Bolus Arm Research Articles

Comparison Between Pantoprazole Intermittent Dosing and Continuous Infusion in Suspected Upper Gastrointestinal Bleeding Prior to Endoscopy: Impact of a Pharmacist-Driven Protocol to Reduce Utilization of Pantoprazole Continuous Infusion.

Current practice for patients with suspected or confirmed upper gastrointestinal bleeding (GIB) is to utilize a proton pump inhibitor (PPI) bolus followed by a continuous infusion for 72 hours. Literature has shown similar outcomes with intermittent bolus dosing compared to continuous infusion. Substitution would lead to reduced costs and utilization of resources. This was a retrospective case-control study conducted via chart review. Utilizing electronic healthcare record reports, patients in the control arm were screened for inclusion if they received a pantoprazole continuous infusion from December 1, 2020, to March 31, 2021. A total of 38 patients were included in the control arm. Patients in the experimental arm were screened for inclusion with pantoprazole intermittent therapy from January 1, 2022, to June 30, 2022. A total of 60 patients were included in the experimental arm. The primary outcome was a 30-day GIB recurrence. Secondary outcomes included 30-day hospital readmission, 30-day Clostridioides difficile (C. difficile), hospital length of stay (LOS), and number of pantoprazole vials utilized. There was a 65% reduction in the 30-day GIB recurrence in the intermittent bolus arm compared to the continuous infusion arm. Thirty-day hospital readmission was 57% lower in the intermittent bolus arm compared to the continuous infusion arm. The LOS between the two arms was almost identical with the median being five days for the intermittent bolus arm and the median being four days for the continuous infusion arm. The 30-day C. difficile infection rate had 5% of patients acquiring C. difficile in the intermittent bolus arm and 2.5% in the continuous infusion arm. The intermittent bolus arm used 55% fewer pantoprazole vials than the continuous infusion arm. In hospitalized patients, the utilization of pantoprazole intermittent bolus is not only comparably efficacious but potentially represents a safer and economically advantageous alternative compared to the current guideline recommendation of a 72-hour pantoprazole continuous infusion. Further studies could provide more robust data to support our findings and challenge the current recommendation for patients who meet the indication criteria.

The Impact of Omitting 5-FU Bolus From mFOLFOX6 Chemotherapy Regimen on Hematological Adverse Events Among Patients With Metastatic Colorectal Cancer.

Metastatic colorectal cancer (mCRC) is often treated with a mFOLFOX6 regimen. The 5-fluorouracil (5-FU) bolus is often omitted from the regimen to reduce the risk of hematological adverse events (AEs) in patients with poor performance status. We aimed to investigate the incidence of hematological AEs in Asian patients with mCRC who were treated with the mFOLFOX6 with and without 5-FU bolus dosing. This retrospective chart review was conducted at King Chulalongkorn Memorial Hospital, Thailand from June 2021 to June 2022. The primary endpoints were hematological AEs. Secondary endpoints were any AEs. The comparison of continuous data was conducted with an independent t-test. The Chi-squared test was used to compare categorical data. From 110 patients, we found that hematological and non-hematological AEs of any grade in the two groups were not significantly different. However, patients in the bolus arm had a significantly lower absolute neutrophil count (ANC) than those in the non-bolus arm (mean difference = 43.13 (95% confidence interval (CI): 20.74, 65.51), P-value = 0.0002). A subgroup analysis in patients who received first-line treatment with mFOLFOX6 showed that the bolus arm had a significantly lower ANC (mean difference = 46.01 (95% CI: 19.99, 72.03), P-value = 0.0007). mCRC patients who were treated with bolus 5-FU had lower ANC. The 5-FU bolus omission from the mFOLFOX6 regimen may be required in patients with a high risk of neutropenia.

Long-term Prolonged-release Tacrolimus-based Immunosuppression in De Novo Kidney Transplant Recipients: 5-Y Prospective Follow-up of Patients in the ADVANCE Study.

ADVANCE was a 24-wk, randomized, open-label, phase-4 study. De novo KTPs received PR-T with basiliximab and mycophenolate mofetil and were randomized to receive an intraoperative corticosteroid bolus plus tapered corticosteroids until day 10 (arm 1) or an intraoperative corticosteroid bolus (arm 2). In this 5-y, noninterventional follow-up, patients received maintenance immunosuppression according to standard practice. The primary endpoint was graft survival (Kaplan-Meier). Secondary endpoints included patient survival, biopsy-confirmed acute rejection-free survival, and estimated glomerular filtration rate (4-variable modification of diet in renal disease). Follow-up study included 1125 patients. Overall graft survival at 1 and 5 y posttransplantation was 93.8% and 88.1%, respectively, and was similar between treatment arms. At 1 and 5 y, patient survival was 97.8% and 94.4%, respectively. Five-year graft and patient survival rates in KTPs who remained on PR-T were 91.5% and 98.2%, respectively. Cox proportional hazards analysis demonstrated similar risk of graft loss and death between treatment arms. Five-year biopsy-confirmed acute rejection-free survival was 84.1%. Mean ± standard deviation values of estimated glomerular filtration rate were 52.7 ± 19.5 and 51.1 ± 22.4 mL/min/1.73 m2 at 1 and 5 y, respectively. Fifty adverse drug reactions were recorded, probably tacrolimus-related in 12 patients (1.5%). Graft survival and patient survival (overall and for KTPs who remained on PR-T) were numerically high and similar between treatment arms at 5 y posttransplantation.

