Results of a Randomized, Double-Blind, Placebo-Controlled, Phase 1b/2 Trial of Nabpaclitaxel + Gemcitabine ± Olaratumab in Treatment-Naïve Participants with Metastatic Pancreatic Cancer.

The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.

Intrahepatic Mass-Forming Cholangiocarcinoma: Is There Additional Prognostic Value in Using Gd-EOB Enhanced MRI?

OBJECTIVE: To investigate the prognostic value of enhancement patterns of intrahepatic mass-forming cholangiocarcinomas (IMCCs) during the hepatobiliary phase (HBP) in gadoxetic acid (Gd-EOB)-enhanced MRI. METHODS: We retrospectively identified 66 consecutive patients with histopathologically proven IMCCs (reference standard: resection) and preoperative Gd-EOB-enhanced MRI. Gd-EOB retention area was subjectively rated based on areas of intermediate signal intensity. Lesions were classified as either hypointense (0-25% retention area) or significantly-retaining (>25% retention area). Clinical, radiological, and prognostic features were compared between these groups. The primary endpoints were recurrence-free survival (RFS) and overall survival (OS) after primary surgical resection. RESULTS: 73% (48/66) of lesions were rated as hypointense and 29% (19/66) as significantly-retaining. While the hypointense subgroup more frequently featured local and distant intrahepatic metastases (p = 0.039 and p = 0.022) and an infiltrative growth pattern (p = 0.005), RFS, OS, and clinical features did not differ significantly with estimated Gd-EOB retention area or quantitatively measured HBP enhancement ratios. Lymph node metastasis was an independent predictor of poor RFS (p = 0.001). CONCLUSIONS: Gd-EOB-enhanced MRI revealed two subtypes of IMCC in the HBP: hypointense and signal-retaining. The hypointense subtype is associated with more frequent intrahepatic metastases and an infiltrative growth pattern, indicating potential tumor aggressiveness. However, this did not result in a significant difference in survival after the primary resection of IMCC.

Cachexia-Affected Survival Based on Inflammatory Parameters Compared to Complex Conventional Nutritional Assessments in Patients with Pancreatic Cancer and Other Gastrointestinal Tumors-The CONKO 020 Investigation.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) is still a complex, devastating disease. Cachexia symptoms frequently impair patient survival. This accompanying syndrome is commonly diagnosed late, when clinical signs become evident. Early diagnosis using conventional measurement methods is often difficult, and the discrimination of this disease from cancer progression is challenging and often overlaps. The aim of this study was to analyze whether conventional nutritional assessments or laboratory biomarkers are better predictive tools for the early detection of patients at risk of reduced survival. METHODS: We analyzed a prospective predefined cohort of 182 patients with gastrointestinal cancer, 120 patients with PDAC and-as controls-62 patients with other gastrointestinal adenocarcinoma (oAC), from whom we have sufficient data of protocol-defined conventional nutritional assessments, clinical data, and specific laboratory parameters. RESULTS: at the time of tumor diagnosis, high inflammatory biomarkers (c-reactive protein (CRP), interleukin-6 (IL-6)) and albumin serum levels were associated with impaired OS in PDAC patients, but not in patients with oAC. Hemoglobin, body mass index (BMI), and bioelectrical assessments alone did not have a prognostic impact at the time of diagnosis. In a multivariate analysis, only CRP (HR 1.91 (1.25-2.92), p = 0.003) was found to be an independent prognostic factor in PDAC patients. Over the course of the disease in PDAC patients, inflammatory biomarkers, albumin, hemoglobin, and bioelectrical assessments were associated with impaired OS. In multivariate testing, CRP (HR 2.21 (1.38-3.55), p < 0.001) and albumin (HR 1.71 (1.05-2.77), p = 0.030) were found to be independent prognostic factors in PDAC patients. CONCLUSION: Specifically for PDAC patients, high inflammatory index and albumin serum levels potentially represent a sufficient early surrogate marker to detect patients at high risk of impaired OS better than complex conventional methods. These findings could help to identify patients who may benefit from early therapeutic interventions.

Prioritization and resource allocation in the context of the COVID-19 pandemic. Recommendations for colorectal and pancreatic cancer in Germany.

