Sequential Drug Administration Research Articles

Administration sequences in single-day chemotherapy regimens for breast cancer: a comprehensive review from a practical perspective.

Breast cancer is one of the most prevalent malignant tumors globally, posing a severe threat to human life and health. Chemotherapy, a cornerstone in the treatment of breast cancer, often overlooks the sequence of drug administration within single-day regimens. This study aims to explore the impact of drug administration order on the efficacy and toxicity of combination chemotherapy protocols for breast cancer. Through a comprehensive review and analysis based on current evidence from evidence-based medicine, we delved into how the order of drug administration affects both efficacy and toxicity. We systematically classified and analyzed commonly used combination drug regimens, providing graded recommendations and a reasoned analysis to offer valuable references for clinical decision-making. Our findings indicate that the sequence of drug administration in complex combination chemotherapy protocols is not arbitrary but necessitates multifaceted considerations. Rational drug sequencing can maximize synergistic effects between drugs, thereby augmenting therapeutic efficacy while effectively mitigating drug-related adverse effects. Additionally, some drug labels and clinical trials have explicitly highlighted the therapeutic benefits of specific drug sequences. This study underscores the importance of considering the sequence of drug administration in clinical practice. It is recommended to prioritize the sequential drug administration according to official drug product labeling, while also considering factors such as the administration sequence from large randomized controlled trials, cell proliferation kinetics specific to cancer types, drug interactions, chronopharmacology, drug irritability, clinical experiences, and patient preferences. By taking these factors into account, the goal is to maximize treatment efficacy and minimize the occurrence of adverse reactions.

Nab-paclitaxel plus S-1 followed by gemcitabine-oxaliplatin as first-line alternating sequential treatment of pancreatic ductal adenocarcinoma.

Alternating sequential administration of drugs may be a promising approach to overcome chemotherapy resistance in advanced pancreatic ductal adenocarcinoma (PDAC). This study was an open-label, single-arm, and prospective trial included patients with untreated advanced PDAC. They received 2 cycles of NS regimen (nab-paclitaxel:125 mg/m2, intravenously injected on days 1 and 8, plus S-1:40-60 mg, orally twice per day for 1-14 days) followed by 2 cycles of GemOx regimen (gemcitabine, intravenously injected on days 1 and 8, and oxaliplatin: 130 mg/m2, intravenously injected on day 1). The primary efficacy endpoint was a progression-free survival rate at 6 months (PFSR-6m). The secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Specific mRNA transcripts were used to explore survival associated genes. Forty-two patients received a minimum of one treatment cycle, and of these, 30 patients completed one alternating treatment consisting of 4 cycles. The PFSR-6m was 71% (95% CI = 58%-87%). The median PFS and OS were 6.53 months (95% CI = 6.03-8.43) and 11.4 months (95% CI = 9.8-14.4), respectively. Common grades 3-4 hematological AEs included neutropenia 30.9%, leukopenia 26.2%, anemia 2.4%, and thrombocytopenia in 11.9%. Patients with OS > 10 months showed high expression of HLA-DQA2 while melanoma-associated antigen genes (MAGE) were notably upregulated in patients with OS < 10 months. The alternating sequential administration of the NS and GemOx regimens may be a novel approach for first-line chemotherapy in patients with advanced PDAC requiring further study (ClinicalTrials.gov Identifier: ChiCTR1900024867).

Optimizing Timing of Intraperitoneal Chemotherapy to Enhance Intravenous Carboplatin Concentration.

Despite advances in systemic chemotherapy, patients with gastric cancer (GC) and peritoneal metastases (PMs) continue to have poor prognoses. Intraperitoneal (IP) administration of Paclitaxel (PTX) combined with systemic chemotherapy shows promise in treating PMs from GC. However, methods of drug administration need to be optimized to maximize efficacy. In this study, we utilized a mouse model with PMs derived from a human GC cell line, administering PTX either IP or intravenously (IV), and Carboplatin (CBDCA) IV 0, 1, and 4 days after PTX administration. The PMs were resected 30 min later, and concentrations of PTX and CBDCA in resected tumors were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results indicated that PTX concentrations were higher with IP administration than with IV administration, with significant differences observed on days 0 and 1. CBDCA concentrations 4 days post-IP PTX administration were higher than with simultaneous IV PTX administration. These findings suggest that IP PTX administration enhances CBDCA concentration in peritoneal tumors. Therefore, sequential IV administration of anti-cancer drugs appears more effective than simultaneous administration with IP PTX, a strategy that may improve prognoses for patients with PMs.

