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INTRODUCTION | auto‐HSCT in stage IV, DLBCL | LYMPHOMA | Diffuse large B‐cell lymphoma (DLBCL) is the most common (30–35%) type of B‐cell lymphoma with an incidence of about 5.6 per 100.000 men and women per year.The standard treatment of DLBCL is R‐CHOP immunochemotherapy (ICT).Upfront auto‐HSCT was studied as a way to improve outcomes as a consolidative treatment option in the pre‐rituximab era, but conflicting results were reported.In the last 10 years, several RCT trials compared ICT and upfront auto‐HSCT. A slight improvement of 2‐year failure‐free survival (FFS) was achieved in the DLCL04 trial in DLBCL patients,Two meta‐analysesBased on these results, we performed our retrospective trial to investigate the possible benefit of upfront auto‐HSCT in stage IV high‐intermediate/high‐risk DLBCL. | PMC10075296 |
MATERIALS AND METHODS | PMC10075296 | |||
Study design | Retrospective cohort single‐center trial. | PMC10075296 | ||
Patient selection | DLBCL | The main inclusion criterion was biopsy‐confirmed CD20(+) DLBCL NOS, according to the WHO 2017 criteria. All patients were from 18 to 65 years old. According to Russian legislation, a majority is reached at the age of 18 and younger patients are treated according to pediatric protocols. The peak age was selected to better match previous RCTAll patients had stage IV and high‐intermediate/high IPI scores (IPI ≥2). Stage IV was assessed by Lugano classification.All patients had to be treated with chemotherapy of x6 R‐CHOP or x6 DA‐EPOCH‐R and achieved complete (CR) or partial (PR) response, classified by Lugano Response Criteria by the end of treatment. If PET‐CT was unavailable, the response was classified by CT and biopsy.A total of 516 patients with C83.3 treated from Jan 2010 to Dec 2019 at NMRC of oncology n.a. N.N.Petrov were analyzed to meet the inclusion criteria of this study. After that, exclusion criteria were applied.Firstly, age‐mismatched (Then, patients with SD/PD (In the end, we obtained 105 patients for further analyses (Figure Study design.The upfront group (Both “steady‐state” (filgrastim 10 μg/kg/day SC), and chemotherapy‐based protocols (DHAP ± R + filgrastim 5 μg/kg/day SC or cyclophosphamide 2 g/mInformed consent was obtained from the patients before data collection, following institutional guidelines, and the study was approved by the Committees for the Ethical Review of Research at NMRC of oncology n.a. N.N.Petrov. | PMC10075296 | |
Statistical analysis | death | DEL | The primary endpoint of this study was progression‐free survival (PFS, measured from the date of diagnosis to confirmed relapse or death from any cause). Secondary endpoints were overall survival (OS, measured from the date of diagnosis to death from any cause), response rate and relapse rate.To determine differences in categorical variables (sex, age, DEL status, etc.) from independent samples, Cox proportional hazards model was used to estimate the effects of the prognostic risk factors by univariate and multivariate settings with loss‐to‐follow‐up point censoring. Proportional hazards assumption was verified for all models. Only factors with The sample size of the study protocol was estimated to test the difference in 3‐year PFS and relapse incidence between selected groups. The closest in design and inclusion criteria RCT with ours reported 13% relapse rate after upfront HDCT with auto‐HSCT.A two‐sided | PMC10075296 |
RESULTS | PMC10075296 | |||
Patients and procedures characteristic | The two trial arms were well balanced. (Table Patient and procedures characteristics.
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Clinical response | There were 63% (22/35) CR in patients, who further enrolled in the upfront group and 100% (70/70) in the control group. After auto‐HSCT in the upfront group, the CR rate significantly increased (Clinical response in upfront group. Inner ring—response after ICT. Outer ring—response after upfront HDCT with auto‐HSCT. | PMC10075296 | ||
Relapse rate and cause of death | A total of 3% (1/35) early (ER) and 6% (2/35) late (LR) relapses occurred in the upfront group (Figure Between‐group comparisons. Inner ring–upfront group, In the control group, 21% (15/70) ER and 6% LR (4/70) occurred (Figure There was a significantly higher early relapse rate in the control group (1/35 vs. 15/70, | PMC10075296 | ||
Survival analysis | PMC10075296 | |||
Progression‐free survival | lymphomas | LYMPHOMAS, DEL | The favor of upfront was demonstrated (Figure Progression‐free survival results. (A) PFS by treatment groups. (B) PFS by DEL. (C) PFS by lung involvement. (D) PFS by ICT.Patients with double‐expressor lymphomas (DEL) demonstrated (Figure Patients, treated by DA‐EPOCH‐R demonstrated (Figure Multivariate PFS analysis demonstrated the benefit in 3‐year PFS (Table Multivariate PFS analysis in all patients, There were too few relapses in the upfront group (Multivariate PFS analysis in the control group, | PMC10075296 |
Overall survival | deaths | Patients in the upfront group demonstrated significantly higher (Figure Overall survival results. (A) OS by treatment groups; (B) OS by relapse occurrence.Multivariate OS analysis confirmed the significant characteristics–upfront auto‐HSCT was associated with better 3‐year OS (HR = 0.11, 95% CI [0.02–0.63], Multivariate OS analysis in all patients, There were too few deaths (Multivariate OS analysis in the control group, | PMC10075296 | |
DISCUSSION | metabolic tumor, tumor, high‐intermediate, toxicity, DLBCL, DEL DLBCL, lymphomas, DSHNHL | TUMOR, REMISSIONS, PROLIFERATION, DISEASE, LYMPHOMAS, DEL | The role of upfront auto‐HSCT in DLBCL remains controversial. EBMT (level of evidence 1)These statements are based on the results of RCT. The improvement of 2‐year FFS (In NCT00355199,SWOG‐S7904 trialOn the other hand, DSHNHL 2002‐1 trial demonstrated only increased toxicity in the HDCT group without survival benefit.Meta‐analysesPFS benefit in high‐intermediate and high‐risk DLBCL patients (Our study demonstrated the positive role of upfront auto‐HSCT in the survival of stage IV DLBCL NOS high/high‐intermediate IPI risk patients.The key point of this study was patient selection. Most previous trials included all types of B‐cell and even T‐cell lymphomas.The decision to perform upfront auto‐HSCT in the described group (Trial arms were completely balanced in all characteristics. A higher proportion of bulky disease in the upfront group is not clinically significant because it does not always correspond with high metabolic tumor volume, calculated by PET‐CT.In this trial, PET‐CT was done once in 71% (25/35) upfront patients and 41% (29/70) of control patients. PET scans before and after the treatment had only 23% (8/35) upfront patients and 17% (12/70) control patients. The number of remissions, evaluated only by CT and biopsy was 40% (14/35) in the upfront and 59% (41/70) in the control group. Low incidence of PET resulted from the scarce of original PET scans and the lack of PET in Russia in the early 2010's.The achievement of CR is the main goal of treatment. Partial responses are considered treatment failure and recommended to manage as a refractory disease.The association of DEL and inferior survival (No difference was estimated between R‐CHOP/upfront and intensive ICT (3‐year RFS 75% vs. 86% respectively, Another trial targeted DEL DLBCL patients with elevated LDH treated by upfront HDCT.In our trial, DEL significantly decreased 3‐year PFS (The non‐GCB COO subtype is usually associated with poor prognosis in DLBCL.A high proliferation index (Ki67) is generally considered a negative prognostic marker in B‐cell lymphomas. A meta‐analysis,The high amount of CD3(+) tumor‐infiltrating lymphocytes (TILs), assessed by immunohistochemistry (IHC), is associated with favorable outcomes in advanced stage DLBCL,It is an interesting result about the superiority of DA‐EPOCH‐R over R‐CHOP in our trial because randomized trials did not find any survival benefit in advanced‐stage DLBCL, treated by DA‐EPOCH‐R.Another controversial result was the influence of unexplained loss of >10% of body weight (High level of LDH associated with poor prognosis and predicts survival in DLBCL patients.This study had several limitations. Firstly, it was retrospective, and the patient selection wasn't randomized. However, strict selection criteria were applied, therefore trial arms were completely balanced. Secondly, we did not use the gene expression profile (GEP) based molecular classification because of the absence of GEP in our institution, and were limited in FISH for financial reasons. Also, there were several missing IHC data, that limited the inclusion of IHC parameters in calculations. And thirdly, because of limited PET data, modern PET‐based predictors like metabolic tumor volume or tumor lesion glycolysis were not analyzed.In conclusion, the upfront auto‐HSCT is still under investigation. Further trials are needed to better select the target group of this treatment option. | PMC10075296 |
