, no standardized approach exists. Advances in stereotactic body RT, motion management, real-time image guidance, and adaptive therapy have renewed hopes of improved outcomes in this devastating disease with one of the lowest survival rates. This case-based guide provides a practical framework for delivering stereotactic body RT for locally advanced pancreatic cancer. In conjunction with multidisciplinary care, an intradisciplinary approach should guide treatment of the high-risk cases outlined within these guidelines for prospective peer review and treatment safety discussions.

While pancreatic adenocarcinoma requires surgical resection definitive cure, treatment paradigms are shifting toward a neoadjuvant approach to systemic therapy. Rationale is twofold: micro-metastatic disease is likely present in a majority of patients, reinforcing the importance of systemic therapy regardless of resectability; moreover, systemic therapy is well-tolerated and improves surgical outcomes when delivered preoperatively. Second, a neoadjuvant approach allows for selection of biology and patients most likely to benefit from potentially morbid surgery. This review examines the increasing body of evidence in support of empiric neoadjuvant therapy in pancreatic adenocarcinoma.

This work seeks to understand whether IL15-incorporating treatments improve response to radiotherapy and uncover mechanistic rationale for overcoming resistance to IL15 agonism using novel therapeutic combinations.

Orthotopic tumor models of PDAC were used to determine response to treatment. IL15-/- and Rag1-/- mouse models were employed to determine dependence on IL15 and CTLs, respectively. Flow cytometry was used to assess immune cell frequency and activation state. Phospho-proteomic analyses were used to characterize intracellular signaling pathways.

We show that the combination of radiation therapy (RT) and an IL15/IL15Ra fusion complex (denoted IL15c) fails to confer anti-tumor efficacy; however, a CD8-driven anti-tumor immune response is elicited with the concurrent administration of an aCD25 Treg-depleting antibody. Using IL15-/- and Rag1-/- mice, we demonstrate that response to RT + IL15c + aCD25 is dependent on both IL15 and CTLs. Furthermore, despite an equivalent survival benefit following treatment with RT + IL15c + aCD25 and combination RT + PD1-IL2v, a novel immunocytokine with PD-1 and IL2Rβγ binding domains, CTL immunophenotyping and phospho-proteomic analysis of intracellular metabolites showed significant upregulation of activation and functionality in CD8 T cells treated with RT + PD1-IL2v. Finally, we show the immunostimulatory response to RT + PD1-IL2v is significantly diminished with a concurrent lack of TCF+ CD8 T cell generation in the absence of functional IL15 signaling.

Our results are illustrative of a mechanism wherein unimpeded effector T cell activation through IL2Rβ signaling and Treg inhibition are necessary in mediating an anti-tumor immune response.

Pancreaticobiliary cancer, encompassing malignancies of both the pancreatic and biliary tract, presents a formidable clinical challenge marked by a uniformly bleak prognosis. The asymptomatic nature of its early stages often leads to delayed detection, contributing to an unfavorable 5-year overall survival rate. Conventional treatment modalities have shown limited efficacy, underscoring the urgent need for alternative therapeutic approaches. In recent years, immunotherapy has emerged as a promising avenue in the fight against pancreaticobiliary cancer. Strategies such as therapeutic vaccines and the use of tumor-infiltrating lymphocytes have garnered attention for their potential to elicit more robust and durable responses. This review seeks to illuminate the landscape of emerging immunotherapeutic interventions, offering insights from both clinical and research perspectives. By deepening our understanding of pancreaticobiliary cancer and exploring innovative treatment modalities, we aim to catalyze improvements in patient outcomes and quality of life.

To assess overall survival (OS), compare the effects of neoadjuvant treatment, and describe surgical outcomes for patients undergoing pancreatic resection following chemotherapy and/or chemoradiotherapy (CRT) for borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC).

We approach BR/LA PDAC using chemotherapy followed by selective CRT to the primary site of disease where either the surgical margin remains radiologically threatened following chemotherapy or as a further downstaging treatment.

Retrospective study of patients between December 2005 and June 2023 at the Royal Marsden Hospital, London, United Kingdom.

A total of 54 patients were included. The OS between R1 and R0 patients was significantly different: 7.5 versus 23 versus 42 versus 51 months for R1 chemo, R1 chemo and CRT, R0 chemo and R0 chemo, and CRT groups, respectively, P < 0.001. Similarly, 9 versus 18 versus 42 versus 41 months for N1 chemo, N1 chemo and CRT, N0 chemo and N0 chemo, and CRT groups, respectively, P = 0.0026. Multivariable Cox regression model demonstrated that perineural invasion (hazard ratio: 2.88, 95% confidence interval: 1.06-7.81; P = 0.038) and perivascular invasion (PVI) (HR: 2.76, 95% CI: 1.24-6.13; P = 0.013) were associated with significantly worse OS. Chemo and CRT conferred OS benefit compared to chemo only (7 vs 23 months, P = 0.004) in PVI-positive patients.

Neoadjuvant chemotherapy followed by CRT compared to chemotherapy alone for resected BD and LA PDAC was demonstrated to significantly improve median OS, in particular, in patients with R1 resection margins, ypN1 nodal status, and perivascular invasion.