PHARMACOGENETICS OF ANESTHESIOLOGICAL SUPPORT

Pharmacogenetics studies the relationship between a person’s individual genetic characteristics and the human body’sresponse to the action of various drugs, particularly the occurrence of undesirable side eff ects. Thanks to the development of the latest technologies and methods, this branch of medical genetics and clinical pharmacology is developing very actively. Data are being accumulated, special databases are being created with the aim of creating individual genetic passports in the future, which will allow the selection of personalized treatment schemes.Anesthesiology is a special area of pharmacogenetic research because, more than any other medical specialty, it ischaracterized by polypharmacy-the simultaneous or sequential administration of many drugs. The same dose of a drug may be inadequate for some patients and may be life-threatening or cause unwanted side eff ects for others. Today, information about genetic factors is being used by clinicians to prescribe drugs to tailor drug therapy to a patient’s genome. In anesthesiology, the principles of pharmacogenetics have been explained for neuromuscular blocking agents, opioid metabolism, different types of anesthetics, and postoperative nausea and vomiting. On the other hand, a large number of anesthetics have a narrow therapeutic index.This review summarizes the most recent data from the scientifi c literature on the pharmacogenetics of diff erent types ofanesthetics. Inhalational anesthetics are halogenated derivatives of methyl ethyl ether, the exact mechanism of action of which is not yet fully understood. One of the rare but very serious side eff ects of all halogenated anesthetics is malignant hyperthermia, a genetically determined autosomal dominant disorder that manifests as a hypermetabolic response to drug administration. The dosage of intravenous anesthetics should also be carefully determined, taking into account the patient’s age, cardiovascular, hepatic, and renal status, concomitant drug therapy, and genetic factors. Ontogeny and genetic variability of drug-metabolizing enzymes are interrelated because genetic variability in drug-metabolizing enzyme expression cannot be assessed until the required protein is suffi ciently expressed. Pharmacogenetic variants may contribute to unpredictable drug exposure at the same weight- based drug dose.There are a number of potentially clinically applicable pharmacogenetic data in newborns, but more research is needed toconfi rm these fi ndings and understand how to incorporate them into clinical care.The selection of drugs and dosing regimens based on a patient’s pharmacogenomic profi le may be an important part of thefuture of medicine. Personalized treatment based on the specifi c variants in the genome will ultimately reduce the incidence of side eff ects and length of hospital stay for patients and save healthcare costs. Although pharmacogenomics and its application in clinical practice are still in their infancy, different variants and their implications for many clinical areas, including anesthesiology, are emerging every day.

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

BackgroundWhile antibiotics remain our primary tools against microbial infection, increasing antibiotic resistance (inherent and acquired) is a major detriment to their efficacy. A practical approach to maintaining or reversing the efficacy of antibiotics is the use of other commonly used therapeutics, which show synergistic antibacterial action with antibiotics. Here, we investigated the extent of antibacterial synergy between the antibiotic gentamicin and the anti-inflammatory ketorolac regarding the dynamics of biofilm growth, the rate of acquired resistance, and the possible mechanism of synergy.MethodsControl (ATCC 12600, ATCC 35984) and clinical strains (L1101, L1116) of Staphylococcus aureus and Staphylococcus epidermidis with varying antibiotic susceptibility profiles were used in this study to simulate implant-material associated low-risk and high-risk biofilms in vitro. The synergistic action of gentamicin sulfate (GS) and ketorolac tromethamine (KT), against planktonic staphylococcal strains were determined using the fractional inhibitory concentration measurement assay. Nascent (6 h) and established (24 h) biofilms were grown on 316L stainless steel plates and the synergistic biofilm eradication activity was determined and characterized using adherent bacteria count, minimum biofilm eradication concentration (MBEC) measurement for GS, visualization by live/dead imaging, scanning electron microscopy, gene expression of biofilm-associated genes, and bacterial membrane fluidity assessment.ResultsGentamicin-ketorolac (GS-KT) combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both ‘low-risk’ and ‘high-risk’ biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin–ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties.ConclusionThe results of this study have a significant impact on the local administration of antibiotics and other therapeutic agents commonly used in the prevention and treatment of orthopaedic infections. Further, these results warrant the study of synergy for the concurrent or sequential administration of non-antibiotic drugs for antimicrobial effect.