CONCLUSION | DEL DLBCL, DLBCL | DEL | In this trial, upfront patients demonstrated significantly better 3‐year OS and PFS. It is a relatively small period, and further follow‐up is needed to confirm the sustainability of our result. The significant difference in early relapse rate and the same tendency in all relapse rates in favor of upfront auto‐HSCT is promising.We suggest, that upfront auto‐HSCT can serve as a familiar and adequate option to significantly improve a prognosis in young high‐risk patients with DEL DLBCL. This clinical implication does not require special additions and can be used in any HSCT unit. However, prospective randomized trials are needed to confirm the significance of DEL in this cohort.In summary, upfront HDCT with auto‐HSCT can be a possible treatment option in DLBCL NOS, age 18–65, stage IV, IPI ≥2 patients. | PMC10075296 |
AUTHOR CONTRIBUTIONS | PMC10075296 | |||
CONFLICT OF INTEREST STATEMENT | The authors have stated explicitly that there are no conflicts of interest in connection with this article. | PMC10075296 | ||
ETHICS STATEMENT | All procedures performed in studies involving human participants were by the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. | PMC10075296 | ||
Supporting information |
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ACKNOWLEDGMENTS | This trial had no financial or material support from external organizations. | PMC10075296 | ||
DATA AVAILABILITY STATEMENT | Data sharing is not applicable to this article as no new data were created or analyzed in this study. | PMC10075296 | ||
REFERENCES | PMC10075296 | |||
1. Introduction | tumor, primary tumors, muscle atrophy, fatigue, Malnutrition, cancer, non-melanoma skin cancer, sarcopenia, inflammation, gastrointestinal tract, cancer deaths, Sarcopenia, cancer cachexia, reduced skeletal muscle mass, impaired muscle function, Cancer | TUMOR, PRIMARY TUMORS, MUSCLE ATROPHY, MALNUTRITION, CANCER, INFLAMMATION, SARCOPENIA, FRAGILITY, SARCOPENIA, CANCER | (1) Background: Malnutrition frequently affects patients with cancer, and it negatively impacts treatment tolerance, clinical outcomes and survival. Thus, appropriate nutritional screening and early nutrition support are extremely recommended. Currently, a significant number of oral supplements (OS) are commercially available; despite this, there is a lack of evidence for recommending specific OS, including leucine-enriched OS, for nutritional support in patients with cancer. (2) Aim: To compare the clinical evolution of patients with cancer (undergoing systemic treatment) that received standard hypercaloric, whey protein-based hyperproteic oral supplements vs. hypercaloric, hyperproteic leucine-enriched OS using a novel morphofunctional nutritional evaluation. (3) Patients and methods: This paper details an open-label, controlled clinical study in which patients were randomly assigned to receive nutritional treatment with whey protein-based hyperproteic oral supplements (control group) vs. hypercaloric, hyperproteic leucine-enriched OS (intervention group) during a twelve-week period. Forty-six patients were included; epidemiological, clinical, anthropometric, ultrasound (muscle echography of the rectus femoris muscle of the quadriceps and abdominal adipose tissue) and biochemical evaluation were performed. All patients received additional supplementation with vitamin D. (4) Results: Nutritional parameters (including bioimpedance, anthropometric, ultrasound and biochemical variables) of all included patients remained stable after the nutritional intervention. Extracellular mass tended to increase in the patients that received the leucine-enriched formula. Functionality (evaluated through the stand-up test) improved in both groups (Cancer is one of the main causes of morbidity and the second cause of mortality worldwide. It is estimated that in 2040, there will be 28.4 million cancer cases globally. According to a recent report, 19.3 million new cancer cases were reported in 2020 worldwide; among them, 18.1 million excluded non-melanoma skin cancer, and around 10.0 million cancer deaths were reported [Malnutrition and sarcopenia are frequent in patients with cancer; it occurs in 30–90% of patients, especially if it affects the gastrointestinal tract [Sarcopenia implies fatigue and decreased muscle strength due to reduced skeletal muscle mass, which is accompanied by muscle atrophy and a decreased quality of muscle tissue. Specifically, the muscle fibers are replaced by fibrotic tissue, which results in increased fragility and impaired muscle function [Recent studies suggested that tumor-derived inflammation and the resulting systemic inflammation are closely related to sarcopenia and cancer cachexia. Specifically, tumor cells release cytokines, inflammatory mediators and activated immune cells [Currently, there is no standardized treatment protocol for sarcopenia and cancer cachexia in patients undergoing systemic treatment. In most patients, it is necessary to increase energy intake; this increase alone does not correct sarcopenia and cancer cachexia due to several reasons including the inflammatory status of the patient. In this context, and when the digestive tract is functioning, the use of oral supplements (OS) is necessary. Currently, several formulas are available, but the evidence favoring one over the other is still lacking; in this context, specific strategies for nutritional supplementation should be explored, including leucine. This is a branched-chain amino acid (BCAA) that exerts downstream effects on muscle protein synthesis and promotes muscle protein anabolism [The European Society for Parenteral and Enteral Nutrition (ESPEN) recommends a protein intake of 1.0–1.5 g/kg/day in cancer patients [In this context, the aim of this study is to compare the clinical evolution of patients with cancer when receiving oral nutritional supplementation with standard hypercaloric, hyperproteic (whey protein-based) OS versus hypercaloric, hyperproteic leucine-enriched oral supplements during a twelve-week period. Patients presented with primary tumors in different locations and were receiving systemic treatment (with chemotherapy, radiotherapy or a combination of both). | PMC10302788 |
2. Material and Methods | PMC10302788 | |||
2.1. Patients | cancer of different origin (, weight loss | END-STAGE KIDNEY DISEASE | This study was approved by the Ethics Committee of the Reina Sofia University Hospital (Cordoba, Spain; reference number 4788), which was conducted in accordance with the Declaration of Helsinki and according to national and international guidelines. This is a prospective open-label study, wherein a written informed consent form was signed by every individual before inclusion into the study. All patients received information before the inclusion and were only included if they agreed to participate. The inclusion criteria were the following: patients whose sex is male or female, aged > 18 years, with cancer of different origin treated with systemic treatment (chemotherapy, radiotherapy or combination treatment) that presented with weight loss > 5% during the previous three months or >10% during the previous six months. Exclusion criteria were the following: end-stage kidney disease and life expectancy < 2 weeks. Sample size was calculated based on the usual number of treated patients during 6 months in this hospital. Forty-six consecutive patients with cancer of different origin ( | PMC10302788 |