P625 Randomized controlled trial on the effect of megaboluses of intravenous corticosteroids added to oral corticosteroids in the treatment of moderately active ulcerative colitis

Abstract Background Oral corticosteroids remain as the first-line treatment for moderately active ulcerative colitis (UC). In controlled studies, they achieved clinical remission in 30-60% of patients at 30 days. In severe systemic diseases, intravenous bolus administration of methyl-prednisolone accelerates the clinical response and increases the therapeutic efficacy of corticosteroids. Aims To assess the additive effect of IV boluses of methyl-prednisolone in an outpatient Schedule on the remission rate of moderately active UC. Methods Randomized, controlled, open study. Inclusion criteria: 1) moderately active (complete May 6-10) distal or extensive UC; 2) never exposed to immunosuppressants or biologicals; 3) without corticosteroid therapy within the last 6 months. Randomization to oral prednisone 60mg/day (ORAL arm) or the same regimen preceded by intravenous boluses of 500mg methyl-prednisolone for 3 days (BOLUS arm). Primary endpoint: clinical and endoscopic remission at week 8 as defined by a complete Mayo score <3 with no subscore >1. Results are expressed in frequencies, medians and interquartile range. Results 75 patients (39 ORAL, 36 BOLUS) were included, 24% at diesease onset, 49% extensive UC, 68% were on maintenance with oral 5ASA, and 31% had ever received systemic corticosteroids. At baseline, complete Mayo score was 9 (7-9), with C-reactive protein 9.25 mg/L (3.85-20.17) and fecal calprotectin 1430 ug/g (501-2702), with no differences in the baseline clinical-epidemiological characteristics between both treatment arms. At 8 weeks, 37% of patients achieved clinical-endoscopic remission (47% BOLUS vs 28% ORAL; p=0.089), 52% mucosal healing -Mayo endoscopic subscore <2- (61% BOLUS vs 44% ORAL; p=0.129), 24% endoscopic remission -Mayo endoscopic=0- (31% BOLUS vs 18% ORAL; p=0.202) and 55% clinical remission - partial Mayo score <2- (61% BOLUS vs 49% ORAL; p=0.281). No associated factors with clinical-endoscopic remission were identified. Conclusion The addition of three intravenous megaboluses at the beginning of a conventional regimen of oral prednisone achieves a non-significant increase in clinical-endoscopic remission rates at the end of corticosteroid treatment in patients with moderately active UC.

Are Diagnostic Computed Tomography Chest Scans Sufficient for Detecting Supraclavicular in Initial Breast Cancer Staging?

<h3>Purpose/Objective(s)</h3> Initial staging workup strategies for locally advanced or suspected stage IV breast cancer can include computed tomography (CT) of the chest, abdomen, pelvis (CAP) and bone scan or, alternatively, a whole-body positron emission tomography/computed tomography (PET/CT). Variations in intravenous contrast injection site and bolus timing, arm positioning, and acquisition techniques on a CT chest scan could limit visualization of supraclavicular (SCV) and supracricoid cervical lymph nodes, which are critical for staging, prognosis, and treatment recommendations. The study's purpose is to determine whether there is a difference between the incidences of SCV and cervical lymphadenopathy detected on staging CT CAP versus PET/CT scans. <h3>Materials/Methods</h3> The records of consecutive newly diagnosed breast cancer patients who received initial staging scans at a single institution from 2012 to 2017 were reviewed in a HIPAA compliant, institutional review board-approved study. De-identified information was reviewed for inclusion: new breast cancer diagnosis, >18 years old, and availability of staging. Exclusion criteria were prior breast cancer treatment, re-staging for known recurrence, and nondiagnostic imaging examinations. Radiology reports were searched for SCV and cervical lymphadenopathy to determine the incidence detected by each imaging modality. A board certified neuroradiologist reviewed and characterized scans that noted cervical or SCV lymphadenopathy. <h3>Results</h3> The initial search resulted in 3,126 PET/CT and 631 CT CAP scans with 588 patients fulfilling the inclusion criteria. PET/CT scans had been performed in 539 patients and 49 received CT CAP and bone scans. The two groups were well matched by stage (Table 1). Metastatic cervical lymphadenopathy was detected by PET-CT in 50 patients (7.9%) versus two (3.7%) with CT CAP. Out of the 50 patients who had cervical lymphadenopathy detected by PET-CT, 30 (60%) had metastatic cervical lymphadenopathy above the level of the lung apex, the typical upper extent of a CT chest field of view. Although 25 (50%) patients had additional areas of distant metastatic disease, cervical lymphadenopathy above the thoracic inlet was the only site of distant metastasis for 13 patients (26%), and would not have been detectable by CT CAP. <h3>Conclusion</h3> PET/CT detected more cervical and SCV lymphadenopathy than CT CAP in initial staging scans for breast cancer, with 60% of those detected on PET/CTs in areas that would have been occult on standard CT chest scans. Such nodal involvement constituted the only site of distant metastatic disease in 26% of the patients. Thus, dedicated CT neck imaging may be a reasonable addition to CT CAP as an initial staging strategy to determine accurate staging and radiation treatment field volumes and borders.