Sequential intrapleural administration of fibrinolytic drugs and dornase alfa for empyema management. Treatment protocol based on its physicochemical stability

ObjectiveIntrapleural administration of fibrinolytics and dornase alfa has been shown in randomized studies to be able to reduce both the need for surgical debridement of empyema and the average hospital stay. However, its application in clinical practice is limited, probably due to the lack of protocols that simplify its administration. The present study aims to analyze the physicochemical stability of the simultaneous urokinase and dornase alfa administration for the subsequent development of a clinical practice use protocol. MethodIn vitro stability test of urokinase, dornase alfa and a combination of both. Its stability was evaluated as (i) absence of particles, (ii) color variation and (iii) pH changes at times 0, 30 minutes, 1, 2 and 4 hours at 37 °C. Each sample was prepared and analyzed in triplicate. ResultsIndividual solutions of urokinase and dornase alfa showed slight changes in pH, finding no changes in either color or presence of suspended particles. The urokinase and dornase alfa combination was not stable after 2 hours, when turbidity emerged due to flocculation and phase separation. After 4 hours, precipitate formation was found. A protocol for clinical use was developed based on urokinase and dornase alfa sequential administration, since it was not possible to guarantee the physicochemical stability of the simultaneous administration of both drugs. ConclusionsThe physicochemical stability data obtained does not allow to ensure a simultaneous administration of both drugs in a safe and effective way, thus a sequential administration protocol is proposed.

Alveolar–arterial oxygen gradient nonlinearly impacts the 28‐day mortality of patients with sepsis: Secondary data mining based on the MIMIC‐IV database

Lung is often implicated in sepsis, resulting in acute respiratory distress syndrome (ARDS). The alveolar-arterial oxygen gradient [D(A-a)O2 ] reflects lung diffusing capacity, which is usually compromised in ARDS. But whether D(A-a)O2 impacts the prognosis of patients with sepsis remains to be explored. Our study aims to investigate the association between D(A-a)O2 and 28-day mortality in patients with sepsis using a large sample, multicenter Medical Information Mart for Intensive Care (MIMIC)-IV database. We extracted a data of 35 010 patients with sepsis from the retrospective cohort MIMIC-IV database, by which the independent effects of D(A-a)O2 on 28-day death risk was investigated, with D(A-a)O2 as being the exposure variable and 28-day fatality being the outcome variable. Binary logistic regression and a two-piecewise linear model were employed to explore the relationship between D(A-a)O2 and the 28-day death risk after confounding factors were optimized including demographic indicators, Charlson comorbidity index (CCI), Sequential Organ Failure Assessment (SOFA) score, drug administration, and vital signs. A total of 18 933 patients were finally included in our analysis. The patients' average age was 66.67 ± 16.01 years, and the mortality at 28 days was 19.23% (3640/18933). Multivariate analysis demonstrated that each 10-mmHg rise of D(A-a)O2 was linked with a 3% increase in the probability of death at 28 days either in the unadjusted model or in adjustment for demographic variables (Odds ratio [OR]: 1.03, 95% CI: 1.02 to 1.03). But, each 10 mmHg increase in D(A-a)O2 was associated with a 3% increase of death (OR: 1.03, 95% CI: 1.023 to 1.033) in the case of adjustment for all covariants. Through smoothed curve fitting and generalized summation models, we found that non-linear relationship existed between D(A-a)O2 and the death at 28-day, which demonstrated that D(A-a)O2 had no any impacts on the prognosis of patients with sepsis when D(A-a)O2 was less than or equal to 300 mmHg, but once D(A-a)O2 exceeded 300 mmHg, however, every 10 mmHg elevation of D(A-a)O2 is accompanied by a 5% increase of the 28-day death (OR: 1.05; 95% CI:1.04 to 1.05, p < 0.0001). Our findings suggests that D(A-a)O2 is a valuable indicator for the management of sepsis patient, and it is recommended that D(A-a)O2 be maintained less than 300 mmHg as far as possible during sepsis process.