2.2. Study Design | nausea | When included in the study, all patients received general education about nutritional support, OS, Mediterranean diet and physical activity; additionally, patients received oral supplementation with calcifediol (in different doses to reach levels of sufficiency, defined with a serum 25OH vitamin D levels > 30 ng/dL) for avoiding confounding results. This was an open clinical trial. Patients were randomly assigned by the clinical investigator to receive either standard hypercaloric, hyperproteic (whey protein-based) OS or hypercaloric, hyperproteic, leucine-enriched oral supplement with a 1:1 allocation during a twelve-week period. Any orexigenic was used. A total of 46 patients were recruited, 23 patients for each arm; during the first week of the study, 2 patients reported nausea with the leucine-enriched oral supplement and switched arms. Nutritional evaluation was performed by the same endocrinologist in all cases; vectorial bioelectrical bioimpedance was performed using a NUTRILAB-Akern impedanciometer (Akern, Florence, Italy); for grip strength, a Jamar | PMC10302788 | |
2.3. Outcomes | Primary outcome was to evaluate the percentage of change in muscle mass of patients after both nutritional interventions. Secondary outcomes included other changes in body composition (lean mass, water, bone, phase angle); anthropometric parameters (calf, arm and abdominal circumference); biochemical nutritional parameters (hemoglobin, lymphocytes, total cholesterol, total, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, transferrin, ferritin, albumin, prealbumin C-reactive protein (C-RP)); functionality (stand-up test and grip strength measured using Jamar | PMC10302788 | ||
2.4. Statistical Analysis | Between-group comparisons were analyzed using the Mann–Whitney U test (nonparametric data) or the Kruskal–Wallis test (nonparametric data, when we compared more than two groups). Paired analysis was performed using Student’s | PMC10302788 | ||
3. Results | urothelial cancer, colorectal cancer, gastrointestinal neuroendocrine tumor, head–neck cancer, tumors, gastric cancer | COLORECTAL CANCER, TUMORS, GASTRIC CANCER | Forty-six patients were included. Most of them were female (54.3%), with a median age of 74 years; the patients presented with tumors of different origin, including colorectal cancer (19.6%), urothelial cancer (32.6%), head–neck cancer (13%), gastric cancer (8.7%), gastrointestinal neuroendocrine tumor (8.7%) and other localizations (17.4%). Over 63% of the evaluated patients underwent surgery, and almost 50% received combined treatment ( | PMC10302788 |
Primary and Secondary Outcomes | cancer | CANCER | The nutritional intervention in all the evaluated patients resulted in body composition maintenance assessed via bioimpedance analysis. Particularly, the BMI decreased in a non-significant manner; furthermore, the lean mass tended to increase after twelve weeks of treatment (Significantly, all patients improved their performance, which was measured using the stand-up test, especially those that received standard OS (control group); in contrast, the arm strength (determined via dynamometry) remained stable in all groups (Clinical comparison in patients with cancer and systemic treatment receiving nutritional supplements with standard hypercaloric, hyperproteic oral supplements versus leucine-enriched oral supplements. (Regarding the biochemical data, when all the patients were analyzed, only the prealbumin levels increased (Finally, the nutritional evaluation performed using echography showed that the muscle mass in the rectus femoris of the quadriceps remained stable after twelve weeks of treatment in all the patients ( | PMC10302788 |
4. Discussion | Cancer, muscle mass, gastrointestinal symptoms, cancers, skeletal muscle mass, tumor, metabolic dysregulation, cancer, cardiac dysfunction, inflammation, tumors, head–neck cancer, skeletal muscle loss, malnutrition, muscle mass gain, ACS, anorexia, | CANCERS, TUMOR, CANCER, MALNUTRITION, INFLAMMATION, TUMORS, CHRONIC DISEASES, ADVERSE EFFECTS, TUMOR PROGRESSION, INSULIN RESISTANCE, VITAMIN D DEFICIENCY, MALNUTRITION, PRIMARY TUMOR, STAGE II COLON CANCER, CANCER | The nutritional status is severely affected in most patients with cancer; this condition affects the treatment tolerability and overall survival [Malnutrition affects patients of both the male and female sexes and all age groups. In cancer, malnutrition is a result of a combination of anorexia, gastrointestinal symptoms and metabolic dysregulation, including insulin resistance [It is well known that nutritional support plays a fundamental role in the prevention, treatment and prognosis of both acute and chronic diseases, especially in cancer patients [Currently, several specific nutritional formulas are available, and their use in precise clinical scenarios is recommended; for example, the use of immunonutrition as a part of abdominal surgery programs or even after surgery in patients with head–neck cancer is recommended [In patients with cancer, an adequate supply of protein is necessary for the maintenance and gain of muscle. Specifically, positive muscle protein balance is necessary for increasing skeletal muscle mass; additionally, the availability of postprandial circulating amino acids is required for stimulating muscle protein synthesis [According to the American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors (ACS guidelines), a healthy body weight, physical activity and a diet rich in vegetables, fruits and whole grains was associated with a longer survival in stage III colon cancer patients. Additionally, they reported an inverse association between red meat consumption and seven-year mortality among 992 individuals with stage III colon cancer and suggested that a higher protein intake might be beneficial for these patients [In all subjects, muscle protein synthesis and breakdown are simultaneous ongoing processes; thus, a positive balance should be presented in order to gain muscle mass. Several studies were focused on protein quality for muscle mass gain, since protein composition and amino acids can affect protein balance, and even exercise-induced muscle protein anabolism [In this context, BCAAs (leucine, isoleucine and valine) have a critical role in promoting protein synthesis in muscle tissue, and for that reason, they were investigated as a target for nutritional therapy [Vitamin D deficiency is frequent in cancers of different origin; its supplementation is strongly recommended for promoting bone health and reducing potential cancer risks [Regarding this, whey protein is a dairy-driven product that is usually used to help people change their weight and body composition and increase muscle strength. Specifically, whey protein is characterized by a significant content of essential and branched-chain amino acids; in consequence, it is a high-quality source of protein. It additionally has a rapid absorption and a higher muscle protein synthesis compared with other protein sources [In contrast to the referred previous publications, a recent metanalysis demonstrated that leucine-isolated supplementation did not improve muscle mass and strength in elderly subjects. However, its combination with vitamin D exhibited a significant benefit for muscle strength, handgrip strength, gait speed and general performance in older adults [Furthermore, some studies reported that leucine is linked to iron and hemoglobin metabolism [A recent review of pre-clinical studies found positive implications of leucine supplementation for reducing skeletal muscle loss (since leucin preserves protein synthesis and decreases protein degradation), attenuating cardiac dysfunction, improving immune competence, preserving energy production capacity and decreasing inflammation [Previous publications suggested a specific effect of leucine on decreasing inflammation [This study has some limitations, with the first limitation being the number of participants in each group and the heterogeneity of the primary tumor location. This was also a short intervention (12 weeks), and the daily intake of OS (using an adherence scale) was not assessed. Additionally, tumor markers were not included. Several reasons explain this exclusion; first, tumor progression was not