In the context of pancreatic cancer, surgical intervention is typically recommended for localized tumours, whereas chemotherapy is the preferred approach in the advanced and/or metastatic setting. However, pancreatic cancer is closely linked to ageing, with an average diagnosis at 72 years. Paradoxically, despite its increased occurrence among older individuals, this population is often underrepresented in clinical studies, complicating the decision-making process. Age alone should not determine the therapeutic strategy but, given the high comorbidity and mortality of this disease, a comprehensive geriatric assessment (CGA) is necessary to define the best treatment, prevent toxicity, and optimize older patient care. In this review, a group of experts from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica, SEOM), the Spanish Cooperative Group for the Treatment of Digestive Tumours (Grupo Español de Tratamiento de los Tumores Digestivos, TTD), and the Multidisciplinary Spanish Group of Digestive Cancer (Grupo Español Multidisciplinar en Cáncer Digestivo, GEMCAD) have assessed the available scientific evidence and propose a series of recommendations on the management and treatment of the older population with pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in oncology due to its advanced stage upon diagnosis and limited treatment options. Surgical resection, the primary curative approach, often results in poor long-term survival rates, leading to the exploration of alternative strategies like neoadjuvant therapy (NAT) and total neoadjuvant therapy (TNT). While NAT aims to enhance resectability and overall survival, there appears to be potential for improvement, prompting consideration of alternative neoadjuvant strategies integrating full-dose chemotherapy (CT) and radiotherapy (RT) in TNT approaches. TNT integrates chemotherapy and radiotherapy prior to surgery, potentially improving margin-negative resection rates and enabling curative resection for locally advanced cases. The lingering question: is more always better? This article categorizes TNT strategies into six main groups based on radiotherapy (RT) techniques: (1) conventional chemoradiotherapy (CRT), (2) the Dutch PREOPANC approach, (3) hypofractionated ablative intensity-modulated radiotherapy (HFA-IMRT), and stereotactic body radiotherapy (SBRT) techniques, which further divide into (4) non-ablative SBRT, (5) nearly ablative SBRT, and (6) adaptive ablative SBRT. A comprehensive analysis of the literature on TNT is provided for both borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), with detailed sections for each.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths, with very limited therapeutic options available. This study aims to comprehensively depict the heterogeneity and identify prognostic targets for PDAC with single-cell RNA sequencing (scRNA-seq) analysis.

ScRNA-seq analysis was performed on 16 primary PDAC and three adjacent lesions. A series of analytical methods were applied for analysis in cell clustering, gene profiling, lineage trajectory analysis and cell-to-cell interactions. In vitro experiments including colony formation, wound healing and sphere formation assay were performed to assess the role of makers.

A total of 32,480 cells were clustered into six major populations, among which the ductal cell cluster expressing high copy number variants (CNVs) was defined as malignant cells. Malignant cells were further subtyped into five subgroups which exhibited specific features in immunologic and metabolic activities. Pseudotime trajectory analysis indicated that components of various oncogenic pathways were differentially expressed along tumor progression. Furthermore, intensive substantial crosstalk between ductal cells and stromal cells was identified. Finally, genes (REG4 and SPINK1) screened out of differentially expressed genes (DEGs) were upregulated in PDAC cell lines. Silencing either of them significantly impaired proliferation, invasion, migration and stemness of PDAC cells.

Our findings offer a valuable resource for deciphering the heterogeneity of malignant ductal cells in PDAC. REG4 and SPINK1 are expected to be promising targets for PDAC therapy.

Pancreatic adenocarcinoma is an aggressive disease marked by high rates of both local and distant failure. In the minority of patients with potentially resectable disease, multimodal treatment paradigms have allowed for prolonged survival in an increasingly larger pool of well-selected patients. Therefore, it is critical for surgical oncologists to be abreast of current guideline recommendations for both surgical management and multimodal therapy for pancreas cancer. We discuss these guidelines, as well as the underlying data supporting these positions, to offer surgical oncologists a framework for managing patients with pancreatic adenocarcinoma.

To evaluate the efficacy and optimal timing of local treatment in patients with borderline resectable (BR) or locally advanced pancreatic cancer (LAPC) treated with upfront FOLFIRINOX.

Between 2015 and 2020, 258 patients with pancreatic ductal adenocarcinoma (PDAC) were analysed. Treatment outcomes were compared between systemic treatment group (ST) and multimodality treatment groups (MT) using Kaplan-Meier curves and log-rank test. The MT were stratified as follows: FOLFIRINOX + radiation therapy (RT) (MT1), FOLFIRINOX + surgical resection (MT2), and FOLFIRINOX + RT + surgical resection (MT3).

With median follow-up period of 18 months, the 2-year overall survival (OS) for the ST was 22.0%, and it was significantly worse than MT (MT1, 46.3%; MT2, 65.7% and MT3; 90.2%; P < .001). The 2-year locoregional progression free survival (LRPFS) and overall PFS in ST were 10.7% and 7.0%, which were also significantly lower than those of MT (2-year LRPFS: MT1, 31.8%; MT2, 45.3%; MT3, 81.0%; 2-year overall PFS: MT1, 23.3%; MT2, 35.0%; MT3, 66.3%; P < .001). In time-varying multivariate Cox proportional hazard model, local treatment contributed to better treatment outcomes, with adjusted hazard ratios of 0.568 (95% confidence interval [CI], 0.398-0.811), 0.490 (95% CI, 0.331-0.726), and 0.656 (95% CI, 0.458-0.940) for OS, LRPFS, and overall PFS, respectively. The time window of 11-17 months after FOLFIRINOX appeared to demonstrate the maximal efficacy of local treatments in OS.