883-P: Utility of CGM Technology in the Inpatient Setting

Effective inpatient insulin management is an important safety issue for our patients. Barriers to appropriate insulin use include incorrect timing of prandial insulin administration, failure to administer basal insulin to persons with type 1 DM, and insulin dosage overtreatment resulting in severe hypoglycemia. We studied the use of Abbott professional (blinded) Libre sensor in patients either on basal bolus insulin therapy (n=20) or on IV insulin (n=20) as a potential aide in minimizing insulin errors. The Wake Forest Baptist Health IRB approved the study and all subjects studied signed informed consent. Continuous BG data were aggregated for each subject and compared to point of care blood glucose (BG), iStat, or lab chemistry values. BG results were assessed for comparability (CGM versus Standard BG testing) and in ability to detect hypoglycemia early in those subjects experiencing hypoglycemia. Analysis of the basal bolus insulin arm revealed that an average difference of standard of care versus CGM glucose reading of 44.80 mg/dL. Differences in basal bolus arm BG comparing 24-hour average CGM glucometric data to standard of care was similar at 43.56 mg/dL. One third of participants in the basal bolus arm had at least one episode of hypoglycemia (BG &amp;lt; 70 mg/dL.) The average BG value in those experiencing a hypoglycemic event in our study group was 59 mg/dL on Standard BG testing. In retrospective review, all episodes of hypoglycemia were detected earlier on CGM technology. In one occurrence, hypoglycemia noted 6 hours sooner on CGM. CGM data consistently shows lower BG values than those using standard methods. Additional data including difference in insulin dosing based on CGM vs. Standard BG testing following completion of the IV insulin arm will be discussed. Disclosure J.A. Aloi: Consultant; Self; Medtronic. Research Support; Self; Medtronic. C.E. Price: None. Funding Wake Forest Baptist Medical Center

Impact of empirically eliminating 5-fluorouracil (5-FU) bolus and leucovorin (LV) in patients with metastatic colorectal cancer (mCRC) receiving first-line treatment with mFOLFOX6.

4022 Background: Systemic chemotherapy with a 5-FU-based regimen, such as mFOLFOX6, is the preferred first line treatment option for mCRC. Due to hematologic toxicities associated with the 5-FU bolus component, providers may choose to eliminate it empirically in patients receiving palliative therapy. This study aimed to assess the impact of empirically eliminating the 5-FU bolus and LV from first line treatment with mFOLFOX6 in mCRC. Methods: This was a retrospective chart review of patients ≥ 18 years old with mCRC receiving palliative first line mFOLFOX6 chemotherapy with (bolus) or without (non-bolus) the 5-FU bolus and LV components from January 1, 2015 through August 31, 2019 at Moffitt Cancer Center. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR) defined as partial response and stable disease at first scan, utilization of growth factor support and safety. Results: Data analysis cutoff was December 31, 2019, with 61 patients included in the bolus arm and 72 in the non-bolus arm. Median follow-up time was 21.8 months. No difference was found in median PFS (8.12 vs. 6.64 months, p=0.787) or OS (29.36 vs. 21.6 months, p=0.395) between the bolus and non-bolus arms, respectively. Observed DCR at first scan was similar between both arms (47.3% vs. 52.7%, p=0.44). Utilization of growth factor support was significantly higher in the bolus arm (73.7% vs. 26.3%, p=0.012). Fewer grade ≥ 3 treatment-related hematologic adverse events (AE) were seen in the non-bolus arm (37.7% vs. 22.2%, p=0.058) (table). Conclusions: This is the only study to date that analyzed the impact of empirically eliminating 5-FU bolus and LV from first line palliative therapy with mFOLFOX6 in mCRC. Results showed no significant difference in median PFS or OS. Despite reduced growth factor utilization, the non-bolus arm demonstrated a favorable safety profile with less treatment-related hematologic grade ≥ 3 AE. The results of this study warrant consideration of empirically eliminating 5-FU bolus and LV from the mFOLFOX6 regimen to avoid additive toxicities without negatively impacting efficacy. [Table: see text]

Intramuscular injection, intravenous infusion, and intravenous bolus of oxytocin in the third stage of labor for prevention of postpartum hemorrhage: a three-arm randomized control trial

