This study evaluates the effects of different high-intensity focused ultrasound irradiation (HIFU) methods on local tumor suppression and systemic antitumor effects, including the abscopal effect, in a mouse model of pancreatic cancer. To ascertain the efficacy of the treatment, pancreatic cancer cells were injected into the thighs of mice and HIFU was applied on one side using continuous waves or trigger pulse waves. Then, tumor volume, tissue changes, and immune marker levels were analyzed. Both the irradiation methods suppressed tumor growth, with the trigger pulse wave showing stronger effects and the difference being significant. Tumor suppression was also observed on the non-irradiated side, suggesting an abscopal effect. These effects vary depending on the irradiation method used. We conclude that HIFU induces both local tumor suppression and a systemic immune response, suggesting its potential for combination with immunotherapy for the treatment of pancreatic cancer.

Pancreatic cancer (PC) is a lethal disease with few effective treatment options. Many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review synthesises all the randomised data available to help better inform patient and clinician decision-making. It updates the previous version of the review, published in 2018.

To assess the effects of chemotherapy, radiotherapy, or both on overall survival, severe or life-threatening adverse events, and quality of life in people undergoing first-line treatment of advanced pancreatic cancer.

We searched for published and unpublished studies in CENTRAL, MEDLINE, Embase, and CANCERLIT, and handsearched various sources for additional studies. The latest search dates were in March and July 2023.

We included randomised controlled trials comparing chemotherapy, radiotherapy, or both with another intervention or best supportive care. Participants were required to have locally advanced, unresectable pancreatic cancer or metastatic pancreatic cancer not amenable to curative intent treatment. Histological confirmation was required. Trials were required to report overall survival.

We used standard methodological procedures expected by Cochrane.

We included 75 studies in the review and 51 in the meta-analysis (11,333 participants). We divided the studies into seven categories: any anti-cancer treatment versus best supportive care; various chemotherapy types versus gemcitabine; gemcitabine-based combinations versus gemcitabine alone; various chemotherapy combinations versus gemcitabine plus nab-paclitaxel; fluoropyrimidine-based studies; miscellaneous studies; and radiotherapy studies. In general, the included studies were at low risk for random sequence generation, detection bias, attrition bias, and reporting bias, at unclear risk for allocation concealment, and high risk for performance bias. Compared to best supportive care, chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.88 to 1.33; absolute risk of death at 12 months of 971 per 1000 versus 962 per 1000; 4 studies, 298 participants; moderate-certainty evidence). The adverse effects of chemotherapy and impacts on quality of life (QoL) were uncertain. Many of the chemotherapy regimens were outdated. Eight studies compared non-gemcitabine-based chemotherapy regimens to gemcitabine. These showed that 5-fluorouracil (5FU) likely reduces OS (HR 1.69, 95% CI 1.26 to 2.27; risk of death at 12 months of 914 per 1000 versus 767 per 1000; 1 study, 126 participants; moderate certainty), and grade 3/4 adverse events (QoL not reported). Fixed dose rate gemcitabine likely improves OS (HR 0.79, 95% CI 0.66 to 0.94; risk of death at 12 months of 683 per 1000 versus 767 per 1000; 2 studies, 644 participants; moderate certainty), and likely increase grade 3/4 adverse events (QoL not reported). FOLFIRINOX improves OS (HR 0.51, 95% CI 0.43 to 0.60; risk of death at 12 months of 524 per 1000 versus 767 per 1000; P < 0.001; 2 studies, 652 participants; high certainty), and delays deterioration in QoL, but increases grade 3/4 adverse events. Twenty-eight studies compared gemcitabine-based combinations to gemcitabine. Gemcitabine plus platinum may result in little to no difference in OS (HR 0.94, 95% CI 0.81 to 1.08; risk of death at 12 months of 745 per 1000 versus 767 per 1000; 6 studies, 1140 participants; low certainty), may increase grade 3/4 adverse events, and likely worsens QoL. Gemcitabine plus fluoropyrimidine improves OS (HR 0.88, 95% CI 0.81 to 0.95; risk of death at 12 months of 722 per 1000 versus 767 per 1000; 10 studies, 2718 participants; high certainty), likely increases grade 3/4 adverse events, and likely improves QoL. Gemcitabine plus topoisomerase inhibitors result in little to no difference in OS (HR 1.01, 95% CI 0.87 to 1.16; risk of death at 12 months of 770 per 1000 versus 767 per 1000; 3 studies, 839 participants; high certainty), likely increases grade 3/4 adverse events, and likely does not alter QoL. Gemcitabine plus taxane result in a large improvement in OS (HR 0.71, 95% CI 0.62 to 0.81; risk of death at 12 months of 644 per 1000 versus 767 per 1000; 2 studies, 986 participants; high certainty), and likely increases grade 3/4 adverse events and improves QoL. Nine studies compared chemotherapy combinations to gemcitabine plus nab-paclitaxel. Fluoropyrimidine-based combination regimens improve OS (HR 0.79, 95% CI 0.70 to 0.89; risk of death at 12 months of 542 per 1000 versus 628 per 1000; 6 studies, 1285 participants; high certainty). The treatment arms had distinct toxicity profiles, and there was little to no difference in QoL. Alternative schedules of gemcitabine plus nab-paclitaxel likely result in little to no difference in OS (HR 1.10, 95% CI 0.82 to 1.47; risk of death at 12 months of 663 per 1000 versus 628 per 1000; 2 studies, 367 participants; moderate certainty) or QoL, but may increase grade 3/4 adverse events. Four studies compared fluoropyrimidine-based combinations to fluoropyrimidines alone, with poor quality evidence. Fluoropyrimidine-based combinations are likely to result in little to no impact on OS (HR 0.84, 95% CI 0.61 to 1.15; risk of death at 12 months of 765 per 1000 versus 704 per 1000; P = 0.27; 4 studies, 491 participants; moderate certainty) versus fluoropyrimidines alone. The evidence suggests that there was little to no difference in grade 3/4 adverse events or QoL between the two groups. We included only one radiotherapy (iodine-125 brachytherapy) study with 165 participants. The evidence is very uncertain about the effect of radiotherapy on outcomes.

