The impact of a multidisciplinary team approach on the management of focal pancreatic lesions: a single tertiary center experience.

Background: Multidisciplinary team (MDT) meetings aim to optimize patient management. We evaluated the impact of MDT discussions on the management and diagnosis of focal pancreatic lesions in a single tertiary center. Methods: All patients with an initial diagnosis of solid or cystic pancreatic lesion discussed in our institution's MDT meeting on pancreatic diseases between January 1, 2020, and December 31, 2021, were included. The impact of MDT discussion on patient management, defined as a modification of the initially proposed therapeutic plan after MDT discussion, as well as the criteria leading to this modification, were the primary outcomes. Impact on diagnosis was the secondary outcome. Results: A total of 522 patients were included. Of these, 185 (35.4%) and 337 (64.6%) had an initial diagnosis of cystic or solid lesion, respectively. The most common referral query was regarding the management plan (349/522; 66.9%). Endoscopy was the procedure most often proposed before MDT discussion (109/522; 20.9%). Overall, the MDT discussion led to modification of the management plan in 377/522 patients (72.2%), with a statistically significant difference between cystic and solid lesions (63.2% vs. 77.2%; P<0.001). Management modifications were mainly driven by revision of cross-sectional radiological images. MDT discussion led to modification of the diagnosis in 92/522 patients (17.6%), with a significant difference regarding cystic lesions (35.7% vs. 7.7%; P<0.001). Conclusion: MDT discussion impacts the management of patients with cystic and solid pancreatic lesions, leading to a modification of the initially proposed management in two-thirds of them, mainly through revision of cross-sectional imaging.

A Two-Step Diagnostic Approach for NTRK Gene Fusion Detection in Biliary Tract and Pancreatic Adenocarcinomas.

BACKGROUND: It is of interest to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers, because of possible treatment with TRK inhibitors for advanced tumors. The aim of the present study was to apply the guidelines for NTRK testing algorithm to a series of patients with bilio-pancreatic cancers. METHODS: Immunohistochemistry screening was applied on formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies, or cytological samples of biliary tract and pancreatic adenocarcinomas. The presence of at least a weak staining in rare tumor cells led to testing by 2 RNA-based NGS panels. RESULTS: For biliary tract tumors, 153 samples have been selected. A total of 140 samples were suitable to perform IHC, and 17 samples were IHC positive. RNA NGS testing of the 17 IHC-positive samples revealed a single NTRK3 gene fusion (ETV6(4)-NTRK3(14)) that was detected by both NGS panels. In this perihilar cholangiocarcinoma, IHC performed on a biopsy showed a weak focal cytoplasmic and nuclear staining. No other NTRK fusion was detected on the 16 other samples with both panels. Overall in the patients screened by IHC and confirmed by NGS, the percentage of NTRK fusions was 0.7%. For pancreatic cancers, 319 samples have been selected and 297 were suitable to perform IHC. Nineteen samples were IHC positive. No fusion was detected by NGS. CONCLUSION: NTRK gene fusions are rare in bilio-pancreatic cancers but testing is of high interest due to possible treatment with specific TRK inhibitors.

CDK4/6 Inhibitors in Pancreatobiliary Cancers: Opportunities and Challenges.

Existing treatment strategies for pancreatobiliary malignancies are limited. Nowadays, surgery is the only path to cure these types of cancer, but only a small number of patients present with resectable tumors at the time of diagnosis. The notoriously poor prognosis, lack of diverse treatment options associated with pancreaticobiliary cancers, and their resistance to current therapies reflect the urge for the development of novel therapeutic targets. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as an attractive therapeutic strategy in a number of cancers since their approval for treatment in patients with ER+/HER- breast cancer in combination with antiestrogens. In this article, we discuss the therapeutic potential of CDK4/6 inhibitors in pancreatobiliary cancers, notably cholangiocarcinoma and pancreatic ductal adenocarcinoma.

The path to personalized treatment in advanced and metastatic biliary tract cancers: a review of new targeted therapies and immunotherapy.