In the context of the COVID-19 pandemic, there has been a scarcity of resources with various effects on the care of cancer patients. This paper provides an English summary of a German guideline on prioritization and resource allocation for colorectal and pancreatic cancer in the context of the pandemic. Based on a selective literature review as well as empirical and ethical analyses, the research team of the CancerCOVID Consortium drafted recommendations for prioritizing diagnostic and treatment measures for both entities. The final version of the guideline received consent from the executive boards of nine societies of the Association of Scientific Medical Societies in Germany (AWMF), 20 further professional organizations and 22 other experts from various disciplines as well as patient representatives. The guiding principle for the prioritization of decisions is the minimization of harm. Prioritization decisions to fulfill this overall goal should be guided by 1. the urgency relevant to avoid or reduce harm; 2. the likelihood of success of the diagnostic or therapeutic measure advised; and 3. the availability of alternative treatment options. In the event of a relevant risk of harm as a result of prioritization, these decisions should be made by means of a team approach. Gender, age, disability, ethnicity, origin and other social characteristics, such as social or insurance status, as well as the vehemence of a patient's treatment request and SARS-CoV-2 vaccination status should not be used as prioritization criteria. The guideline provides concrete recommendations for 1. diagnostic procedures, 2. surgical procedures for cancer, and 3. systemic treatment and radiotherapy in patients with colorectal or pancreatic cancer within the context of the German healthcare system.

Correction: Felsenstein M. et al. Perineural Invasion in Pancreatic Ductal Adenocarcinoma (PDAC): A Saboteur of Curative Intended Therapies? J. Clin. Med. 2022, 11, 2367.

In the original publication [...].

Cancer-Associated Venous Thromboembolism-Diagnostic and Therapeutic Considerations: An Update Based on the Revised AWMF S2k Guideline.

Patients with cancer are prone to develop venous thromboembolism (VTE) with negative impact on quality of life, morbidity, and mortality. Treatment of established VTE is often complex in patients with cancer. Treatment of cancer-associated VTE (CAT) basically comprises initial and maintenance treatment, for 3 to 6 months, secondary preventions, and treatment in special situations. Therapeutic anticoagulation is the treatment of choice in CAT. In addition to the efficacy and safety of low-molecular-weight heparin (LMWH) that had been recommended for decades, direct oral anti-factor Xa inhibitors, a subgroup of direct oral anticoagulants (DOACs), demonstrated their advantages along with the accompanying concerns in several randomized controlled treatment trials of CAT. The latest guidelines, such as the German AWMF-S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," agree with each other on most aspects with respect to the treatment of CAT. Encompassing recent clinical studies, and meta-analyses, as well as the focus on some special management aspects of CAT, the objective of this review is to present a current overview and recommendations for the treatment of CAT.

A surgical strategy for intrahepatic cholangiocarcinoma - the hilar first concept.

PURPOSE: The present study assesses long-term overall survival (OS) and disease-free survival (DFS) after curative resection for intrahepatic cholangiocarcinoma (ICCA) depending on resection margin (RM) status and lymph node (LN) status. METHODS: Clinical data of all consecutively resected patients with ICCA at a single high-volume center between 2005 and 2018 were collected. Minimum follow-up was 36 months. Perioperative and long-term oncological outcome was assessed. RESULTS: One hundred ninety-two cases were included in the analysis. Thirty- and 90-day-mortality was 5.2% (n = 10) and 10.9% (n = 21). OS was 26 months with 1-, 2-, and 5-year-OS rates of 72%, 53%, and 26%. One-, 2-, and 5-year-DFS rates were 54%, 42%, and 35% (N0 vs. N1: 29 vs. 9 months, p = 0.116). R1 was not found to be an independent risk factor for reduced survival in the overall cohort (p = 0.098). When differentiating according to the LN status, clear resection margins were significantly associated with increased DFS for N0 cases (50 months vs. 9 months, p = 0.004). For N1 cases, no significant difference in DFS was calculated for R0 compared to R1 cases (9 months vs. 9 months, p = 0.88). For N0 cases, clear resection margins > 10 mm were associated with prolonged OS (p = 0.048). CONCLUSION: For N1 cases, there was no significant survival benefit when comparing R0 versus R1, while the complication rate remained high for the extended resection types. In view of merging multimodal treatment, the hilar first concept assesses locoregional LN status for optimal surgical therapy.