BackgroundOxytocin for postpartum hemorrhage (PPH) prophylaxis is commonly administered by either intramuscular (IM) injection or intravenous (IV) infusion with both routes recommended equally and little discussion of potential differences between the two. This trial assesses the effectiveness and safety of 10 IU oxytocin administered as IM injection versus IV infusion and IV bolus during the third stage of labor for PPH prophylaxis.MethodsIn two tertiary level Egyptian maternity hospitals, women delivering vaginally without exposure to pre-delivery uterotonics were randomized to one of three prophylactic oxytocin administration groups after delivery of the baby. Blood loss was measured 1 h after delivery, and side effects were recorded. Primary outcomes were mean postpartum blood loss and proportion of women with postpartum blood loss ≥500 ml in this open-label, three-arm, parallel, randomized controlled trial.ResultsFour thousand nine hundred thirteen eligible, consenting women were randomized. Compared to IM injection, mean blood loss was 5.9% less in the IV infusion arm (95% CI: -8.5, − 3.3) and 11.1% less in the IV bolus arm (95% CI: -14.7, − 7.8). Risk of postpartum blood loss ≥500 ml in the IV infusion arm was significantly less compared to IM injection (0.8% vs. 1.5%, RR = 0.50, 95% CI: 0.27, 0.91). No side effects were reported in any arm.ConclusionsIntravenous oxytocin is more effective than intramuscular injection for the prevention of PPH in the third stage of labor. Oxytocin delivered by IV bolus presents no safety concerns after vaginal delivery and should be considered a safe option for PPH prophylaxis.Trial registrationclinicaltrials.gov #NCT01914419, posted August 2, 2013.

A randomized trial comparing the pharmacology of magnesium sulfate when used to treat severe preeclampsia with serial intravenous boluses versus a continuous intravenous infusion

BackgroundMagnesium sulfate is the preferred pharmacological intervention for the prevention and treatment of eclamptic seizures in pregnancy. Pain associated with intramuscular injections and the need for an electronic infusion pump for use intravenously represent significant barriers to broader utilization. We hypothesize that an alternative regimen based on serial intravenous (IV) boluses can produce serum concentrations comparable to those produced by a continuous infusion.MethodsAn open-label randomized trial was performed at two hospitals in Egypt. Women with severe preeclampsia were eligible and enrolled between January 2015 and February 2016. Two hundred subjects were randomized by random numbers generated centrally in distinct blocks and stratified by study site. They were assigned to a continuous infusion arm, (4 g loading dose with 1 g/hr. continuous infusion) or a serial IV bolus arm, (6 g loading dose with 2 g bolus every 2 h using a Springfusor® pump). Sparsely sampled magnesium serum concentrations were collected, nonlinear mixed effect modeling was conducted and Monte Carlo simulations were used to generate 200 simulated subjects in each treatment arm. The simulated populations were used to determine area under the concentration-time curve (AUC) as a measure of total drug exposure and compared.ResultsSimulated area under the magnesium serum concentration-time curve was significantly higher in the serial IV bolus arm than in the continuous infusion arm (1107 ± 461 mmol•min /L vs. 1010 ± 398 mmol•min /L, (P = 0.02)). Four percent of women in the serial bolus arm considered the treatment unacceptable or very unacceptable compared to 2% in the continuous infusion arm, (P = 0.68).ConclusionsSerial IV boluses achieve serum magnesium concentrations statistically significantly higher but clinically comparable to those achieved with a continuous infusion and offer a third option for the administration of MgSO4 to women with preeclampsia that may reduce barriers to utilization.Trial registrationTrial no. NCT02091401, March 17, 2014.

A randomised study for optimising crossover from ticagrelor to clopidogrel in patients with acute coronary syndrome

Ticagrelor has been endorsed by guidelines as the P2Y12 inhibitor of choice in patients with acute coronary syndrome. Clinically, some patients on ticagrelor will require a switch to clopidogrel; however, the optimal strategy and pharmacodynamics effects of switching remain unknown. Patients with an indication to switch were randomly assigned to either a bolus arm (Clopidogrel 600 mg bolus followed by 75 mg daily, n=30) or a no-bolus arm (Clopidogrel 75 mg daily, n=30). Blood samples were collected at baseline, 12, 24, 48, 54, 60 and 72 hours (h) for assessment of platelet reactivity. The primary outcome was P2Y12 reactivity units (PRU) at 72 h. Secondary outcomes included: PRUs at each time point, incidence of high on-treatment platelet reactivity (HPR), major adverse cardiac events (MACE) and TIMI bleeding at 30 days. Serial PRUs increased after switching to clopidogrel in both groups. At 72 h, no difference in PRU was observed (165.8 ± 71.0 vs 184.1 ± 67.7, bolus vs no bolus, respectively, p=0.19). At 48 h the PRUs were significantly lower in the bolus arm (114 ± 73.1 vs 165.1 ± 70.5, respectively; p=0.0076) and at 72 h, there was a significant reduction in incidence of HPR (26.7 % vs 56.7 %, p=0.02). No differences in MACE or TIMI bleeding were observed. Although a bolus strategy was not associated with improved platelet inhibition at 72 h; at 48 h, platelet inhibition was superior with reduced incidence of HPR. Larger studies will be required to determine its clinical significance. Until then, decision for giving a bolus of clopidogrel at the time of a switch may in part be dependent on the indication for switching, especially if there are concerns for bleeding risk.