PURPOSE OF REVIEW: To summarize targeted therapies and immunotherapy as treatment for advanced/metastatic biliary tract cancers and discuss ongoing clinical trials. RECENT FINDINGS: For the first time since gemcitabine-cisplatin was set as the standard of care in first-line advanced/metastatic biliary tract cancers in the ABC-02 trial, the combination of durvalumab and gemcitabine-cisplatin has demonstrated a statistically significant improvement of median overall survival in the TOPAZ-1 phase 3 trial. The ABC-06 trial showed a significant increase of median overall survival for FOLFOX and active symptom control compared with active symptom control alone in second-line regardless of molecular and genetic alterations. However, faced with a heterogeneous cancer, patient prognosis remains poor, leaving room for new, personalized, treatment options such as targeted therapies. Efficacy of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors has been demonstrated in different phase 2 trials for previously treated intrahepatic cholangiocarcinomas harboring FGFR2 fusions. Ivosidenib increases significantly median progression-free survival in previously treated cholangiocarcinomas with isocitrate dehydrogenase-1 (IDH-1) mutation. Other targeted therapies are tested for tumors with HER2 amplifications/mutations, BRAFV600E mutations or KRASG12C mutations. SUMMARY: In this review, we aim to follow the changes in the treatment of these tumors, moving from very few chemotherapy options to immunotherapy and targeted therapies in the context of molecular selection of biliary tract cancers subtypes.

Implementation of a new health information technology for the management of cancer chemotherapies.

BACKGROUND: Cancer chemotherapy drugs are classified as high-risk molecules. Safety of the cancer chemotherapy process is often achieved with the implementation of a health information technology to each step or to the entire process. However, computerisation could lead to the emergence of new unintended medication errors. The aim of the study was to evaluate the impact of new software designed for the management of anticancer chemotherapies. METHOD: The cartography of the process and the failure modes, effects and criticality analysis were performed by a multidisciplinary team. Criticality indexes were calculated considering or not the implementation of the commercial software (CytoWeb). Quality and satisfactory indicators were measured before the implementation and during the use of the software. RESULTS: Our results demonstrated the complexity of the cancer chemotherapy process in the hospital. Risk analysis highlighted the positive impact of CytoWeb on the process safety but pointed out some steps that were not positively influenced by the software. Although a decrease of 38.6% of error rate was observed with the electronic system, new unintended medication errors emerged. These errors were due to inadequate use of the software (encoding of the wrong drug, the wrong dose, the wrong patient parameters or lab results and lack of prescriber adherence). Our satisfaction survey showed that the hospital pharmacists and doctors were less satisfied by the software than the nurses, mostly in terms of task achievement and time saving. Survey's results highlighted some weaknesses in the user training and in the collaboration between the medical staff. CONCLUSIONS: Our work showed the emergence of unintended medication errors linked to computerisation that were due to an inadequate use of the software. Other issues were highlighted such as the lack of collaboration between the medical staff, the lack of prescriber implication and weaknesses in the user training or in the information related to CytoWeb.

Personalized medicine in pancreatic cancer: the revolution has begun.

Pancreatic ductal adenocarcinoma carries a dismal prognosis. Both chemotherapy and targeted therapies have been disappointing when administered to unselected populations. Recently, progress has been made in our understanding of the genomic landscape of this cancer which displays remarkable heterogeneity suggesting a reorientation of management and research strategies based on molecular characterization and adapted personalized therapy. Resectable disease offers new opportunities for translational research through functional imaging response evaluation and tumor tissue acquisition before and after neoadjuvant therapy. There is urgent need for clinical trials based on molecular profiling in pancreatic ductal adenocarcinoma. In this review we discuss opportunities and limitations of these new strategies, underlining the importance of tissue acquisition and integration of molecular biomarkers in future molecularly driven clinical trials.

