Colon to Rectum
Combination therapy with golimumab and guselkumab for ulcerative colitis (VEGA):
Data from a phase 2 proof-of-concept study suggest that combination therapy with guselkumab and golimumab may be more effective for ulcerative colitis than therapy with either drug alone.
Lancet Gastroenterol Hepatol. 2023;8(4):307–20
Feagan BG, Sands BE, Sandborn WJ, Germinaro M, Vetter M, Shao J, Sheng S, Johanns J, Panés J; VEGA Study Group
Background: Despite the introduction of new monoclonal antibodies and oral therapies for the treatment of ulcerative colitis, clinical remission rates remain low, underscoring the need for innovative treatment approaches. The authors assessed whether guselkumab plus golimumab combination therapy was more effective for ulcerative colitis than either monotherapy.
Methods: They did a randomized, double-blind, controlled, proof-of-concept trial at 54 hospitals, academic medical centers, or private practices in 9 countries. Eligible adults (aged ≥ 18 to 65 years) had a confirmed diagnosis of ulcerative colitis at least 3 months before screening and moderately-to-severely active ulcerative colitis (Mayo score 6–12) with a centrally-read baseline endoscopy subscore of 2 or higher. Patients were randomly assigned (1:1:1) using a computer-generated randomization schedule to combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks). The primary end point was clinical response at week 12 (defined as a ≥ 30% decrease from baseline in the full Mayo score and a ≥ 3 points absolute reduction with either a decrease in rectal bleeding score of ≥ 1 point or a rectal bleeding score of 0 or 1). Efficacy was analyzed in the modified intention-to-treat population up to week 38, which included all randomly assigned patients who received at least 1 (partial or complete) study intervention dose. Safety was analyzed up to week 50, according to study intervention received among all patients who received at least 1 (partial or complete) dose of study intervention.
Findings: Between November 20, 2018, and November 15, 2021, 358 patients were screened for eligibility, of whom 214 patients were randomly assigned to combination therapy (n = 71), golimumab monotherapy (n = 72), or guselkumab monotherapy (n = 71). Of the 214 patients included, 98 (46%) were women and 116 (54%) were men and the mean age was 38.4 ± 12.0 years. At week 12, 59 of 71 patients (83%) in the combination therapy group had achieved clinical response compared with 44 of 72 patients (61%) in the golimumab monotherapy group (adjusted treatment difference 22.1% [80% confidence interval [CI]: 12.9–31.3]; nominal p = 0.0032) and 53 of 71 patients (75%) in the guselkumab monotherapy group (adjusted treatment difference 8.5% [80% CI: -0.2–17.1; nominal p = 0.2155). At week 50, 45 of 71 patients (63%) in the combination therapy group, 55 of 72 patients (76%) in the golimumab monotherapy group, and 46 of 71 patients (65%) in the guselkumab monotherapy group had reported at least 1 adverse event. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. One case of tuberculosis was reported in the combination therapy group and 1 case of colon adenocarcinoma was reported in the guselkumab monotherapy group; both occurred after week 12. Two deaths were reported after the final dose of study intervention (poisoning in the combination therapy group and COVID-19 in the guselkumab monotherapy group).
Interpretation: Data from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials.
Prof. Dr. B.G. Feagan, Western University, London, ON, Canada,
E-Mail: brian.feagan@alimentiv.com
Etrasimod as induction and maintenance therapy for ulcerative colitis:
The S1P receptor modulator etrasimod was more effective than placebo in 2 phase 3 trials and well tolerated in patients with moderately to severely active ulcerative colitis.
Lancet. 2023;401(10383):1159–71
Sandborn WJ, Vermeire S, Peyrin-Biroulet L, Dubinsky MC, Panes J, Yarur A, Ritter T, Baert F, Schreiber S, Sloan S, Cataldi F, Shan K, Rabbat CJ, Chiorean M, Wolf DC, Sands BE, D'Haens G, Danese S, Goetsch M, Feagan BG
Background: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these 2 phase 3 trials, the authors aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis.
Methods: In 2 independent randomized, multicenter, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centers in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centers in 37 countries. Randomization was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs. no), baseline corticosteroid use (yes vs. no), and baseline disease activity (modified Mayo score [MMS]; 4–6 vs. 7–9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy end points were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials.