Combination chemotherapy remains standard of care for metastatic pancreatic cancer. Both FOLFIRINOX and gemcitabine plus a taxane improve OS compared to gemcitabine alone. Furthermore, the evidence suggests that fluoropyrimidine-based combination chemotherapy regimens improve OS compared to gemcitabine plus nab-paclitaxel. The effects of radiotherapy were uncertain as only one low-quality trial was included. Selection of the most appropriate chemotherapy for individuals still remains unpersonalised, with clinicopathological stratification remaining elusive. Biomarker development is essential to assist in rationalising treatment selection for patients.

Current guidelines for treatment for locally advanced pancreatic cancer recommend chemotherapy ± radiation, or radiation alone when multimodal therapy is contraindicated. In a subset of patients, guideline-recommended treatment (GRT) achieves sufficient response to qualify for potentially curative resection. This study evaluated trends in treatment utilization and aimed to identify barriers to GRT.

Patients with clinical T4M0 disease in the National Cancer Database from 2010 to 2017 were included. Potential predictors were assessed by relative risk regression with Poisson distribution and compared by log-link function.

In total, 28 056 patients met the criteria. Among 17 059 (67.67%) patients treated primarily with chemotherapy, 41.19% also had radiation and 8.89% went onto resection. Many received no cancer-directed treatment or failed to receive GRT. Another 710 patients had radiation (±surgery) without chemotherapy despite few contraindications to chemotherapy. Over time, patients were more likely to undergo resection after chemotherapy (aRR = 1.58; p < 0.0001) and less likely to have chemoradiation (aRR = 0.78; p < 0.0001) or go untreated (aRR = 0.90; p < 0.0001). Socioeconomic factors (race, education, income, and insurance status) affected the likelihood of receiving chemotherapy and surgery. Median overall survival (OS) was significantly improved for patients treated with chemotherapy and particularly in those patients who went on to receive RT or undergo surgical resection. OS was also longer for patients treated at high-volume academic centers. Patients insured by Medicaid, Medicare, or those without insurance had worse OS.

Despite improvement over time, many patients go untreated. Clinical factors were influential, but the impact of vulnerable social standing suggests persistent inequity in access to care.

For patients with locally advanced pancreatic cancer (LAPC), who are candidates for radiation therapy, dose-escalated radiation therapy (RT) offers unique benefits over traditional radiation techniques. In this review, we present a historical perspective of dose-escalated RT for LAPC. We also outline advances in SBRT delivery, one form of dose escalation and a framework for selecting patients for treatment with SBRT.

Techniques for delivering SBRT to patients with LAPC have evolved considerably, now allowing for dose-escalation and superior respiratory motion management. At the same time, advancements in systemic therapy, particularly the use of induction multiagent chemotherapy, have called into question which patients would benefit most from radiation therapy. Multidisciplinary assessment of patients with LAPC is critical to guide management and select patients for local therapy. Results from ongoing trials will establish if there is a role of dose-escalated SBRT after induction chemotherapy for carefully selected patients.

Patients with LAPC have more therapeutic options than ever before. Careful selection for SBRT may enhance patient outcomes, pending the maturation of pivotal clinical trials.

Despite the advancements made in oncology in recent years, the treatment of pancreatic cancer remains a challenge. Five-year survival rates for this cancer do not exceed 10%. Among the reasons contributing to poor treatment outcomes are the oligosymptomatic course of the tumor, diagnostic difficulties due to the anatomical location of the organ, and the unique biological features of pancreatic cancer. The mainstay of treatment for resectable cancer is surgery and adjuvant chemotherapy. For unresectable and metastatic cancers, chemotherapy remains the primary method of treatment. At the same time, for about thirty years, there have been attempts to improve treatment outcomes by using radiotherapy combined with systemic treatment. Unlike chemotherapy, radiotherapy has no established place in the treatment of pancreatic cancer. This paper addresses the topic of radiotherapy in pancreatic cancer as a valuable method that can improve treatment outcomes alongside chemotherapy.

Patients with advanced pancreatic cancer have a poor prognosis and high burden of cancer-related symptoms. It is necessary to assess the trade-off of clinical benefits and possible harms of treatments with anticancer drugs (TAD). This systematic review aims to compare the effectiveness of TAD versus supportive care or no treatment, considering all patient-important outcomes.

We searched PubMed, Embase, Cochrane Library, and Epistemonikos. Two reviewers performed selection, data extraction and risk of bias assessment. We assessed certainty of the evidence using the GRADE approach.

We included 14 randomised controlled trials. Chemotherapy may result in a slight increase in overall survival (MD: 2.97 months (95%CI 1.23, 4.70)) and fewer hospital days (MD: -6.7 (-8.3, -5.1)), however, the evidence is very uncertain about its effect on symptoms, quality of life, functional status, and adverse events. Targeted/biological therapy may result in little to no difference in overall survival and a slight increment in progression-free survival (HR: 0.83 (95%CI 0.63, 1.10)), but probably results in more adverse events (RR: 5.54 (95%CI 1.24, 23.97)). The evidence is very uncertain about the effect of immunotherapy in overall survival and functional status.

The evidence is very uncertain about whether the benefits of using treatment with anticancer drugs outweigh their risks for patients with advanced pancreatic cancer. This uncertainty is further highlighted when considering immunotherapy or a second line of chemotherapy and thus, best supportive care would be an appropriate alternative. Future studies should assess their impact on all patient-important outcomes to inform patients in setting their goals of care.