Adding local treatment in BR/LAPC patients treated with upfront FOLFIRINOX seemed to contribute in improved treatment outcomes, and it showed maximal efficacy in OS when applied 11-17 months after the initiation of FOLFIRINOX. We suggest that administration of sufficient period of upfront FOLFIRINOX may intensify the efficacy of local treatments, and well controlled prospective trials are expected.

Stereotactic body radiotherapy (SBRT) in pancreatic cancer allows high delivery of radiation doses on tumors without affecting surrounding tissue. This review aimed at the SBRT application in the treatment of pancreatic cancer.

We retrieved articles published in MEDLINE/PubMed from January 2017 to December 2022. Keywords used in the search included: "pancreatic adenocarcinoma" OR "pancreatic cancer" AND "stereotactic ablative radiotherapy (SABR)" OR "stereotactic body radiotherapy (SBRT)" OR "chemoradiotherapy (CRT)". English language articles with information on technical characteristics, doses and fractionation, indications, recurrence patterns, local control and toxicities of SBRT in pancreatic tumors were included. All articles were assessed for validity and relevant content.

Optimal doses and fractionation have not yet been defined. However, SBRT could be the standard treatment in patients with pancreatic adenocarcinoma in addition to CRT. Furthermore, the combination of SBRT with chemotherapy may have additive or synergic effect on pancreatic adenocarcinoma.

SBRT is an effective modality for patients with pancreatic cancer, supported by clinical practice guidelines as it has demonstrated good tolerance and good disease control. SBRT opens a possibility of improving outcomes for these patients, both in neoadjuvant treatment and with radical intent.

Neoadjuvant treatment (NAT) for borderline (BD) or locally advanced (LA) primary pancreatic cancer (PDAC) is now a widely adopted approach. We present a case series of patients who have achieved a complete pathological response of the primary tumour on final histology following neoadjuvant chemotherapy +/- chemoradiation and radical surgery.

Patients who underwent radical pancreatic resection following neoadjuvant treatment between March 2006 and March 2023 at a single institution were identified by retrospective case note review of a prospectively maintained database.

Ten patients were identified to have a complete primary pathological response (ypT0) on postoperative histology. Before treatment, five patients were considered BD and five were LA according to National Comprehensive Cancer Network guidelines. All patients underwent staging Computed Tomography (CT) and nine underwent 18Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET/CT) imaging, with a mean maximum standardized uptake value (SUVmax) of the primary lesion at 6.14 ± 1.98 units. All patients received neoadjuvant chemotherapy, and eight received further chemoradiotherapy prior to resection. Mean pre- and post-neoadjuvant treatment serum Ca19-9 was 148.0 ± 146.3 IU/L and 18.0 ± 18.7 IU/L, respectively (p = 0.01). The mean duration of NAT was 5.6 ± 1.7 months. The mean time from completion of NAT to surgery was 13.1 ± 8.3 weeks. The mean lymph node yield was 21.1 ± 10.4 nodes, with one patient found to have 1 lymph node involved. All resections were reported to be R0. The mean length of stay was 11.8 ± 6.2 days. At the time of analysis, one death was reported at 35 months postoperatively. Two cases of recurrence were reported at 16 months (surgical bed) and 33 months (pulmonary). All other patients remain alive and under active surveillance. The current overall survival is 26.6 ± 20.7 months and counting.

Complete primary pathological response is uncommon but possible following neoadjuvant treatment in patients with PDAC. Further work to identify the common denominator within this unique cohort may lead to advances in the therapeutic approach and offer hope for patients diagnosed with borderline or locally advanced pancreatic ductal adenocarcinoma.

NRG/Radiation Therapy Oncology Group 0848 is a 2-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiation therapy (RT) after adjuvant chemotherapy (second step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed on each patient who underwent RT. This analysis aims to evaluate adherence to protocol-specified contouring and treatment planning and to report the types and frequencies of deviations requiring revisions.

In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume through the creation of specific regions of interest. The planning target volume was a uniform 0.5 cm clinical treatment volume expansion. One of 2 radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and resubmitted until approved. Treatment started after final approval of the RT plan.

From 2014 to 2018, 354 patients were enrolled in the second randomization. Of these, 160 patients received RT and were included in the QA analysis. Resubmissions were more common for patients planned with 3-dimensional conformal RT (43%) than with intensity modulated RT (31%). In total, at least 1 resubmission of the treatment plan was required for 33% of patients. Among patients requiring resubmission, most only needed 1 resubmission (87%). The most common reasons for resubmission were unacceptable deviations with respect to the preoperative gross target volume (60.7%) and the pancreaticojejunostomy (47.5%).

One-third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on real-time, pretreatment QA in trials evaluating the use of RT, particularly for pancreas cancer. Rigorous QA is critically important for clinical trials involving RT to ensure that the true effect of RT is assessed. Moreover, RT QA serves as an educational process through providing feedback from specialists to practicing radiation oncologists on best practices.