Sequência rápida de intubação em pediatria: Atualização e proposta de protocolo

Endotracheal intubation is a frequent procedure in intensive care units and emergency care. The rapid intubation sequence (SRI) consists of a series of steps for sequential administration of sedative drugs and neuromuscular blockers, providing the ideal conditions for endotracheal intubation. The objective of this study is to carry out a bibliographic review of the medications used in pediatric SRI, and to propose the institution of an updated protocol that includes a safe analgesic medication. It is suggested to include dextrocetamine or fentanyl, depending on the clinical condition, for SRI.

Concurrent or Sequential Administration of Drugs for COVID-19 and Influenza

&#x0D; With the continued COVID-19 pandemic and the resurgence of seasonal influenza, there is the potential that some populations may need drugs for the prevention and/or treatment of COVID-19 and/or influenza at the same time (i.e., concurrent use) or close together (i.e., sequential use).&#x0D; No evidence was identified regarding the clinical effectiveness, safety, or evidence-based guidelines for the concurrent or sequential use of cilgavimab and tixagevimab, nirmatrelvir and ritonavir, and/or oseltamivir that met the criteria for this review.&#x0D;

An international survey of adherence to Surviving Sepsis Campaign Guidelines 2016 regarding fluid resuscitation and vasopressors in the initial management of septic shock.

Our survey aimed to evaluate adherence to Surviving Sepsis Campaign (SSC) Guidelines 2016 among intensive care practitioners and to identify issues that remain controversial or lack clarity. Members of the European Society of Intensive Care Medicine (ESICM) were surveyed using an anonymous web-based survey written by an international group of experts. The primary outcome measure was the rate of adherence to specific recommendations. Secondary outcomes were to describe areas of controversy and lack of data and to associate specific practices with clinician characteristics. Overall 820 questionnaires were completed. The SCC recommendations 2016 most adhered to were the choice of norepinephrine as first-line vasoactive drug (96.5%), vasopressor prescription based on therapeutic goal rather than dose (83.4%), targeting a specific mean arterial blood pressure during vasopressor use (77.9%), monitoring of blood pressure invasively (62.8%) and adding vasopressin or epinephrine as a second vasoactive agent (83.4%). We identified an internal conflict with regards to parallel versus sequential administration of fluids and vasoactive drugs and regional differences in practice that may be related to drug availabilities. The use of vasopressors and fluid use in septic shock is largely compliant with current guidelines but several controversies should be addressed in future guideline iterations.

Usefulness of a novel transarterial chemoinfusion plus external-beam radiation therapy for advanced hepatocellular carcinoma with tumor thrombi in the inferior vena cava and right atrium: Case study.