Dextrose boluses versus burette dextrose infusions in prevention of hypoglycemia among preterms admitted at Mulago Hospital: an open label randomized clinical trial.

Hypoglycemia is a major cause of morbidity and mortality among preterm infants and its management remains a challenge in resource limited settings. Use of dextrose infusion by the recommended infusion pumps is not feasible in our environment due to their high costs and yet the current use of mini dextrose boluses with syringes as adapted at Mulago national referral and tertiary teaching hospital has unknown efficacy in prevention of hypoglycemia. We determined the efficacy of dextrose infusions by burettes versus two hourly dextrose boluses in prevention of hypoglycemia among preterms admitted in the first 72 hours at Special Care Unit, Mulago Hospital. One hundred and forty preterms aged 0 to 24 hours of life were randomized to receive 10% IV dextrose either as mini boluses or by infusion using burettes in an open label clinical trial. Blood glucose was measured at 0, two hourly for next 6 hours, 6 hourly for next 12 hours and thereafter 12 hourly until end of 72 hours following admission. Primary end point was incidence of hypoglycemia (random blood sugar (RBS) < 2.6 mmol/l) which was expressed as relative risk (RR). Efficacy of the dextrose infusion was computed using 1-RR. From February 2012 to April 2012, 68 preterms in the bolus arm and 72 in the infusion arm were studied. Hypoglycemia was detected in 34% (48/140). The incidence of hypoglycemia in the bolus arm was 59% (40/68) compared to 11% (8/72) in the infusion arm (RR; 0.19, 95% CI; 0.09-0.37). Efficacy (1-RR) of infusion by burettes versus boluses in prevention of hypoglycemia among preterms was 0.81 (95% CI; 0.63-0.90). Continuous 10% dextrose infusion by burettes reduced the incidence of hypoglycemia by 81% in the first 72 hours of admission compared to two hourly 10% mini dextrose boluses among preterms admitted at Special Care Unit, Mulago Hospital. (ClinicalTrials.gov Identifier: NCT01688674).

Randomized Clinical Trial of the 2 mg Hydromorphone Bolus Protocol Versus the “1+1” Hydromorphone Titration Protocol in Treatment of Acute, Severe Pain in the First Hour of Emergency Department Presentation

We compare a high initial dose of 2 mg intravenous hydromorphone against titration of 1 mg intravenous hydromorphone followed by an optional second dose. Patients aged 21 to 64 years with severe pain were randomly allocated to 2 mg intravenous hydromorphone in a single bolus or the "1+1" hydromorphone titration protocol. 1+1 Patients received 1 mg intravenous hydromorphone followed by a second 1 mg dose 15 minutes later if they answered yes when asked, Do you want more pain medication? The primary outcome was the between-group difference in proportion of patients who declined additional analgesia at 60 minutes. Of the 350 enrolled patients, 334 had sufficient data for analysis. The proportion who declined additional analgesics was 67.5% in the 2 mg bolus arm and 67.3% in the 1+1 titration arm (difference 0.2%; 95% confidence interval -9.7% to 10.2%). The between-group difference in numeric rating scale pain scores was 0.4 numeric rating scale units (95% confidence interval -0.3 to 1.1). The incidence of adverse effects was similar; 42.3% of 1+1 patients achieved satisfactory analgesia at 1 hour with only 1 mg hydromorphone. A hydromorphone 1+1 titration protocol provides similar pain relief to an initial 2 mg bolus dose, with no apparent clinical advantage to the latter. The 1+1 titration protocol had an opioid-sparing effect because 50% less opioid was needed to achieve satisfactory analgesia for 42.3% of patients allocated to this protocol.

Hyperglycemic Emergencies in Adults

Hyperglycemic Emergencies in Adults

Exploring mechanisms of excess mortality with early fluid resuscitation: insightsfrom the FEAST trial