Body composition is associated with disease aetiology and prognosis in patients undergoing resection of intrahepatic cholangiocarcinoma.

BACKGROUND: Body composition alterations are frequent in patients with cancer or chronic liver disease, but their prognostic value remains unclear in many cancer entities. OBJECTIVE: We investigated the impact of disease aetiology and body composition after surgery for intrahepatic cholangiocarcinoma (iCCA), a rare and understudied cancer entity in European and North American cohorts. METHODS: Computer tomography-based assessment of body composition at the level of the third lumbar vertebra was performed in 173 patients undergoing curative-intent liver resection for iCCA at the Department of Surgery, Charité - Universitätsmedizin Berlin. Muscle mass and -composition as well as subcutaneous and visceral adipose tissue quantity were determined semi-automatically. (Secondary) sarcopenia, sarcopenic obesity, myosteatosis, visceral and subcutaneous obesity were correlated to clinicopathological data. RESULTS: Sarcopenia was associated with post-operative morbidity (intraoperative transfusions [p = 0.027], Clavien-Dindo ≥ IIIb complications [p = 0.030], post-operative comprehensive complication index, CCI [p < 0.001]). Inferior overall survival was noted in patients with myosteatosis (33 vs. 23 months, p = 0.020). Fifty-eight patients (34%) had metabolic (dysfunction)-associated fatty liver disease (MAFLD) and had a significantly higher incidence of sarcopenic (p = 0.006), visceral (p < 0.001) and subcutaneous obesity (p < 0.001). Patients with MAFLD had longer time-to-recurrence (median: 38 vs. 12 months, p = 0.025, log-rank test). Multivariable cox regression analysis confirmed only clinical, and not body, composition parameters (age > 65, fresh frozen plasma transfusions) as independently prognostic for overall survival. CONCLUSION: This study evidenced a high prevalence of MAFLD in iCCA, suggesting its potential contribution to disease aetiology. Alterations of muscle mass and adipose tissue were more frequent in patients with MAFLD.

Prediction of regional lymph node metastasis in intrahepatic cholangiocarcinoma: it's not all about size.

OBJECTIVES: Lymph node metastases (LNM) are frequent in patients with intrahepatic cholangiocarcinoma (iCC) and worsen their prognosis even after surgery. Our aim was to investigate the predictive value of lymph node (LN) short axis, the most common discriminator for identifying LNM in tumor-imaging and to develop a predictive model for regional LNM in iCC taking computed tomography (CT) features of extranodal disease into account. MATERIALS AND METHODS: We enrolled 102 patients with pathologically proven iCC who underwent CT prior to hepatic resection and hilar lymph node dissection (LND) from 2005 to 2021. Two blinded radiologists assessed various imaging characteristics and LN diameters, which were analyzed by bivariate and multivariate logistic regression to develop a prediction model for LNM. RESULTS: Prevalence of LNM was high (42.4 %) and estimated survival was shorter in LN-positive patients (p = 0.07). An LN short axis diameter of ≥ 9 mm demonstrated the highest predictive power for LNM. Three additional, statistically significant imaging features, presence of intrahepatic metastasis (p = 0.003), hilar tumor infiltration (p = 0.003), and tumor growth along the liver capsule (p = 0.004), were integrated into a prediction model, which substantially outperformed use of LN axis alone in ROC analysis (AUC 0.856 vs 0.701). CONCLUSIONS: LN diameter alone proved to be a relevant but unreliable imaging-marker for LNM prediction in iCC. Our proposed prognostic model, which additionally considers intrahepatic metastases and hilar and capsular infiltration, significantly improves discriminatory power. Hilar and capsular involvement might indicate direct tumor extension to lymphatic liver structures.

Impact of Smoking, Body Weight, Diabetes, Hypertension and Kidney Dysfunction on Survival in Pancreatic Cancer Patients-A Single Center Analysis of 2323 Patients within the Last Decade.