the goal of this study, and the primary site and stage at the diagnosis were heterogenous, which would have limited the conclusions. It is important to mention that the treatment tolerance was similar in both groups after the first week and until the twelfth week of treatment, but specific day-per-day adherence was not assessed in this study. The gastrointestinal symptoms are frequent in patients with cancer due to systemic treatment-related adverse effects and the local effects of the tumor [In contrast, this study has several strengths; first of all, it is a real reflection of the clinical practice, in which patients with tumors of different locations and stages undergo different lines of systemic treatment and require an appropriate nutritional evaluation combined with early nutritional support. Additionally, we performed a head-to-head comparison of two different OS in cancer patients undergoing systemic treatment (we did not use the placebo in the control group). Furthermore, a comprehensive nutritional evaluation was performed, including anthropometric, echography, functional and biochemical parameters; finally, vitamin D supplementation was included in order to avoid confounding results. | PMC10302788 |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10302788 | ||
Author Contributions | Conceptualization, A.D.H.-M. and M.J.M.P.; data curation, S.L.I., S.C.P., A.S.S., R.A.E., C.M.J. and R.R.-A.; funding acquisition, A.D.H.-M.; practical performance, S.L.I., S.C.P., A.S.S., R.A.E., C.M.J., R.R.-A., G.M.G. and M.Á.G.M.; formal and data analysis, A.D.H.-M.; preparation of manuscript, A.D.H.-M., M.J.M.P. and C.M.J.; critical review of manuscript, A.D.H.-M., R.R.-A., M.J.M.P. and A.C.C. All authors have read and agreed to the published version of the manuscript. | PMC10302788 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Reina Sofia University Hospital (Cordoba, Spain) (4788, 28 October 2020). | PMC10302788 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10302788 | ||
Data Availability Statement | All data was included in the article. | PMC10302788 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10302788 | ||
References | cancer | CANCER, NEUROENDOCRINE TUMOR | Study design.Biochemical comparison in patients with cancer and systemic treatment receiving nutritional supplements with standard hypercaloric, hyperproteic oral supplements versus leucine-enriched oral supplements. Legend: C-RP—c-reactive protein; ns—non-significative; * Clinical comparison in patients with cancer and systemic treatment receiving nutritional supplements with standard hypercaloric, hyperproteic oral supplements versus leucine-enriched oral supplements using ultrasound techniques. (Baseline clinical characteristics of the patients. Comparison between groups based on the nutritional intervention.Legend: NET: neuroendocrine tumor; ECOG: ECOG performance status scale; RT: radiotherapy. | PMC10302788 |
Background | hernia, hernias | COMPLICATION | Incisional hernia is a frequent complication following loop ileostomy reversal. Incisional hernias are associated with morbidity, loss of health-related quality of life and costs and warrant the investigation of prophylactic measures. Prophylactic mesh implantation at the time of surgical stoma reversal has shown to be a promising and safe method to prevent incisional hernias in this setting. However, the efficacy of this method has not yet been investigated in a large multicentre randomised-controlled trial (RCT) with adequate external validity. The P.E.L.I.O.N. trial will evaluate the efficacy of prophylactic mesh reinforcement after loop ileostomy closure in decreasing the rate of incisional hernia versus standard closure alone. | PMC9890770 |
Methods | postoperative pain, hematomas, hernias, seromas | SITE INFECTION, HEMATOMAS, POSTOPERATIVE COMPLICATIONS, SEROMAS | P.E.L.I.O.N. is a multicentre, patient- and observer-blind RCT. Patients undergoing loop ileostomy closure will undergo intraoperative 1:1 randomisation into either abdominal wall closure with a continuous slowly absorbable suture in small-stitch technique without mesh reinforcement (control group) or abdominal wall closure with an additional reinforcement with a retromuscular non-absorbable, macro-pore (pore size ≥ 1000 μm or effective porosity >0%) light-weight monofilament or mixed structure mesh. A total of 304 patients (152 per group) will need to be randomised in the study. Based on inclusion and exclusion criteria, 1,014 patients are expected to be screened for eligibility in order to recruit the necessary number of patients. The primary endpoint will be the frequency of incision hernias within 24 months according to the European Hernia Society definition. Secondary endpoints will be the frequency of surgical site occurrences (including surgical site infections, wound seromas and hematomas, and enterocutaneous fistulas), postoperative pain, the number of revision surgeries and health-related quality of life. Safety will be assessed by measuring postoperative complications ≥ grade 3 according to the Dindo-Clavien classification. | PMC9890770 |
Discussion | Depending on the results of the P.E.L.I.O.N. trial, prophylactic mesh implantation could become the new standard for loop ileostomy reversal. | PMC9890770 | ||
Trial registration | DRKS00027921, U1111-1273-4657 | PMC9890770 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-023-07089-3. | PMC9890770 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC9890770 | ||
Administrative information | 26121 | Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see Sven Müller, Helios Klinikum Gifhorn, Campus 6, 38518 Gifhorn, GermanyDirk Weyhe, Klinik für Allgemein- und Viszeralchirurgie, Universitätsmedizin Oldenburg, Pius-Hospital Oldenburg, Georgstraße 12, 26121 Oldenburg, GermanyAndre Mihaljevic, Patrick Heger, Nadir Nasir, Colette Doerr-Harim: Department of General and Visceral Surgery and Clinical Trial Centre Department of Surgery (ulmCARES), University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, GermanyFlorian Herrle, Chirurgische Klinik, Universitätsklinikum Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, GermanyPhilipp Horvath, Robert Bachmann: Klinik für Allgemeine, Viszeral- und Transplantationschirurgie, Universitätsklinikum Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, GermanyViktor von Ehrlich-Treuenstätt, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Ludwig-Maximilians-Universität München, Marchioninistraße 15, 81377 München, GermanyAnja Sander, Alexander Ritz, Christina Klose: Institute of Medical Biometry (IMBI), University of Heidelberg, Im Neuenheimer Feld 130.3, 69120 HeidelbergErich Grohmann, Deutsche ILCO e. V., Nietzschestr. 11, 53177 Bonn, GermanyAndre L. Mihaljevic: Department of General and Visceral Surgery, Clinical Trial Centre Department of Surgery (ulmCARES), University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, GermanyPhone: +49 (0) 0731-500-53502Fax: +49-(0) 731 500-53503E-mail: andre.mihaljevic@uniklinik-ulm.de | PMC9890770 | |
Introduction | PMC9890770 | |||
Background and rationale {6a} | loop ileostomies, abdominal pain, hernia, infections, SSI | SITE INFECTION, INFECTIONS, LEAKAGE | Diverting loop ileostomy is used in colorectal surgery to reduce the consequences of leakage of a bowel anastomosis. According to the Federal Statistical Office of Germany, approximately 15,000 diverting loop ileostomies and 11,500 loop ileostomy closures are performed annually in Germany [Multiple studies have shown that IH causes substantial morbidity and a reduction in the quality of life due to abdominal pain and discomfort, a reduction in the daily activity as well as mortality [Because of the important consequences for patients and national healthcare systems, the prevention of incisional hernia has been a subject of intensive investigation over the last decades. For ventral IHs, prophylactic mesh placement at the time of abdominal wall closure is now an accepted technique. Its efficacy has been tested in numerous randomised controlled trials (RCTs) [For ostomy reversal, much less evidence is available. Probably because concerns of safety have been voiced regarding an increased risk of surgical site infections (SSI) and mesh infections. Three non-randomised studies have been published on prophylactic mesh placement for ostomy reversal [In addition, one recent RCT trial (ROCSS, NCT02238964) compared prophylactic mesh placement in an intraperitoneal onlay position (IPOM) at the time of ostomy reversal to primary closure [ | PMC9890770 |