BackgroundEarly rapid fluid resuscitation (boluses) in African children with severe febrile illnesses increases the 48-hour mortality by 3.3% compared with controls (no bolus). We explored the effect of boluses on 48-hour all-cause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. We hypothesize that boluses may cause excess deaths from neurological or respiratory events relating to fluid overload.MethodsPre-defined presentation syndromes (PS; severe acidosis or severe shock, respiratory, neurological) and predominant terminal clinical events (cardiovascular collapse, respiratory, neurological) were described by randomized arm (bolus versus control) in 3,141 severely ill febrile children with shock enrolled in the Fluid Expansion as Supportive Therapy (FEAST) trial. Landmark analyses were used to compare early mortality in treatment groups, conditional on changes in shock and hypoxia parameters. Competing risks methods were used to estimate cumulative incidence curves and sub-hazard ratios to compare treatment groups in terms of terminal clinical events.ResultsOf 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severe metabolic acidosis or severe shock PS, 625 (26%) had a respiratory PS and 976 (41%) had a neurological PS, either alone or in combination. Mortality was greatest among children fulfilling criteria for all three PS (28% bolus, 21% control) and lowest for lone respiratory (2% bolus, 5% control) or neurological (3% bolus, 0% control) presentations. Excess mortality in bolus arms versus control was apparent for all three PS, including all their component features. By one hour, shock had resolved (responders) more frequently in bolus versus control groups (43% versus 32%, P <0.001), but excess mortality with boluses was evident in responders (relative risk 1.98, 95% confidence interval 0.94 to 4.17, P = 0.06) and 'non-responders' (relative risk 1.67, 95% confidence interval 1.23 to 2.28, P = 0.001), with no evidence of heterogeneity (P = 0.68). The major difference between bolus and control arms was the higher proportion of cardiogenic or shock terminal clinical events in bolus arms (n = 123; 4.6% versus 2.6%, P = 0.008) rather than respiratory (n = 61; 2.2% versus 1.3%, P = 0.09) or neurological (n = 63, 2.1% versus 1.8%, P = 0.6) terminal clinical events.ConclusionsExcess mortality from boluses occurred in all subgroups of children. Contrary to expectation, cardiovascular collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid resuscitation. These results should prompt a re-evaluation of evidence on fluid resuscitation for shock and a re-appraisal of the rate, composition and volume of resuscitation fluids.Trial registrationISRCTN69856593

Immediate Post‐Administration Safety of Bolus Gentamicin

ABSTRACTAimTo compare the adverse effect profile in the 1‐hour post‐administration period for a 3‐minute gentamicin 40 mg/mL bolus with a 30‐minute gentamicin 1 mg/mL infusion.MethodAustralian guidelines recommend that IV gentamicin doses greater than 240 mg need to be diluted and infused over 20 to 120 minutes, while lower doses can be administered as a bolus using the undiluted injection solution (40 mg/mL) over 2 to 5 minutes. Patients receiving at least 2 gentamicin doses of 240 mg or greater were administered an undiluted IV bolus (40 mg/mL) over 3 minutes on one occasion and a 1 mg/mL infusion over 30 minutes on another in a randomised crossover design. Patients were assessed for pain, swelling and redness at the injection site, tinnitus, dizziness, headache and nausea at 0, 15, 30 and 60 minutes after administration of the gentamicin dose.Results47 patients completed the study. Mean administration rates in the bolus and infusion arms were 105 ± 27 mg/min and 12 ± 8.1 mg/min, respectively. During the bolus phase, more patients complained of increased pain at the injection site immediately after completion of the bolus dose (34% vs 9%, p &lt; 0.01), but this effect had dissipated at the 15‐minute assessment (4% vs 4%). There were no differences in any other parameters at any of the assessment times.ConclusionBolus gentamicin of up to 480 mg (undiluted 40 mg/mL injection) administered over 3 minutes can be used as an alternative to a diluted gentamicin infusion, but may cause transient IV site pain.

A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: A Hellenic Cooperative Oncology Group study

BackgroundColon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer.MethodsThe study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m2 intravenously (IV), LV 200 mg/m2 and 5FU 450 mg/m2 bolus (Arm A) versus LV 200 mg/m2 and 5FU 500 mg/m2 IV bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two-week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years.ResultsThe probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms.ConclusionsIrinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN12610000148077

Epigenetic Priming with Decitabine Prior to Standard Induction Chemotherapy in Less-Than-Favorable Risk Acute Myelogenous Leukemia (AML).