Pancreatic cancer is rising as one of the leading causes of cancer-related death worldwide. Patients often present with advanced disease, limiting curative treatment options and therefore making management of the disease difficult. Systemic chemotherapy has been an established part of the standard treatment in patients with both locally advanced and metastatic pancreatic cancer. In contrast, the use of radiotherapy has no clear defined role in the treatment of these patients. With the evolving imaging and radiation techniques, radiation could become a plausible intervention. In this review, we give an overview over the available data regarding radiotherapy, chemoradiation, and stereotactic body radiation therapy. We performed a systematic search of Embase and the PubMed database, focusing on studies involving locally advanced pancreatic cancer (or non-resectable pancreatic cancer) and radiotherapy without any limitation for the time of publication. We included randomised controlled trials involving patients with locally advanced pancreatic cancer, including radiotherapy, chemoradiation, or stereotactic body radiation therapy. The included articles represented mainly small patient groups and had a high heterogeneity regarding radiation delivery and modality. This review presents conflicting results concerning the addition of radiation and modality in the treatment regimen. Further research is needed to improve outcomes and define the role of radiation therapy in pancreatic cancer.

Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable METHOD: A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log-rank model and Kaplan-Meier analysis.

The PURPLE database included 754 cases with localised PDAC, including 148 (20%) cases with borderline resectable pancreatic cancer (BRPC). Of the 148 BRPC patients, 44 (30%) underwent immediate surgery, 80 (54%) received NA chemotherapy, and 24 (16%) were inoperable. The median age of NA therapy patients was 63 years and FOLFIRINOX (53%) was more often used as NA therapy than gemcitabine/nab-paclitaxel (31%). Patients who received FOLFIRINOX were younger than those who received gemcitabine/nab-paclitaxel (60 years vs. 67 years, p = .01). Surgery was performed in 54% (43 of 80) of BRPC patients receiving NA chemotherapy, with 53% (16 of 30) achieving R0 resections. BRPC patients undergoing surgery had a median OS of 30 months, and 38% (9 of 24) achieved R0 resection. NA chemotherapy patients had a median OS of 20 months, improving to 24 months versus 10 months for patients receiving FOLFIRINOX compared to gemcitabine/nab-paclitaxel (Hazard Ratio (HR) .3, p < .0001).

NA chemotherapy use in BRPC is increasing in Australia. One half of patients receiving NA chemotherapy proceed to curative resection, with 53% achieving R0 resections. Patients receiving Infusional 5-flurouracil, Irinotecan and Oxaliplatin (FOLIRINOX) had increased survival than gemcitabine/nab-paclitaxel. Treatment strategies are being explored in the MASTERPLAN and DYNAMIC-Pancreas trials.

To identify, describe, and organise currently available evidence regarding systemic oncological treatments (SOTs) (chemotherapy, targeted/biological therapies, and immunotherapy) compared to best supportive care (BSC) for patients with advanced pancreatic cancer (PC).

We conducted a scoping review and evidence mapping, adhering to PRISMA-ScR checklist. We searched MEDLINE, EMBASE, Cochrane Library, Epistemonikos, PROSPERO, and clinicaltrials.gov for eligible studies. We included systematic reviews (SRs), randomised controlled trials (RCTs), quasi-experimental, and observational studies evaluating SOTs compared to BSC or no treatment in patients with advanced PC. Two independent reviewers performed the screening process and data extraction. We developed evidence maps as an interactive visualization display, including the assessed interventions and outcomes.

Of the 50,601 records obtained from our search, we included 43 studies: 2 SRs, 16 RCTs, 4 quasi-experimental studies, 20 observational studies, and 1 protocol for a quasi-experimental study. Forty-two studies reported survival-related outcomes and most favoured SOTs, while five reported toxicity and most favoured BSC. Other patient-centred outcomes, such as quality of life, were scarcely reported.

This study highlights the current evidence gaps in studies assessing treatments for patients with advanced PC, mainly the lack of reports of non-survival-related outcomes, pointing out research areas that need further attention to make better recommendations for these patients.

Locally advanced and borderline resectable pancreatic cancers are being increasingly recognized as a result of significant improvements in imaging modalities. The main tools used in diagnosis of these tumors include endoscopic ultrasound, computed tomography, magnetic resonance imaging, and diagnostic laparoscopy. The definition of what constitutes a locally advanced or borderline resectable tumor is still controversial to this day. Borderline resectable tumors have been treated with neoadjuvant therapy approaches that aim at reducing tumor size, thus improving the chances of an R0 resection. Both chemotherapy and radiotherapy (solo or in combination) have been used in this setting. The main chemotherapy agents that have shown to increase resectability and survival are FOLFORINOX (a combination of folinic acid, fluorouracil, irinotecan, and oxaliplatin) and gemcitabine-nab-paclitaxel. Surgery on these tumors remains a significantly challenging task for pancreatic surgeons. More studies are needed to determine the best agents to be used in the neoadjuvant and adjuvant settings, biologic markers for prognostic and operative predictions, and validation of previously published retrospective results.

Patients with advanced pancreatic cancer (PC) have a high risk of dying in the short or medium-term. This overview aimed to assess the evidence regarding systemic oncological treatments (SOT) versus supportive care for advanced PC.

We searched for systematic reviews (SRs) in MEDLINE, Embase, The Cochrane Library, Epistemonikos, and PROSPERO. Two authors assessed eligibility independently. Data extraction and methodological quality assessment were conducted by one author and cross-checked by another one. We evaluated the overlap of primary studies, performed a de novo meta-analysis, and assessed the certainty of evidence. Primary outcomes were overall survival (OS), quality of life (QoL), functional status (FS), and toxicity.

We identified three SRs that assessed SOT versus supportive care in patients with advanced PC. All SRs had critically low methodological quality. At 12 months, OS improved with chemotherapy, radiotherapy followed by chemotherapy, and immunotherapy, but the certainty of the evidence supporting these findings is very low. The evidence on chemotherapy is very uncertain about its effects on QoL; it suggests a slight increase in toxicity and little to no difference in FS. The evidence on immunotherapy is very uncertain about its effects in toxicity.

The identified evidence is very uncertain about the benefits of oncological treatments on OS and QoL in patients with advanced PC with a high risk of dying in the short or medium-term, so its use should be proposed only to selected patients. Further studies that include a thorough assessment of patient-centred outcomes are needed.