Objectives {7} | hernia | The high rate of IH after loop ileostomy closure with its associated morbidity, loss of health-related quality of life and costs (hernia repair, loss of workforce) warrants the investigation of prophylactic measures. Prophylactic mesh implantation at the time of surgical stoma reversal has shown to be a promising and safe method to prevent IH formation in this setting. However, the efficacy of this method has not yet been investigated in a large multicentre RCT with adequate external validity. P.E.L.I.O.N will fill this evidence gap. The aim of the PELION trial is to evaluate the efficacy of prophylactic mesh reinforcement after loop ileostomy closure in decreasing the rate of IH versus standard closure alone. | PMC9890770 | |
Trial design {8} | P.E.L.I.O.N is a randomised controlled observer- and patient-blinded multicentre surgical superiority trial with two parallel study groups. | PMC9890770 | ||
Methods: participants, interventions and outcomes | PMC9890770 | |||
Study setting {9} | The study will be carried out in 10 high-volume academic hospitals in Germany. A list of study sites can be found in Supplement | PMC9890770 | ||
Eligibility criteria {10} | PMC9890770 | |||
Inclusion criteria for patients | To obtain a homogenous but still representative patient population for analysis and high-external validity, all patients with primary loop ileostomy closure and without further interventions or conditions to the abdominal wall, which might interfere with the primary outcome measure and reduce the reproducibility and interpretability of the data, are eligible for inclusion and will be informed about the P.E.L.I.O.N. trial:Planned elective loop ileostomy closureAdult patients (≥ 18 years of age)Life expectancy > 2 yearsWritten informed consentAbility to understand the character and individual consequences of the clinical trial | PMC9890770 | ||
Exclusion criteria for patients | hernia, ileostomyChronic renal failure, necrosis | NECROSIS |
American Society of Anesthesiologist (ASA) physical status class ≥ 4Infected/septic surgical site (risk for surgical site occurrences (SSO) of grade 4 according to Ventral Hernia Working Group (VHWG) classification) (see Supplement Presence of parastomal hernia in loop ileostomy site with fascia defect > 8cm (Table Presence of a concomitant incisional hernia that impedes loop ileostomy reversal or placement of the mesh at the ileostomy site (Table Patients with prior mesh placement on site of ileostomyChronic renal failure under haemodialysis/peritoneal dialysisPatients under strong immunosuppression or other medications likely to impede wound healing as judged by the operating surgeon. Examples of strong immunosuppression are:Steroid therapy ≥ 10 mg/dayTherapy with antitumor necrosis factor α (anti-TNF-α) within the last 4 weeksTherapy with everolimus or sirolimus within the last 4 weeksTherapy Avastin within the last 4 weeksCongenital haemorrhagic diathesis with need of perioperative treatmentParticipation in another interventional trial with interference on intervention and primary outcome of this trialDetails of exclusion criteria 3 and 4Presence of a parastomal hernia or incisional hernia on clinical exam, but - Parastomal hernia is smaller or larger than 8 cm - Or if unclear whether incisional hernia impedes loop ileostomy reversal or placement of the mesh at the ileostomy site | PMC9890770 |
Eligibility criteria for trial sites and surgeons |
Only high-volume To ensure standardisation of the procedure and to minimise training effects, all Furthermore, all | PMC9890770 | ||
Who will take informed consent? {26a} | Patients scheduled for elective loop ileostomy closure are screened preoperatively. An authorised physician with a GCP training will inform the patient about the trial (visit 1). Patients are enrolled given their ability to understand the extent and nature of the trial as well as their written informed consent after detailed patient information. | PMC9890770 | ||
Additional consent provisions for collection and use of participant data and biological specimens {26b} | No biological samples will be collected during the trial. | PMC9890770 | ||
Interventions | PMC9890770 | |||
Explanation for the choice of comparators {6b} | Patients in both groups will receive ileostomy closure according to the current standard of care, i.e. direct fascia closure according to the small-stitch technique with a slowly absorbable suture. In addition, in the intervention group, the abdominal wall closure will be augmented with a non-absorbable, macro-pore light-weight mesh. Patients in the intervention group might therefore benefit from a potential decreased IH rate; however, the efficacy of the experimental intervention has not yet been shown. A real clinical equipoise exists between the two comparators (see the “ | PMC9890770 | ||
Intervention description {11a} | PMC9890770 | |||
Experimental intervention | stoma | STERILE, CAVITY |
The re-establishment of intestinal continuity will be achieved by either stapled or by hand-sewn anastomosis, according to the surgeon’s preference, and the bowel will be positioned back into the peritoneal cavity.Changing of surgical gloves must be performed before mesh implantation. Either after surgical stoma closure or, latest, before mesh placement.A retromuscular space is created by blunt dissection overlapping the suture line in cranio-caudal direction by 4–6cm. In the medial-to-lateral direction, the dissection is limited by the linea alba and linea semilunaris in case the stoma is placed within the rectus sheath. In case the stoma is outside the rectus sheath or below the linea arcuata (no posterior rectus sheath), a retromuscular space should be formed by dissection overlapping the future fascial suture line by 4–6cm in all directions.The posterior rectus sheath (if the stoma is within the rectus sheath) will be closed with a continuous polydioxanone suture (PDS Plus, USP 2-0) with tissue bites of 5 mm and intersuture spacing of 5 mm applied exclusively to the fascia omitting subcutaneous fat and muscle tissue (small-stitch technique, SST). In case the stoma is outside the rectus sheath or below the linea arcuata (no posterior rectus sheath), the posterior abdominal wall should be closed with a continuous polydioxanone suture (PDS Plus, USP 2-0) with tissue bites of 5 mm and intersuture spacing of 5 mm applied exclusively to the fascia omitting subcutaneous fat and muscle tissue (small-stitch technique, SST).The retromuscular space should be irrigated with 500 ml of sterile fluid (lavage) before mesh placement. The type of solution is at the discretion of the surgeon, e.g. saline solution (NaCl 0.9%), Ringer’s or any antiseptic solutions like polyhexanide (PHX), Lavanox or others can be used for this purpose as long as its application is approved for this purpose.A non-absorbable, macro-pore (pore size ≥ 1000μm [The mesh should be fixed to the posterior fascia tension-free with single knots if deemed necessary by the operating surgeon. The suture material is at the discretion of the operating surgeon.The rectus muscle should The anterior rectus sheath will be closed in the same manner as the posterior sheath with a continuous polydioxanone suture (PDS Plus, USP 2-0) with tissue bites of 5 mm and intersuture spacing of 5 mm applied exclusively to the fascia omitting subcutaneous fat and muscle tissue (small-stitch technique, SST).Subcutaneous drains can be placed at the discretion of the operating surgeon.The skin will be closed according to the surgeon’s preference (suture, staples, pursestring).Further perioperative and postoperative treatment will be equal for both groups according to the respective local standard of care. | PMC9890770 |
Control intervention | stoma | CAVITY |