Abstract 3079Poster Board III-16Epigenetic silencing of tumor suppressor genes (TSGs) is among the most common acquired abnormalities observed in AML and is prototypically linked to DNA methylation. Aberrant DNA methylation is most prevalent in adverse risk AML patients (Melki, Vincent et al. 1999; Toyota, Kopecky et al. 2001). Reactivated expression of TSGs is commonly implicated in the clinical activity of DNA hypomethylating agents since these genes often have roles in cellular differentiation, apoptosis, DNA repair, and checkpoint control (Jones and Taylor 1980; Pinto, Zagonel et al. 1989; Petti, Mandelli et al. 1993; Schimmer, Pedersen et al. 2003; Schmelz, Sattler et al. 2005; Schmelz, Wagner et al. 2005; Tamm, Wagner et al. 2005). We, and others, have demonstrated that DNA hypomethylating agents can sensitize resistant cancer cells to cytotoxic agents in vitro (Avramis, Mecum et al. 1989; Anzai, Frost et al. 1992; Plumb, Strathdee et al. 2000; Fulda, Kufer et al. 2001; Niitsu, Hayashi et al. 2001; Arnold, Goel et al. 2003; Eramo, Pallini et al. 2005; Kanda, Tada et al. 2005; Qiu, Mirkin et al. 2005) yet this approach has been sparsely studied in clinical trials. We hypothesized that pre-treatment with a hypomethylating agent would increase the efficacy of standard induction chemotherapy for AML. DesignWe conducted a phase I dose-escalation study of decitabine administered just prior to a single, standard induction with infusional cytarabine (100 mg/m2 for 7 days) and daunorubicin (60 mg/m2 × 3 doses) as initial treatment for patients with less-than favorable risk AML. Three dose levels of decitabine (20 mg/m2 for 3, 5 or 7 days), delivered either as a bolus (Arm A) or by continuous infusion (Arm B), were used as priming for standard induction chemotherapy. PatientsAt current data cut-off, 25 (of 30 patients planned) were fully evaluable: median age was 56 (range 23–60); 21 (84%) patients had adverse risk AML because of karyotype (No. 15, 60%), or other adverse features (FLT3-ITD or antecedent hematologic disorder, No. 11, 44%), and the remaining 4 (16%) patients had intermediate risk AML. Toxicity was similar to that of standard induction chemotherapy alone. Two patients treated at the highest dose level had grade 3 mucositis that resolved prior to count recovery. We observed no excess hematologic toxicity and all patients had peripheral blood count recovery within 30 days or were found to have persistent AML. There was no induction mortality and no patients required ICU transfer. A maximum tolerated dose was not achieved. ResponseTwenty-one patients (84%) responded to therapy: 14 CR (56%), 7 PR (28%). Of the patients with PR to protocol treatment, 5 achieved remission with a second, standard induction bringing the overall CR rate to 76%. The final cohort of patients is currently accruing. All patients went on to receive additional AML therapy and 14 have received an allogeneic HSCT. Pharmacodynamic analyses of DNA hypomethylation prior to and immediately following priming demonstrate genome-wide DNA hypomethylation at all dose levels. Detailed analyses of DNA methylation are ongoing. ConclusionComplete remission is requisite for the cure of AML and this study demonstrates that it is safe to combine the epigenetic modifier, decitabine, with full-dose, standard, cytotoxic chemotherapy as an approach to improve remission rates. Our results suggest that epigenetic priming is potentially superior to standard induction therapy alone as initial therapy for patients with less than favorable risk AML and provide the foundation for a subsequent phase II study. DisclosuresOff Label Use: Phase I study of decitibine use in AML.

A randomised phase III trial of adjuvant radio-chemotherapy comparing Irinotecan, 5FU and Leucovorin to 5FU and Leucovorin in patients with rectal cancer: A Hellenic Cooperative Oncology Group Study

The primary objective was to compare the 3-year survival of rectal cancer patients randomised postoperatively to irinotecan (IRI), Leucovorin (LV) and bolus 5-fluorouracil (5FU) or LV-bolus 5FU with radiotherapy. Secondary objectives included disease-free survival, local relapse and toxicity.The study included 321 eligible patients. The treatment consisted of weekly administration of IRI 80mg/m2 intravenously (IV), LV 200mg/m2 and 5FU 450mg/m2 bolus (arm A) versus LV 200mg/m2 and 5FU 450mg/m2 IV bolus (arm B). One cycle included four infusions and treatment was continued for a total of six cycles. The first cycle was followed by pelvic irradiation plus 5FU.There were no differences between the arms in 3-year overall, disease-free and local relapse-free survival. Grades 3 and 4 toxicity was similar in both the arms with the exception of leucopaenia, neutropaenia and alopecia, which were higher in the IRI arm.IRI added to adjuvant radiochemotherapy with LV and bolus 5FU was not shown to improve survival, whereas the incidence of severe leucopaenia was significantly higher in the IRI arm.

SNS-595 Demonstrates Clinical Responses in a Phase 1 Study in Acute Leukemia.