In addition to being risk factors for pancreatic cancer, parameters such as smoking, diabetes, or obesity might also act as potential prognostic factors for the survival of patients initially diagnosed with pancreatic cancer. By implementing one of the largest retrospective study cohorts of 2323 pancreatic adenocarcinoma (PDAC) patients treated at a single high-volume center, potential prognostic factors for survival were evaluated on the basis of 863 cases. Since parameters such as smoking, obesity, diabetes, and hypertension can cause severe chronic kidney dysfunction, the glomerular filtration rate was also considered. In the univariate analyses, albumin (p < 0.001), active smoking (p = 0.024), BMI (p = 0.018), and GFR (p = 0.002) were identified as metabolic prognostic markers for overall survival. In multivariate analyses, albumin (p < 0.001) and chronic kidney disease stage 2 (GFR < 90 mL/min/1.37 m2; p = 0.042) were identified as independent metabolic prognostic markers for survival. Smoking presented a nearly statistically significant independent prognostic factor for survival with a p-value of 0.052. In summary, low BMI, status of active smoking, and reduced kidney function at the time of diagnosis were associated with lower overall survival. No prognostic association could be observed for presence of diabetes or hypertension.

Interventional Treatment Strategies in Intrahepatic Cholangiocarcinoma and Perspectives for Combined Hepatocellular-Cholangiocarcinoma.

cHCC-CCA is an uncommon type of liver cancer that exhibits clinical and pathological characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), which are the two main forms of primary liver cancer. The similarity to HCC and CCA makes therapeutical strategies challenging. The poor prognosis of CCA in general, as well as for cHCC-CCA, is mainly attributable to the fact that diagnosis is often at an advanced stage of disease. During the last decade, locoregional therapies usually performed by interventional radiologists and its established role in HCC treatment have gained an increasing role in CCA treatment as well. These comprise a wide range of options from tumor ablation procedures such as radiofrequency ablation (RFA), microwave ablation (MWA), computed tomography high-dose rate brachytherapy (CT-HDRBT), and cryoablation to transarterial chemoembolization (TACE), including the option of intra-arterial administration of radioactive spheres (transarterial radioembolization-TARE), and much attention has focused on the potential of individual concepts in recent years. The purpose of this review is to provide an overview of current radiologic interventions for CCA (excluding options for eCCA), to review and appraise the existing literature on the topic, and to provide an outlook on whether such interventions may have a role as treatment for cHCC-CCA in the future.

Inflammation-Based Prognostic Scores in Pancreatic Cancer Patients-A Single-Center Analysis of 1294 Patients within the Last Decade.

Inflammatory properties are known to promote tumor progression leading to an impaired median overall survival (mOS). Various small studies have focused on a wide range of inflammation-based prognostic indicators. By using sufficient data from 1294 out of 2323 patients diagnosed with pancreatic cancer between 2009 and 2021 at our cancer center, inflammatory markers such as the neutrophil to lymphocyte ratio (NRL), the platelet to lymphocyte ratio (PLR), the lymphocyte to monocyte ratio (LMR) and the CRP to albumin ratio (CAR) were evaluated. We identified a new combined score, termed the inflammatory benchmark index (IBI). We performed univariate and multivariate overall survival analyses and identified optimal prognostic cut-off values for each parameter. In univariate analyses, advanced age (p < 0.001), gender (p < 0.001), tumor stage (p < 0.001), CA19-9 (p = 0.001), NLR (p = 0.001), LMR (p = 0.004), PLR (p = 0.004), CAR (p = 0.001) and IBI (p = 0.001) were identified as prognostic markers. In multivariate analyses advanced age (p < 0.001), gender (p = 0.001), tumor stage (p < 0.001), CA19-9 (p < 0.001), NLR (p = 0.001), LMR (p = 0.038), CAR (p < 0.001) and IBI (p < 0.001) were independent prognostic markers. These findings emphasize the impact of inflammation in pancreatic cancer, provide easily accessible prognostic values for the clinician, and may be useful as stratification parameters for trials aimed at patient inflammation or immune response.

Gd-EOB MRI for HCC subtype differentiation in a western population according to the 5th edition of the World Health Organization classification.