The re-establishment of intestinal continuity will be achieved either by staples or by hand-sewn anastomosis, according to the surgeon’s preference, and the bowel will be positioned back into the peritoneal cavity.Changing of surgical gloves.The posterior rectus sheath (if the stoma is within the rectus sheath) will be closed with a continuous polydioxanone suture (PDS Plus, USP 2-0) with tissue bites of 5 mm and intersuture spacing of 5 mm applied exclusively to the fascia omitting subcutaneous fat and muscle tissue (small-stitch technique, SST). In case the stoma is outside, the rectus sheath or below the linea arcuata (no posterior rectus sheath), the posterior abdominal wall should be closed with a continuous polydioxanone suture (PDS Plus, USP 2-0) with tissue bites of 5 mm and intersuture spacing of 5 mm applied exclusively to the fascia omitting subcutaneous fat and muscle tissue (small-stitch technique, SST).The rectus muscle should The Subcutaneous drains can be placed at the discretion of the operating surgeon.The skin will be closed according to the surgeon’s preference (suture, staples, pursestring).Further perioperative and postoperative treatment will be equal for both groups according to the respective local standard of care. | PMC9890770 |
Criteria for discontinuing or modifying allocated interventions {11b} | As P.E.L.I.ON. is investigating two surgical interventions, no criteria for discontinuing or modifying the allocated intervention are applicable. | PMC9890770 | ||
Strategies to improve adherence to interventions {11c} | As P.E.L.I.ON. is investigating two surgical interventions, strategies to improve adherence to the intervention are unnecessary as the patient cannot “withdraw” from the intervention during surgery. | PMC9890770 | ||
Relevant concomitant care permitted or prohibited during the trial {11d} | Further perioperative and postoperative treatment will be according to the local standard of care. This also includes the use of abdominal belts which is at the discretion of the operating surgeon. There will be no restrictions for additional treatments during the trial. | PMC9890770 | ||
Provisions for post-trial care {30} | DER | For trials that are conducted according to the Medical Association’s professional code (Berufsordnung der Bundesärztekammer) § 15, there is no obligation for a specific trial liability insurance. However, patients will be insured against travel accidents for their follow-up visits ( | PMC9890770 | |
Outcomes {12} | PMC9890770 | |||
Primary outcome measure | hernia | RECURRENCE | An Patients will be assessed for the primary endpoint at 12 and 24 months after the trial intervention. At these dates, patients will be examined by a clinician blinded for the trial intervention and by a radiologic examination performed by a blinded assessor. Radiologic exams allowed for assessment in the trial are for example sonography, computed tomography (CT) or magnetic resonance imaging (MRI) scans. To reduce radiation exposure, sonography is the preferred imaging method. No radiation-associated imaging should be initiated solely for the purpose of the P.E.L.I.O.N trial. However, results of radiation-associated imaging like CT scans that are performed for other indications (e.g. oncological follow-up) can be used in the trial. In this case, an additional ultrasound of the abdominal wall is not necessary. In case of conflicting results between clinical and radiologic exams, the radiologic imaging is decisive to increase sensitivity [Possible outcomes of clinical and radiological hernia assessment and outcome decisions in the P.E.L.I.O.N. trialFor patients who are unable or unwilling to attend the follow-up visits, a telephone follow-up is incorporated. As the patient-reported outcome questionnaire developed by Tastaldi et al. (Hernia Recurrence Inventory, HRI) was modified and will be used in all patients [ | PMC9890770 |
Sample size {14} | death | REGRESSION, EVENT | Sample size calculation is based on the rate of the primary endpoint (IH rate) within 24 months after surgery. Based on the assumption that the percentage of patients developing an IH in the control group is 30% (4–7), we hypothesise a reduction to 15% in the intervention arm (conservative reduction rate below that reported in the above-mentioned trials). Consequently, a sample size per group of 121 patients is needed for the group comparison by the chi-squared test to achieve 80% power in detecting this difference in IH rate at a two-sided level of significance of 5%. It is assumed that using a logistic regression model adjusting for IH risk (low-risk vs. high-risk patients: BMI ≥ 27) and including centre as a random effect in the primary analysis will lead to less unexplained variance and thus to an increased power.The intercurrent event re-laparotomy affecting the loop ileostomy closure site and death without prior observation of IH are expected to be very rare, with just a few patients each. Based on previous trials, to account for the loss of information, a rate of 20% of dropouts, loss to FU and relevant ICEs (handled with the hypothetical strategy) is considered. Therefore, a total of 304 patients (152 per group) will be randomised. The other ICEs are ignored in the primary estimand and not accounted for in the sample size calculation. Calculation was performed using PASS 16.0.12. Only high-volume trial sites committing to include at least 10 patients per year will be chosen as trial sites. | PMC9890770 |
Recruitment {15} | RECRUITMENT | To enrol the required number of patients in the planned recruitment period, 13 trial sites will participate in this trial. The trial will be performed by the Clinical Trial Network of the German Society of Surgery (CHIR-Net, In order to minimise loss to follow-up, the following measures are being implemented:A pragmatic trial design with high-external validity, meaning that trial sites will have little problems to adapt their standard clinical workflow to the follow-up visitsFinancial reimbursement of travel costs for patients covering additional costs for trial-specific visitsAll trial sites are trained in performing surgical clinical trials (CHIR-Net) and have successfully participated in similar trialsOnly high-volume trial sites committing to include at least 10 patients per year will be chosen as trial sites. | PMC9890770 | |
Assignment of interventions: allocation | PMC9890770 | |||
Sequence generation {16a} | To ensure equal distribution of patient characteristics, randomisation will be used. Allocation of treatments will be performed using a web-based randomisation tool ( | PMC9890770 | ||
Concealment mechanism {16b} | Allocation concealment will be ensured as the result of the randomisation will be unknown to the study team until the patient has been randomised through the web-based tool. Block size will be kept confidential to the study team. Randomisation will be performed in the operation theatre, after the closure of the posterior rectus sheath/posterior fascia. This prevents potential bias by different intraoperative techniques. Before randomisation, the surgeon needs to rule out an infected/septic surgical site (risk for surgical site occurrences (SSO) of grade 4 according to Ventral Hernia Working Group (VHWG) classification) [ | PMC9890770 | ||
Implementation {16c} | Randomisation will be performed by a study team in the operation theatre. Names of this team member and the operating surgeon are noted as these team members are unblinded. They will not be involved in the outcome assessment of the trial. | PMC9890770 | ||
Assignment of interventions: blinding | PMC9890770 | |||
Who will be blinded {17a} | Blinding will be performed according to the evidence-based guidelines published by Probst et al. [Patients are blinded as they are under general anaesthesia during the trial intervention. Neither the discharge letter nor the operation report will contain any information regarding group allocation. This will be monitored by the clinical monitor.Surgeons performing the operation are unblinded to the trial intervention. To minimise performance bias, randomisation is performed after the closure of the posterior wall of the abdomen.For blinded outcome assessment, the person performing randomisation and the surgical team conducting the control/experimental intervention (“unblinded” study members) will be documented. All outcome assessments must be performed by blinded clinical assessors The trial statistician is blinded as she/he has no access to unblinded data during the study. Furthermore, the statistician will perform according to a pre-defined statistical analysis plan which will be finished prior to database closure.For primary endpoint evaluation, a clinical as well as radiological examination needs to be performed. Clinical outcome assessment must be performed by a surgeon. Blinding the radiologic examination can be achieved easily, as these physicians are not part of the prior trial interventions or the clinical trial centre. For clinical evaluation, the same prerequisites apply as outlined above, i.e. surgeons performing the clinical evaluation must be independent of the “unblinded” trial team. | PMC9890770 | ||