Locally advanced pancreatic cancer (LAPC) constitutes approximately one-third of all pancreatic cancer, with standard of care inconsistently defined and achieving modest outcomes at best. While resection after downstaging offers the chance for cure, only a fraction of patients with LAPC become candidates for resection. Chemotherapy remains the mainstay of treatment for the remainder. In these patients, ablative therapy may be given for local control of the tumor. Irreversible electroporation (IRE) is an attractive ablative technique. IRE changes the permeability of tumor cell membranes to induce apoptosis. Unlike other ablative therapies, IRE causes little thermal injury to the target area, making it ideal for LAPC involving major vessels. Compared to systemic chemotherapy alone, IRE seems to offer some survival benefit. Although early studies reported notable morbidity and mortality rates, IRE presents opportunities for those who cannot undergo resection and who otherwise have limited options. Another role of IRE is to extend the margins of resected tumors when there is a concern for R1 resection. Perhaps most exciting, IRE is thought to have effects beyond local ablation. IRE has immunomodulatory effects, which may induce in vivo vaccination and may potentially synergize with immunotherapy. Through electrochemotherapy, IRE may enhance drug delivery to residual tumor cells. Ultimately the role of IRE in the treatment of LAPC still needs to be validated through well designed randomized trials. Investigations of its future possibilities are in the early stages. IRE offers the potential to provide more options to LAPC patients.

The mechanisms responsible for radioresistance in pancreatic cancer have yet to be elucidated, and the suppressive tumor immune microenvironment must be considered. We investigated whether the radiotherapy-augmented Warburg effect helped myeloid cells acquire an immunosuppressive phenotype, resulting in limited treatment efficacy of pancreatic ductal adenocarcinoma (PDAC). Radiotherapy enhanced the tumor-promoting activity of myeloid-derived suppressor cells (MDSC) in pancreatic cancer. Sustained increase in lactate secretion, resulting from the radiation-augmented Warburg effect, was responsible for the enhanced immunosuppressive phenotype of MDSCs after radiotherapy. Hypoxia-inducible factor-1α (HIF-1α) was essential for tumor cell metabolism and lactate-regulated activation of MDSCs via the G protein-coupled receptor 81 (GPR81)/mTOR/HIF-1α/STAT3 pathway. Blocking lactate production in tumor cells or deleting Hif-1α in MDSCs reverted antitumor T-cell responses and effectively inhibited tumor progression after radiotherapy in pancreatic cancer. Our investigation highlighted the importance of radiation-induced lactate in regulating the inhibitory immune microenvironment of PDAC. Targeting lactate derived from tumor cells and the HIF-1α signaling in MDSCs may hold distinct promise for clinical therapies to alleviate radioresistance in PDAC.

Despite ongoing efforts, patients with locally advanced pancreatic cancer (LAPC) continue to have a dismal prognosis. Such tumors are unresectable, and optimal treatment with chemotherapy and/or radiation therapy is still not established. While chemotherapy is conventionally aimed at preventing metastatic spread of disease, radiation therapy acts locally, improving local control which can potentially improve overall survival and most importantly quality of life. Here, we aim to review the primary literature assessing the role of diverse radiation therapy strategies for patients with LAPC. Many radiation regimens can be considered, and no standard treatment has demonstrated a clear improvement in clinical outcomes. We advise that the modality of choice be dependent on the availability of equipment, the dose and fractionation of treatment, as well as the dose received by normal tissue. Moreover, a candid discussion with the patient concerning treatment goals is equally as essential. Three notable strategies for LAPC are intensity-modulated radiation therapy, volumetric modulated arc therapy, and proton. These radiation modalities tend to have improved dose distribution to the target volumes, while minimizing the radiation dose to surrounding normal tissues. Stereotactic body radiation therapy can also be considered in LAPC patients in cases where the tumor does not invade the duodenum or other neighboring structures. Because of the high doses delivered by stereotactic body radiation therapy, proper respiratory and tumor motion management should be implemented to reduce collateral radiation dosing. Despite improved clinical outcomes with modern radiation modalities, evolving techniques, and more accurate planning, future studies remain essential to elucidate the optimal role for radiation therapy among patients with LAPC.

Pancreatic cancer is a highly lethal disease with a dismal prognosis. It will probably become the second leading cause of cancer-related death within the next decade in Western countries. Over 80% of patients undergo palliative treatment for unresectable pancreatic cancer due to locally advanced disease or metastases. Those patients often develop gastric outlet obstruction (GOO), obstructive jaundice and pain during the course of their disease. Symptoms such as vomiting, anorexia, pruritus and jaundice will impact the quality of life (QOL) and could delay the administration of the chemotherapy. Palliative therapy in pancreatic cancer aims to relieve the symptoms durably and to improve the QOL. Palliative surgery was traditionally considered as a gold standard with the "double by-pass" including biliary-digestive and gastro-jejunal anastomosis. However, since the development of endoscopic stenting and minimally invasive surgery, the choice of the best modalities remains debated. While there is still a place for surgical gastrojejunostomy (GJ) in case of duodenal or GOO, endoscopic biliary stenting during endoscopic retrograde cholangiopancreatography (ERCP) is now accepted as the gold standard in case of obstructive jaundice. In pain management, endoscopic ultrasound guided or percutaneous celiac plexus neurolysis is recommended. The selection of the best technique should consider the effectiveness and the morbidity of the treatment, the performance status of the patient and the disease stage. While endoscopic stenting is associated with earlier recovery and shorter length of stay, recurrence of symptoms and reintervention are less frequent after palliative surgery. Finally, controversy exists on whether to perform prophylactic palliative surgery in the absence of symptoms when unresectable disease is discovered during surgical exploration.

The majority of pancreatic cancers present locally advanced and carry a high mortality rate. Treatment is challenging, with mixed data suggesting use of chemotherapy alone or in combination with radiotherapy. The use of radiotherapy has previously been limited due to lack of ability to deliver radiation to the tumour mass without causing significant toxicity to surrounding organs. Stereotactic body radiotherapy (SBRT) allows delivery of higher biologically equivalent dose in a shorter treatment duration. We sought to investigate the safety and application of this technique in our centre.

We enrolled 27 patients from 2015, identified as locally advanced unresectable with histologically confirmed, non-metastatic, pancreatic adenocarcinoma. All patients had endoscopically inserted fiducial markers and where possible concurrent chemotherapy was administered. Dose schedules ranged from 25 to 42 Gy in 5 or 3 fractions.