Randomized controlled clinical trials (RCTs) are at the heart of "evidence-based" medicine. Conducting well-designed RCTs for surgical procedures is often challenged by inadequate recruitment accrual, blinding, or standardization of the surgical procedure, as well as lack of funding and evolution of the treatment strategy during the many years over which such trials are conducted. In addition, most clinical trials are performed in academic high-volume centers with highly selected patients, which may not necessarily reflect a "real-world" practice setting. Large databases provide easy and inexpensive access to data on a large and diverse patient population at a variety of treatment centers. Furthermore, large database studies provide the opportunity to answer questions that would be impossible or very arduous to answer using RCTs, including questions regarding health policy efficacy, trends in surgical practice, access to health care, the impact of hospital volume, and adherence to practice guidelines, as well as research questions regarding rare disease, infrequent surgical outcomes, and specific subpopulations. Prospective data registries may also allow for quality benchmarking and auditing. There are several high-quality RCTs providing evidence to support current practices in hepatopancreatobiliary (HPB) oncology. Evidence from big data bridges the gap in several instances where RCTs are lacking. In this article, we review the evidence from RCTs and big data in HPB oncology identify the existing lacunae, and discuss the future directions of research in HPB oncology.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2023 was held in Quebec City, Quebec 2-4 February 2023. The purpose of the conference was to develop consensus statements on emerging and evolving treatment paradigms. Participants included Canadian medical oncologists, radiation oncologists, pathologists and surgical oncologists from across Ontario, Quebec, and the Atlantic provinces. Consensus statements were developed following rapid review presentations and discussion of available literature. The recommendations proposed here represent the consensus opinions of physicians involved in the care of patients with gastrointestinal malignancies who participated in this meeting.

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.

Pancreatic ductal adenocarcinoma (PDAC) is a challenging disease process with a 5-year survival rate of only 11%. Neoadjuvant therapy in patients with localized pancreatic cancer has multiple theoretical benefits, including improved patient selection for surgery, early delivery of systemic therapy, and assessment of response to therapy. Herein, we review key surgical considerations when selecting patients for neoadjuvant therapy and curative-intent resection. Accurate determination of resectability at diagnosis is critical and should be based on not only anatomic criteria but also biologic and clinical criteria to determine optimal treatment sequencing. Borderline resectable or locally advanced pancreatic cancer is best treated with neoadjuvant therapy and resection, including vascular resection and reconstruction when appropriate. Lastly, providing nutritional, prehabilitation, and supportive care interventions to improve patient fitness prior to surgical intervention and adequately address the adverse effects of therapy is critical.

Recent studies have shown that patients with pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant chemo(radio)therapy followed by surgery have an improved outcome compared to patients treated with upfront surgery. Hence, patients with PDAC are more and more frequently treated with chemotherapy in the neoadjuvant setting. PDAC patients are at a high risk of developing venous thromboembolism (VTE), which is associated with decreased survival rates. As patients with PDAC were historically offered immediate surgical resection, data on VTE incidence and associated preoperative risk factors are scarce. Current guidelines recommend primary prophylactic anticoagulation in selected groups of patients with advanced PDAC. However, recommendations for patients with (borderline) resectable PDAC treated with chemotherapy in the neoadjuvant setting are lacking. Nevertheless, the prevention of complications is crucial to maintain the best possible condition for surgery. This narrative review summarizes current literature on VTE incidence, associated risk factors, risk assessment tools, and primary thromboprophylaxis in PDAC patients treated with neoadjuvant chemo(radio)therapy.

Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC.

We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based.

A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC.

In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

FOLFIRINOX is increasingly used in the management of pancreatic ductal adenocarcinoma (PDAC). However, neoadjuvant therapy is associated with toxicity, possible disease progression, and biopsy-related and biliary complications that may preclude operative exploration. Data on the true attrition rate outside of clinical trials or resected surgical series are lacking.

Patients with nonmetastatic PDAC who initiated FOLFIRINOX from 2015 to 2020 were identified from our institution's pharmacy records. Multivariable regression and Cox proportional hazard models were used for adjusted analyses of categorical and survival outcomes, respectively.

Of 254 patients who initiated first-line neoadjuvant FOLFIRINOX, 199 (78.3%) underwent exploration, and 54 (21.3%) did not complete their chemotherapy cycles due to poor tolerability (46.3%), poor response (31.5%), or disease progression (14.8%), among other causes (7.4%). A total of 109 (42.9%) patients experienced grade 3/4 FOLFIRINOX-related toxicity, of whom 73 (28.7%) and 100 (39.4%) required an emergency department visit or inpatient admission, respectively. Finally, not undergoing surgical exploration was associated with impaired overall survival (hazard ratio 7.0; 95% CI 3.8 to 12.8; p < 0.001). Independent predictors of not undergoing exploration were remote history of chemotherapy receipt (odds ratio [OR] 0.06; p = 0.02), inability to complete FOLFIRINOX cycles (OR 0.2, p = 0.003), increase in ECOG score (OR 0.2, p < 0.001), and being single or divorced (OR 0.3, p = 0.018).

Among 254 patients with nonmetastatic PDAC initiated on FOLFIRINOX, of whom 52% were locally advanced, a total of 199 (78.3%) were explored, 142 (71.4%) underwent successful resection, and 129 (90.8%) were resected with negative margins. Despite 109 (42.9)% of patients experiencing significant toxicity, most patients could be managed through treatment-related complications to complete planned neoadjuvant chemotherapy and undergo planned surgical exploration.

Neoadjuvant treatment with nab-paclitaxel and gemcitabine for potentially operable pancreatic adenocarcinoma has not been well studied in a prospective interventional trial and could down-stage tumors to achieve negative surgical margins.