OBJECTIVES: To investigate the value of gadoxetic acid (Gd-EOB)-enhanced magnetic resonance imaging (MRI) for noninvasive subtype differentiation of HCCs according to the 5th edition of the WHO Classification of Digestive System Tumors in a western population. METHODS: This retrospective study included 262 resected lesions in 240 patients with preoperative Gd-EOB-enhanced MRI. Subtypes were assigned by two pathologists. Gd-EOB-enhanced MRI datasets were assessed by two radiologists for qualitative and quantitative imaging features, including imaging features defined in LI-RADS v2018 and area of hepatobiliary phase (HBP) iso- to hyperintensity. RESULTS: The combination of non-rim arterial phase hyperenhancement with non-peripheral portal venous washout was more common in "not otherwise specified" (nos-ST) (88/168, 52%) than other subtypes, in particular macrotrabecular massive (mt-ST) (3/15, 20%), chromophobe (ch-ST) (1/8, 13%), and scirrhous subtypes (sc-ST) (2/9, 22%) (p = 0.035). Macrovascular invasion was associated with mt-ST (5/16, p = 0.033) and intralesional steatosis with steatohepatitic subtype (sh-ST) (28/32, p < 0.001). Predominant iso- to hyperintensity in the HBP was only present in nos-ST (16/174), sh-ST (3/33), and clear cell subtypes (cc-ST) (3/13) (p = 0.031). Associations were found for the following non-imaging parameters: age and sex, as patients with fibrolamellar subtype (fib-ST) were younger (median 44 years (19-66), p < 0.001) and female (4/5, p = 0.023); logarithm of alpha-fetoprotein (AFP) was elevated in the mt-ST (median 397 µg/l (74-5370), p < 0.001); type II diabetes mellitus was more frequent in the sh-ST (20/33, p = 0.027). CONCLUSIONS: Gd-EOB-MRI reproduces findings reported in the literature for extracellular contrast-enhanced MRI and CT and may be a valuable tool for noninvasive HCC subtype differentiation. CLINICAL RELEVANCE STATEMENT: Better characterization of the heterogeneous phenotypes of HCC according to the revised WHO classification potentially improves both diagnostic accuracy and the precision of therapeutic stratification for HCC. KEY POINTS: • Previously reported imaging features of common subtypes in CT and MRI enhanced with extracellular contrast agents are reproducible with Gd-EOB-enhanced MRI. • While uncommon, predominant iso- to hyperintensity in the HBP was observed only in NOS, clear cell, and steatohepatitic subtypes. • Gd-EOB-enhanced MRI offers imaging features that are of value for HCC subtype differentiation according to the 5th edition of the WHO Classification of Digestive System Tumors.

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. METHODS: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. FINDINGS: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. INTERPRETATION: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Internal drainage for interdisciplinary management of anastomotic leakage after pancreaticogastrostomy.

BACKGROUND: Anastomotic leakage and postoperative pancreatic fistula (POPF) may occur after pancreatic head resection, also in the setting of pancreato-gastric reconstruction. For adequate complication management, a variety of non-standardized treatments are available. Still, data on clinical evaluation of endoscopic methods remain scarce. Based on our interdisciplinary experience on endoscopic treatment of retro-gastric fluid collections after left-sided pancreatectomies, we developed an innovative endoscopic concept with internal peri-anastomotic stent placement for patients with anastomotic leakage and/or peri-anastomotic fluid collection. METHODS: Over the period of 6 years (2015-2020) we retrospectively evaluated 531 patients after pancreatic head resections at the Department of Surgery, Charité-Unversitätsmedizin Berlin. Of these, 403 received reconstruction via pancreatogastrostomy. We identified 110 patients (27.3%) with anastomotic leakage and/or peri-anastomotic fluid collection and could define four treatment groups which received either conservative treatment (C), percutaneous drainage (PD), endoscopic drainage (ED), and/or re-operation (OP). Patients were grouped in a step-up approach for descriptive analyses and in a stratified, decision-based algorithm for comparative analyses. The study's primary endpoints were hospitalization (length of hospital stay) and clinical success (treatment success rate, primary/secondary resolution). RESULTS: We characterized an institutional, post-operative cohort with heterogenous complication management following pancreato-gastric reconstruction. The majority of patients needed interventional treatments (n = 92, 83.6%). Of these, close to one-third (n = 32, 29.1%) were treated with endoscopy-guided, peri-anastomotic pigtail stents for internal drainage as either primary, secondary and/or tertiary treatment modality. Following a decision-based algorithm, we could discriminate superior primary-(77,8% vs 53.7%) and secondary success rates (85.7% vs 68.4%) as well as earlier primary resolutions (11.4 days, 95%CI (5.75-17.13) vs 37.4 days, 95%CI (27.2-47.5)] in patients receiving an endoscopic compared to percutaneous management. CONCLUSION: This study underscores the importance of endoscopy-guided approaches for adequate treatment of anastomotic leakage and/or peri-anastomotic fluid collections after pancreatoduodenectomy. We herein report a novel, interdisciplinary concept for internal drainage in the setting of pancreato-gastric reconstruction.