With an overall median follow up of 9 months (range, 3-32.7), the median survival was 11.6 months. Of those alive at 1 year, the local control rate was 67%. Six patients had Grade 3 toxicity, and other six had Grade 2 toxicity. None had Grade 4 or above toxicity. The most common symptom recorded was fatigue.

SBRT for locally advanced pancreatic cancer is technically complex but feasible in a high volume centre. SBRT is unique, allowing safe delivery of high radiation dose resulting in good local control and decreases treatment time making it an attractive option for patients with unresectable pancreatic cancer.

Background Non-resected locally advanced and microscopic positive-margin resected (R1) pancreatic adenocarcinoma are associated with a dismal prognosis. The combination of high dose radiotherapy and concomitant chemotherapy is among the strategies that are used to improve the outcome. The aims of this study were to evaluate the acute and late toxicities and patients' outcome in a retrospective study from a single center. Material and methods From 2009 to 2015, 24 patients, with non-resected locally advanced or R1 resected pancreatic adenocarcinoma, have been treated with concomitant radiochemotherapy, with a median dose of 60 Gy and gemcitabine (50 mg/m² administered bi-weekly). The acute and late toxicities were evaluated during and after the treatment. Results The actuarial overall survival rates were 39% at 24 months and 8.6% at 36 months. The disease-free survival rates were 32.5% at 24 months and 12.2% at 36 months. Acute toxicities were mainly grade 1 (G1) to grade 2 (G2) except for one patient who presented with severe digestive bleeding potentially linked to the treatment. Late toxicities consisted mainly of G1 digestive toxicities. Conclusion This study confirms the feasibility of high dose radiotherapy combined with gemcitabine-based chemotherapy in patients with locally advanced pancreatic adenocarcinoma. While the outcome remains unsatisfactory, some patients seem to have benefited from this aggressive therapy, which merits to be investigated further.

For unresectable locally advanced (UR-LA) pancreatic cancer, chemoradiotherapy has been recommended by the NCCN guidelines. We designed a chemoradiotherapy protocol using nab-paclitaxel combined with gemcitabine (GnP) for patients with UR-LA pancreatic cancer. The purpose of this phase I study was to determine a recommended dose (RD) for this novel regimen.

Patients with UR-LA pancreatic cancer were eligible. The frequency of dose-limiting toxicities (DLTs) was evaluated, and the RD was determined. Patients were classified according to the designated dose levels of chemoradiotherapy using the GnP regimen. After additional 6 cycles of the GnP regimen were administered, surgery was considered if the patients had stable disease and tumor marker levels had normalized.

DLT (grade 4 thrombocytopenia) was observed only in 1 of 12 patients, and the RD was set at level 3. Grade 3-4 leukopenia was observed in 9 (75.0%) patients, and neutropenia in 7 (58.3%). The response rate was 41.7%, and the disease control rate was 100%. Conversion surgery was performed in 6 (50%) patients, and curative resection (R0) was performed in all 6 patients (100%). Stratification according to the Evans classification system demonstrated one patient with grade 1b, one with grade 2, two with grade 3, and two with grade 4 disease.

The RD for weekly administration was 800 mg/m2 for gemcitabine and 100 mg/m2 for nab-paclitaxel with a 50.4 Gy radiation. The GnP regimen at this dosage was promising with 6 of 12 patients proceeding to conversion surgery, and should be evaluated further in a phase II trial.

Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options. Over the past few decades, many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review attempts to synthesise all the randomised data available to help better inform patient and clinician decision-making when dealing with this difficult disease.

To assess the effect of chemotherapy, radiotherapy or both for first-line treatment of advanced pancreatic cancer. Our primary outcome was overall survival, while secondary outcomes include progression-free survival, grade 3/4 adverse events, therapy response and quality of life.

We searched for published and unpublished studies in CENTRAL (searched 14 June 2017), Embase (1980 to 14 June 2017), MEDLINE (1946 to 14 June 2017) and CANCERLIT (1999 to 2002) databases. We also handsearched all relevant conference abstracts published up until 14 June 2017.

All randomised studies assessing overall survival outcomes in patients with advanced pancreatic ductal adenocarcinoma. Chemotherapy and radiotherapy, alone or in combination, were the eligible treatments.

Two review authors independently analysed studies, and a third settled any disputes. We extracted data on overall survival (OS), progression-free survival (PFS), response rates, adverse events (AEs) and quality of life (QoL), and we assessed risk of bias for each study.

We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy.We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated.Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate-quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO-101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone.Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high-quality evidence) but increased the rate of side effects when compared with bolus dosing.When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low-quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high-quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab-paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high-quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine-containing multi-drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low-quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL.We did not find any survival advantages when comparing 5FU combinations to 5FU alone.

Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients.

Pancreatic adenocarcinoma is a frequent and severe disease, either diagnosed as metastatic pancreatic adenocarcinoma (MPA) or as locally advanced pancreatic carcinoma (LAPC). Though no improvement in patients outcome have been made between 1996 and 2011, since 5 years new treatment options have become available to treat our patients. New standard first line regimens, such as FOLFIRINOX and gemcitabine combined with nab-paclitaxel, have improved overall survivals and second line treatments have been tested and validated. Other first-line treatments have failed, but research remains active and trials are ongoing with promising new anti-cancer agents. These new effective regimens used for MPA have yielded promising results in LAPC patients in open cohorts or phase II trials and a recent trial have failed to demonstrate the added value of classical external radiotherapy in this setting. Here, we review current standards of care in LAPC and MPA, consider the latest challenges and strategic questions, and examine what we may hope for in the future.

To describe the population benefit of radiotherapy in a high-income setting if evidence-based guidelines were routinely followed.

Australian decision tree models were utilized. Radiotherapy alone (RT) benefit was defined as the absolute proportional benefit of radiotherapy compared with no treatment for radical indications, and of radiotherapy over surgery alone for adjuvant indications. Chemoradiotherapy (CRT) benefit was the absolute incremental benefit of concurrent chemoradiotherapy over RT. Five-year local control (LC) and overall survival (OS) benefits were measured. Citation databases were systematically queried for benefit data. Meta-analysis and sensitivity analysis were performed.