BackgroundInvasion beyond inferior vena cava (IVC) to right atrium (RA) is a rare complication in patients with advanced hepatocellular carcinoma (HCC), and results in fatal oncologic emergencies, including pulmonary embolism and right heart failure.AimAs there is no gold standard treatment for unresectable HCC with tumor thrombi involving IVC and RA, we considered it valuable to assess safety and efficacy of a combination of hepatic arterial infusion chemoembolization (HAIC) therapy and external‐beam radiation therapy (EBRT).Methods and resultsThe “New FP” was chosen as the HAIC therapy, in which the enhanced permeation and retention effect was achieved using a cisplatin‐Lipiodol suspension combined with continuous infusion of 5‐fluorouracil (5‐FU). Sixteen patients with HCC with tumor thrombi in IVC, RA, and pulmonary arteries were enrolled. modified response evaluation criteria in solid tumors‐based evaluation of response to the combination treatment was as follows: complete response, 6.2% (1 patient); partial response, 81.3% (13 patients); stable disease, 12.5% (2 patients); progressive disease, 0%. The median overall survival time (MST) was 19.0 months. Notably, MST of patients receiving sequential sorafenib monotherapy (39.0 months) was significantly longer than that of the rest (15.3 months).ConclusionThe combination of New FP and EBRT is an efficacious treatment option for unresectable HCC involving IVC and RA, complicated with pulmonary embolism. Sequential administration of molecular‐targeted drugs may prolong survival in such patients.

Assessment of Outcomes Associated With the Use of Newly Approved Oncology Drugs in Medicare Beneficiaries

A lack of generalizability of pivotal cancer clinical trial data to treatment of older adults with Medicare could affect therapeutic decision-making in clinical practice. To evaluate the differences in survival, duration of therapy, and treatment patterns between clinical trial patients and older adults with Medicare receiving cancer drugs for metastatic solid cancers in usual practice. This retrospective cohort study, performed from May 1, 2018, to August 30, 2020, used the linked Surveillance, Epidemiology, and End Results (SEER) program and Medicare database to examine sequential US Food and Drug Administration (FDA)-approved cancer drug indications (2008-2013) for locally advanced or metastatic solid tumors to assess whether pivotal trials reflect the outcomes of Medicare patients with cancer treated in usual practice. Treatment with FDA-approved cancer drugs for metastatic solid cancers in pivotal clinical trials and in the SEER-Medicare database. Overall survival, duration of treatment, and dose reductions among trial participants and treated Medicare patients. A total of 11 828 trial participants (mean age, 61.8 years; 6718 [56.8%] male; and 7605 [64.3%] White) and 9178 SEER-Medicare patients (mean age, 72.7 years; 4800 [52.3%] male; and 7437 [81.0% White]) were compared. Twenty-nine indications for 22 cancer drugs were included. Median overall survival among Medicare patients was shorter than among patients in the clinical trial intervention arm for 28 of 29 indications (median difference, -6.3 months; range, -28.7 to 2.7 months). Median duration of therapy among Medicare patients was shorter for 23 of the 27 indications with data available (median difference, -1.9 months; range, -12.4 to 1.4 months). For 9 indications, there was information available regarding dose reductions in the package insert or trial publication. In all but 1 instance, dose reductions or single prescriptions were more common in the Medicare population compared with dose reductions among the clinical trial patients; for example, in the Medicare patients, 600 of 1032 (58.1%) received dose reduction or a single prescription and 172 of 1032 (16.7%) received a single prescription vs 734 of 3416 (21.5%) in the trial intervention arm. The exception was afatinib for non-small cell lung cancer: 34 of 71 (47.9%) received dose reduction or a single prescription and 15 of 71 (21.1%) received a single prescription among the Medicare patients vs 120 of 230 (52.2%) receiving dose reductions among the trial intervention group. In this cohort study, patients receiving Medicare who were treated with FDA-approved cancer drugs did not live as long as treated clinical trial participants and commonly received treatment modifications. This study suggests that cancer clinical data relevant to newly approved drugs lack generalizability to Medicare beneficiaries with cancer; therefore, these agents should be used with caution.