A single-arm, open-label phase 2 trial (NCT02427841) enrolled patients with pancreatic adenocarcinoma deemed to be borderline resectable or clinically node-positive from March 17, 2016 to October 5, 2019. Patients received preoperative gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on Days 1, 8, 15, every 28 days for two cycles followed by chemoradiation with 50.4 Gy intensity-modulated radiation over 28 fractions with concurrent fluoropyrimidine chemotherapy. After definitive resection, patients received four additional cycles of gemcitabine and nab-paclitaxel. The primary endpoint was R0 resection rate. Other endpoints included treatment completion rate, resection rate, radiographic response rate, survival, and adverse events.

Nineteen patients were enrolled, with the majority having head of pancreas primary tumors, both arterial and venous vasculature involvement, and clinically positive nodes on imaging. Among them, 11 (58%) underwent definitive resection and eight of 19 (42%) achieved R0 resection. Disease progression and functional decline were primary reasons for deferring surgical resection after neoadjuvant treatment. Pathologic near-complete response was observed in two of 11 (18%) resection specimens. Among the 19 patients, the 12-month progression-free survival was 58%, and 12-month overall survival was 79%. Common adverse events were alopecia, nausea, vomiting, fatigue, myalgia, peripheral neuropathy, rash, and neutropenia.

Gemcitabine and nab-paclitaxel followed by long-course chemoradiation represents a feasible neoadjuvant treatment strategy for borderline resectable or node-positive pancreatic cancer.

Surgery is the only curative treatment for non-metastatic pancreatic adenocarcinoma, but less than 20% of patients present a resectable disease at diagnosis. Treatment strategies and disease definition for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) vary in the different cancer centres. Preoperative chemotherapy (CT) is the standard of care for both BRPC and LAPC patients, however literature data are still controversial concerning the type, dose and duration of the different CT regimens, as well as regarding the integration of radiotherapy (RT) or chemoradiation (CRT) in the therapeutic algorithm. In this unsettled debate, we aimed at focusing on the therapeutic regimens currently in use and relative literature data, to report international trials comparing the available therapeutic options or explore the introduction of new pharmacological agents, and to analyse possible new scenarios in microenvironment evaluation before and after neoadjuvant therapies or in patients' selection at a molecular level.

The role of postoperative chemotherapy in patients with resected pancreatic cancer who receive neoadjuvant treatment is unknown. Clinicians use changes in CA19-9 and histopathologic scores to assess treatment response. We sought to investigate if CA19-9 normalization in response to NAT can help guide the need for postoperative treatment.

Patients with elevated baseline CA19-9 (CA19-9 > 37U/mL) who received NAT followed by surgery between 2011 and 2019 were retrospectively reviewed. Treatment response was determined by CA19-9 normalization following NAT and histopathologic scoring. The role of postoperative chemotherapy was analyzed in light of CA19-9 normalization and histopathologic response.

We identified and included 345 patients. Following NAT, CA19-9 normalization was observed in 125 patients (36.2%). CA19-9 normalization was associated with a favorable histopathologic response (41.6% vs 23.2%, p < 0.001) and a lower ypT (p < 0.001) and ypN stage (p = 0.003). Receipt of adjuvant chemotherapy was associated with improved overall survival in patients in whom CA19-9 did not normalize following NAT (26.8 vs 16.4 months, p = 0.008). In patients who received 5FU-based NAT and in whom CA19-9 did not normalize, receipt of 5FU-based adjuvant chemotherapy was associated with improved OS (p = 0.014).

CA19-9 normalization in response to NAT was associated with favorable outcomes and can serve as a biomarker for treatment response. In patients where CA19-9 did not normalize, receipt of postoperative chemotherapy was associated with improved OS. These patients also benefited from additional 5FU-based postoperative chemotherapy following 5FU-based NAT.

Studies suggest select patients from across the pancreatic adenocarcinoma (PDAC) disease spectrum may benefit from adding radiation therapy (RT) to multi-modality care. In resectable PDAC, there is an evolving role for neoadjuvant RT with adjuvant RT reserved for patients with increased recurrence risk. In borderline resectable PDAC, neoadjuvant chemoradiation likely improves R0 resection rates and in unresectable PDAC, definitive RT may prolong survival for some patients. Recent developments in RT delivery are promising but additional studies are needed to determine the benefit of these technologies and to optimize the role of RT in multi-modality care.

There is no agreed upon standard of care for borderline-resectable pancreatic cancer (BRPC) or locally-advanced pancreatic cancer (LAPC) patients regarding the benefit of chemotherapy or radiation alone or in combination.

We completed a retrospective cohort analysis of BRPC and LAPC patients at a cancer center with expertise in multi-disciplinary pancreatic ductal adenocarcinoma (PDAC) treatment over a 5-year period from 03/01/2014 to 03/01/2019 (cut-off date). The total evaluable newly diagnosed, treatment naïve, BRPC, and LAPC patients with adequate organ function and ability to obtain treatment after multidisciplinary review was 52 patients. After analysis, patients were evaluated for rates of resection, extent of resection (R0 or R1), median progression-free survival (mPFS), and median overall survival (mOS).