Regional hyperthermia with cisplatin added to gemcitabine versus gemcitabine in patients with resected pancreatic ductal adenocarcinoma: The HEAT randomised clinical trial.

BACKGROUND: Regional hyperthermia (RHT) with cisplatin added to gemcitabine showed efficacy in gemcitabine-pre-treated patients with advanced pancreatic ductal adenocarcinoma. We conducted a randomised clinical trial to investigate RHT with cisplatin added to gemcitabine (GPH) compared with gemcitabine (G) in the adjuvant setting of resected pancreatic ductal adenocarcinoma. METHODS: This randomised, multicentre, open-label trial randomly assigned patients to either GPH (gemcitabine 1000 mg/m2 on day 1, 15 and cisplatin 25 mg/m2 with RHT on day 2, 3 and 15,16) or to G (gemcitabine 1000 mg/m2 on day 1,8,15), four-weekly over six cycles. Disease-free survival (DFS) was the primary end-point. Secondary end-points included overall survival (OS) and safety. RESULTS: A total of 117 eligible patients (median age, 63 years) were randomly allocated to treatment (57 GPH; 60 G). With a follow-up time of 56.6 months, the median DFS was 12.7 compared to 11.2 months for GPH and G, respectively (p = 0.394). Median post-recurrence survival was significantly prolonged in the GPH-group (15.3 versus 9.8 months; p = 0.031). Median OS reached 33.2 versus 25.2 months (p = 0.099) with 5-year survival rates of 28.4% versus 18.7%. Excluding eight patients who received additional capecitabine in the G-arm (investigators choice), median OS favoured GPH (p = 0.052). Adverse events CTCAE (Common Terminology Criteria for Adverse Events) grade ≥3 occurred in 61.5% (GPH) versus 63.6% (G) of patients. Two patients in the G-group died because of treatment-related toxic effects. CONCLUSIONS: The randomised controlled Hyperthermia European Adjuvant Trial study failed to demonstrate a significant difference in DFS. However, it suggests a difference in post-recurrence survival and a trend for improved OS. CLINICALTRIALS: gov, number NCT01077427.

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial.

PURPOSE: This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS: We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS: Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 (nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 (nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent (nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION: The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Transarterial Yttrium-90 Radioembolization in Intrahepatic Cholangiocarcinoma Patients: Outcome Assessment Applying a Prognostic Score.

Radioembolization (RE) is a viable therapy option in patients with intrahepatic cholangiocarcinoma (ICC). This study delineates a prognostic score regarding overall survival (OS) after RE using routine pre-therapeutic parameters. A retrospective analysis of 39 patients (median age, 61 [range, 32−82] years; 26 females, 13 males) with ICC and 42 RE procedures was conducted. Cox regression for OS included age, ECOG, hepatic and extrahepatic tumor burden, thrombosis of the portal vein, ascites, laboratory parameters and dose reduction due to hepatopulmonary shunt. Median OS after RE was 8.0 months. Using univariable Cox, ECOG ≥ 1 (hazard ratio [HR], 3.8), AST/ALT quotient (HR, 1.86), high GGT (HR, 1.002), high CA19-9 (HR, 1.00) and dose reduction of 40% (HR, 3.8) predicted shorter OS (each p < 0.05). High albumin predicted longer OS (HR, 0.927; p = 0.045). Multivariable Cox confirmed GGT ≥ 750 [U/L] (HR, 7.84; p < 0.001), ECOG > 1 (HR, 3.76; p = 0.021), albumin ≤ 41.1 [g/L] (HR, 3.02; p = 0.006) as a three-point pre-therapeutic prognostic score. More specifically, median OS decreased from 15.3 months (0 risk factors) to 7.6 months (1 factor) or 1.8 months (≥2 factors; p < 0.001). The proposed score may aid in improved pre-therapeutic patient identification with (un-)favorable OS after RE and facilitate the balance between potential life prolongation and overaggressive patient selection.