Findings: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and January 28, 2021. Patients in ELEVATE UC 12 were enrolled between September 15, 2020, and August 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74/274 patients [27%] vs. 10/135 patients [7%]; p < 0.0001) and at week 52 (88/274 patients [32%] vs. 9/135 patients [7%]; p < 0.0001). In ELEVATE UC 12, 55 of 222 patients (25%) in the etrasimod group had clinical remission compared with 17 of 112 patients (15%) in the placebo group at the end of the 12-week induction period (p = 0.026). Adverse events were reported in 206 of 289 patients (71%) in the etrasimod group and 81 of 144 patients (56%) in the placebo group in ELEVATE UC 52 and 112 of 238 patients (47%) in the etrasimod group and 54 of 116 patients (47%) in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported.
Interpretation: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis.
W.J. Sandborn, M.D., Professor of Medicine, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA,
E-Mail: wsandborn@health.ucsd.edu
Combination therapy with trifluridine-tipiracil (FTD-TPI) and bevacizumab in colorectal cancer:
Combination therapy resulted in longer overall survival than FTD-TPI alone in a phase 3 trial among patients with refractory metastatic colorectal cancer.
N Engl J Med. 2023;388(18):1657–67
Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, Pápai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators
Background: In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival.
Methods: The authors randomly assigned, in a 1:1 ratio, adult patients who had received no more than 2 previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability).
Results: A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI]: 0.49–0.77; p < 0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI: 0.36–0.54; p < 0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio = 0.54; 95% CI: 0.43–0.67).
Conclusions: Among patients with refractory metastatic colorectal cancer, treatment with trifluridine-tipiracil (FTD-TPI) plus bevacizumab resulted in longer overall survival than FTD-TPI alone.
Dr. J. Tabernero, Department of Medical Oncology, Vall d'Hebron Hospital Campus, Barcelona, Spain,
E-Mail: jtabernero@vhio.net
Liver and Bile
Antiviral therapy for hepatitis B virus (HBV) infection in cirrhosis:
A recent study suggests that antiviral therapy of low-level viremia (HBV DNA < 2000 IU/ml) may not reduce the risk of decompensation or hepatocellular carcinoma (HCC).
Hepatology. 2023;77(5):1746–56
Huang DQ, Tamaki N, Lee HW, Park SY, Lee YR, Lee HW, Lim SG, Lim TS, Kurosaki M, Marusawa H, Mashiba T, Kondo M, Uchida Y, Kobashi H, Furuta K, Izumi N, Kim BK, Sinn DH
Background: Comparative outcomes of hepatitis B virus (HBV)-infected compensated cirrhosis with low-level viremia (LLV) versus maintained virological response (MVR) are unclear. A large, multiethnic, multicenter study was conducted to examine the natural history of LLV versus MVR in compensated cirrhosis.
Patients and methods: The authors enrolled patients with HBV-infected compensated cirrhosis (n = 2316) from 19 hospitals in South Korea, Singapore, and Japan. They defined the LLV group as untreated patients with ≥ 1 detectable serum HBV-DNA (20–2000 IU/ml), Spontaneous-MVR group as untreated patients with spontaneously achieved MVR, and antiviral therapy (AVT)-MVR group as patients achieving AVT-induced MVR. Study end points were HCC or hepatic decompensation.
Results: The annual HCC incidence was 2.7 per 100 person-years (PYs), 2.6 per 100 PYs, and 3.3 per 100 PYs for LLV (n = 742), Spontaneous-MVR (n = 333), and AVT-MVR (n = 1241) groups, respectively (p = 0.81 between LLV vs. Spontaneous-MVR groups and p = 0.37 between LLV vs. AVT-MVR groups). Similarly, the annual decompensation incidence was 1.6 per 100 PYs, 1.9 per 100 PYs, and 1.6 per 100 PYs for LLV, Spontaneous-MVR, and AVT-MVR groups, respectively (p = 0.40 between LLV vs. Spontaneous-MVR groups and p = 0.83 between LLV vs. AVT-MVR groups). Multivariable analyses determined that HCC and decompensation risks in the LLV group were comparable to those with Spontaneous-MVR and AVT-MVR groups (all p > 0.05). Propensity score matching also reproduced similar results for HCC and decompensation risks (all p > 0.05 between LLV vs. Spontaneous-MVR groups and between LLV vs. AVT-MVR groups).
Conclusions: Untreated low-level viremia in hepatitis B virus-infected compensated cirrhosis is not associated with increased risk of disease progression compared with Spontaneous-maintained virological response (MVR) and antiviral therapy (AVT)-MVR. These data have important implications for practice and further research.
