The ICaRAS randomised controlled trial: Intravenous iron to treat anaemia in people with advanced cancer - feasibility of recruitment, intervention and delivery.

BACKGROUND: Anaemia is highly prevalent in people with advanced, palliative cancer yet sufficiently effective and safe treatments are lacking. Oral iron is poorly tolerated, and blood transfusion offers only transient benefits. Intravenous iron has shown promise as an effective treatment for anaemia but its use for people with advanced, palliative cancer lacks evidence. AIMS: To assess feasibility of the trial design according to screening, recruitment, and attrition rates. To evaluate the efficacy of intravenous iron to treat anaemia in people with solid tumours, receiving palliative care. DESIGN: A multicentre, randomised, double blind, placebo-controlled trial of intravenous iron (ferric derisomaltose, Monofer®). Outcomes included trial feasibility, change in blood indices, and change in quality of life via three validated questionnaires (EQ5D5L, QLQC30, and the FACIT-F) over 8 weeks. (ISRCTN; 13370767). SETTING/PARTICIPANTS: People with anaemia and advanced solid tumours who were fatigued with a performance status ⩽2 receiving support from a specialist palliative care service. RESULTS: 34 participants were randomised over 16 months (17 iron, 17 placebo). Among those eligible 47% of people agreed to participate and total study attrition was 26%. Blinding was successful in all participants. There were no serious adverse reactions. Results indicated that intravenous iron may be efficacious at improving participant haemoglobin, iron stores and select fatigue specific quality of life measures compared to placebo. CONCLUSION: The trial was feasible according to recruitment and attrition rates. Intravenous iron increased haemoglobin and may improve fatigue specific quality of life measures compared to placebo. A definitive trial is required for confirmation.

Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis.

Importance: Intravenous iron is recommended by many clinical guidelines based largely on its effectiveness in reducing anemia. However, the association with important safety outcomes, such as infection, remains uncertain. Objective: To examine the risk of infection associated with intravenous iron compared with oral iron or no iron. Data Sources: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials (RCTs) from 1966 to January 31, 2021. Ongoing trials were sought from ClinicalTrials.gov, CENTRAL, and the World Health Organization International Clinical Trials Search Registry Platform. Study Selection: Pairs of reviewers identified RCTs that compared intravenous iron with oral iron or no iron across all patient populations, excluding healthy volunteers. Nonrandomized studies published since January 1, 2007, were also included. A total of 312 full-text articles were assessed for eligibility. Data Extraction and Synthesis: Data extraction and risk of bias assessments were performed according to the Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) and Cochrane recommendations, and the quality of evidence was assessed using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Two reviewers extracted data independently. A random-effects model was used to synthesize data from RCTs. A narrative synthesis was performed to characterize the reporting of infection. Main Outcomes and Measures: The primary outcome was risk of infection. Secondary outcomes included mortality, hospital length of stay, and changes in hemoglobin and red blood cell transfusion requirements. Measures of association were reported as risk ratios (RRs) or mean differences. Results: A total of 154 RCTs (32 920 participants) were included in the main analysis. Intravenous iron was associated with an increased risk of infection when compared with oral iron or no iron (RR, 1.17; 95% CI, 1.04-1.31; I2 = 37%; moderate certainty of evidence). Intravenous iron also was associated with an increase in hemoglobin (mean difference, 0.57 g/dL; 95% CI, 0.50-0.64 g/dL; I2 = 94%) and a reduction in the risk of requiring a red blood cell transfusion (RR, 0.93; 95% CI, 0.76-0.89; I2 = 15%) when compared with oral iron or no iron. There was no evidence of an effect on mortality or hospital length of stay. Conclusions and Relevance: In this large systematic review and meta-analysis, intravenous iron was associated with an increased risk of infection. Well-designed studies, using standardized definitions of infection, are required to understand the balance between this risk and the potential benefits.

Differences in the On- and Off-Tumor Microbiota between Right- and Left-Sided Colorectal Cancer.

This study aims to determine differences in the on- and off-tumor microbiota between patients with right- and left-sided colorectal cancer. Microbiome profiling of tumor and tumor-adjacent biopsies from patients with right-sided (n = 17) and left-sided (n = 7) colorectal adenocarcinoma was performed using 16S ribosomal RNA sequencing. Off-tumor alpha and beta diversity were significantly different between right- and left-sided colorectal cancer patients. However, no differences in on-tumor diversity were observed between tumor locations. Comparing the off-tumor microbiota showed the right colon to be enriched with species of the Lachnoclostridium, Selenomonas, and Ruminococcus genera. Whereas the left colon is enriched with Epsilonbacteraeota phylum, Campylobacteria class, and Pasteurellales and Campylobacterales orders, in contrast, the on-tumor microbiota showed relatively fewer differences in bacterial taxonomy between tumor sites, with left tumors being enriched with Methylophilaceae and Vadin BE97 families and Alloprevotella, Intestinibacter, Romboutsia, and Ruminococcus 2 genera. Patients with left-sided colorectal cancer had large taxonomic differences between their paired on- and off-tumor microbiota, while patients with right-sided colorectal cancer showed relatively fewer taxonomic differences. Collectively, this suggests that the right and left colon show distinctive bacterial populations; however, the presence of a colonic tumor leads to a more consistent microbiota between locations.