Treatment of acetylcholinesterase inhibitor-induced seizures with polytherapy targeting GABA and glutamate receptors

The initiation and maintenance of cholinergic-induced status epilepticus (SE) are associated with decreased synaptic gamma-aminobutyric acid A receptors (GABAAR) and increased N-methyl-d-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). We hypothesized that trafficking of synaptic GABAAR and glutamate receptors is maladaptive and contributes to the pharmacoresistance to antiseizure drugs; targeting these components should ameliorate the pathophysiological consequences of refractory SE (RSE). We review studies of rodent models of cholinergic-induced SE, in which we used a benzodiazepine allosteric GABAAR modulator to correct loss of inhibition, concurrent with the NMDA antagonist ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDAR-dependent. Models included lithium/pilocarpine-induced SE in rats and soman-induced SE in rats and in Es1−/− mice, which similar to humans lack plasma carboxylesterase, and may better model soman toxicity. These model human soman toxicity and are refractory to benzodiazepines administered at 40 min after seizure onset, when enough synaptic GABAAR may not be available to restore inhibition. Ketamine-midazolam combination reduces seizure severity, epileptogenesis, performance deficits and neuropathology following cholinergic-induced SE. Supplementing that treatment with valproate, which targets a non-benzodiazepine site, effectively terminates RSE, providing further benefit against cholinergic-induced SE. The therapeutic index of drug combinations is also reviewed and we show the improved efficacy of simultaneous administration of midazolam, ketamine and valproate compared to sequential drug administration. These data suggest that future clinical trials should treat both the lack of sufficient inhibition and the excess excitation that characterize RSE, and include early combination drug therapies.This article is part of the special issue entitled ‘Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield’.

FOLFIRINOX versus sequential 5-FU, oxaliplatin, and irinotecan-based regimens in patients with recurrent pancreatic cancer (rPDAC).

e16791 Background: There is a paucity of data to guide treatment for rPDAC after curative resection and gemcitabine-based adjuvant chemotherapy. Our aim was to investigate whether combination treatment upfront with all active agents is better than sequential administration of these drugs in patients with rPDAC following curative therapy. Methods: We retrospectively analyzed overall survival (OS), progression-free survival (PFS), response rate (RR), and adverse events (AEs) in patients treated for rPDAC. Patients received FOLFIRNOX upfront versus sequential therapy in the following order based on patient’s presence of toxicities (FOLFOX —&gt; FOLFIRI, FOLFOX—&gt; liposomal irinotecan/5FU, liposomal irinotecan/5FU —&gt; FOLFOX). Each treatment was administered per NCCN guidelines with regulated staging scans, blood work, and office visits. Data was collected about chemotherapy dose, ECOG performance status (PS), RR, PFS, OS, and AEs. Results: 55 patients were identified with ECOG PS ≤ 2 and male:female ratio 35:20. Results for FOLFIRINOX, FOLFOX followed by FOLFIRI, FOLFOX followed by liposomal irinotecan/5FU, and vice versa are as follows respectively: PFS 4.0, 3.5, 3.5, and 3.0 months; OS 8.0, 7.5, 7.0, and 8.3 months; RR 10%, (8%, 3%), (9%, 4%), and (3%, 5%). One of the patients in the mFOLFIRINOX was able to undergo metastasectomy. The table summarizes the toxicities and dose modifications seen. Conclusions: Upfront FOLFIRINOX versus sequential regimens of oxaliplatin and irinotecan-containing regimens resulted in similar PFS and OS but higher AEs as expected. However, surgery was only possible in patients receiving FOLFIRINOX. Our findings support the use of sequential treatment in rPDAC who are not potential surgical candidates. Further investigative work is warranted to optimize sequencing of active agents in this setting where prognosis has historically been poor. [Table: see text]

Efficacy of granulocyte colony stimulating factor in combination with erythropoiesis stimulating agents for treatment of anemia in patients with lower risk myelodysplastic syndromes: A systematic review.

Anemic patients with lower risk myelodysplastic syndromes are frequently treated with erythropoiesis stimulating agents (ESA), eventually in combination with granulocyte colony stimulating factor (G-CSF). However, the evidence for the efficacy of a combined treatment remains controversial. The goal of our analysis was to assess the available evidence for a combined treatment. We performed a systematic review and identified only nine eligible studies. In two randomized controlled trials (n = 98), erythroid response rates were 33% and 40% after low-/standard-doses of ESA alone (10,000-30,000 rHuEPO equivalents/week) versus 65% and 73% after combination treatment. In seven trials with sequential drug administration (n = 393), erythroid response rates ranged from 12% to 71% after full-doses of ESA alone (60,000-80,000 rHuEPO equivalents/week) and from 35% to 74% after combination therapy. Our analysis supports an additional efficacy of G-CSF added to low-/standard-dose ESA, but the available data remains controversial, if G-CSF is added to full-dose ESA.