Dr. Dr. B.K. Kim, Department of Internal Medicine, Yonsei University College of Medicine, Yonsei-ro, Seodaemun-gu, Seoul, South Korea,
or
Dr. Dr. D.H. Sinn, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, South Korea,
E-Mail: beomkkim@yuhs.ac
E-Mail: dh.sinn@samsung.com
Risk assessment in non-alcoholic fatty liver disease (NAFLD):
The fibrosis 4 (FIB4) score allows a simple risk assessment of patients with low (FIB4 < 1.3) or high (FIB4 > 2.67) risk of cirrhosis. A current cohort study identifies diabetes status and PNPLA3-rs738409 genotype as suitable risk assessment for patients with indeterminate FIB4 score (FIB4 1.3–2.67).
Gastroenterology. 2023;164(6):966–77.e17
Chen VL, Oliveri A, Miller MJ, Wijarnpreecha K, Du X, Chen Y, Cushing KC, Lok AS, Speliotes EK
Background and aims: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain.
Methods: The authors included participants from 2 independent cohorts, the Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. They conducted time-to-event analyses using Fine-Gray competing risk models.
Results: 7893 and 46,880 participants from MGI and UKBB were included, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥ 2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3–2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (> 2.67) and 2.9–4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 < 1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of > 2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype.
Conclusions: PNPLA3-rs738409 genotype and diabetes identified patients with non-alcoholic fatty liver disease currently considered indeterminate risk (FIB4 1.3–2.67) who had a similar risk of cirrhosis as those considered high risk (FIB4 > 2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.
V. Chen, M.D., Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA,
E-Mail: vichen@med.umich.edu
Liver resection for hepatocellular carcinoma (HCC) in patients with metabolic syndrome:
A recent study demonstrates that patients with metabolic syndrome who undergo liver resection for HCC are at high risk for postoperative serious complications and death. Careful patient selection considering baseline characteristics, liver function and type of surgery is possible using a new online model: childb.shinyapps.io/NomogramMajorMorbidity90days.
Hepatology. 2023;77(5):1527–39
Berardi G, Ratti F, Sposito C, Nebbia M, D'Souza DM, Pascual F, Dogeas E, Tohme S, D'Amico FE, Alessandris R, Simonelli I, Del Basso C, Russolillo N, Moro A, Fiorentini G, Serenari M, Rotellar F, Zimmitti G, Famularo S, Ivanics T, Hoffman D, Onkendi E, Essaji Y, Lopez Ben S, Caula C, Rompianesi G, Chopra A, Abu Hilal M, Torzilli G, Sapisochin G, Corvera C, Alseidi A, Helton S, Troisi RI, Simo K, Conrad C, Cescon M, Cleary S, Kwon CHD, Ferrero A, Ettorre GM, Cillo U, Geller D, Cherqui D, Serrano PE, Ferrone C, Mazzaferro V, Aldrighetti L, Kingham TP
Background: Metabolic syndrome (MS) is rapidly growing as risk factor for HCC. Liver resection for hepatocellular carcinoma (HCC) in patients with MS is associated with increased postoperative risks. There are no data on factors associated with postoperative complications.
Aims: The aim was to identify risk factors and develop and validate a model for postoperative major morbidity after liver resection for HCC in patients with MS, using a large multicentric Western cohort.
Materials and methods: The univariable logistic regression analysis was applied to select predictive factors for 90 days major morbidity. The model was built on the multivariable regression and presented as a nomogram. Performance was evaluated by internal validation through the bootstrap method. The predictive discrimination was assessed through the concordance index. Results: A total of 1087 patients were gathered from 24 centers between 2001 and 2021. 484 patients (45.2%) were obese. Most liver resections were performed using an open approach (59.1%), and 743 (68.3%) underwent minor hepatectomies. 376 patients (34.6%) developed postoperative complications, with 13.8% major morbidity and 2.9% mortality rates. 713 patients had complete data and were included in the prediction model. The model identified obesity, diabetes, ischemic heart disease, portal hypertension, open approach, major hepatectomy, and changes in the non-tumoral parenchyma as risk factors for major morbidity. The model demonstrated an AUC of 72.8% (95% confidence interval: 67.2–78.2%) (https://childb.shinyapps.io/NomogramMajorMorbidity90days/).
Conclusions: Patients undergoing liver resection for hepatocellular carcinoma and metabolic syndrome are at high risk of postoperative major complications and death. Careful patient selection, considering baseline characteristics, liver function, and type of surgery, is key to achieving optimal outcomes.
Dr. Dr. G. Berardi, Department of General, Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo Forlanini Hospital, Rome, Italy,
Esophagus to Small Intestine
Efficacy and safety for drugs for gastroparesis:
In a network meta-analysis, oral dopamine antagonists and tachykinin-1 antagonists were more efficacious than placebo, but confidence in the evidence was low to moderate for most comparisons.