Oral and Intravenous Iron Therapy Differentially Alter the On- and Off-Tumor Microbiota in Anemic Colorectal Cancer Patients.

Iron deficiency anemia is a common complication of colorectal cancer and may require iron therapy. Oral iron can increase the iron available to gut bacteria and may alter the colonic microbiota. We performed an intervention study to compare oral and intravenous iron therapy on the colonic tumor-associated (on-tumor) and paired non-tumor-associated adjacent (off-tumor) microbiota. Anemic patients with colorectal adenocarcinoma received either oral ferrous sulphate (n = 16) or intravenous ferric carboxymaltose (n = 24). On- and off-tumor biopsies were obtained post-surgery and microbial profiling was performed using 16S ribosomal RNA analysis. Off-tumor α- and ß-diversity were significantly different between iron treatment groups. No differences in on-tumor diversity were observed. Off-tumor microbiota of oral iron-treated patients showed higher abundances of the orders Clostridiales, Cytophagales, and Anaeroplasmatales compared to intravenous iron-treated patients. The on-tumor microbiota was enriched with the orders Lactobacillales and Alteromonadales in the oral and intravenous iron groups, respectively. The on- and off-tumor microbiota associated with intravenous iron-treated patients infers increased abundances of enzymes involved in iron sequestration and anti-inflammatory/oncogenic metabolite production, compared to oral iron-treated patients. Collectively, this suggests that intravenous iron may be a more appropriate therapy to limit adverse microbial outcomes compared to oral iron.

Rectal cancer: Watch-and-wait and continuing the rectal-preserving strategy with local excision for incomplete response or limited regrowth.

BACKGROUND: Deferral of conventional surgery for rectal cancer after neo-adjuvant chemo-radiotherapy is gaining increasing interest, particularly for patients who are too frail to undergo major surgery but also those who wish to avoid the adverse effects of major surgery. We elected to undertake a pragmatic approach to include all comers in a cohort with the aim of reflecting the clinical outcomes for patients on a deferral from conventional rectal surgery pathway, treated with neo-adjuvant chemo-radiation (CRT) with or without selective local excision (LE) offered to those who failed to demonstrate a complete clinical response (cCR). METHODS: Rectal cancer patients treated with neo-adjuvant CRT were stratified to a group of complete responders to CRT on a "watch and wait" (WW) pathway and a group who were treated with an additional local excision for persistent tumour. RESULTS: Regrowth was noted in 26% (11/42) in the WW group after 2 years surveillance, disease free survival was 94.5% (80-99%) at 1 year and 74.9% (44-76.4%) at 3 years. Recurrence was noted in 45% (10/22) in the CRT + LE group, disease free survival at 1 and 3 years was 74% (53.4-88.1) and 66.2% (45.6-82.4) respectively. CONCLUSION: A WW strategy for cCR is a viable pathway in the non-operative management of rectal cancer. We found the use of CRT + LE is a useful option for those who hope to avoid surgery but caution should be exercised due to substantially higher risk of recurrence.

Carbon Dioxide Embolism Associated With Transanal Total Mesorectal Excision Surgery: A Report From the International Registries.

BACKGROUND: Carbon dioxide embolus has been reported as a rare but clinically important risk associated with transanal total mesorectal excision surgery. To date, there exists limited data describing the incidence, risk factors, and management of carbon dioxide embolus in transanal total mesorectal excision. OBJECTIVE: This study aimed to obtain data from the transanal total mesorectal excision registries to identify trends and potential risk factors for carbon dioxide embolus specific to this surgical technique. DESIGN: Contributors to both the LOREC and OSTRiCh transanal total mesorectal excision registries were invited to report their incidence of carbon dioxide embolus. Case report forms were collected detailing the patient-specific and technical factors of each event. SETTINGS: The study was conducted at the collaborating centers from the international transanal total mesorectal excision registries. MAIN OUTCOME MEASURES: Characteristics and outcomes of patients with carbon dioxide embolus associated with transanal mesorectal excision were measured. RESULTS: Twenty-five cases were reported. The incidence of carbon dioxide embolus during transanal total mesorectal excision is estimated to be ≈0.4% (25/6375 cases). A fall in end tidal carbon dioxide was noted as the initial feature in 22 cases, with 13 (52%) developing signs of hemodynamic compromise. All of the events occurred in the transanal component of dissection, with mean (range) insufflation pressures of 15 mm Hg (12-20 mm Hg). Patients were predominantly (68%) in a Trendelenburg position, between 30° and 45°. Venous bleeding was reported in 20 cases at the time of carbon dioxide embolus, with periprostatic veins documented as the most common site (40%). After carbon dioxide embolus, 84% of cases were completed after hemodynamic stabilization. Two patients required cardiopulmonary resuscitation because of cardiovascular collapse. There were no deaths. LIMITATIONS: This is a retrospective study surveying reported outcomes by surgeons and anesthetists. CONCLUSIONS: Surgeons undertaking transanal total mesorectal excision must be aware of the possibility of carbon dioxide embolus and its potential risk factors, including venous bleeding (wrong plane surgery), high insufflation pressures, and patient positioning. Prompt recognition and management can limit the clinical impact of such events. See Video Abstract at http://links.lww.com/DCR/A961.