Adjuvant pharmacotherapy in the management of elderly patients with pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth or fifth leading cause of death from cancer in Western industrialized countries. Surgical resection is the only chance of cure, but only 15-20 % of cases are potentially resectable at presentation, and despite complete resection, the overall prognosis remains relatively poor. Adjuvant therapy has modestly improved cure rates. The majority of patients with pancreatic cancer are over the age of 65 years. But this age group is underrepresented within clinical trials, and it is unknown whether older patients achieve similar results to younger ones in terms of survival and treatment tolerance. In addition, there are no clinical trials dedicated to the elderly. Retrospective studies coming from the non-resectable setting provide some understanding on outcomes in older patients with PDAC. To date, we can reasonably argue that selected elderly patients with PDAC can benefit from curative surgery and postoperative chemotherapy as do their younger counterparts, without a significant increase in morbidity and mortality. Gemcitabine should be preferred to 5-fluorouracil on the basis of a better risk-benefit balance.

Tolerance and efficacy of gemcitabine and gemcitabine-based regimens in elderly patients with advanced pancreatic cancer.

OBJECTIVES: Gemcitabine is the backbone therapy of patients with advanced pancreatic cancer. Its tolerability and efficacy remain poorly studied in elderly. METHODS: We selected patients coming from phase 2 and 3 studies, conducted between January 2001 and December 2004 in our department, evaluating gemcitabine-based first-line chemotherapy. We evaluated the treatment efficacy, tolerability, and compared patients younger than 70 years (group A) and aged 70 years and older (group B). We assessed the contribution of patient-, tumor- and treatment-related variables on the prognostic of patients aged 70 years and older. RESULTS: Ninety-nine patients were studied: groups A (n = 57) and B (n = 42) treated by gemcitabine alone (n = 61) and gemcitabine-based combination (n = 38). Tumor growth control (66.6% vs 59.6%), time to progression (119 vs 104 days), and overall survival (240 vs 220 days) were comparable for groups A and B, respectively. For patients (n = 47) receiving a second-line chemotherapy (group A, n = 33; group B, n = 14), the efficacy and toxicity were similar in both group. Baseline alanine aminotransferase and Karnofski performance status were independent negative prognostic factors for elderly patients. CONCLUSIONS: Our study suggests that elderly patients undergoing gemcitabine do as well than younger patients.

The multidisciplinary management of gastrointestinal cancer. Biliary tract cancers: from pathogenesis to endoscopic treatment.

Cholangiocarcinoma is the second most common hepatobiliary tumour. Even if it is a rare tumour, its incidence is increasing over these last decades, probably due in part to a better knowledge of the disease and to an improvement of the diagnosis. Accurate diagnosis and staging are key steps to determine the appropriate treatment. The only curative treatment of this cancer is surgical resection. To date, no neoadjuvant or adjuvant treatments have ever proved any survival benefit, and are not recommended outside clinical trials. Liver transplantation (with or without neoadjuvant treatment) can be an option for highly selected cases. Unfortunately, these tumours are generally diagnosed at an advanced stage or are unresectable. For most of these patients, palliative therapeutic options exist and are in further development, based on multimodal promising combinations including chemotherapy, targeted agents, radiation, endoscopic stenting and photodynamic treatment.

Adjuvant therapy in gastric and cardia cancer: should we irradiate?

PURPOSE OF REVIEW: The purpose of this review is to comment on the current status and the place of the (neo)adjuvant therapy of gastric cancer, and on the standardization of care in this setting. RECENT FINDINGS: The definition of optimal surgery remains controversial in gastric cancer. A recent review by the Dutch Gastric Cancer Group supports the so-called 'over-D1' extended lymphadenectomy, without pancreatectomy and splenectomy, as the optimal procedure, avoiding an increased postoperative mortality. The results from the phase III INT 116 trial should not definitively assign adjuvant chemoradiation as a robust standard of care, mainly due to the lack of optimal surgery in this trial. However, the concept of adjuvant chemoradiation will likely become more and more used, and will influence the design of future studies, reinforced by the incorporation of novel agents. If adjuvant chemotherapy failed to significantly increase survival, the use of perioperative chemotherapy (ECF regimen x 3 pre- and postoperative) was recently reported to improve survival, without affecting postoperative mortality and morbidity; mature results from this large phase III Medical Research Council Adjuvant Gastric Cancer Infusional Chemotherapy trial should be considered as an important step implementing neoadjuvant chemotherapy as a new standard of care. Neoadjuvant therapy of locally advanced tumors also offers an ideal setting to assess new combinations, including cytotoxics, biologics and conformational radiation, coupled with translational research. SUMMARY: Much remains to be done before anticipating an incontestable standard of care in gastric cancer, although the recent phase III trials indicate that multimodality therapy could impact on the prognosis of gastric cancer.