Feasibility and Efficacy of Adjuvant Chemotherapy With Gemcitabine After Liver Transplantation for Perihilar Cholangiocarcinoma - A Multi-Center, Randomized, Controlled Trial (pro-duct001).

Background: Liver transplantation (LT) is considered a therapeutic option for unresectable perihilar cholangiocarcinoma (PHC) within defined criteria. It remains uncertain whether patients can safely receive adjuvant chemotherapy after LT. Methods: We performed a prospective, multi-center, randomized, non-blinded two-arm trial (pro-duct001). Patients after LT for unresectable PHC within defined criteria were randomized to adjuvant gemcitabine (LT-Gem group) and LT alone (LT alone group). The primary objective was to investigate if adjuvant chemotherapy is feasible in ≥ 85% of patients after LT. The primary endpoint was the percentage of patients completing the 24 weeks course of adjuvant chemotherapy. Secondary endpoints included overall survival (OS) and disease-free (DFS), and complication rates. Results: Twelve patients underwent LT for PHC, of which six (50%) were eligible for randomization (LT-Gem: three patients, LT alone: three patients). Two out of three patients discontinued adjuvant chemotherapy after LT due to intolerance. The study was prematurely terminated due to slow enrollment. One patient with PHC had underlying primary sclerosing cholangitis (PSC). Tumor-free margins could be achieved in all patients. In both the LT-Gem and the LT alone group, the cumulative 1-, 3-, and 5-year OS and DFS rates were 100%, 100%, 67%, and 100%, 67% and 67%, respectively. Conclusions: This prospective, multi-center study was prematurely terminated due to slow enrollment and a statement on the defined endpoints cannot be made. Nevertheless, long-term survival data are consistent with available retrospective data and confirm defined criteria for LT. Since more evidence of LT per se in unresectable PHC is urgently needed, a prospective, non-randomized follow-up study (pro-duct002) has since been launched.

Dual Targeting of the EGFR/HER2 Pathway in Combination with Systemic Chemotherapy in Refractory Pancreatic Cancer-The CONKO-008 Phase I Investigation.

BACKGROUND: Primary objective of this present trial was to define the maximum tolerable dose of lapatinib in combination with oxaliplatin, 5-fluorouracil, and folinic acid (OFF) in refractory pancreatic cancer. The secondary objective was to assess the safety and efficacy of lapatinib plus OFF. METHODS: We conducted a phase I trial using an accelerated dose escalation design in patients with refractory pancreatic cancer. Lapatinib was given on days 1 to 42 in combination with folinic acid 200 mg/m2 day + 5-fluorouracil 2000 mg/m2 (24 h) on days 1, 8, 15, and 22, and oxaliplatin 85 mg/m2 days 8 and 22 of a 43-day cycle (OFF). Toxicity and efficacy were evaluated. RESULTS: In total, eighteen patients were enrolled: dose level 1 (1000 mg) was assigned to seven patients, dose level 2 (1250 mg), five patients; and dose level 3 (1500 mg), six patients. Dose-limiting toxicities were diarrhea and/or neutropenic enterocolitis observed in two of six patients: one diarrhea III°, one diarrhea IV°, as well as neutropenic enterocolitis. The maximum tolerable dose of lapatinib was 1250 mg OD. CONCLUSIONS: The combination of lapatinib 1250 mg OD with platinum-containing chemotherapy is safe and feasible in patients with refractory pancreatic cancer and warrants further investigation.