Abstract GS1-01: Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: An EBCTCG meta-analysis of 21,000 women in 16 randomised trials

Abstract Background: Much contemporary adjuvant chemotherapy uses conventional 3-weekly scheduling. Yet, cytokinetic modelling suggests that increasing the dose density of cytotoxic therapy by shortening the intervals between courses, or by using sequential rather than concurrent treatment schedules may enhance efficacy.1 At least 15 randomised trials have directly tested this hypothesis and this meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) brings together the worldwide evidence to clarify the balance of risks and benefits of dose-dense chemotherapy. Methods: Individual patient data were provided for 98% (21,537/21,944) of women randomised in relevant trials: 7 randomised trials (10,004 women, 2240 breast cancer recurrences, 1481 breast cancer deaths) that compared 2-weekly dose-dense chemotherapy versus the same chemotherapy given 3-weekly, and 9 trials (11,533 women, 2773 breast cancer recurrences, 1711 breast cancer deaths) that compared sequential with concurrent anthracycline and taxane-based chemotherapy. Primary outcomes were time to recurrence and breast cancer mortality. Results: Highly significant reductions in disease recurrence [rate ratio (RR)=0.83 (95%CI 0.76-0.91), p=0.00004] were seen with 2-weekly compared with 3-weekly chemotherapy, and 10 year breast cancer mortality was 3.0% lower [16.7% vs 19.7%: RR=0.85 (95% CI 0.76-0.95), p=0.003]. Overall survival was also improved [RR=0·86 (95% CI 0·78−0·95), p=0.003]. Similarly, for sequential versus concurrent taxane plus anthracycline chemotherapy the rate ratio for disease recurrence was 0.86 (95% CI 0.79-0.93, p=0.0001), 10-year breast-cancer mortality was 2.3% lower [19.2% vs 21.5%: RR=0.87 (95% CI 0.79-0.96), p=0.005], and overall survival was improved [RR=0·85 (0·78−0·94), p=0.0008]. The proportional reductions in recurrence with dose-dense chemotherapy were similar and highly significant (both p&amp;lt;0.002) in ER-positive and in ER-negative disease, and did not differ significantly by any other patient or tumour characteristics, including age, HER2 status, nodal status, tumour size, or grade. Increasing dose density did not have any material adverse effect on non-breast-cancer mortality, which was similar with 2-weekly and with 3-weekly chemotherapy [RR=0·93 (95% CI 0·74−1·17), p=0.6] and was if anything lower with sequential than with concurrent chemotherapy [RR=0·73 (95% CI 0·55−0·97), p=0.03]. Trial publications also indicate that, with haematopoietic growth factor support, dose-dense chemotherapy does not substantially increase toxicity. Conclusion: Increasing the dose density of adjuvant chemotherapy is safe and results in fewer disease recurrences and fewer deaths from breast cancer. Reference: 1 Norton, L. Evolving concepts in the systemic therapy of breast cancer. Seminars in Oncology, 1997: S10-3 – S10-10. Citation Format: Gray R, Bradley R, Braybrooke J, Davies C, Pan H, Peto R, Bliss J, Cameron D, Mackey J, Del Mastro L, Swain S, Untch M, Bergh J, Pritchard K, Norton L, for the EBCTCG. Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: An EBCTCG meta-analysis of 21,000 women in 16 randomised trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-01.

Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells

Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16INK4a and p14ARF, deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991), a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM.

Sequential Therapeutic Response Modeling for Tumor Treatment Using Computational Hybrid Control Systems Approach.