Adjuvant gemcitabine and concurrent continuous radiation (45 Gy) for resected pancreatic head carcinoma: a multicenter Belgian Phase II study.

PURPOSE: To evaluate the feasibility and tolerance of a postoperative course of gemcitabine (GEM) combined with continuous radiation after curative resection of pancreatic adenocarcinoma. METHODS AND MATERIALS: Thirty patients (median age, 61 years; performance status, 0 to 1) with Stage II and III curatively resected pancreatic head adenocarcinoma were included. Gemcitabine 1000 mg/m2 (3 out of 4 weeks, two cycles) was given within 8 weeks of surgery and followed by GEM 300 mg/m2 weekly combined with continuous radiation (45 Gy in 25 fractions, 1.8 Gy per fraction). RESULTS: For GEM alone, all patients received the two courses with dose reductions in 14 of 30 patients (46%). All but 3 patients completed full chemoradiation; 1 stopped radiation because of subocclusion of a gastroenterostomy, and 2 did not start owing to disease progression. Reduction in GEM during radiation was necessary in 12 of 30 patients (40%). No toxic death was noted; World Health Organization Grade 3/4 hematologic and nonhematologic toxicities were seen in 10 of 30 patients (33%) and 3 of 30 patients (10%), respectively. After a median follow-up of 19 months, no late toxicity was reported. Eleven patients died from progressive disease; median disease-free survival and overall survival were 14.5 and 19 months, respectively. CONCLUSION: This adjuvant combination is well tolerated and can be safely administered after curative surgery for pancreatic cancer. Further evaluation of this regimen is ongoing.

Postoperative adjuvant gemcitabine and concurrent radiation after curative resection of pancreatic head carcinoma: a phase II study.

PURPOSE: The addition of radiation to adjuvant 5-fluorouracil for the treatment of pancreatic cancer has not yet shown any definite benefit. Gemcitabine (GEM) has potential activity in advanced pancreatic cancer and is a powerful radiosensitizer. We evaluated the feasibility of postoperative administration of GEM alone, followed by concurrent GEM and irradiation (RT) after curative resection for pancreatic adenocarcinoma. METHODS AND MATERIALS: GEM 1000 mg/m(2) on Days 1 and 8 every 21 days for three courses was given within 8 weeks after surgery and was followed by GEM 300 mg/m(2) weekly +40 Gy in a split course. Twenty-two patients (median age 59 years, range 39-74, Performance Status 0-1) with Stage II and III curatively resected pancreatic head adenocarcinoma were included. RESULTS: For GEM alone, all patients received the three planned courses, with dose reductions in 7 (32%) of 22 patients. All patients, except two, completed full chemoradiation; one received only 20 Gy because of both World Health Organization Grade 4 vomiting and thrombopenia and the other stopped RT after 32 Gy because of early disease progression. No reduction in GEM during RT was necessary; no toxic death was noted; and World Health Organization Grade 3-4 hematologic and nonhematologic toxicities occurred in 8 (36%) and 7 (nausea, vomiting) (32%) of 22 patients respectively. No late toxicity developed. After a median follow-up of 15 months, 11 patients were alive, and 2 patients had died of causes unrelated to their disease or toxicity, The median disease-free survival and overall survival was 6 and 15 months, respectively. CONCLUSION: This adjuvant regimen was well tolerated and can be easily administered after curative surgery for pancreatic cancer. Its intensification with continuous RT is currently being investigated.

New frontiers in the pharmacological prevention of post-ERCP pancreatitis: the cytokines.