Patients were treated with chemotherapy alone (gemcitabine and nab-paclitaxel = 77% (20/26); FOLFIRINOX = 19% (5/26); single agent gemcitabine 3.8% (1/26)), or chemotherapy followed by chemoradiation (gemcitabine +5 Gy × 5 weeks), or chemoradiation alone prior to re-staging and potential resection. Of the 29% (15/52) of patients who went on to surgical resection, 73% (11/15) achieved R0 resection. An R0 resection was achieved in 35% (9/26) of patients treated with chemotherapy alone, 7.6% (1/13) in a patient treated with chemotherapy followed by radiation, and 7.6% (1/13) with concurrent chemoradiotherapy alone. Chemotherapy alone achieved a mPFS of 16.4 months (p  < 0.0025) and mOS of 26.2 months (p  < 0.0001), chemotherapy followed by chemoradiation was 13.0 months and 14.9 months respectively, while concurrent chemoradiotherapy was 6.9 months and 7.3 months.

BRPC and LAPC patients capable of surgery after only receiving neoadjuvant treatment with chemotherapy had higher rates of R0 resection with prolonged median PFS and OS compared with any patient needing combination chemotherapy with radiotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with a high rate of recurrence and a dismal 5-year survival rate. Contributing to the poor prognosis of PDAC is the lack of early detection, a complex network of signaling pathways and molecular mechanisms, a dense and desmoplastic stroma, and an immunosuppressive tumor microenvironment. A recent shift toward a neoadjuvant approach to treating PDAC has been sparked by the numerous benefits neoadjuvant therapy (NAT) has to offer compared with upfront surgery. However, certain aspects of NAT against PDAC, including the optimal regimen, the use of radiotherapy, and the selection of patients that would benefit from NAT, have yet to be fully elucidated. This review describes the major signaling pathways and molecular mechanisms involved in PDAC initiation and progression in addition to the immunosuppressive tumor microenvironment of PDAC. We then review current guidelines, ongoing research, and future research directions on the use of NAT based on randomized clinical trials and other studies. Finally, the current use of and research regarding targeted therapy for PDAC are examined. This review bridges the molecular understanding of PDAC with its clinical significance, development of novel therapies, and shifting directions in treatment paradigm.

Stereotactic body radiotherapy (SBRT) is an effective radiation therapy technique that has allowed for shorter treatment courses, as compared to conventionally dosed radiation therapy. As its name implies, SBRT relies on daily image guidance to ensure that each fraction targets a tumor, instead of healthy tissue. Magnetic resonance imaging (MRI) offers improved soft-tissue visualization, allowing for better tumor and normal tissue delineation. MR-guided RT (MRgRT) has traditionally been defined by the use of offline MRI to aid in defining the RT volumes during the initial planning stages in order to ensure accurate tumor targeting while sparing critical normal tissues. However, the ViewRay MRIdian and Elekta Unity have improved upon and revolutionized the MRgRT by creating a combined MRI and linear accelerator (MRL), allowing MRgRT to incorporate online MRI in RT. MRL-based MR-guided SBRT (MRgSBRT) represents a novel solution to deliver higher doses to larger volumes of gross disease, regardless of the proximity of at-risk organs due to the (1) superior soft-tissue visualization for patient positioning, (2) real-time continuous intrafraction assessment of internal structures, and (3) daily online adaptive replanning. Stereotactic MR-guided adaptive radiation therapy (SMART) has enabled the safe delivery of ablative doses to tumors adjacent to radiosensitive tissues throughout the body. Although it is still a relatively new RT technique, SMART has demonstrated significant opportunities to improve disease control and reduce toxicity. In this review, we included the current clinical applications and the active prospective trials related to SMART. We highlighted the most impactful clinical studies at various tumor sites. In addition, we explored how MRL-based multiparametric MRI could potentially synergize with SMART to significantly change the current treatment paradigm and to improve personalized cancer care.

Survival outcomes for localized pancreatic adenocarcinoma remains poor. Multimodality therapeutic regimens are critical to maximizing survival outcomes for these patients, which includes the use of systemic therapy, surgery, and radiation. In this review, the evolution of radiation techniques are discussed with a focus on modern techniques such as intensity modulated radiation and stereotactic body radiation therapy. However, the current role of radiation within the most common clinical scenarios for pancreatic cancer in the neoadjuvant, definitive, and adjuvant settings continues to be highly debated. The role of radiation in these settings is reviewed in the context of historical and modern clinical studies. In addition, emerging concepts including dose-escalated radiation, magnetic resonance-guided radiation therapy, and particle therapy are discussed to promote an understanding of how such concepts may change the role of radiation in the future.

To date, the optimal recommended specific neoadjuvant regimens for resectable or borderline resectable pancreatic cancer (RPC or BRPC) remain an unanswered issue.

We systematically searched the electronic databases to identify randomized controlled trials (RCTs) comparing different neoadjuvant therapy strategies for RPC or BRPC. The primary outcome was overall survival (OS). Comprehensive analyses and evaluations were performed using the single-arm, paired, and network meta-analyses.