48% of all cancer patients have indications for radiotherapy, 34% curative and 14% palliative. RT provides 5-year LC benefit in 10.4% of all cancer patients (95% Confidence Interval 9.3, 11.8) and 5-year OS benefit in 2.4% (2.1, 2.7). CRT provides 5-year LC benefit in an additional 0.6% of all cancer patients (0.5, 0.6), and 5-year OS benefit for an additional 0.3% (0.2, 0.4). RT benefit was greatest for head and neck (LC 32%, OS 16%), and cervix (LC 33%, OS 18%). CRT LC benefit was greatest for rectum (6%) and OS for cervix (3%) and brain (3%). Sensitivity analysis confirmed a robust model.

Radiotherapy provides significant 5-year LC and OS benefits as part of evidence-based cancer care. CRT provides modest additional benefits.

Chemotherapy for pancreatic cancer has diversified following the addition of more treatment regimens; however, in spite of this, pancreatic cancer remains a fatal disease. Preoperative (neoadjuvant) chemotherapy (NAC) or neoadjuvant chemoradiation therapy (NACRT) has been developed and implemented. For patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), a number of clinical trials have been conducted; NACRT was demonstrated to improve resectability, R0 resection rate, overall survival rate, disease-free survival rate and even an LAPC and BRPC survival advantage over NAC. However, from the knowledge obtained from resected specimens following preoperative treatment, residual pancreatic cancer tissues following NAC are rich in chemoresistant cancer stem-like cells and epithelial-mesenchymal transition (EMT) markers. Conversely, metformin, angiotensin receptor blocker, statins and low-dose paclitaxel are well-known as drugs that inhibit EMT, which is associated with cancer stem cell-like characteristics. Although clinical effectiveness is unlikely to be achieved using one of these as an anticancer agent, it is reasonable to use these drugs for patients with comorbidities in the treatment of pancreatic cancer. Furthermore, gemcitabine (GEM) affects antitumor immunity by stimulating the expression of major histocompatibility complex class I-related chain A on the surface of cancer cells to enhance the cytotoxicity of natural killer cells. Considering EMT and antitumor immunity, there is a possibility that GEM and nanoparticle albumin-bound paclitaxel therapy is the most suitable regimen for treating pancreatic cancer. However, even as preoperative treatment progresses, R0 resection is the most important factor for the long-term survival of pancreatic cancer patients.

Most patients with pancreatic cancer will present with metastatic or locally advanced disease. Unfortunately, most patients with localized disease will experience recurrence even after multimodality therapy. As such, pancreatic cancer patients arrive at a common endpoint where decisions pertaining to palliative care come to the forefront. This article summarizes surgical, endoscopic, and other palliative techniques for relief of obstructive jaundice, relief of duodenal or gastric outlet obstruction, and relief of pain due to invasion of the celiac plexus. It also introduces the utility of the palliative care triangle in clarifying a patient's and family's goals to guide decision making.

Radiotherapy (RT) with or without chemotherapy is currently used in definitive therapy for advanced pancreatic cancer. We sought to evaluate the prognostic significance, pattern of care, and use of RT in locally advanced and metastatic pancreatic cancer.

Between 2002 and 2011, patients with invasive pancreatic carcinoma and prior exposure to systemic chemotherapy were included. We used Cox regression model and propensity score matching for prognostic analyses and logistic regression for analyzing the factors impacting the use of RT.

We identified 217 pancreatic cancer patients (74 with unresectable stage II or III and 143 with stage IV). Of all patients, 90.8% had adenocarcinoma, and only 19.2% (42/217) received RT with doses ranging from 50 to 55 Gy in 25 to 28 fractions using modern RT techniques. Logistic regression showed stage (P < 0.001) and initial CA 19-9 level (P = 0.026) were significantly predictive of the choice of RT as a first-line treatment, whereas the second-line use of RT was associated with the response to first-line chemotherapy and longer progression-free survival. Patients with RT had a better median survival than those without it (14.6 vs 8.1 months, P < 0.001). In the multivariate analysis and propensity score matching, RT remained a good prognostic factor for overall survival.

The use of RT might be associated with a favorable clinical outcome in patients with locally advanced and metastatic pancreatic cancer. Further exploration of RT as a first-line therapy or second-line therapy for locally advanced or even metastatic pancreatic cancer is warranted.

Pancreatic adenocarcinoma remains a devastating disease with a 5-year survival rate not exceeding 6%. Treatment of this disease remains a major challenge. This article reviews the state-of-the-art in the management of this disease and the new innovative approaches that may help to accelerate progress in treating its victims. After careful pre-therapeutic evaluation, only 15-20% of patients diagnosed with a pancreatic cancer (PC) are eligible for upfront radical surgery. After R0 or R1 resection in such patients, evidence suggests a significantly positive impact on survival of adjuvant chemotherapy comprising 6 months of gemcitabine or fluorouracil/folinic acid. Delayed adjuvant chemoradiation is considered as an option in cases of positive margins. Borderline resectable pancreatic cancer (BRPC) is defined as a tumour involving the mesenteric vasculature to a limited extend. Resection of these tumours is technically feasible, yet runs the high risk of a R1 resection. Neoadjuvant treatment probably offers the best chance of achieving successful R0 resection and long-term survival, but the best treatment options should be determined in prospective randomised studies. Gemcitabine has for 15 years been the only validated therapy for advanced PC. Following decades of negative phase III studies, increasing evidence now suggests that further significant improvements to overall survival can be achieved via either Folfirinox or gemcitabine + nab-paclitaxel regimens. Progress in systemic therapy may improve the chances of resection in borderline resectable pancreatic cancer (BRPC) or locally advanced PC. This requires first enhancing knowledge of the genetic events driving carcinogenesis, which may then be translated into clinical studies.