Acute pancreatitis is a major complication of endoscopic retrograde cholangiopancreatography (ERCP), its incidence varying with the indications for the procedure (<5% for the management of common bile duct stones and up to 20% in the case of sphincter of Oddi dysfunction) and also with events occurring during the ERCP such as acinarization and pancreatic sphincterotomy. If the triggering event of premature intra-acinar activation of trypsinogen is unknown, the acinar cell injury leads to oxidative stress, nuclear translocation of nuclear factor kappa B and subsequent transcription of chemo- and pro-inflammatory cytokines. These events are followed by chemoattraction and activation of monomacrophages, T lymphocytes and neutrophils which are responsible for acinar necrosis and amplification of the pro-inflammatory cascade. Finally, after amplification by Kupffer cells, systemic inflammatory response syndrome and multiple organ failure occur. All these events take place within a very short period of time, thus offering a very short therapeutic window during which it is theoretically possible to modulate the severity of human pancreatitis. Prophylactic immunomodulation of this pro-inflammatory cascade is attractive, using anti-inflammatory cytokines, specific inhibitors of pro-inflammatory cytokines or inhibitors of the nuclear translocation of the nuclear factor kappa B. Good results have been obtained in experimental models, reducing the acute pancreatitis severity and its systemic complications. The use of immunomodulators in the prevention of human post-ERCP pancreatitis is actually restricted to recombinant interleukin-10. Three of four randomized clinical trials, confirmed by a meta-analysis, have shown that prophylactic injection of recombinant interleukin-10 can significantly reduce the incidence of acute pancreatitis and may decrease the length of the hospital stay. The use of recombinant interleukin-10 in this indication has to be established in a multicenter prospective trial and we need to investigate the safety and efficacy of other immunomodulatory drugs and develop new specific targets.

Adjuvant chemotherapy for colorectal cancer.

Colorectal cancer is the second leading cause of cancer death in Western countries. If surgery remains the only cure, recurrence rates for colon cancer range from 30% to 60% for stage III tumors. Adjuvant chemotherapy is the standard treatment for stage III colon tumors and consists of monthly administration of bolus 5-fluorouracil and leucovorin for 5 consecutive days a month over a 6-month period (Mayo regimen). Adjuvant chemotherapy for stage II colon cancer remains controversial, and its administration is not routinely recommended except in certain high-risk and selected patients. Immunotherapy, new drug-based therapies or combinations, and cyclooxygenase-2 inhibitors are being tested in the adjuvant setting. Total mesorectum excision is now the gold standard surgical technique for rectal cancer resection, and this procedure has dramatically decreased local recurrence. Nevertheless, adjuvant chemoradiotherapy is commonly indicated in the United States. In Europe, neoadjuvant radiotherapy is recommended for stage II and III resectable rectal cancers; the role of chemotherapy remains mostly investigational.

Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis.

Interleukin (IL)-10, a potent anti-inflammatory cytokine, limits the severity of acute pancreatitis and downregulates transforming growth factor (TGF)-beta release by inflammatory cells on stimulation. Proinflammatory mediators, reactive oxygen species, and TGF-beta can activate pancreatic stellate cells and their synthesis of collagen I and III. This study evaluates the role of endogenous IL-10 in the modulation of the regeneration phase following acute pancreatitis and in the development of pancreatic fibrosis. IL-10 knockout (KO) mice and their C57BL/6 controls were submitted to repeated courses (3/wk, during 6 wk, followed by 1 wk of recovery) of cerulein-induced acute pancreatitis. TGF-beta(1) release was measured on plasma, and its pancreatic expression was assessed by quantitative RT-PCR and immunohistochemistry. Intrapancreatic IL-10 gene expression was assessed by semiquantitative RT-PCR, and intrapancreatic collagen content was assessed by picrosirius staining. Activated stellate cells were detected by immunohistochemistry. S phase intrapancreatic cells were marked using tritiated thymidine labeling. After repeated acute pancreatitis, IL-10 KO mice had more severe histological lesions and fibrosis (intrapancreatic collagen content) than controls. TGF-beta(1) plasma levels, intrapancreatic transcription, and expression by ductal and interstitial cells, as well as the number of activated stellate cells, were significantly higher. IL-10 KO mice disclosed significantly fewer acinar cells in S phase, whereas the opposite was observed for pseudotubular cells. Endogenous IL-10 controls the regeneration phase and limits the severity of fibrosis and glandular atrophy induced by repeated episodes of acute pancreatitis in mice.