Procedure for unblinding if needed {17b} | Unblinding can be performed if medically indicated by the treating surgeon with the help of an unblinded study team member. Unblinding will be documented and reported to the steering group of the trial. | PMC9890770 | ||
Data collection and management | PMC9890770 | |||
Plans for assessment and collection of outcomes {18a} | The trial will be performed by the Clinical Trial Network of the German Society of Surgery (CHIR-Net, | PMC9890770 | ||
Plans to promote participant retention and complete follow-up {18b} | In order to minimise loss to follow-up, the following measures have been implemented:A pragmatic trial design with high-external validity, meaning that trial sites will have little problems to adapt their standard clinical workflow to the follow-up visitsFinancial reimbursement of travel costs for patients covering additional costs for trial-specific visitsAll trial sites are trained in performing surgical clinical trials (CHIR-Net) and have successfully participated in similar trialsOnly high-volume trial sites committing to include at least 10 patients per year will be chosen as trial sites | PMC9890770 | ||
Data management {19} | All protocol-required information collected during the trial must be entered by the investigator, or designated representative, in the eCRF. The investigator, or designated representative, should complete the eCRF pages as soon as possible after information is collected, preferably on the same day that a trial subject is seen for an examination, treatment or any other trial procedure. Any outstanding entries must be completed immediately after the final examination. An explanation should be given for all missing data. Further protocol deviations are explicitly asked for in the eCRF and have to be described by trial centres. The completed eCRF must be reviewed and signed by the investigator named in the trial protocol or by a designated sub-investigator.The IMBI is responsible for the data management within the trial. The study data will be collected and managed using REDCap (Research Electronic Data Capture) [ | PMC9890770 | ||
Confidentiality {27} | The data protection concept stipulates that patients are only included in the study after they have been informed and after having signed the informed consent form (ICF). They will be informed as to the strict confidentiality of their data, but that their medical records may be reviewed for trial purposes by authorised individuals other than their treating physician. It is the responsibility of the investigator to maintain patients’ confidentiality. During the trial, patients will be identified solely by means of their individual identification code, and participating patients’ data will be recorded only in pseudonymised form. Trial-specific documents will be stored in accordance with local data protection law/ICH-GCP guidelines and will be handled in the strictest confidence. For the protection of these data, organisational procedures are implemented to prevent the distribution of data to unauthorised persons. Each trial site will maintain a personal subject identification list (screening numbers with the corresponding subject names) to enable records to be identified. The patients’ data will be transferred in a pseudonymised form from the trial centre to cooperating partners (coordinating investigator, data management). Names and all confidential data of participating patients will be handled in line with the obligations of medical secrecy, the European General Data Protection Regulation GDPR (Datenschutzgrundverordnung, DSGVO), the Federal Data Protection Act (Bundesdatenschutzgesetz) and the state Data Protection Act (Landesdatenschutzgesetz). Third parties have no access to original documents. After completion of the trial, data collected during the study will be kept on file for 10 years. It is guaranteed that the data protection provisions are followed. | PMC9890770 | ||
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} | No plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis are implemented in the P.E.L.I.O.N. trial. | PMC9890770 | ||
Statistical methods | PMC9890770 | |||
Interim analyses {21b} | Due to the long observation period for the primary endpoint, an interim analysis would only be possible using a short-term endpoint as a surrogate. However, no reliable short-term endpoint is available. Therefore, no interim analyses are planned for the present trial. However, the DSMB will oversee unblinded data on a regular basis. | PMC9890770 | ||
Methods for additional analyses (e.g. subgroup analyses) {20b} | hernia/hernia, diabetes mellitus, hernia, non-COPD, abdominal aortic aneurysm, SSI, seroma, hematoma, COPD | CARDIOVASCULAR DISEASE, DIABETES MELLITUS, POSTOPERATIVE COMPLICATION, COPD, RENAL DISEASE, SEROMA, REGRESSION, HEMATOMA, COMPLICATIONS | Pre-specified subgroup analysis will be performed in the FAS population for the rate of IH in the following subgroups: (a) body mass index (< 27 vs. ≥ 27), (b) neoadjuvant therapy (yes/no), (c) COPD vs. non-COPD, (d) previous laparotomy vs. previous minimal invasive surgery and (e) history of hernia/hernia repair vs. no history of hernia/hernia repair.Furthermore, uni- and multivariate analyses using two-level binary logistic regression models will be performed to find risk factors for IH. Factors that will be included in the model (besides the fixed factors treatment group and IH risk, and the random factor centre which are already used in the primary model) are age, BMI, sex, presence/absence of diabetes mellitus with chronic complications, corticosteroid use, preoperative (radio)chemotherapy, renal disease, smoking, previous laparotomies, COPD, cardiovascular disease, history of hernia or hernia repair, history of abdominal aortic aneurysm, ASA classification, occurrence of SSI, postoperative complication (Dindo-Clavien), seroma formation, hematoma formation and length of hospital stay.Furthermore, the treatment effect will be assessed descriptively within several subgroups of interest to identify potential prognostic and predictive factors. | PMC9890770 |
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} | SECONDARY | For patients with incomplete follow-up, missing data will be shown as missing on appropriate tables and listings. Imputation of main secondary outcomes will be performed. | PMC9890770 | |
Plans to give access to the full protocol, participant-level data and statistical code {31c} | The full protocol is accessible with this publication. Participant-level data will be available anonymised after the publication of the final results of the study. | PMC9890770 | ||
Oversight and monitoring | PMC9890770 | |||
Composition of the coordinating centre and trial steering committee {5d} | The trial will have a steering committee consisting of the trial statistician (AS), three clinical experts (AM, SM, DW) and a patient representative (EG). The steering committee will supervise the conduct of the trial and will issue recommendations for early termination, modifications or continuation of the trial, if necessary. | PMC9890770 | ||