Twelve RCTs involving 1279 patients with RPC or BRPC were enrolled. The paired meta-analysis showed that neoadjuvant therapy improved OS for both RPC (hazard ratio (HR) 0.69, 95% c.i. 0.54 to 0.87) and BRPC (HR 0.60, 0.42 to 0.86) compared with upfront surgery (UP-S). Neoadjuvant chemotherapy (NAC) also improved OS for both RPC (HR 0.63, 0.47 to 0.85) and BRPC (HR 0.44, 0.27 to 0.71), while neoadjuvant chemoradiotherapy (NACR) improved OS only for BRPC (HR 0.68, 0.52 to 0.89) and not for RPC (HR 0.79, 0.54 to 1.16). Network meta-analysis found that NAC was superior to NACR in OS for RPC/BRPC (HR 0.58, 0.37 to 0.90). Neoadjuvant chemotherapy based on modified fluorouracil/folinic acid/irinotecan/oxaliplatin (NAC-mFFX) and neoadjuvant chemotherapy based on abraxane/gemcitabine (NAC-AG) ranked first and second in OS for RPC/BRPC.

Both RPC and BRPC could obtain OS benefits from neoadjuvant therapy compared with UP-S, and NAC improved OS both in RPC and BRPC while NACR only improved OS in BRPC. Furthermore, NAC was superior to NACR, and NAC-mFFX and NAC-AG might be recommended sequentially as the best neoadjuvant therapy strategies.

The increased adoption of stereotactic body radiation therapy has allowed for delivery of higher doses, potentially associated with better outcomes but at the risk of higher toxicity. The intimate association of radiosensitive organs at risk (eg, stomach, duodenum, bowel) has historically limited the delivery of ablative doses to the pancreas. The advent of magnetic resonance-guided radiation therapy with improved soft-tissue contrast allows for gated delivery without an internal target volume and online adaptive replanning to maximize the therapeutic ratio. Patient selection requires additional resources, including increased patient on-table time, physician time, and physics support. Within our center's workflow, integrating an educational video at consultation as well as optimizing biofeedback mechanisms have significantly improved the experience for our patients.

Neoadjuvant therapy (NAT) is rarely associated with a complete histopathologic response in patients with pancreatic ductal adenocarcinoma (PDAC) but results in downstaging of regional nodal disease. Such nodal downstaging after NAT may have implications for the use of additional adjuvant therapy (AT).

To examine the prognostic implications of AT in patients with node-negative (N0) disease after NAT and to identify factors associated with progression-free (PFS) and overall survival (OS).

A retrospective review was conducted using data from 2 high-volume, tertiary care academic centers (University of Pittsburgh Medical Center and the Medical College of Wisconsin). Prospectively maintained pancreatic cancer databases at both institutes were searched to identify patients with localized PDAC treated with preoperative therapy and subsequent surgical resection between 2010 and 2019, with N0 disease on final histopathology.

Patients received NAT consisting of chemotherapy with or without concomitant neoadjuvant radiation (NART). For patients who received NART, chemotherapy regimens were gemcitabine or 5-fluoururacil based and included stereotactic body radiotherapy (SBRT) or intensity-modulated radiation therapy (IMRT) after all intended chemotherapy and approximately 4 to 5 weeks before anticipated surgery. Adjuvant therapy consisted of gemcitabine-based therapy or FOLFIRINOX; when used, adjuvant radiation was commonly administered as either SBRT or IMRT.

The association of AT with PFS and OS was evaluated in the overall cohort and in different subgroups. The interaction between AT and other clinicopathologic variables was examined on Cox proportional hazards regression analysis.

In this cohort study, 430 consecutive patients were treated between 2010 and 2019. Patients had a mean (SD) age of 65.2 (9.4) years, and 220 (51.2%) were women. The predominant NAT was gemcitabine based (196 patients [45.6%]), with a median duration of 2.7 cycles (IQR, 1.5-3.4). Neoadjuvant radiation was administered to 279 patients (64.9%). Pancreatoduodenectomy was performed in 310 patients (72.1%), and 160 (37.2%) required concomitant vascular resection. The median lymph node yield was 26 (IQR, 19-34); perineural invasion (PNI), lymphovascular invasion (LVI), and residual positive margins (R1) were found in 254 (59.3%), 92 (22.0%), and 87 (21.1%) patients, respectively. The restricted mean OS was 5.2 years (95% CI, 4.8-5.7). On adjusted analysis, PNI, LVI, and poorly differentiated tumors were independently associated with worse PFS and OS in N0 disease after NAT, with hazard ratios (95% CIs) of 2.04 (1.43-2.92; P < .001) and 1.68 (1.14-2.48; P = .009), 1.47 (1.08-1.98; P = .01) and 1.54 (1.10-2.14; P = .01), and 1.90 (1.18-3.07; P = .008) and 1.98 (1.20-3.26; P = .008), respectively. Although AT was associated with prolonged survival in the overall cohort, the effect was reduced in patients who received NART and strengthened in patients with PNI (AT × PNI interaction: hazard ratio, 0.55 [95% CI, 0.32-0.97]; P = .04).

The findings of this cohort study suggest a survival benefit for AT in patients with N0 disease after NAT and surgical resection. This survival benefit may be most pronounced in patients with PNI.

This review discusses the benefits of performing multidisciplinary trials through the cooperative group mechanism, outlines the process from trial concept to activation, and discusses opportunities for surgeons to become involved in cancer cooperative trials.

The management of pancreatic ductal adenocarcinoma (PDAC) has evolved over the last two decades. Surgical resection remain the only potential cure for this cancer. Therefore, there is an emerging emphasis on neoadjuvant therapy to maximize the probability of resection, and identify failures early. The benefit of FOLFIRINOX in various clinical stages of PDAC have been practice changing. The addition of nab-paclitaxel to the traditional gemcitabine regimen added another option for treatment. In addition, immunotherapy and targeted therapies are applicable, based on molecular features and germline alterations; albeit, these are applicable to only a small minority of patients. In this review article, we discuss the key extant literature relevant to various stages of pancreatic cancer. We also summarize ongoing clinical trials which may guide future treatments.