SNS-595 is a replication-dependent DNA damaging agent that causes irreversible G2 arrest and rapid apoptosis. A secondary mechanism for SNS-595 is a unique inhibition of topoisomerase (topo) II that causes highly selective DNA damage with low dependence on topo II for its potent anti-tumor activity. SNS-595 is in phase 1 and 2 clinical trials in hematologic and solid malignancies, with clinical responses in AML, ovarian cancer, NSCLC and SCLC. We initiated an escalating-dose phase 1 trial of SNS-595, administered as a weekly x 3 (Arm A) or twice weekly x 2 bolus (Arm B), in patients (pts) with advanced or refractory acute leukemias.Objectives:1.establish safety, tolerability and MTD of SNS-595 given on 2 schedules;2.characterize PK;3.assess clinical activity;4.explore potential biomarkersMethods: SNS-595 was administered as a slow IV push on days 1, 8, 15 (Arm A) or days 1, 4, 8, 11 (Arm B). Minimum cycle length was 42 days (Arm A) and 39 days (Arm B). Additional cycles were permitted if pts achieved stable disease or better. The starting dose was 18 mg/m2 weekly on Arm A, and 9 mg/m2 twice weekly on Arm B and escalated by cohort. PK analyses for SNS-595 were performed during cycle 1. Pre- and post-dose bone marrow aspirates were obtained from a subset of pts to assess biomarkers.Results: To date, 49 pts have been enrolled and are evaluable, Arm A: 25 pts, Arm B: 24 pts, 31 males and 18 females with a median age of 65 years. Diagnoses included AML (43 pts), ALL (4 pts), and 1 pt each with acute lymphoblastic leukemia and acute biphenotypic leukemia. Most pts had relapsed/refractory leukemia from prior therapy (median 3 prior regimens (range 1–7)). Dose escalation has proceeded to 90mg/m2/d (Arm A) and dose-limiting toxicity (DLT) of Grade (G) 3 mucositis was observed in 3 pts on Arm B at the 50mg/m2 dose level. Five additional pts were accrued at 40mg/m2 on Arm B, the likely recommended phase 2 dose for Arm B. To date, 2/11 pts at 40mg/m2 have G3 mucositis (Arm B); 3 DLTs have been observed on Arm A - G4 myelosuppression at the 27mg/m2 weekly dose (also had progressive disease), prolonged myelosuppression at the 50mg/m2 weekly dose, and bowel obstruction at the 72mg/m2 weekly dose. Non-DLTs included nausea/vomiting and diarrhea; drug-related G3 & 4 events were limited to stomatitis (3 pts) and diarrhea (1 pt). Blast reduction (>95%) and response is associated with time above a threshold concentration of SNS-595; evidence of DNA-damage induced by SNS-595 is detectable post-dose. Clinical activity - reductions in marrow blasts to ≤5% - was noted at doses at or above 50mg/m2 (5 pts in Arm A) and 40mg/m2 (1 pt in Arm B). Complete Responses (CR) have been observed at the 50mg/m2 dose level (Arm A, 1 pt) and at the 40mg/m2 level (Arm B, 1 pt). A 3rd pt with AML and splenomegally achieved partial response at the 50mg/m2 dose level (Arm B) and had G3 mucositis. In addition, 1 pt with AML and splenomegally (at 72 mg/m2 Arm A) achieved clinical benefit with reduction in splenomegaly and blast counts.Conclusion: SNS-595 appears to be well-tolerated in pts with advanced leukemias, with preliminary signs of clinical activity as measured by CR and decreases in leukemic blasts. The likely recommended phase 2 dose in Arm B is 40mg/m2 twice weekly x 2 and further accrual to Arm A continues.

A Phase 1 Dose-Escalation Study of the Novel Cell Cycle Active Agent SNS-595 in Advanced Leukemias.

SNS-595 is a novel, cell cycle active cytotoxic naphthyridine analog that induces G2 arrest in a variety of preclinical tumor models. We initiated an escalating-dose phase 1 trial of SNS-595, administered as a weekly x 3 (arm A) or twice weekly x 2 bolus (arm B), in patients with advanced or refractory acute leukemias.Objectives: The primary objectives were to:establish safety, tolerability, and MTD of SNS-595 given on each schedule,characterize pharmacokinetics (PK) of SNS-595 when given on these schedules.Secondary objectives were:assessment of clinical activity,exploration of potential biomarkers.Methods: SNS-595 was administered as a slow IV push on days 1, 8, 15 (arm A) or days 1, 4, 8, 11 (arm B). Minimum cycle length was 42 days (arm A) and 39 days (arm B). Additional cycles were permitted if patients achieved stable disease or better. The starting dose was 18 mg/m2/d on arm A, and 9 mg/m2/d on arm B and escalated by cohort using a modified Fibonacci schema. PK analyses for SNS-595 were performed on plasma samples collected during cycle 1. Pretreatment peripheral blood and bone marrow aspirate samples were collected for exploratory analyses of the level and functional activity of the DNA damage repair proteins DNA-PK and MSH2.Results: To date, 21 patients have been enrolled and are evaluable in the live database, including 13 patients assigned to arm A and 8 assigned to arm B, 12 males and 9 females with a median age of 64 years. Diagnoses included AML (19 patients) and ALL (2 patients). All patients had disease refractory to or relapsed from prior therapy (median 3 prior regimens (range 1–6)). Dose escalation has proceeded to 50 mg/m2/d (arm A) and 19 mg/m2/d (arm B). No dose-limiting toxicities have been observed to date. Non-dose limiting toxicities included nausea/vomiting, diarrhea, and mucositis . Grade 4 neutropenic fever was observed in only one patient. Plasma exposures at the first two dose levels in each arm increased linearly, resulting in AUCs of 5.5 – 17.8 ughr/mL for 9–27 mg/m2 doses. CL, Vss, and terminal half-lives were similar to those reported previously in solid tumor patients, and averaged ~2 L/hr/m2, 58 L/m2, and 23 hr, respectively. No patients have achieved complete response to date, although 6 patients (distributed across all dosing groups) experienced >50% reductions in peripheral blasts following cycle 1.Conclusion: SNS-595 appears to be well-tolerated in patients with advanced leukemias, with preliminary and promising signs of clinical activity as measured by decreases in leukemic blasts. Bone marrow ablation has not yet been achieved; patient accrual and dose-escalation are ongoing.