Composition of the data monitoring committee, its role and reporting structure {21a} | hernia | SECONDARY, RECRUITMENT, COMPLICATIONS, POSTOPERATIVE COMPLICATIONS | The trial’s Data Safety and Monitoring Board (DSMB) will be composed of two independent clinical experts in the field of hernia surgery. Furthermore, an independent statistician will be part of the DSMB. The DSMB members will receive a written report twice a year and should advise whether to continue, modify or stop the trial based on the rate and severity of specific intervention-associated complications (see secondary endpoints SSO) and of major (≥ grade 3) postoperative complications according to Dindo-Clavien (within 30 days after ileostomy closure). Furthermore, they should review adherence to protocol especially for the trial-relevant primary outcome measure and will inform the coordinating investigator about relevant imbalances between groups. DSMB members will also be asked to give advice on whether results from other relevant trials justify continuing recruitment of further patients. The working procedures of the DSMB will be recorded in the DSMB charter of this trial. | PMC9890770 |
Adverse event reporting and harms {22} | hematomas, seromas | HEMATOMAS, ADVERSE EVENTS, POSTOPERATIVE COMPLICATION, SECONDARY, ADVERSE EVENT, SITE INFECTION, SEROMAS, DER, COMPLICATIONS | Since trial interventions in P.E.L.I.O.N are medical routine, and the trial is conducted under the Medical Association’s professional code (Berufsordnung der Bundesärztekammer) §15, there is no need to record every adverse event. Instead of documenting serious adverse events (SAE), the following secondary endpoints will be used to assess safety in the P.E.L.I.O.N trial:Postoperative complications within 30 days according to the Dindo-Clavien classification (DCC) ≥3 [Superficial or deep surgical site infections (SSIs) within 1 year after index operation according to the CDC definition [Rate of wound seromas at former ostomy site within 30 days after the index operationRate of hematomas at former ostomy site within 30 days after the index operationEnterocutaneous fistulas within 24 months after the index operation [Number of revision surgeries because of complications related to ileostomy closure within 24 months after the index operation | PMC9890770 |
Frequency and plans for auditing trial conduct {23} | RECRUITMENT, COMPLICATIONS, POSTOPERATIVE COMPLICATIONS | Clinical monitoring will be performed regularly by the independent monitoring department of the Furthermore, for a specific number of long-term postoperative visits (12 and 24 months postoperative), monitoring will confirm that primary outcome assessment is performed by blinded outcome assessors. For other items, the proportion of source data verification will be at least 20% but can be increased according to centres’ experience and needs. The frequency of monitoring visits will be determined depending on recruitment numbers and individual performance of each centre based on feedback from project and data management and according to the risk-based monitoring approach.The steering committee will meet at least twice a year. Furthermore, the DSMB members will receive a written report twice a year and should advise whether to continue, modify or stop the trial based on the rate and severity of specific intervention-associated complications and of major (≥ grade 3) postoperative complications according to Dindo-Clavien (within 30 days after ileostomy closure). The decision to discontinue recruitment will be made by the coordinating investigator and the steering committee after the DSMB gave its recommendation. The coordinating investigator and/or the steering committee may call upon the DSMB in case a safety issue arises during the course of the trial. | PMC9890770 | |
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} | Any amendment to the protocol will be communicated to the participating trial sites immediately by email. Furthermore, regular investigator meetings will be held during the twice yearly CHIR-Net meetings to resolve questions and discuss the progress of the trial. Trial registries, REC/IRBs, will be contacted by the project management and the steering group. | PMC9890770 | ||
Dissemination plans {31a} | Trial results will be communicated to participating trial sites prior to publication. The final report will be reviewed by all trial sites. Results will be made available in an open access journal. Results will be communicated to appropriate patient organisations like the ILCO e.V. Trial results will be presented at an international conference. | PMC9890770 | ||
Discussion | RECRUITMENT | Given the high rate of IH after loop ileostomy closure with its associated morbidity, loss of health-related quality of life and costs, prophylactic measures after ostomy closure are urgently needed. Prophylactic mesh implantation at the time of surgical stoma reversal has shown to be a promising and safe method to prevent IH formation. However, the efficacy of this method has not yet been investigated in a large multicentre RCT with adequate external validity. P.E.L.I.O.N will fill this evidence gap. The aim of the PELION trial is to evaluate the efficacy of prophylactic mesh reinforcement after loop ileostomy closure in decreasing the rate of IH versus standard closure alone. Recruitment of patients has started in October 2022 and is going as projected.Besides P.E.L.I.O.N, four planned randomised controlled trials are registered in available international registries, all with relevant weaknesses in the trial design, making interpretation and generalisation of the results doubtful (see Table Planned studies currently registered | PMC9890770 | |
Trial status | MAY | The current protocol number is 1.1, May 12, 2022.Recruitment has started in October 2022.Recruitment is planned to be completed at the beginning of 2024. | PMC9890770 | |
Acknowledgements | N/A | PMC9890770 | ||
Authors’ contributions {31b} | CDH | SM: substantial contributions to the conception and design of the work and analysis methods and draft of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. DW: substantial contributions to the conception and design of the work and analysis methods and draft of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. PH: substantial contributions to design of the work and draft of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. FH: substantial contributions to the conception and design of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. PH: substantial contributions to the conception and design of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. NN: substantial contributions to the conception and design of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. RB: substantial contributions to the conception and design of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. MA: substantial contributions to the conception and design of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. CK: substantial contributions to the design of the work and data management and has drafted the work or substantively revised it and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. AR: substantial contributions to the conception and design of the work and statistical methods and has drafted the work or substantively revised it and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. AS: substantial contributions to the conception and design of the work and statistical methods and has drafted the work or substantively revised it and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. EG: substantial contributions to the conception and design of the work and statistical methods and has drafted the work or substantively revised it and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. CDH: substantial contributions to the conception and design of the work and analysis methods and draft of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. VvET: substantial contributions to the conception and design of the work and analysis methods and draft of the work and has approved the submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved and the resolution documented in the literature. | PMC9890770 | |
Authors’ information | N/A | PMC9890770 | ||
Funding {4} | Open Access funding enabled and organized by Projekt DEAL. The P.E.L.I.O.N trial is financed by the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung BMBF, Förderkennzeichen 01KG2023). The funding body has no influence on study design and conduct, analysis and interpretation of data as well as submission of the report for publication. | PMC9890770 |
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