Locally advanced (unresectable) pancreatic cancer (LAPC) is surgically unresectable and often treated with chemotherapy. Most previous studies, that have evaluated conversion surgery after chemotherapy, included heterogeneous patients and chemotherapy regimens, making it challenging to determine the impact of FOLFIRINOX. The present study evaluated the survival benefit of conversion surgery in patients with LAPC who received FOLFIRINOX chemotherapy, and analyzed the prognostic factors.

Patients with LAPC who received FOLFIRINOX as first-line therapy for at least four cycles were included. During chemotherapy, surgical eligibility was determined based on radiologic and metabolic response to the treatment. Clinicopathologic characteristics were compared between the curative-intent surgery and non-resection groups, and the prognostic factors were analyzed.

A total of 279 patients were included. The rates of partial response (PR) and stable disease (SD) were 34.1% and 51.4%, respectively, and 16.8% patients underwent curative-intent surgery. The median survival was significantly longer in the resection group than in the non-resection group (56 vs 21 months, P < .001). In a multivariate analysis, curative-intent surgery (HR 0.260; P < .001) was the most important factor.

Conversion surgery after FOLFIRINOX chemotherapy effectively rescues patients with LAPC. Patients without progression after FOLFIRINOX could be considered as potential candidates for conversion surgery.

Pancreatic ductal adenocarcinoma (PDAC) remains a significant worldwide health problem with a poor prognosis. A borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) is a tumor with limited vascular involvement that is technically resectable but with a high risk of positive margins (R1 resection).

To identify the current challenges that exist in the management of BR-PDAC.

A review of the literature was conducted to identify articles discussing the definitions and management of BR-PDAC.

Several anatomic definitions of BR-PDAC exist, and there is significant heterogeneity in their utilization across published trials. To improve the odds of a margin negative (R0) resection, a neoadjuvant treatment approach involving chemotherapy with or without radiation is currently preferred. While supporting the efficacy of a neoadjuvant approach in BR-PDAC, the largest published randomized trials have utilized older gemcitabine-based regimens. Recently published Phase II evidence and meta-analyses have supported the use of modern multi-agent regimens such as FOLFIRINOX. The utility of adding radiation to a chemotherapy backbone remains in question. Due to remnant fibrosis and edema following neoadjuvant therapy, accurately selecting patients for resection based on a restaging CT scan is challenging. Furthermore, the role of adjuvant therapy in BR-PDAC patients receiving neoadjuvant therapy needs to be defined.

Though progress has been made, the optimal management of BR-PDAC is uncertain. Phase III trials utilizing modern chemotherapeutic regimens are needed to establish a standard of care.

The purpose of this work was to describe pancreatic ductal adenocarcinoma (PDAC) patterns of locoregional spread and recurrence to help guide clinicians on (neo)adjuvant radiation therapy (RT) planning strategies and target volume delineation.

A comprehensive review of clinical data was performed to describe PDAC patterns of locoregional spread, including extrapancreatic tumor extension, perineural invasion, regional lymph node involvement, and patterns of disease recurrence as influenced by (neo)adjuvant treatment strategy.

This review describes PDAC patterns of spread, disease progression, and evolving treatment techniques. Based upon this data, we advocate for inclusion of elective at-risk regions of extrapancreatic extension, perineural invasion, and lymphatic spread for patients receiving neoadjuvant RT.

This review provides a nuanced description of PDAC patterns of spread and recurrence to guide clinicians on target volume delineation and planning strategies to maximize the effectiveness of neo(adjuvant) RT delivery for patients with PDAC. Further prospective studies are needed to better define the optimal RT dose, fractionation regimens, and target volumes to be used in the (neo)adjuvant setting.

Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response.

Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/m²) with concurrent capecitabine and RT in cohort sizes of 3 starting at the lowest dose. Dose limiting toxicity was defined as grade 3 or higher toxicity. Patients were restaged 4 to 6 weeks post-CRT completion, and surgical resection was offered to those with stable/responsive disease. We scored the tumor interface response (IR) postchemotherapy and post-CRT into type I (remained/became more defined) and type II (became less defined). Overall survival (OS) and progression-free survival (PFS) from time of CRT were estimated using Kaplan-Meier method. P ≤ .05 was considered significant.

Twenty-three patients started and finished on protocol (LAPC = 14, BRPC = 9). No grade 3 and 4 toxicities were reported in level 1 (n = 3) or level 2 (n = 3) initial groups. Two patients in the initial level 3 group developed dose limiting toxicity, establishing level 2 dose as the maximal tolerated dose. Level 2 group was expanded for additional 15 patients (for a total of 23 on trial), 5 of whom developed grade 3 toxicities. Seven patients underwent surgical resection. Median OS and PFS were 21.2 and 8.1 months, respectively. Type I IR was associated with better OS (P = .004) and PFS (P = .03) compared with type II IR.

We established the maximum tolerated dose for nab-paclitaxel in a consolidative CRT regimen for pancreatic ductal adenocarcinoma. Preliminary efficacy results warrant phase 2 trial evaluation. IR may be used for personalized treatment.