Controversy remains regarding neoadjuvant approaches in the treatment of pancreatic cancer. Neoadjuvant therapy has several potential advantages over adjuvant therapy including earlier delivery of systemic treatment, in vivo assessment of response, increased resectability rate in borderline resectable patients and increased margin-negative resection rate. At present, there are no randomized data favoring neoadjuvant over adjuvant therapy and multiple neoadjuvant approaches are under investigation. Combination chemotherapy regimens including 5-fluorouracil, irinotecan and oxaliplatin, gemcitabine with or without abraxane, or docetaxel and capecitabine have been used in the neoadjuvant setting. Radiation and chemoradiation have also been incorporated into neoadjuvant strategies, and delivery of alternative fractionation regimens is being explored. This review provides an overview of neoadjuvant therapies for pancreatic cancer.

Adenocarcinoma of the pancreas remains a highly lethal disease, with less than 5% survival at 5 years. Borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC) account for approximately 30% of newly diagnosed cases of PC. The objective of BRPC therapy is to downstage the tumor to allow resection; the objective of LAPC therapy is to control disease and improve survival. There is no consensus on the definitions of BRPC and LAPC, which leads to major limitations in designing clinical trials and evaluating their results. A multimodality approach is always needed to ensure proper utilization and timing of chemotherapy, radiation, and surgery in the management of this disease. Combination chemotherapy regimens (5-fluorouracil, leucovorin, irinotecan, oxaliplatin, and gemcitabine [FOLFIRINOX] and gemcitabine/nab-paclitaxel) have improved overall survival in metastatic disease. The role of combination chemotherapy regimens in BRPC and LAPC is an area of active investigation. There is no consensus on the dose, modality, and role of radiation therapy in the treatment of BRPC and LAPC. This article reviews the literature and highlights the areas of controversy regarding management of BRPC and LAPC.

Pancreatic cancer is one of the worst cancers with regard to survival, even at early stages of the disease. This review evaluates all the evidence for the stages in which the cancer is not primarily resectable with surgery, known as borderline resectable or locally advanced unresectable. Recently, advancements in radiation techniques and use of better combination chemotherapies have improved survival and tolerance. There is no consensus on description of stages or treatment sequences (chemotherapy, chemoradiation, radiation), nor on the best chemotherapy regimen. The evidence behind the treatment paradigm for these stages of pancreatic cancer is summarized.

Currently, pancreatic adenocarcinoma mainly occurs after 60 years of age, and its prognosis remains poor despite modest improvements in recent decades. The aging of the population will result in a rise in the incidence of pancreatic adenocarcinoma within the next years. Thus, the management of pancreatic cancer in the elderly population is gaining increasing relevance. Older cancer patients represent a heterogeneous group with different biological, functional and psychosocial characteristics that can modify the usual management of this disease, including pharmacokinetic and pharmacodynamic changes, polypharmacy, performance status, comorbidities and organ dysfunction. However, the biological age, not the chronological age, of the patient should be the limiting factor in determining the most appropriate treatment for these patients. Unfortunately, despite the increased incidence of this pathology in older patients, there is an underrepresentation of these patients in clinical trials, and the management of older patients is thus determined by extrapolation from the results of studies performed in younger patients. In this review, the special characteristics of the elderly, the multidisciplinary management of localized and advanced ductal adenocarcinoma of the pancreas and the most recent advances in the management of this condition will be discussed, focusing on surgery, chemotherapy, radiation and palliative care.

This article focuses on the management of locally advanced pancreatic cancer, which should be treated as a distinct entity separate from metastatic disease and borderline resectable disease. Although the role, timing, and sequencing of radiation relative to systemic therapy in this disease are controversial, an emerging treatment paradigm involves induction chemotherapy, followed by consolidative chemoradiation in patients who do not progress. In addition, new chemotherapy regimens as well as novel radiosensitizers have shown promise and need to be tested further in the locally advanced setting. Advances in radiotherapy have enabled stereotactic body radiotherapy and should continue to be prospectively evaluated.

While gastrointestinal (GI) hemorrhage is common in the general population, few studies have evaluated large numbers of GI hemorrhage patients with pancreatic cancer. The clinical features and potential risk factors of GI hemorrhage with pancreatic cancer was investigated in the present study and the effect of GI hemorrhage on survival rate was examined. Patients enrolled in the present study had pathologically proven pancreatic cancer, and received treatment between August 2006 and 2012. Their medical records were retrospectively reviewed. The data for the present study were obtained from a review of 246 patients with pancreatic cancer (average age, 63.4±10.92 years; 190 male cases, 56 female cases). In addition, 73 cases had stage I-II, 173 had stage III-IV, and only 67 cases (27.2%) were candidates for curative pancreatectomy. Among them, 32 cases (13.0%) were clinically diagnosed with GI hemorrhage. A total of 24 cases were male patients and the other 8 cases were female, the cases of hemorrhage history and alcoholism were 2 and 29 cases, respectively. The major initial clinical symptoms of GI hemorrhage included 18 patients with melena or blood stool (56.25%), 9 with haematemesis (28.13%), 3 with abdominal distention (9.37%) and 2 with stomach ache (6.25%). The independent risk factor for GI hemorrhage was tumor initial stage of IV. A continuous increase in carbohydrate antigen 19-9 (CA19-9) may be a warning of GI hemorrhage, particularly when it is >1,000 U/ml. The most frequent method of hemostasis was combination therapy (n=12, 37.5%). Only 3 cases (9.3%) of these 32 GI hemorrhage patients were blood stanched and only 10 patients (31.2%) received gastroscopy. The time from GI hemorrhage to fatality is extremely short (median 30 days, range from 1 h to 65 days), and the median overall survival time of the patients with GI hemorrhage was 9.0 months (range, 2.0-16.0 months) and was significantly shorter than that of patients without GI hemorrhage [14.5 months (range, 0.5-48.0 months)]. In conclusion, although GI hemorrhage was not common in patients with pancreatic cancer, it is critical. GI hemorrhage was controlled with endoscopic hemostasis. Clinicians should fully assess the risk factors of GI hemorrhage (such as alcohol, smoking, past hemorrhage history, initial stage, tumor location and CA19-9 level at diagnosis of pancreatic cancer) when the pancreatic cancer patients were on admission, particularly for patients of the late stage, preventive measures should be investigated to reduce suffering.

