Explore the vast range of titles available.

In men with metastatic, hormone-sensitive prostate cancer who were receiving testosterone suppression, the addition of enzalutamide led to significantly longer progression-free and overall survival than the addition of standard nonsteroidal antiandrogen therapy. The better outcome was less clear among patients who had received docetaxel.

Background Hepatopancreaticobiliary malignancies with peritoneal carcinomatosis exhibit poor survival with current therapies: hepatocellular carcinoma 11 months with sorafenib, and pancreaticobiliary 9–14 months with systemic chemotherapy. However, limited data exist on the utility of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in these patients. Methods We retrospectively reviewed our institutional hepatopancreaticobiliary malignancies with peritoneal carcinomatosis which underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy from 2007 to 2017 and analyzed perioperative and oncologic outcomes. Results Seventeen patients were included: 9 hepatocellular carcinoma, 8 pancreaticobiliary (4 cholangiocarcinoma, 3 gallbladder, 1 pancreatic). Peritoneal cancer index, number of organs resected, completeness of cytoreduction, and 30-day morbidity were equivalent. Hepatocellular carcinoma received significantly less neoadjuvant therapy (11%, p = 0.008), though adjuvant therapy rates were similar. At a median follow-up of 15 months, progression-free survival was similar amongst all cohorts. However, overall survival was longer in hepatocellular carcinoma (42 months vs. cholangiocarcinoma 19 months, gallbladder 8 months, pancreatic 15 months, p = 0.206) with 59% 3-year overall survival (vs. 0% cholangiocarcinoma, 0% gallbladder, 0% pancreatic). Conclusions Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy may offer a survival benefit in select hepatocellular carcinoma patients with peritoneal carcinomatosis, though has dubious utility in pancreaticobiliary malignancies.

The prognosis for late-stage digestive system tumors is poor, largely due to the development of chemotherapy resistance. Although immunotherapy, particularly immune checkpoint inhibitors, has transformed the treatment landscape for some patients, strategies to further enhance the efficacy of combination therapies are still lacking, and the underlying mechanisms remain incompletely understood. To systematically address these therapeutic challenges and explore potential solutions, this review delineates the key mechanisms driving chemoresistance in digestive system tumors. It encompasses both cell-intrinsic mechanisms-such as enhanced drug efflux and DNA repair pathways-and extrinsic factors mediated by the tumor microenvironment (TME), including immune cell infiltration and metabolic reprogramming. A special emphasis is placed on the dual immunomodulatory roles of chemotherapy-induced immunogenic cell death (ICD) and its remodeling impact on the immune landscape. Given the considerable heterogeneity across digestive system cancers-including gastric, colorectal, and hepatic malignancies-the review also synthesizes recent advances in innovative combination strategies. These include immunochemotherapy, oncolytic virus, targeting of cancer stem cells (CSCs), epigenetic modulation, and nanoparticle-based drug delivery systems. Ultimately, this work aims to offer a theoretical foundation and strategic directions to overcome clinical drug resistance and advance precision oncology in digestive system tumors.

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.

Background The Coronavirus Disease 2019 (COVID-19) pandemic modified the organization of cancer care pathways worldwide. Few prospective long-term data assessing these therapeutic modifications are available. Methods Clin-COVIDICA was a prospective cohort aiming at determining the clinical impact of COVID-19-related therapeutic modifications in patients with digestive cancer in our center. All consecutive patients undergoing an oncologic treatment for a digestive cancer from March 1 to April 30, 2020, were enrolled in the cohort and followed-up for 24 months. The primary endpoint was progression-free survival (PFS). Secondary endpoints included COVID-19 rate, adverse events (AE) and overall survival (OS). Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Results Of the 401 patients included, 39.6% were female, mean age was 68 years old and most frequent tumor were colorectal (50.0%) and pancreatic (17.9%) cancers. All in all, 55 patients (13.7%) have undergone therapeutic modifications. The most frequent were a switch to an oral drug (capecitabine, 30.9%), treatment holidays (29.1%) and treatment cancellation (18.2%). Considering patients with palliative treatment ( n  = 339), there was a non-significant trend for longer OS (52.0 months versus 36.4 months, p  = 0.07) and a significant longer PFS (15.4 months versus 6.2 months, p  = 0.009) in patients with therapeutic modifications. There were more all grades AEs in patients without therapeutic modifications (84.4% vs. 65.5%, p = < 0.001), but more severe AEs (grade 3–5) among patients with therapeutic modifications (18.2% versus 8.7%, p  = 0.048), especially for patients with a switch to an oral drug, which resulted in 8 severe adverse events and one death. Six patients (1.5%) had a COVID-19, with one COVID-19-related death and one definitive cancellation of a curative surgery due to the consequences of COVID-19. Discussion We observed no negative survival impact of therapeutic modifications due to the COVID-19 pandemic in digestive cancer management. This may be due to the selection of patients with less aggressive disease. More severe AEs were observed upon therapeutic modifications, especially switching to oral capecitabine. Trial registration Clinicaltrials.gov: NCT04389684; date of registration (15/05/2020).