Tumorigenesis is due to uncontrolled cell division arising from mutations and alterations in the proliferative controls of the cell population. The fight against tumor growth and development has often relied on combination therapy that has been acclaimed as one of the main standards of care in cancer therapeutics and prevention of drug-related resistances. The toxicity of the combinatorial drugs raises a significant concern whenever patients take two or more drugs concurrently at the maximum tolerated dose. A promising solution in tumor treatment involves the administration of the drugs in an alternating or sequential fashion rather than a simultaneous manner. In this paper, we investigate how feasible such an approach is from a mathematical perspective and propose a switched hybrid control systems framework. We explore the response of tumor cells dynamics to sequential drugs administration with the aid of a time-dependent switching strategy. A transit compartmentalized model is employed to describe the tumor cells progression to death. The design of the time-based drug switching logic ensures the proliferating tumor cells are repressed. Simulation results are provided using the tumor growth dynamics with sequential drugs intake to demonstrate the effectiveness of the proposed method in reducing the tumor size. This paper is the first attempt to provide a switched hybrid control systems framework on sequential drug administration to biomedical researchers and clinicians.

Reloadable multidrug capturing delivery system for targeted ischemic disease treatment.

Human clinical trials of protein therapy for ischemic diseases have shown disappointing outcomes so far, mainly because of the poor circulatory half-life of growth factors in circulation and their low uptake and retention by the targeted injury site. The attachment of polyethylene glycol (PEG) extends the circulatory half-lives of protein drugs but reduces their extravasation and retention at the target site. To address this issue, we have developed a drug capture system using a mixture of hyaluronic acid (HA) hydrogel and anti-PEG immunoglobulin M antibodies, which, when injected at a target body site, can capture and retain a variety of systemically injected PEGylated therapeutics at that site. Furthermore, repeated systemic injections permit "reloading" of the capture depot, allowing the use of complex multistage therapies. This study demonstrates this capture system in both murine and porcine models of critical limb ischemia. The results show that the reloadable HA/anti-PEG system has the potential to be clinically applied to patients with ischemic diseases, who require sequential administration of protein drugs for optimal outcomes.

The CXCR4 antagonist plerixafor enhances the effect of rituximab in diffuse large B-cell lymphoma cell lines.

BackgroundDiffuse large B-cell lymphoma (DLBCL) is an aggressive disease with variable clinical outcome, accounting for at least 25-30 % of adult non-Hodgkin lymphomas. Approximately one third of DLBCL patients are not cured by the currently used treatment regimen, R-CHOP. Hence, new treatment strategies are needed. Antagonizing the CXCR4 receptor might be promising since the CXCR4-CXCL12 axis is implicated in several aspects of tumor pathogenesis as well as in protection from chemotherapeutic response. In Burkitt lymphoma, the CXCR4 antagonist plerixafor has already been shown to enhance the therapeutic effect of rituximab, the immunotherapeutic agent of R-CHOP; but this is yet to be confirmed for DLBCL. We, therefore, investigated the effect of plerixafor on DLBCL cellular response to rituximab.MethodsIn this in vitro study, human DLBCL cell lines were treated with rituximab and/or plerixafor, concomitantly or in sequence. The trypan blue exclusion method and MTS-based assays were used to evaluate cellular proliferation, whereas flow cytometry was used for assessment of apoptosis status and CXCR4 surface expression level. Linear mixed effects models were used to assess statistical significance.ResultsWe observed that simultaneous addition of plerixafor and rituximab resulted in a significant decrease in DLBCL cellular proliferation, compared to monotherapeutic response. The effect was dose-dependent, and concomitant administration was observed to be superior to sequential drug administration. Accordingly, the fraction of apoptotic/dead cells significantly increased following addition of plerixafor to rituximab treatment. Furthermore, exposure of DLBCL cells to plerixafor resulted in a significant decrease in CXCR4 fluorescence intensity.ConclusionsBased on our results, implying that the anti-proliferative/pro-apoptotic effect of rituximab on DLBCL cells can be synergistically enhanced by the CXCR4 antagonist plerixafor, addition of plerixafor to the R-CHOP regimen can be suggested to improve treatment outcome for DLBCL patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40364-016-0067-2) contains supplementary material, which is available to authorized users.