Gastroenterology. 2023;164(4):642–54
Ingrosso MR, Camilleri M, Tack J, Ianiro G, Black CJ, Ford AC
Background and aims: Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. The authors evaluated this in a network meta-analysis of randomized controlled trials (RCTs).
Methods: They searched the literature to September 7, 2022 and judged the efficacy of drugs based on global symptoms of gastroparesis; individual symptoms, including nausea, vomiting, abdominal pain, bloating, or fullness; and safety according to total adverse events and adverse events leading to withdrawal. Data were extracted as intention-to-treat analyses, assuming dropouts to be treatment failures and reporting pooled relative risks (RRs) of not improving with 95% confidence intervals (CIs), ranking drugs according to p-score.
Results: The authors identified 29 RCTs (3772 patients). Based on global symptoms, clebopride ranked first for efficacy (RR = 0.30; 95% CI: 0.16–0.57; p-score = 0.99) followed by domperidone (RR = 0.68; 95% CI: 0.48–0.98; p-score = 0.76). No other drug was superior to placebo. Only 2 drug classes were efficacious: in rank order, oral dopamine antagonists (RR = 0.58; 95% CI: 0.44–0.77; p-score = 0.96) and tachykinin-1 antagonists (RR = 0.69; 95% CI: 0.52–0.93; p-score = 0.83). For individual symptoms, oral metoclopramide ranked first for nausea (RR = 0.46; 95% CI: 0.21–1.00; p-score = 0.95), fullness (RR = 0.67; 95% CI: 0.35–1.28; p-score = 0.86), and bloating (RR = 0.53; 95% CI: 0.30–0.93; p-score = 0.97), based on only 1 small trial. Only prucalopride was more likely to be associated with adverse events than placebo.
Conclusions: In a network meta-analysis, oral dopamine antagonists and tachykinin-1 antagonists were more efficacious than placebo for gastroparesis, but confidence in the evidence was low to moderate for most comparisons. There is an unmet need for efficacious therapies for gastroparesis.
Prof. Dr. A.C. Ford, Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK,
E-Mail: alexf12399@yahoo.com
Pancreas
Drainage of large pancreatic walled-off necroses (WON) using plastic versus lumen-apposing metal stents (LAMS):
Drainage of large WON (> 15 cm) using LAMS with a diameter of 20 mm was not superior to conventional plastic stents in this randomized monocenter trial. Both approaches were associated with comparable needs for necrosectomy and hospital stay without gross differences in adverse events.
Gut. 2023;72(6):1167–73
Gásdal Karstensen J, Novovic S, Feldager Hansen E, Bojer Jensen A, Lovendahl Jorgensen H, Laksafoss Lauritsen M, Parsberg Werge M, Nordblad Schmidt P
Objective: In treating pancreatic walled-off necrosis (WON), lumen-apposing metal stents (LAMS) have not proven superior to the traditional double pigtail technique (DPT). Among patients with large WON (> 15 cm) and their associated substantial risk of treatment failure, the increased drainage capacity of a novel 20-mm LAMS might improve clinical outcomes. Hence, the authors conducted a study comparing the DPT and 20-mm LAMS in patients with large WON.
Design: A single-center, open-label, randomized, controlled superiority trial using an endoscopic step-up approach in patients with WON exceeding 15 cm in size. The primary end point was the number of necrosectomies needed to achieve clinical success (clinical and CT resolution), while the secondary end points included technical success, adverse events, length of stay and mortality.
Results: 22 patients were included in the DPT group and 20 in the LAMS group, with no significant differences in patient characteristics. The median size of WON was 24.1 cm (P25–P75: 19.6–31.1). The technical success rates were 100% for DPT and 95% for LAMS (p = 0.48), while clinical success rates were 95.5% and 94.7%, respectively (p = 1.0). The mean number of necrosectomies was 2.2 for DPT and 3.2 for LAMS (p = 0.42). Five patients (12%) developed procedure-related serious adverse events (DPT = 4, LAMS = 1, p = 0.35). The median length of stay was 43 (P25–P75: 40–67) and 58 days (P25–P75: 40–86) in the DPT and LAMS groups (p = 0.71), respectively, with an overall mortality of 4.8%.
Conclusions: For treating large walled-off necrosis, lumen-apposing metal stents are not superior to double pigtail technique. The techniques are associated with comparable needs for necrosectomy and hospital stay, and no gross difference in adverse events.
Prof. Dr. J. Gásdal Karstensen, Pancreatitis Centre East (PACE), Gastro Unit, Department of Gastroenterology and Gastrointestinal Surgery, Hvidovre Hospital, Hvidovre, Denmark,