The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results. This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous 177Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg (177Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). The primary endpoint of progression-free survival has been previously reported; here, we report the key secondary endpoint of overall survival in the intention-to-treat population. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the 177Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239. From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assigned for treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months (range 0·4–95·0) in the 177Lu-Dotatate group and 76·5 months (0·1–92·3) in the control group. The secondary endpoint of overall survival was not met: median overall survival was 48·0 months (95% CI 37·4–55·2) in the 177Lu-Dotatate group and 36·3 months (25·9–51·7) in the control group (HR 0·84 [95% CI 0·60–1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the 177Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given 177Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported 177Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up. 177Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11·7 month difference in median overall survival with 177Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up. Advanced Accelerator Applications, a Novartis company.

Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.

Background Gastrojejunostomy (GJJ) and stent placement are the most commonly used palliative treatments for malignant gastric outlet obstruction (GOO). In a recent randomized trial, stent placement was preferred in patients with a relatively short survival and GJJ in patients with a longer survival. As health economic aspects have only been studied in general terms, we estimated the cost of GJJ and that of stent placement in such patients. Methods In the SUSTENT study, patients were randomized to GJJ (n = 18) or stent placement (n = 21). Pancreatic cancer was the most common cause of GOO. We compared initial costs and costs during follow-up. For cost-effectiveness, the incremental cost-effectiveness ratio was calculated. Results Food intake improved more rapidly after stent placement than after GJJ, but long-term relief of obstructive symptoms was better after GJJ. More major complications (P = 0.02) occurred and more reinterventions were performed (P < 0.01) after stent placement than after GJJ. Initial costs were higher for GJJ compared to stent placement (€8315 vs. €4820, P < 0.001). We found no difference in follow-up costs. Total costs per patient were higher for GJJ compared to stent placement (€12433 vs. €8819, P = 0.049). The incremental cost-effectiveness ratio of GJJ compared to stent placement was €164 per extra day with a gastric outlet obstruction scoring system (GOOSS) ≥2 adjusted for survival. Conclusions Medical effects were better after GJJ, although GJJ had higher total costs. Since the cost difference between the two treatments was only small, cost should not play a predominant role when deciding on the type of treatment assigned to patients with malignant GOO (ISRCTN 06702358).

Background Oxaliplatin is a chemotherapy agent active against digestive tumors. Peripheral neuropathy is one of the most important dose-limiting toxicity of this drug. It occurs in around 60–80% of the patients, and 15% of them develop severe neuropathy. The pathophysiology of oxaliplatin neurotoxicity remains unclear. SCN9A is a gene codifying for a subtype sodium channel (type IX, subunit α) and mutations in this gene are involved in neuropathic perception. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin. Methods Blood samples from 94 patients diagnosed of digestive cancer that had received oxaliplatin in adjuvant or metastatic setting were obtained from three hospitals in Madrid. These patients were classified into two groups: “cases” developed oxaliplatin-induced grade 3–4 neuropathy ( n  = 48), and “controls” ( n  = 46) had no neuropathy or grade 1. The neuropathy was evaluated by an expert neurologist and included a clinical examination and classification according to validated neurological scales: National Cancer Institute Common Toxicity Criteria ( NCI-CTC ), Oxaliplatin-Specific Neurotoxicity Scale (OSNS ) and Total Neuropathy score (TNS ). Genotyping was performed for 3 SCN9A missense polymorphisms: rs6746030 (R1150W), rs74401238 (R1110Q) and rs41268673 (P610T), and associations between genotypes and neuropathy were evaluated. Results We found that SCN9A rs6746030 was associated with protection for severe neuropathy (OR = 0.39, 95% CI = 0.16–0.96; p  = 0.041). Multivariate analysis adjusting for diabetes provided similar results ( p  = 0.036). No significant differences in neuropathy risk were detected for rs74401238 and rs41268673. Conclusion SCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.