Recent research has shown treating pancreatic cancer with volumetric-modulated arc therapy (VMAT) to be superior to either intensity-modulated radiation therapy or 3-dimensional conformal radiotherapy (3D-CRT), with respect to reducing normal tissue toxicity, monitor units, and treatment time. Furthermore, using avoidance sectors with RapidArc planning can further reduce normal tissue dose while maintaining target conformity. This study looks at the methods in reducing dose to the ipsilateral kidney, in pancreatic head cases, while observing dose received by other critical organs using avoidance sectors. Overall, 10 patients were retrospectively analyzed. Each patient had preoperative/unresectable pancreatic tumor and were selected based on the location of the right kidney being situated within the traditional 3D-CRT treatment field. The target planning target volume (286.97 ± 85.17 cm(3)) was prescribed to 50.4 Gy using avoidance sectors of 30°, 40°, and 50° and then compared with VMAT as well as 3D-CRT. Analysis of the data shows that the mean dose to the right kidney was reduced by 11.6%, 15.5%, and 21.9% for avoidance angles of 30°, 40°, and 50°, respectively, over VMAT. The mean dose to the total kidney also decreased by 6.5%, 8.5%, and 11.0% for the same increasing angles. Spinal cord maximum dose, however, increased as a function of angle by 3.7%, 4.8%, and 6.1% compared with VMAT. Employing avoidance sector angles as a complement to VMAT planning can significantly reduce high dose to the ipsilateral kidney while not greatly overdosing other critical organs.

The recent development of intensity-modulated radiation therapy (IMRT) and improvements in image-guided radiotherapy (IGRT) have provided considerable advances in the utilization of radiation therapy (RT) for the management of pancreatic cancer. IGRT allows for the reduction of treatment volumes, potentially less chance of a marginal miss, and quality assurance of gastrointestinal filling, while IMRT has been shown to reduce both sudden and late side effects compared with 3-dimensional conformal RT. Here, we review published data and provide essential recommendations on the utilization of IMRT and IGRT for the management of patients with pancreatic cancer.

We report updated outcomes of single- versus multifraction stereotactic body radiation therapy (SBRT) for unresectable pancreatic adenocarcinoma.

We included 167 patients with unresectable pancreatic adenocarcinoma treated at our institution from 2002 to 2013, with 1-fraction (45.5% of patient) or 5-fraction (54.5% of patients) SBRT. The majority of patients (87.5%) received chemotherapy.

Median follow-up was 7.9 months (range: 0.1-63.6). The 6- and 12-month cumulative incidence rates (CIR) of local recurrence for patients treated with single-fraction SBRT were 5.3% (95% confidence interval [CI], 0.2%-10.4%) and 9.5% (95% CI, 2.7%-16.2%), respectively. The 6- and 12-month CIR with multifraction SBRT were 3.4% (95% CI, 0.0-7.2%) and 11.7% (95% CI, 4.8%-18.6%), respectively. Median survival from diagnosis for all patients was 13.6 months (95% CI, 12.2-15.0 months). The 6- and 12- month survival rates from SBRT for the single-fraction group were 67.0% (95% CI, 57.2%-78.5%) and 30.8% (95% CI, 21.9%-43.6%), respectively. The 6- and 12- month survival rates for the multifraction group were 75.7% (95% CI, 67.2%-85.3%) and 34.9% (95% CI, 26.1%-46.8%), respectively. There were no differences in CIR or survival rates between the single- and multifraction groups. The 6- and 12-month cumulative incidence rates of gastrointestinal toxicity grade ≥3 were 8.1% (95% CI, 1.8%-14.4%) and 12.3% (95% CI, 4.7%-20.0%), respectively, in the single-fraction group, and both were 5.6% (95% CI, 0.8%-10.5%) in the multifraction group. There were significantly fewer instances of toxicity grade ≥2 with multifraction SBRT (P=.005). Local recurrence and toxicity grade ≥2 were independent predictors of worse survival.

Multifraction SBRT for pancreatic cancer significantly reduces gastrointestinal toxicity without compromising local control.

At the time of diagnosis, around 20% of patients with pancreatic cancer present at a resectable stage, 50% have metastatic disease and 30% have locally advanced tumour, non-metastatic but unresectable because of superior mesenteric artery or coeliac encasement. Despite advances in chemoradiotherapy and improved systemic chemotherapeutic agents, patients with locally advanced pancreatic cancer suffer from high rates of distant metastatic failure and from local progression, with a median survival time ranging from 5 to 11 months. In the past 30 years, modest improvements in median survival have been attained for these patients treated by chemoradiotherapy or chemotherapy protocols. The optimal therapy for patients with locally advanced pancreatic carcinoma remains controversial. This review aims to evaluate the role of radiotherapy for these patients.

The purpose of this phase I study was to determine the safety, toxicity, maximum tolerated dose, and pharmacokinetics of capecitabine when administered concurrently with radiotherapy in patients with localised, inoperable pancreatic adenocarcinoma.

Eligible patients, with adequate performance status and organ function, were treated in escalating dose cohorts with capecitabine, administered 7 days a week, twice daily, and radiotherapy (50.4 Gy in 28 fractions over 38 days). Cohorts of six patients were treated at four planned dose levels. Pharmacokinetic (PK) studies were undertaken on day 1 of treatment.

Twenty-five patients, performance status ECOG ≤2, were recruited to the study. Dose-limiting toxicities were grade 3 vomiting (1 patient) and grade 3 fatigue (1 patient), both at 1,000 mg/m². The recommended phase II dose was 825 mg/m². No grade 3/4 haematological toxicities were observed. PK studies did not suggest any effect of pancreatic malignancy or concurrent radiotherapy on the PK parameters of capecitabine and its metabolites.

Capecitabine-based chemo-radiotherapy, using a twice daily dosing schedule of 825 mg/m² given 7 days per week concurrently with 50.4 Gy external beam radiotherapy, is well tolerated in patients with locally advanced pancreatic cancer.